Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH2:17][C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:7]=3[NH:8][C:9](=[O:10])[C:4]2=[N:3][CH:2]=1.[Br:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O.[H-].[Na+].O>CS(C)=O.C(O)(=O)C.CN(C)C=O>[Br:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=[C:17]1[C:6]2[N:5]3[CH:1]=[CH:2][N:3]=[C:4]3[C:9](=[O:10])[NH:8][C:7]=2[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]1=2
Reactant: O=Cc1cccc(Br)c1
Reactant: O=c1[nH]c2c(n3ccnc13)Cc1ccccc1-2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CS(C)=O
Product: O=c1[nH]c2c3ccccc3c(=Cc3cccc(Br)c3)c2n2ccnc12
Temperature: 20 °C
Reaction time: 15 h
Yield: 16.9 %

Procedure:
To a suspension of 2.2 g of 5H,10H-imidazo-[1,2-a]indeno[1,2-e]pyrazin-4-one in 45 ml of anhydrous dimethyl sulphoxide, maintained under a nitrogen atmosphere and at a temperature in the region of 20° C., are added 2 g of 3-bromobenzaldehyde followed, over 5 minutes, by 0.72 g of 80% sodium hydride. The mixture is stirred for 15 hours at the same temperature, followed by slow addition of 45 ml of distilled water and 12 ml of acetic acid. The insoluble product formed is isolated by filtration, washed with distilled water and air-dried. The product obtained (3.1 g) is chromatographed on neutral silica gel, eluting with a dichloromethane/methanol mixture (90/10 by volume). The fractions containing the expected product are concentrated to dryness and the product obtained (1.9 g) is dissolved in a boiling mixture of 40 ml of acetic acid and 50 ml of dimethylformamide and, after cooling and storing for 15 hours at a temperature in the region of 5° C., the insoluble product formed is isolated by filtration, washed twice with 10 ml in total of acetic acid and twice with 10 ml in total of isopropyl ether and then dried under reduced pressure (1 mmHg; 0.13 kPa) at 80° C. 0.65 g of 10-(3-bromo-benzylidene)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one is thus obtained, melting at 340° C. (decomposition) (Analysis, % calculated C: 61.56, H: 3.10, Br: 20.48, N: 10.77, O: 4.10, % found C: 61.4, H: 3.2, N: 11.0).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:15][C@@H:16]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)[C@@H:17]([OH:31])[C:18]([O:20]C1(C)CCC(C(C)C)CC1)=[O:19].[OH-].[K+]>CO.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[S:15][C@@H:16]([C:32]1[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=1)[C@@H:17]([OH:31])[C:18]([OH:20])=[O:19]
Reactant: COc1ccc([C@H](Sc2cc(Oc3ccccc3)ccc2N)[C@@H](O)C(=O)OC2(C)CCC(C(C)C)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc([C@H](Sc2cc(Oc3ccccc3)ccc2N)[C@@H](O)C(=O)O)cc1
Yield: 65.2 %

Procedure:
4.2 g of l-menthyl (2S, 3S)-3-(2-amino-5-phenoxyphenyl)thio-2-hydroxy-3-(4- methoxyphenyl)propionate [prepared as described in step (a) above] were suspended in 42 ml of methanol, and a solution of 0.89 g of caustic potash dissolved in 5 ml of water was added to the resulting suspension. The resulting mixture was then stirred under reflux for 1 hour. At the end of this time, the methanol was removed by evaporation under reduced pressure, and 60 ml of Water and 60 ml of diethyl ether were added to the residue. The resulting mixture was stirred, and the ethereal layer was then removed. Ethyl acetate was added to the aqueous layer. after which 14.5 ml of 1N aqueous hydrochloric acid were added to neutralize the mixture. The ethyl acetate layer was then separated and dried over anhydrous anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, and the residual gum Was crystallized using diethyl ether and diisopropyl ether. The crystals obtained were collected by filtration to afford 2.05 g of the title compound. melting at 151-152° C.
Reaction SMILES: [C:1]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].[Cl:11][C:12]1[CH:17]=[CH:16][C:15](O)=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:3][C@H:2]([CH3:4])[C:1]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[CH:14][CH:13]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: C[C@H](O)C(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](Oc1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reaction time: 24 h

Procedure:
To a stirred solution of known tert-butyl L-(+)-lactate (217 mg), 4-chlorophenol (219 μl) and triphenylphosphine (584 mg) in dry tetrahydrofuran (8 ml) on an ice bath, diethylazodicarboxylate (350 μl) was added dropwise over about 10 minutes. After the addition, the ice bath was removed and the mixture was further stirred at room temperatures for 24 hours. The reaction mixture was evaporated with a rotary evaporator (water bath temperaure 38° C.). The residue thus obtained was purified by silica gel chromatography [silica gel 50 g, eluant:ethyl acetate-hexane (1:10)] to give tert-butyl (2R)-(+)-2-(4'-chlorophenoxy)propionate (256 mg).
Reaction SMILES: Cl.[NH2:2][CH2:3][C@H:4]1[C@@H:8]([Cl:9])[CH2:7][N:6]([C:10]2[N:19]=[C:18]3[C:13]([C:14](=[O:26])[C:15]([C:23]([OH:25])=[O:24])=[CH:16][N:17]3[CH:20]3[CH2:22][CH2:21]3)=[CH:12][C:11]=2[F:27])[CH2:5]1.S(=O)(=O)(O)O.[CH2:33](O)[CH3:34]>>[NH2:2][CH2:3][C@H:4]1[C@@H:8]([Cl:9])[CH2:7][N:6]([C:10]2[N:19]=[C:18]3[C:13]([C:14](=[O:26])[C:15]([C:23]([O:25][CH2:33][CH3:34])=[O:24])=[CH:16][N:17]3[CH:20]3[CH2:22][CH2:21]3)=[CH:12][C:11]=2[F:27])[CH2:5]1
Reactant: CCO
Reactant: NC[C@@H]1CN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C[C@@H]1Cl
Agent: Cl
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cn(C2CC2)c2nc(N3C[C@@H](CN)[C@@H](Cl)C3)c(F)cc2c1=O

Procedure:
7-(cis-3-Aminomethyl-4-chloro-1-pyrrolidinyl)1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid hydrochloride was suspended in absolute ethanol. Sulfuric acid was added to the suspension and the mixture was refluxed for 15 hours with stirring. After evaporation of ethanol, chloroform and a 20% aqueous sodium hydroxide solution were added to the residue, and the mixture was adjusted to pH 9. The organic layer was separated and chloroform was evaporated under reduced pressure. The resulting crystals were collected by filtration to give ethyl 7-(cis-3-aminomethyl-4-chloro-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, m.p. 163°-167° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[N:4][C:5]([NH:8][C:9]2[CH:19]=[CH:18][C:17]3[CH2:16][CH:15]4[NH:20][CH:12]([CH2:13][CH2:14]4)[C:11]=3[C:10]=2[O:21][CH3:22])=[N:6][CH:7]=1.I[CH2:36][CH3:37]>>[Cl:1][C:2]1[C:3]([NH:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[N:4][C:5]([NH:8][C:9]2[CH:19]=[CH:18][C:17]3[CH2:16][CH:15]4[N:20]([CH2:36][CH3:37])[CH:12]([CH2:13][CH2:14]4)[C:11]=3[C:10]=2[O:21][CH3:22])=[N:6][CH:7]=1
Reactant: CCI
Reactant: COc1c(Nc2ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n2)ccc2c1C1CCC(C2)N1
Product: CCN1C2CCC1c1c(ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)c1OC)C2
Yield: 23 %

Procedure:
Following a procedure analogous to 68a, N-{(1R,2R)-2-[5-Chloro-2-(3-methoxy-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide (25 mg, 0.049 mmol), iodoethane were converted to the title compound as a light pink solid (6 mg, 23%), as a mixture of diastereomers. 1HNMR (400 MHz, CDCl3) δ 7.9 (s, 1H), 7.7 (m, 1H), 7.4 (m, 1H), 7.2 (m, 1H), 5.7 (m, 1H), 3.8 (m, 1H), 3.7 (m, 1H), 3.5 (s, 3H), 3.3-3.0 (m, 3H), 2.9 (s, 3H), 2.8 (m, 1H), 2.6 (m, 1H), 2.2-1.8 (m, 9H), 1.7-1.6 (m, 3H), 1.4-1.2 (m, 1H), 1.1-1.0 (m, 4H); MS (m/e) 535 (M+1); mp 102-106° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=1>>[F:20][C:17]([F:18])([F:19])[C:14]1[CH:15]=[CH:16][C:11]([O:10][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[N:12][CH:13]=1
Reactant: Oc1ccc(C(F)(F)F)cn1
Reactant: O=Cc1ccc(F)cc1
Product: O=Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1

Procedure:
4-(5-Trifluoromethyl-pyridin-2-yloxy)-benzaldehyde was prepared from 4-fluorobenzaldehyde (2.48 g, 20 mmol) and 2-hydroxy-5-trifluoromethylpyridine (3.29 g, 20 mmol) following general procedure B. (4.62 g)
Reaction SMILES: [CH3:1][N:2]=[C:3]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][N:5]2[C:13](=[O:16])[CH2:14][CH2:15][CH:4]12>CCO.[Pd]>[CH3:1][NH:2][C@@H:3]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][N:5]2[C:13](=[O:16])[CH2:14][CH2:15][C@H:4]12
Reactant: CN=C1c2ccccc2CN2C(=O)CCC12
Agent: [Pd]
Solvent: CCO
Product: CN[C@@H]1c2ccccc2CN2C(=O)CC[C@H]12
Yield: 6.9 %

Procedure:
A mixture of 10methylimino-1,2,3,5,10,10a-hexahydropyrrolo[1,2-b]isoquinolin-3-one (159 mg) and Pd/C (10%, 110 mg) in EtOH (10 mL) was hydrogenated in a shaker apparatus at 50 psi overnight, and then filtered. The filtrate was concentrated in vacuo and the residue was chromatographed on silica gel eluting with CH2Cl2/MeOH/NH4OH (150/8/1) to give an oil (11 mg): 1H NMR (300 MHz) δ 7.25 (m, 4 H), 4.92 (d, J=18.0 Hz, 1 H), 4.31 (d, J=17.7 Hz, 1 H), 3.95 (m, 1 H), 3.43 (d, J=2.7 Hz, 1 H), 2.38 (s, NCH3); MS (FAB), m/e 217 (100, M+H), 154 (55), 136 (45).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1([CH3:21])[C@@H:9]([CH:10]=[C:11]([Br:13])Br)[C@H:8]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].Cl[C:23]([O:25][CH2:26][CH2:27][CH3:28])=[O:24].P(O)(O)([O-])=O.[Na+]>CCCCCC.O1CCCC1.CCOCC>[CH3:21][C:7]1([CH3:6])[C@@H:9](/[CH:10]=[C:11](\[Br:13])/[C:23]([O:25][CH2:26][CH2:27][CH3:28])=[O:24])[C@H:8]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CCCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](C=C(Br)Br)C1(C)C
Agent: O=P([O-])(O)O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCOC(=O)/C(Br)=C/[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Temperature: -115 °C
Reaction time: 0.25 h

Procedure:
50 ml of a solution of 16N butyllithium in hexane were added over 25 minutes at -115° C. to a solution of 28.3 g of tert-butyl (1R,cis) 2,2-dimethyl-3-(2,2-dibromovinyl)-cyclopropane-1-carboxylate in 120 ml of tetrahydrofuran and 120 ml of ether and after stirring the mixture at -115° C. for 15 minutes, 10 ml of n-propyl chloroformate were progressively added thereto. The mixture was stirred at -115° C. for 20 minutes, at -65° C. for one hour and was poured into an aqueous monosodium phosphate solution. The mixture was extracted with ether and the organic phase was washed with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 95-5 cyclohexane-ethyl acetate mixture to obtain 3.52 g of tert.-butyl (1R,cis) 2,2-dimethyl-3(Z)-[2-bromo-2-propyloxycarbonyl-ethenyl]-cyclopropane-1-carboxylate and 3.16 g of the corresponding 3(E)-isomer.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[O:13][CH3:14].S(=O)(=O)(O)O.[CH3:20]O>>[OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:20])=[O:9])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: CO
Reactant: COc1cc(C=CC(=O)O)ccc1O
Agent: O=S(=O)(O)O
Product: COC(=O)C=Cc1ccc(O)c(OC)c1

Procedure:
The preparation was effected analogously to Example 1 from 25 g (0.129 mol) of 4-hydroxy-3-methoxy-cinnamic acid and 180 ml of methanol with concentrated sulphuric acid as the catalyst. For purification, it was chromatographed on silica gel with dichloromethane/diethyl ether (19:1). This gave 21.78 g of methyl 4-hydroxy-3-methoxy-cinnamate as a pale yellow oil.
Reaction SMILES: C[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([F:12])[CH:5]=1)=[O:3].[O:13]([Br:15])[Na:14].[OH-].[Na+].BrBr.C(O)(=[O:27])C1C=CC=CC=1.[Na]>O1CCOCC1.O>[O:13]([Br:15])[Na:14].[F:12][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][CH3:11])[C:2]([OH:3])=[O:27]
Reactant: O=C(O)c1ccccc1
Reactant: COc1ccc(C(C)=O)cc1F
Agent: BrBr
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C(=O)O)cc1F
Temperature: 25 °C

Procedure:
3-fluoro-4-methoxyacetophenone (11.5 g) was dissolved in 100 ml dioxane and NaOBr solution (as prepared below) was added dropwise, with constant stirring with a stir bar at room temperature. The NaOBr solution was prepared by dissolving 40 g of NaOH in 500 ml of water, cooling to 0° C. in an ice bath, and adding bromine (12.5 ml) dropwise while stirring with stir bar; bromine was added slowly so that the reaction mixture did not exceed 5° C. After overnight stirring of the 3-fluoro-4-methoxyacetophenone, dioxane and NaOBr solution, the reaction mixture was diluted with water (200 ml). Since the reaction mixture was basic, the product, benzoic acid, was in water as its sodium salt. The resultant mixture was partitioned between ether and water. The ether layer was washed with dilute aqueous NaOH to extract any remaining product as Na salt. The aqueous layers were combined and acidified to pH 1 to precipitate the benzoic acid. The resulting acid was extracted with ether. The ether layer was washed with water a few times, dried with MgSO4, and filtered. Rotary evaporation of the ether fraction afforded 3-fluoro-4-methoxybenzoic acid (IV) in 85% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[C:12]([CH3:20])[CH:11]=1.[I-:21]>S([O-])([O-])(=O)=O.[Ag+2].CO>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([I:21])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[C:12]([CH3:20])[CH:11]=1
Reactant: [I-]
Reactant: COC(=O)c1ccc(-c2ccc(OC)cc2F)cc1C
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COC(=O)c1ccc(-c2cc(I)c(OC)cc2F)cc1C

Procedure:
methyl 2′-fluoro-4′-methoxy-3-methylbiphenyl-4-carboxylate (100 mg, 0.365 mmol), methanol (3 mL), iodide (93 mg, 0.366 mmol) and silver sulfate (114 mg, 0.366 mmol) were stirred at room temperature for 1.5 hours. Reaction crude was quenched by Na2SO3 (sat., aq.). Volatiles were removed from the grayish brown mixture. The pot residue was worked up with H2O/EtOAc/Na2SO4/filtration/concentration to afford the title compound. LCMS (ESI) calc.=400.00; found=400.96 (M+1)+.
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH2:10]Br)[CH:7]=[CH:6][C:5]=1[Cl:12].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C@H:21]2[C@@:23]3([C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[NH:25][C:24]3=[O:32])[CH2:22]2)=[CH:17][CH:16]=1>>[Cl:12][C:5]1[CH:6]=[CH:7][C:8]([CH2:10][N:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@:23]3([CH2:22][C@H:21]3[C:18]3[CH:17]=[CH:16][C:15]([Cl:14])=[CH:20][CH:19]=3)[C:24]2=[O:32])=[CH:9][C:4]=1[C:3]([OH:2])=[O:13]
Reactant: COC(=O)c1cc(CBr)ccc1Cl
Reactant: O=C1Nc2ccccc2[C@]12C[C@H]2c1ccc(Cl)cc1
Product: O=C(O)c1cc(CN2C(=O)[C@@]3(C[C@H]3c3ccc(Cl)cc3)c3ccccc32)ccc1Cl

Procedure:
The title compound was prepared in analogy to Example 1 starting from 5-Bromomethyl-2-chloro-benzoic acid methyl ester (commercially available), (1S,2R) and (1R,2S)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C24H17Cl2NO3: 437, observed (M+H)+: 438.3. 1H NMR (400 MHz, DMSO-d6) δppm 2.07-2.15 (m, 1 H) 2.39 (dd, J=7.83, 5.05 Hz, 1H) 3.20 (t, J=8.72 Hz, 1 H) 5.06 (s, 2 H) 6.16 (d, J=7.58 Hz, 1 H) 6.73 (t, J=7.58 Hz, 1 H) 6.97 (d, J=7.83 Hz, 1 H) 7.09 (t, J=7.83 Hz, 1 H) 7.28-7.40 (m, 4 H) 7.43-7.57 (m, 2 H) 7.73 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].[Br:23][C:24]1[N:28]2[N:29]=[C:30]([Cl:34])[CH:31]=[C:32](Br)[C:27]2=[N:26][CH:25]=1>CN(C=O)C.C(OCC)(=O)C>[Br:23][C:24]1[N:28]2[N:29]=[C:30]([Cl:34])[CH:31]=[C:32]([N:8]([CH2:7][C:6]3[CH:15]=[CH:16][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:27]2=[N:26][CH:25]=1
Reactant: Clc1cc(Br)c2ncc(Br)n2n1
Reactant: COc1ccc(CNc2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(Br)cnc23)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
N-(4-Methoxybenzyl)aniline (215 mg, 1 mmol) was dissolved in dry DMF (4 mL), placed under a nitrogen atmosphere, and cooled to 0° C. in an ice bath. Potassium t-butoxide (1 mL, 1 mmol, 1M THF solution) was added and the mixture was allowed to stir for 10 min at 0° C. and room temperature for 30 min. The resulting mixture was cool to 0° C. Solid 3,8-dibromo-6-chloroimidazo[1,2-b]pyridazine (310 mg, 1 mmol) from Example XXIV, step 1a was added. The mixture was allowed to stir for 30 min at 0° C. and overnight at room temperature. The mixture was diluted with ethyl acetate (100 mL), washed sequentially with 10% LiCl, water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo and the resulting material was purified by silica gel chromatography (ethyl acetate/heptane, 25 min gradient: 5-50% ethyl acetate) to provide 0.27 g of 3-bromo-6-chloro-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-amine.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([OH:18])[CH3:17].CCCCCC.CCOCC>C(Cl)Cl>[CH2:1]([C:8]1[CH:9]=[C:10]([C:11](=[NH:12])[O:18][CH2:16][CH3:17])[CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: N#Cc1cccc(Cc2ccccc2)c1
Solvent: CCOCC
Solvent: CCCCCC
Solvent: ClCCl
Product: CCOC(=N)c1cccc(Cc2ccccc2)c1
Temperature: -4 °C
Reaction time: 0.25 h

Procedure:
Anhydrous hydrochloric acid was gently bubbled for 90 minutes into a solution containing 3-benzylbenzonitrile (1.0 g, 5.2 mmol) and absolute ethanol (0.45 mL, 7.8 mmol) in methylene chloride (7 mL) maintained at −4° C. After standing at 4° C. for a week, the reaction mixture was poured into 2:1 hexane/ether (500 mL), left at room temperature for 15 minutes and filtered. The residue was washed with 2:1 hexane/ether (50 mL) and dried in vacuo at room temperature. Yield 1.1 g (77 percent). mp 121-122° C.; 1H NMR (CDCl3) δ 12.58 (br, 1H), 8.29-8.25 (m, 2H), 7.49-7.44 (m, 2H), 7.32-7.27(m, 2H), 7.22-7.18(m, 3H), 4.93 (q, J=6.9 Hz, 2H), 4.09 (s, 2H), 1.60 (t, J=6.9 Hz, 3H); EI/MS 240 m/e (M+1);
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:39])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:35])([CH3:34])[CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[NH:10][CH:9]2[C:36](O)=[O:37])[CH:5]=[CH:6][CH:7]=1.CC1(C)[O:45][C@@H:44]([CH2:46][CH2:47][NH2:48])[CH2:43][O:42]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:45][C@H:44]([CH2:43][OH:42])[CH2:46][CH2:47][NH:48][C:36]([CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:39])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:35])([CH3:34])[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[NH:10]1)=[O:37]
Reactant: COc1ccc(CC(C)(C)CC2NC(C(=O)O)C(c3cccc(Cl)c3F)C2(C#N)c2ccc(Cl)cc2F)cc1
Reactant: CC1(C)OC[C@H](CCN)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(CC(C)(C)CC2NC(C(=O)NCC[C@H](O)CO)C(c3cccc(Cl)c3F)C2(C#N)c2ccc(Cl)cc2F)cc1
Yield: 27.8 %

Procedure:
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[3-(4-methoxy-phenyl)-2,2-dimethyl-propyl]-pyrrolidine-2-carboxylic acid prepared in Example 126c (0.5 g, 0.87 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.25 g, 1.7 mmol), HATU (0.6 g, 1.7 mmol) and iPr2NEt (0.45 mL, 2.6 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-[3-(4-methoxy-phenyl)-2,2-dimethyl-propyl]-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.16 g, 29%).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[CH:3][C:2]=1[CH3:8].C([Li])CCC.CN(C)[C:16](=[O:18])[CH3:17].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:7][C:5]1[CH:4]=[CH:3][C:2]([CH2:8][C:16](=[O:18])[CH3:17])=[N:1][CH:6]=1
Reactant: Cc1ccc(C)nc1
Reactant: CC(=O)N(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)Cc1ccc(C)cn1
Temperature: 0 °C

Procedure:
To a stirred solution of 2,5-lutidine (2.68 g) in tetrahydrofuran (16 ml) was added a solution of n-butyllithium in n-hexane (1.66M, 16.6 ml) dropwise at −50° C. under a nitrogen atmosphere, and the mixture was warmed to 0° C. The mixture was cooled to −50° C., and N,N-dimethylacetamide (2.56 ml) was added dropwise. Then the mixture was warmed to room temperature, poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (100 ml×3). The combined organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 100 g, n-hexane:ethyl acetate=1:2) to give 1-(5-methylpyridin-2-yl)propan-2-one (2.60 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([S:10][CH2:11][C:12]([NH:14][CH2:15][C:16](=[O:19])[CH2:17][CH3:18])=O)=[CH:8][N:9]=1)(=[O:3])[CH3:2].S(=O)(=O)(O)O.C([O-])(=O)C.[Na+]>C(OC(=O)C)(=O)C>[CH2:17]([C:16]1[O:19][C:12]([CH2:11][S:10][C:7]2[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][CH:8]=2)=[N:14][CH:15]=1)[CH3:18]
Reactant: CCC(=O)CNC(=O)CSc1cnc(NC(C)=O)s1
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCc1cnc(CSc2cnc(NC(C)=O)s2)o1
Temperature: 57.5 °C
Reaction time: 2 h
Yield: 42.6 %

Procedure:
To a solution of [[2-(acetylamino)-5-thiazolyl]thio]-N-(2-oxobutyl)acetamide (10.5 g, 34.8 mmol) in acetic anhydride (100 mL) was added conc. sulfuric acid (10 mL). The mixture was stirred at 55-60° C. for 2 h and sodium acetate (15 g, 0.18 mol) was added to the mixture. The mixture was concentrated in vacuo. To the residue was added cold water (100 mL). The precipitated solid was collected, washed with water and dried. It was purified by a flash column chromatography (SiO2; methylene chloride: MeOH/100:5) to afford N-[5-[[(5-ethyl-2-oxazolyl)methyl]thio]-2-thiazolyl]acetamide (4.2 g, 43%) as a solid, mp 147-148° C.
Reaction SMILES: [Li]CCCC.CCCCCC.[C:12]([C:14]1([F:22])[CH:19]2[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]2)[CH2:15]1)#[CH:13].[CH:23]1([C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C1COCC1>[CH:31]1([C:29]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([OH:30])[C:13]#[C:12][C:14]2([F:22])[CH:19]3[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]3)[CH2:15]2)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: O=C(c1ccccc1)C1CCCCC1
Reactant: C#CC1(F)CN2CCC1CC2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(C#CC1(F)CN2CCC1CC2)(c1ccccc1)C1CCCCC1
Reaction time: 0.5 h

Procedure:
A 1.6 N solution of BuLi in hexane (730 μA, 1.16 mmol) was added dropwise to a solution of 3-ethynyl-3-fluoroquinuclidine 57 (162 mg, 1.06 mmol) in THF (5 ml) at 0° C. After stirring for 30 minutes, cyclohexyl(phenyl)methanone (207 mg, 1.16 mmol) in THF (1 ml) was added slowly. After 30 minutes, the reaction was quenched by the addition of saturated aqueous NH4Cl solution and diluted with AcOEt. The organic phase was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by chromatography over silica gel (CH2Cl2/MeOH 97.5/2.5) and 1-cyclohexyl-3-(3-fluoro-1-azabicyclo[2.2.2]oct-3-yl)-1-phenylprop-2-yn-1-ol 111 was obtained as colorless foam (mixture of diastereomers, 30 mg, 8%).