Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH:18][CH2:19][C:20](=[O:26])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].Br[CH:28]([CH3:39])[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].Cl>C(OCC)(=O)C>[C:8]([NH:18][CH2:19][C:20](=[O:26])[CH2:21][CH2:22][C:23]([O:25][CH:28]([C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[CH3:39])=[O:24])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: CC(Br)C(=O)OCc1ccccc1
Reactant: O=C(O)CCC(=O)CNC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(OC(=O)CCC(=O)CNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 76.7 %

Procedure:
Triethylamine was added drop-wise to a stirred solution of 5-(Cbz-amino)-4-oxopentanoic acid (4.00 g; 15.0 mmol) and the product of 2a (3.65 g; 15.0 mmol) in ethyl acetate (50 mL). The stirred mixture was refluxed for 2 days under argon. After cooling to ambient temperature, 0.5 M HCl solution (50 mL) was added and the mixture was shaken thoroughly. The aqueous layer was extracted with ethyl acetate (2×20 mL). The combined ethyl acetate solutions were washed with saturated NaHCO3 solution (2×15 mL) and saturated NaCl solution (1×15 mL), then dried (MgSO4). After filtration and evaporation an amber oil was obtained that was purified by flash chromatography on a 60×55 mm silica gel 60 column eluted with ethyl acetate-hexane (1:1) (1000 mL), collecting 8×100 mL fractions. Evaporation of fractions 3-5 resulted in 4.92 g (77%) product (oil).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:19]=[CH:18][C:6]2[S:7][C:8]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:9]=3[CH2:10][CH:11](O)[C:5]=2[CH:4]=1.C1C=CC=CC=1.S(Cl)([Cl:30])=O>N1C=CC=CC=1.O>[F:1][C:2]([F:21])([F:20])[C:3]1[CH:19]=[CH:18][C:6]2[S:7][C:8]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:9]=3[CH2:10][CH:11]([Cl:30])[C:5]=2[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: OC1Cc2c(Cl)cccc2Sc2ccc(C(F)(F)F)cc21
Solvent: c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: FC(F)(F)c1ccc2c(c1)C(Cl)Cc1c(Cl)cccc1S2

Procedure:
To the mixture of 0.5 g of 2-trifluoromethyl-9-chloro-10,11-dihydrodibenzo[b,f]thiepin-11-ol, 5 ml of anhydrous benzene and one drop of anhydrous pyridine were added dropwise with stirring 0.3 g of thionyl chloride with ice-cooling and the resulting mixture was reacted at room temperature for 10 minutes, then refluxed for 20 minutes, and freed of benzene under reduced pressure. To the thus obtained residue was added water and the mixture was extracted with benzene. The extract was washed with water, saturated sodium bicarbonate, then water, dried over anhydrous sodium sulfate and freed of benzene to obtain 2-trifluoromethyl-9-chloro-11-chloro-10,11-dihydrodibenzo[b,f]-thiepin as colorless crystals having a melting point of 88°-90° C.
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C([O:12][CH:13]=[C:14]([C:20](OCC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>>[Cl:9][C:8]1[C:2]([Cl:1])=[C:3]2[C:5]([C:13]([OH:12])=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:20]=[N:4]2)=[CH:6][CH:7]=1
Reactant: Nc1cccc(Cl)c1Cl
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1cnc2c(Cl)c(Cl)ccc2c1O
Temperature: 60 °C
Yield: 87.7 %

Procedure:
2,3-Dichloroaniline (7.83 g) and diethyl ethoxymethylenemalonate (9.76 g) are heated at 130° C. for 1.5 hours. The reaction is cooled to 60° C. and the solution poured into hexanes. The intermediate enamine is collected and dried. The solid is added to 70 mL diphenyl ether and heated to 250° C. for 1.5 hours with removal of ethanol with a Dean-Stark trap. The reaction is cooled to room temperature. The product is collected by filtration, washed thoroughly with hexanes, and dried to yield 11.32 g of ethyl 7,8-dichloro-4-hydroxyquinoline-3-carboxylate. A mixture of this ester (0.48 g) and 4-chlorobenzylamine (1.0 mL) are heated at 180° C. for 1 hour. The reaction is cooled to room temperature and diethyl ether is added. The resulting solid is filtered, washed twice with diethyl ether, and dried. The solid is adsorbed onto silica and purified by Biotage Flash 40S chromatography (eluent 2% MeOH:CH2Cl2). The product-containing fractions are evaporated to give a white solid (0.12 g).
Reaction SMILES: [CH3:1][CH:2](C(OCC)=O)C(OCC)=O.[NH2-].[Na+].Cl[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=1>C1COCC1>[CH2:1]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=1)[CH3:2]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
Diethyl methylmalonate (52.2 g) was added dropwise to a suspension of sodamide (11.7 g) in dry THF (150 ml) with stirring at ambient temperature under nitrogen. The mixture was boiled under reflux for 1 hour and then a solution of 2-chloro-5-nitropyridine (47.7 g) in dry THF (150 ml) was added dropwise cautiously with stirring. After the addition the mixture was boiled under reflux for 3 hours, then cooled and evaporated to remove approximately 80% of the solvent. The residue was poured into water (1 l) and extracted with ether to give an oil which partially crystallised on standing. A mixture of the residue, concentrated sulphuric acid (50 ml) and water (25 ml) was boiled under reflux for 4 hours then cooled in ice and neutralised using concentrated aqueous sodium hydroxide solution. The mixture was left to stand at ambient temperature for 64 hours and then filtered to give a solid which was extracted continuously with dichloromethane in a soxhlet extractor. The dichloromethane was cooled, dried and evaporated. The residue was filtered and the filtrate was distilled under vacuum to give 2-ethyl-5-nitropyridine, b.p. 82°-92° C. at 1 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:5][C:6](=[O:9])[C:7]=1[Cl:8])=[O:4].[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1>C1C=CC=CC=1>[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:6](=[O:9])/[C:7](/[Cl:8])=[C:2](/[Cl:1])\[C:3]([OH:5])=[O:4])=[CH:13][CH:12]=1
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Reactant: Nc1ccc(F)cc1
Solvent: c1ccccc1
Product: O=C(O)/C(Cl)=C(/Cl)C(=O)Nc1ccc(F)cc1
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
8.35g (0.05 mol) of 2,3-dichloromaleic anhydride was dissolved in 50 ml of benzene. To the resulting solution 20 ml of benzene solution containing 5.55g (0.05 mol) of 4-fluoroaniline was added dropwise over a period of 20 min. at temperatures of 5°-10° C under agitation. After completing the addtion, the mixture was agitated at 5°-10° C for 30 min. to form crystals, which were separated by filtration and washed with benzene to obtain 13.15g of N-(4-fluorophenyl)-2,3-dichloromaleamic acid in the form of white crystal melting at 222°-225° C (yield, 95%). The results of elementary analysis were as follows:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[O:10].[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[C:32]([C:33](O)=[O:34])[C:27]=2[O:26][CH2:25]1>>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:4]2[C@H:3]([CH2:2][NH:1][C:33]([C:32]3[C:27]4[O:26][CH2:25][O:24][C:28]=4[CH:29]=[CH:30][CH:31]=3)=[O:34])[CH2:8][C@H:7]3[C@@H:5]2[CH2:6]3)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cccc2c1OCO2
Reactant: Cc1nc(C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3cccc4c3OCO4)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [(1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone with benzo[1,3]dioxole-4-carboxylic acid. LC-MS (basic): tR=0.87 min; [M+H]+=480.1.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH2:9][CH3:10])[CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[CH2:21][CH2:22][N:23]([CH2:34][CH2:35]Cl)[S:24]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)(=[O:26])=[O:25]>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH2:35][CH2:34][N:23]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)(=[O:26])=[O:25])[CH2:22][CH2:21]2)=[C:4]([CH2:9][CH3:10])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N(CCCl)CCCl)cc1
Reactant: CCc1cc(Br)ccc1N
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(Br)ccc1N1CCN(S(=O)(=O)c2ccc(C)cc2)CC1

Procedure:
A mixture of 4-bromo-2-ethylaniline (1.4 mL), diisopropylethylamine (4.4 mL) and N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide (3 g) was refluxed for 5 hr. After cooling, the solvent was evaporated, and the residue was purified by column chromatography (chloroform) to give 1-(4-bromo-2-ethylphenyl)-4-(toluene-4-sulfonyl)piperazine (3 g). To a mixture of 1-(4-bromo-2-ethylphenyl)-4-(toluene-4-sulfonyl)piperazine (3 g), methylboronic acid (1.2 g), palladium acetate (112 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (411 mg) and potassium fluoride (2.3 g) was added tetrahydrofuran (30 mL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform) to give 1-(2-ethyl-4-methylphenyl)-4-(toluene-4-sulfonyl)piperazine (2.9 g). A mixture of 1-(2-ethyl-4-methylphenyl)-4-(toluene-4-sulfonyl)piperazine (2.9 g), hydrobromic acid (16 mL) and acetic acid (16 mL) was refluxed for 8 hr. After cooling, the reaction mixture was alkalified with 1N aqueous sodium hydroxide solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. 4N hydrogen chloride/ethyl acetate (3 mL) was added and the mixture was filtered to give 1-(2-ethyl-4-methylphenyl)piperazine hydrochloride (1.7 g). To a mixture of 4-bromo-2-methanesulfonylbenzoic acid (1.1 g), 1-(2-ethyl-4-methylphenyl)piperazine hydrochloride (963 mg) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM) (1.5 g) were added chloroform (6 mL), methanol (6 mL) and N-methylmorpholine (440 μL), and the mixture was stirred at room temperature overnight. After evaporation of the solvent, the residue was purified by column chromatography (chloroform) to give the title compound (1.8 g).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([O:15][CH3:16])(=[O:14])[CH2:12][SH:13].C(N(CC)CC)C>CS(C)=O>[F:10][C:8]1[CH:7]=[CH:6][C:3]2[CH:4]=[C:12]([C:11]([O:15][CH3:16])=[O:14])[S:13][C:2]=2[CH:9]=1
Reactant: O=Cc1ccc(F)cc1F
Reactant: COC(=O)CS
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2ccc(F)cc2s1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 2,4-difluorobenzaldehyde (5.0 g) in dimethylsulfoxide (100 ml) were added methyl thioglycolate (3.45 ml) and triethylamine (10 ml), and the mixture was stirred at 80° C. overnight. The reaction mixture was poured into ice-cold water. The mixture was extracted with ethyl acetate, washed with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:1) to give 6-fluoro-2-methoxycarbonylbenzo[b]thiophene (1.32 g) as colorless powder. GC-EI-Mass m/Z 210 (M).
Reaction SMILES: CC([CH:5]1[CH2:10][CH:9]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[O:12])[CH2:8][CH2:7][N:6]1C([O-])=O)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[CH2:14][NH:13][C:11]([CH:9]1[CH2:10][CH2:5][NH:6][CH2:7][CH2:8]1)=[O:12]
Reactant: CC(C)(C)C1CC(C(=O)NCc2ccc(Cl)cc2Cl)CCN1C(=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccc(Cl)cc1Cl)C1CCNCC1
Temperature: 25 °C
Yield: 66 %

Procedure:
A 500 mL round bottom flask equipped with a magnetic stir bar was charged with 1,1-di methylethyl-4-({[(2,4-dichlorophenyl)methyl]amino}carbonyl)-1-piperidinecarboxylate (27.6 g, 71.2 mmol) and DCM (117 mL) at room temperature. Trifluoroacetic acid (117 mL) was added slowly, and the reaction was maintained at room temperature for 1 hour after which time LC/MS determined that the reaction was complete (Rt=6.03 min and m/e 287 [M+1]+). The volatiles were removed by rotary evaporation and the crude oil was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution (3×200 mL). The organic phase was dried over Na2SO4, filtered and concentrated to give 13.5 g of the title compound (47 mmol, 66%) as a pale yellow solid. MS (ES) m/e 287 [M+H]+. 1H NMR (400 MHz, DMSO-D6) □ 8.6 (m, 1H), 7.4 (d, 1H), 7.3 (d, 1H), 4.3 (m, 2H), 3.2 (m, 2H), 2.8 (m, 2H), 2.5 (m, 1H shouldering on DMSO peak), 1.8 (m, 2H), 1.7 (m, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N:24](C(OC(C)(C)C)=O)[CH3:25])[CH:19]=3)[S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1>O1CCOCC1>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][CH3:25])[CH:19]=3)[S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10]2)=[CH:34][CH:35]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(C(=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)S(C)(=O)=O)c1
Solvent: C1COCCO1
Product: CNc1cccc(C(=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)S(C)(=O)=O)c1
Yield: 58 %

Procedure:
2.7 g of 1-[bis(4-chlorophenyl)methyl]-3-{[3-(N-tertbutyloxycarbonyl-N-methylamino)phenyl](methylsulfonyl)methylene}azetidine in 30 cm3 of dioxane and 30 cm3 of a 4.7 N solution of hydrochloric dioxane are stirred for 20 hours. The reaction medium is evaporated to dryness under reduced pressure (2.7 kpa), taken up in 50 cm3 of water and 50 cm3 of ethyl acetate, stirred and neutralized carefully with a saturated aqueous sodium bicarbonate solution. The organic phase is separated, dried over magnesium sulfate, treated with animal charcoal and then concentrated under reduced pressure (2.7 kpa) to a volume of about 25 cm3, then filtered, concentrated to dryness under reduced pressure. 1.3 g of 1-[bis(4-chlorophenyl)methyl]-3-[(3-methylaminophenyl)(methylsulfonyl)methylene]azetidine are obtained in the form of white crystals melting at 228° C. [NMR spectrum in DMSO-d6, T=300K, δ in ppm (300 MHz): 2.65 (3H, s, J=6 Hz, NCH3), 2.95 (3H, s, SCH3), 3.80 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.80 (1H, s, NCH), 5.85 (1H, q, J=6 Hz, NH), 6.55 (3H, m, 3 CH arom.), 7.15 (1H, t, J=7 Hz, CH arom.), 7.40 (4H, d, J=7 Hz, 4CH arom.), 7.50 (4H, m, 4CH arom.)].
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[NH2:44][C:45]1[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][C:46]=1[O:53][C:54]([F:57])([F:56])[F:55]>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]2[CH:41]=[C:40]([NH:44][C:45]3[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][C:46]=3[O:53][C:54]([F:55])([F:56])[F:57])[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: N#Cc1ccc(N)c(OC(F)(F)F)c1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3ccc(C#N)cc3OC(F)(F)F)ccc2F)N=C1N

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 4-amino-3-trifluoromethoxy-benzonitrile according to procedure B followed by deprotection yielded the title compound as an off-white solid. MS (ESI): m/z=464.3 [M+H]+.
Reaction SMILES: N[CH:2]1[CH2:7][CH2:6][CH:5]([CH:8](C)[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:26]CC)C>>[O:26]=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH2:4][CH2:3]1
Reactant: CC(CNS(=O)(=O)C(C)C)C1CCC(N)CC1
Reactant: CCOCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)S(=O)(=O)NCCC1CCC(=O)CC1
Reaction time: 24 h
Yield: 100 %

Procedure:
N-[2-[4-aminocyclohexyl]propyl] 2-propanesulfonamide: To a suspension of 17 mg (0.45 mmol) of lithium aluminum hydride in 1 ml of diethylether, 25 mg (0.09 mmol) of the material prepared in Preparation 4 in 0.5 ml of diethyl ether was added. The mixture was stirred overnight for 24 hrs. Na2SO4.10H2O was added, and the mixture stirred for 30 min at ambient temperature. The solid was filtered and the organic solution was concentrated in vacuo. Afforded 24 mg (100%) of the title compound.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:30][CH2:29][CH2:28]5)=[CH:23][CH:22]=4)[N:20]=3)[N:17]=2)=[CH:8][CH:7]=1)=[O:5].[CH3:46][Mg]Cl.[Cl-].[NH4+]>C1COCC1>[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)=[C:19]([C:21]4[CH:22]=[CH:23][C:24]([C:27]5([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37])[CH2:28][CH2:29][CH2:30]5)=[CH:25][CH:26]=4)[N:20]=3)[N:17]=2)=[CH:8][CH:7]=1)(=[O:5])[CH3:46]
Reactant: C[Mg]Cl
Reactant: CON(C)C(=O)c1ccc(-c2ccc3nc(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)n3n2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(-c2ccc3nc(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)n3n2)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 23 %

Procedure:
To a solution of tert-butyl {1-[4-(6-{4-[methoxy(methyl)carbamoyl]phenyl}-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-30 (0.25 g, 0.47 mmol) in THF (10 mL) at 0° C. under an argon atmosphere was added methylmagnesium chloride (3 M in THF, 0.40 mL, 1.19 mmol, 2.5 equiv) portionwise through a septum. The resulting mixture was stirred at 0° C. and at room temperature for 5 h. Additional methylmagnesium chloride (3 M in THF, 0.16 mL, 0.48 mmol, 1.0 equiv) was added and the resulting mixture was stirred for 12 h. The resulting mixture was added to a saturated aqueous ammonium chloride solution (25 mL). The aqueous mixture was extracted with EtOAc (3×25 mL). The combined organic phases were dried (Na2SO4 anh.) and concentrated under reduced pressure. The resulting yellow oil (0.23 g) was purified using MPLC (Biotage Isolera; Snap 10 g cartridge, 100% hexane 2.0 min, gradient to 50% hexane/50% EtOAc 2.0 min, 50% hexane/50% EtOAc 2.0 min, gradient to 100% EtOAc 5.0 min, 100% EtOAc 21.0 min) to give tert-butyl (1-{4-[6-(4-acetylphenyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate (0.053 g, 23%):
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:17])[C:7](=[O:16])[NH:8][N:9]=1.[C:18]([O:22][C:23]([N:25]1[CH2:28][C:27](=[CH2:29])[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.C(N(CC)CC)C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:18]([O:22][C:23]([N:25]1[CH2:28][C:27](=[CH:29][C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][CH:15]=2)[O:12][CH2:11][C:10]2[N:5]3[CH:6]([CH3:17])[C:7](=[O:16])[NH:8][N:9]=2)[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC1C(=O)NN=C2COc3ccc(Br)cc3N21
Reactant: C=C1CN(C(=O)OC(C)(C)C)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC1C(=O)NN=C2COc3ccc(C=C4CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Yield: 51.6 %

Procedure:
A solution of 6-bromo-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Preparation #1, Step D, 0.30 g, 1.013 mmol), 3-methylene-azetidine-1-carboxylic acid tert-butyl ester (0.343 g, 2.026 mmol), Pd(OAc)2 (0.023 g, 0.101 mmol), tri-O-tolylphosphine (0.0617 g, 0.203 mmol) and triethylamine (0.308 mg, 3.04 mmol) in CH3CN (10 mL) was heated at 110° C. for 14 h. The mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was purified by preparative TLC (eluting with 50% EtOAc in petroleum ether) to give 3-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylmethylene)-azetidine-1-carboxylic acid tert-butyl ester as yellow solid (0.201 g, 52%), which was used directly in the next step. LC/MS (Table 1, Method 2) Rt=1.264 min; MS m/z: 385 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:32])=[C:5]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[C:6]=1[C:7]([NH:9][C@H:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)[CH3:11])=[O:8].[CH3:33][S:34]([NH2:37])(=[O:36])=[O:35].Cl.CN(C)CCCN=C=NCC>C1COCC1.CN(C=O)C.CN(C)C1C=CN=CC=1>[CH3:1][C:2]1[S:3][C:4]([CH3:32])=[C:5]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:26][CH:27]=2)[C:6]=1[C:7]([NH:9][C@H:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:37][S:34]([CH3:33])(=[O:36])=[O:35])=[O:18])=[CH:14][CH:13]=1)[CH3:11])=[O:8]
Reactant: Cc1sc(C)c(C(=O)N[C@@H](C)c2ccc(C(=O)O)cc2)c1Cc1ccc(C(F)(F)F)cc1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1sc(C)c(C(=O)N[C@@H](C)c2ccc(C(=O)NS(C)(=O)=O)cc2)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-{(1S)-1-[({2,5-dimethyl-4-[4-(trifluoromethyl)benzyl]-3-thienyl}carbonyl)amino]ethyl}benzoic acid from Example 12 (200 mg, 0.433 mmol) in a mixture of THF (5 mL) and DMF (2.5 mL), were successively added methanesulfonamide (52.0 mg, 0.542 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (166 mg, 0.866 mmol) and 4-dimethylaminopyridine (66.0 mg, 0.542 mmol). The mixture was stirred overnight at r.t. and quenched with acetic acid. After 10 min., the mixture was diluted with water and partitioned between 1N HCl and EtOAc. The organic layer was washed with 1N HCl (2×) and brine, dried and concentrated. The residue was purified by Combi Flash chromatography system (50% THF/CHCl3 in 13 min.) to afford the desired product as a white solid. MS (−APCI): m/z 537 (M−1)−.
Reaction SMILES: [NH2:1]/[C:2](=[N:13]\[O:14][C:15](=O)[C:16]([CH3:19])([CH3:18])[CH3:17])/[CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>C1COCC1>[C:16]([C:15]1[O:14][N:13]=[C:2]([CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[N:1]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCC/C(N)=N/OC(=O)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCc1noc(C(C)(C)C)n1
Reaction time: 2 h
Yield: 98 %

Procedure:
To a stirred suspension of tert-butyl ((3Z)-3-amino-3-{[(2,2-dimethylpropanoyl)oxy]imino}propyl)carbamate, obtained in step II as describe above (51 g; 177 mmol; 1 eq.), in dry THF (1000 ml) under N2, is added dropwise at RT a solution of tetrabutylammonium fluoride solution (177.5 ml; 1 M; 177.5 mmol; 1 eq.) in dry THF (400 ml). At the end of addition, the initial white suspension becomes a yellow solution. The reaction is followed by NMR. After 2 h the reaction is complete. The reaction mixture is poured into EtOAc (1 l) and is washed with water (3×700 ml) and brine (3×700 ml). The organic layer is dried over MgSO4, filtered off and evaporated, affording the title compound as a beige solid (46.6 g, 98%).