Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Al:1](Cl)(Cl)Cl.O.O.O.O.O.O.[Al:11].[CH3:12][C:13]([O-:15])=[O:14].[Na+]>O>[C:13]([O-:15])(=[O:14])[CH3:12].[Al+3:1].[C:13]([O-:15])(=[O:14])[CH3:12].[C:13]([O-:15])(=[O:14])[CH3:12].[Al:11]
Reactant: Cl[Al](Cl)Cl
Agent: CC(=O)[O-]
Agent: [Al]
Agent: [Na+]
Solvent: O
Product: [Al+3]

Procedure:
Aluminum acetate buffer solution—A solution of aluminum was prepared by dissolving 0.1028 g of AlCl3 hexahydrate in 42.6 mL DI water. A 4 mL aliquot of the aluminum solution was mixed with 16 mL of a 0.1 M NaOAc solution at pH 4 to provide a 2 mM Al stock solution.
Reaction SMILES: C([O:8][CH2:9][CH2:10][NH:11][S:12]([C:15]1[C:16]([OH:34])=[C:17]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=2[Cl:33])=[O:24])[CH:18]=[CH:19][C:20]=1[Cl:21])(=[O:14])=[O:13])C1C=CC=CC=1.I[Si](C)(C)C>ClCCl>[OH:8][CH2:9][CH2:10][NH:11][S:12]([C:15]1[C:16]([OH:34])=[C:17]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=2[Cl:33])=[O:24])[CH:18]=[CH:19][C:20]=1[Cl:21])(=[O:14])=[O:13]
Reactant: O=C(Nc1ccc(Cl)c(S(=O)(=O)NCCOCc2ccccc2)c1O)Nc1cccc(Cl)c1Cl
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(S(=O)(=O)NCCO)c1O)Nc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.5 %

Procedure:
To a solution of N-[3-[N″-(2-benzyloxyethyl)aminosulfonyl]4-chloro-2-hydroxyphenyl]-N′-(2,3-dichlorophenyl) urea (46 mg, 0.08 mmol) in 3mL of dichloromethane was added iodotrimethylsilane (38 mg, 0.19 mmol). The mixture was stirred for 16 hours at room temperature. Purification by column chromatography on silica gel, eluting with ethyl acetate/hexane (60/40, v/v), gave the desired product (14 mg, 37%). LC-MS (m/z) 455.8 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][CH2:10][CH2:11][CH2:12]4.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][CH2:35][Cl:36]>CN(C=O)C>[Cl:36][CH2:35][CH2:34][CH2:33][O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][CH2:10][CH2:11][CH2:12]4
Reactant: CC(C)(C)OC(=O)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(O)cc13
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(OCCCCl)cc13
Temperature: 50 °C
Yield: 73.9 %

Procedure:
To a stirred solution of 3-hydroxy-N-(tert-butyloxycarbonyl)morphinan (20 mg, 0.058 mmol) in dry DMF (0.3 mL) was added potassium carbonate (24 mg, 0.174 mmol), 1-bromo-3-chloropropane (17.3 μL, 0.174 mmol) sequentially and the mixture was stirred at 50° C. After starting material disappeared on TLC, solvent was removed and column chromatography gave 18 mg (74%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 7.05 (1H, m); 6.83 (1H, d); 6.75 (1H, d.d.); 4.28 (1H, d); 4.05 (2H, t); 3.90 (1H, m); 3.83 (3H, t); 3.15 (1H, m); 2.60 (2H, m); 2.30 (1H, m); 2.15 (1H, m); 1.30 (9H, s); 1.00˜1.80 (10H, m).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])/[CH:4]=[CH:5]/[C:6]([C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[F:15])=[O:7].C([O:19][C:20]1O[C:23](C(O)=O)=[N:22][CH:21]=1)C>>[OH:19][C:20]1[CH:21]=[N:22][CH:23]=[C:4]([C:5]=1[C:6](=[O:7])[C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[F:15])[C:3]([O:2][CH3:1])=[O:16]
Reactant: CCOc1cnc(C(=O)O)o1
Reactant: COC(=O)/C=C/C(=O)c1cc(Cl)ccc1F
Product: COC(=O)c1cncc(O)c1C(=O)c1cc(Cl)ccc1F

Procedure:
Diels-Alder reaction of intermediate (XX) with the known 5-ethoxyoxazole-2-carboxylic acid (XXI) (step w) to give methyl 5-hydroxy-4-(2'-fluoro-5'-chlorobenzoyl)nicotinate (XXII);
Reaction SMILES: [ClH:1].[F:2][C:3]1([F:44])[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][N:22]([CH2:25][CH2:26][C:27]([CH3:42])([S:38]([CH3:41])(=[O:40])=[O:39])[C:28]([NH:30][O:31]C4CCCCO4)=[O:29])[C:21](=[O:43])[CH:20]=3)=[CH:15][CH:14]=2)[CH2:5][CH2:4]1>O1CCOCC1.O>[ClH:1].[F:44][C:3]1([F:2])[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][N:22]([CH2:25][CH2:26][C:27]([CH3:42])([S:38]([CH3:41])(=[O:39])=[O:40])[C:28]([NH:30][OH:31])=[O:29])[C:21](=[O:43])[CH:20]=3)=[CH:17][CH:18]=2)[CH2:5][CH2:4]1
Reactant: CC(CCn1ccc(-c2ccc(OCCCN3CCC(F)(F)CC3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(CCn1ccc(-c2ccc(OCCCN3CCC(F)(F)CC3)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O

Procedure:
HCl (4.0 M in 1,4-dioxane, 1.0 mL) was added to a solution of 4-[4-{4-[3-(4,4-difluoropiperidin-1-yl)propoxy]phenyl}-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (209 mg, 0.334 mmol) in 1,4-dioxane/water (1:1, 5 mL). After 10 minutes the reaction was concentrated to give a white solid, the solid was triturated with 2-propanol at 50° C. for 1 h. The title compound was isolated by filtration as a white solid (146 mg, the hydrochloride salt, 75%). LCMS m/z 542.8 (M+1) 1H NMR (400 MHz, DMSO-d6) δ ppm 1.57 (s, 3H) 2.22 (br. s., 3H) 2.38 (br. s., 5H) 3.11 (s, 3H) 3.13-3.26 (m, 2H) 3.31 (br. s., 2H) 3.74 (br. s., 3H) 4.14 (t, J=5.76 Hz, 3H) 6.59-6.72 (m, 2H) 7.05 (d, J=8.78 Hz, 2H) 7.63-7.79 (m, 3H) 11.03 (br. s., 1H) 11.18 (br. s., 1H)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.II>O=C(C=C(C)C)C>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[C:11]2[C:2](=[CH:3][CH:4]=1)[NH:1][C:5]([CH3:10])([CH3:6])[CH:4]=[C:3]2[CH3:2])=[O:7]
Reactant: COC(=O)c1ccc(N)cc1
Agent: II
Solvent: CC(=O)C=C(C)C
Product: COC(=O)c1ccc2c(c1)C(C)=CC(C)(C)N2

Procedure:
Skraup reaction of methyl 4-aminobenzoate (5.0 g) and iodine (1.7 g) in mesityl oxide (25 ml) was performed according to the method described in example 1.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH:4]=[C:2]1[CH3:3].[CH2:9]=[C:10]1[CH2:13][CH2:12][C:11]1=[CH2:14]>ClCCl>[CH3:3][C:2]12[C:1](=[O:8])[O:7][C:5](=[O:6])[CH:4]1[CH2:14][C:11]1[CH2:12][CH2:13][C:10]=1[CH2:9]2
Reactant: CC1=CC(=O)OC1=O
Reactant: C=C1CCC1=C
Solvent: ClCCl
Product: CC12CC3=C(CC3)CC1C(=O)OC2=O
Reaction time: 1272 h

Procedure:
Into a 500-mL, single-neck round bottom glass flask containing a magnetic stirring bar was weighed 96.62 grams (0.862 moles) of citraconic anhydride. The flask was then fitted with a three-neck adapter to which was attached a thermometer, a condenser and a 250-mL addition funnel. To the funnel was added 86.0 grams of a distilled dimethylenecyclobutane (DMCB) cut containing 90.2% (by GC) 1,2-isomer (77.6 grams, or 0.968 moles, of 1,2-dimethylenecyclobutane). The flask was purged with dry nitrogen. The DMCB was then added dropwise to the citraconic anhydride with stirring. No temperature increase due to reaction exotherm was evident. When the DMCB addition was complete, the mixture was allowed to stand for 53 days at room temperature to complete the reaction. At the end of this period, gas chromatography revealed that the peak corresponding to unreacted citraconic anhydride had essentially disappeared. The product was then dissolved in dichloromethane and filtered to remove insoluble gelatinous material. Dichloromethane and unreacted volatiles were removed at 60° C. on a rotary evaporator to yield a crystalline product. The crude yield was 156.18 grams (94%). 152 g of product was then recrystallized from 165 grams of cyclohexane with strong stirring. Yield of recrystallized MBODA was 132.17 grams (80%). Melting point was 64°-68° C. The 1H and 13C NMR spectra of the product were consistent with the following structure; no impurities were seen in the product by NMR except for a small amount of cyclohexane. ##STR6##
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:11]=[O:12])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.C[Sn](C)(C)[C:15]1[S:16][CH:17]=[CH:18][N:19]=1>>[S:16]1[CH:17]=[CH:18][N:19]=[C:15]1[C:2]1[CH:3]=[C:4]([CH:11]=[O:12])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1
Reactant: O=Cc1cc(Br)cc2ccoc12
Reactant: C[Sn](C)(C)c1nccs1
Product: O=Cc1cc(-c2nccs2)cc2ccoc12

Procedure:
From 5-Bromo-benzofuran-7-carbaldehyde (400 mg) and 2-trimethylstannanylthiazole (1.22 g).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:38])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][CH:16]2[C:35](O)=[O:36])[CH:12]=[CH:13][CH:14]=1.CC1(C)[O:44][C@@H:43]([CH2:45][CH2:46][NH2:47])[C:42]([CH3:49])([CH3:48])[O:41]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:44][C@H:43]([C:42]([OH:41])([CH3:49])[CH3:48])[CH2:45][CH2:46][NH:47][C:35]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=2[F:38])[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:33])([CH3:34])[CH3:32])[NH:17]1)=[O:36]
Reactant: CC1(C)O[C@@H](CCN)C(C)(C)O1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)CC1NC(C(=O)NCC[C@H](O)C(C)(C)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 43.3 %

Procedure:
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 52c (0.67 g, 1.15 mmol) was reacted with 2-((S)-2,2,5,5-tetramethyl-[1,3]dioxolan-4-yl)-ethylamine prepared in Example 131a (0.4 g, 2.3 mmol), HATU (0.79 g, 2.1 mmol) and iPr2NEt (1 mL, 5.8 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-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-4-methyl-pentyl)-amide as a white solid (0.29 g, 43%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br.[OH-].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C1(C)C=CC=CC=1>[C:1]1([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCCCCBr
Reactant: Oc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccccc1
Temperature: 25 °C

Procedure:
44.8 g (or 0.477 mol) of phenol, 38.6 g (or 0.2 mol) of n-bromooctane, 6 g of tetrabutylammonium bromide, 26.8 g of potassium hydroxide, 100 ml of water and 100 ml of toluene were charged into a 500 ml, three-necked, round-bottom flask equipped with a mechanical stirrer, a thermometer and water-cooled reflux condenser. This medium was stirred and was then heated to reflux for 20 hours. The reaction mixture was then cooled to room temperature. The phases were settled and separated. The organic phase was washed with 100 ml of a 0.5N sodium hydroxide solution and then with five 100 ml fractions of water. It was then dried over magnesium sulfate and the solvent was then driven off under reduced pressure at a temperature of 85° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([Br:12])[C:9]=1[O:10][CH3:11])=[O:4].[OH-].[Na+]>O1CCCC1>[Br:12][C:8]1[C:9]([O:10][CH3:11])=[C:5]([C:3]([OH:4])=[O:2])[S:6][CH:7]=1
Reactant: COC(=O)c1scc(Br)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1c(Br)csc1C(=O)O
Temperature: 25 °C
Reaction time: 96 h
Yield: 90 %

Procedure:
The product from Step A above (22.5 g, 84.36 mmol) was dissolved in 60 mL of tetrahydrofuran and added with 125 mL of a 1.0M NaOH aqueous solution. The mixture was stirred at room temperature for 4 d, then washed with ether (60 mL×2), acidified to pH ˜2 using a 1.0M HCl aqueous solution. Solids were precipitated out after acidification, and collected by filtration. The solid was dissolved in methylene chloride-ethyl acetate (˜4:1, v/v). The organic solution was washed with H2O and brine, dried with Na2SO4, and concentrated in vacuo to a light yellow solid, further dried on hight vacuum, yielding 17.95 g of 4-bromo-3-methoxy-2-thiophene carboxylic acid (90%, MH+=237.0).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[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]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:56][C:57]1[CH:62]=[CH:61][N:60]([CH2:63][CH2:64][O:65][Si:66]([C:69]([CH3:72])([CH3:71])[CH3:70])([CH3:68])[CH3:67])[C:59](=[O:73])[CH:58]=1>ClCCl>[C:69]([Si:66]([CH3:68])([CH3:67])[O:65][CH2:64][CH2:63][N:60]1[CH:61]=[CH:62][C:57]([NH:56][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[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]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:30])=[CH:58][C:59]1=[O:73])([CH3:72])([CH3:71])[CH3:70]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)cc1=O
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CCO[Si](C)(C)C(C)(C)C)c(=O)c2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11.4 %

Procedure:
To a mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (0.2 g, 0.428 mmol) in dichloromethane (20 mL) was added iPr2NEt (138 mg, 1.07 mmol), followed by the addition of diphenylphosphinic chloride (Aldrich) (203 mg, 0.856 mmol). The mixture was stirred at room temperature for 30 min, then 4-amino-1-(2-(tert-butyldimethylsilyloxy)ethyl)pyridin-2(1H)-one (115 mg, 428 μmol) was added. The reaction mixture was stirred at room temperature for 3 h, then concentrated. The residue was purified by flash chromatography (silica gel, 40 g, 5% to 80% EtOAc in hexanes) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-oxo-1,2-dihydro-pyridin-4-yl)-amide as a white solid (35 mg, 11%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:8][CH:7]2[CH:5]([O:6]2)[C:4](=[O:9])[CH2:3]1.[OH-].[K+].[CH3:13]O>O>[CH3:13][O:6][C:5]1[C:4](=[O:9])[CH2:3][C:2]([CH3:10])([CH3:1])[CH2:8][CH:7]=1
Reactant: CC1(C)CC(=O)C2OC2C1
Reactant: CO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COC1=CCC(C)(C)CC1=O
Reaction time: 20 h
Yield: 68 %

Procedure:
A solution of 4,4-dimethyl-7-oxa-bicyclo[4.1.0]heptan-2-one (44.0 g, 0.31 mol) in methanol (150 mL) was added to a solution of 85% potassium hydroxide (20.7 g, 0.31 mol) in methanol (450 mL) at room temperature. The mixture was kept at this temperature for 20 hours and was then heated to reflux for 30 minutes. After cooling, the solution was diluted with water (1.2 L) and extracted with ethyl ether (350 mL×5). The organic extracts were collected, washed with brine, dried on Na2SO4 and evaporated under vacuum to remove most of the solvent. The crude material was purified by distillation to obtain pure the title compound (32.8 g, 68% yield) as an oil.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:17][C:16]=2[CH2:28][NH:29][CH3:30])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]1([CH:37]=[CH:38][CH2:39][C:40](Cl)=[O:41])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:1]([N:8]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])=[CH:17][C:16]=2[CH2:28][NH:29][CH3:30])[CH2:11][CH2:10]1)[C:40](=[O:41])[CH2:39][CH:38]=[CH:37][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNCc1cc(C(=O)OC(C)(C)C)ccc1[C@H]1CC[C@H](NCc2ccccc2)CC1
Reactant: O=C(Cl)CC=Cc1ccccc1
Product: CNCc1cc(C(=O)OC(C)(C)C)ccc1[C@H]1CC[C@H](N(Cc2ccccc2)C(=O)CC=Cc2ccccc2)CC1

Procedure:
from trans-N-benzyl-4-(4-tert.butoxycarbonyl-methylaminomethylphenyl)cyclohexylamine and 4-phenyl-3-butenoylchloride. Colourless oil. Rf value: 0.26 (alumina, petroleum ether/ethyl acetate/methanol=10:10:1, v:v:v).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.Cl.[CH3:28][C:29]([CH:34]1[CH2:39][O:38][CH2:37][CH2:36][NH:35]1)([CH3:33])[C:30]([OH:32])=[O:31]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:35]2[CH2:36][CH2:37][O:38][CH2:39][CH:34]2[C:29]([CH3:33])([CH3:28])[C:30]([OH:32])=[O:31])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CC(C)(C(=O)O)C1COCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(C)(C)C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 38.9 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (3.02 g, 6 mmol) was reacted with 2-methyl-2-(morpholin-3-yl)propanoic acid hydrochloride (1.26 g, 6 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (1.39 g, 39%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2([NH:16][C:17](=[O:20])[CH2:18][Cl:19])[CH2:13][O:12]C(C)(C)[O:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.FC(CC(O)=O)(F)F.[NH4+].[OH-]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([NH:16][C:17](=[O:20])[CH2:18][Cl:19])([CH2:13][OH:12])[CH2:9][OH:10])[CH:5]=[CH:4][N:3]=1
Reactant: CC1(C)OCC(NC(=O)CCl)(c2ccnc(Br)c2)CO1
Agent: O=C(O)CC(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(CCl)NC(CO)(CO)c1ccnc(Br)c1
Reaction time: 2 h

Procedure:
A solution of N-[5-(2-bromo-pyridin-4-yl)-2,2-dimethyl-[1,3]dioxan-5-yl]-2-chloro-acetamide (10.0 g, 27.6 mmol) in DCM (150 ml) was cooled to 0° C. for 10 min. and trifluoromethyl acetic acid (15.0 ml) was added. Stirring continued for 2 h and the resultant contents were concentrated under reduced pressure. The residue formed was basified with aq. NH4OH solution and the product was extracted with ethyl acetate (3×200 ml) by washing organic layer with brine (5.0 ml) and dried over anhy. Na2SO4. Organic layer was concentrated under reduced pressure to obtain title compound as a brown liquid which was carried to next step without any purification. Yield=8.1 g (91%). TLC (70% ethyl acetate in hexane) Rf=0.15; LCMS: RtH8=0.12 [M+1]+=322.9 and 324.9; HPLC RtH9=5.266 min (61%), 5.104 (25%).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][N:11]=[N:10][C:9]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:6][CH:7]=1>CO.[Pd]>[C:20]1([C:9]2[N:10]=[N:11][CH:12]=[C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:8]=2[C:5]2[O:6][CH:7]=[C:3]([CH3:2])[N:4]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1coc(-c2c(-c3ccccc3)cnnc2-c2ccccc2)n1
Agent: [Pd]
Solvent: CO
Product: Cc1coc(-c2c(-c3ccccc3)cnnc2-c2ccccc2)n1
Reaction time: 1.5 h
Yield: 6.8 %

Procedure:
To a solution of 4-(bromomethyl)-2-(3,5-diphenylpyridazin-4-yl)oxazole (250 mg, 0.64 mmol) in methanol (8 mL), Pd/C (80 mg, wt/wt) was added and the resulting reaction mixture was stirred under hydrogen atmosphere for 1.5 h. The reaction mixture was filtered through a celite bed, washed with methanol and concentrated under reduced pressure to obtain the crude product which was purified by preparative TLC to furnish 2-(3,5-diphenylpyridazin-4-yl)-4-methyloxazole (compound 20) (13.6 mg, 6.8%) as pale yellow gummy liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7](B2OC(C)(C)C(C)(C)O2)=[C:6]([CH3:19])[CH:5]=1.FC(F)(F)S(O[C:27]1[CH:28]2[CH2:33][CH:30]([CH2:31][CH:32]=1)[C:29]2([CH3:35])[CH3:34])(=O)=O>>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([C:27]2[CH:28]3[CH2:33][CH:30]([CH2:31][CH:32]=2)[C:29]3([CH3:35])[CH3:34])=[C:6]([CH3:19])[CH:5]=1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: CC1(C)C2CC=C(OS(=O)(=O)C(F)(F)F)C1C2
Product: COC(=O)c1ccc(C2=CCC3CC2C3(C)C)c(C)c1
Yield: 69.5 %

Procedure:
3-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester of Example 28, Step A (1.00 g, 3.62 mmol) and 6,6-dimethyl-bicyclo[3.1.1]hept-2-en-2-yl trifluoromethanesulfonate (1.17 g, 4.34 mmol) were reacted in the manner of Example 1, Step F. Purification by flash column chromatography on silica gel, eluting with a solvent gradient of from 0 to 5% ethyl acetate in hexane, afforded the title compound (0.680 g) as a light yellow oil.
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[CH3:24][O:25][CH2:26][CH2:27][NH:28][CH2:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1>CN(C=O)C>[CH3:24][O:25][CH2:26][CH2:27][NH:28][CH2:29][C:30]1[CH:31]=[CH:32][C:33]([NH:34]/[C:4](=[C:11]2\[C:12](=[O:23])[NH:13][C:14]3[C:19]\2=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)/[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:35][CH:36]=1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: COCCNCc1ccc(N)cc1
Solvent: CN(C)C=O
Product: COCCNCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 89 from 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(2-methoxyethylaminomethyl)-aniline in DMF.
Reaction SMILES: N1C=CN=C1CN1C(=O)COC2N=C(C3C=CC(C4(N)CCC4)=CC=3)C(C3C=CC=CC=3)=CC1=2.C(OC(=O)[NH:41][C:42]1([C:46]2[CH:51]=[CH:50][C:49]([C:52]3[C:53]([C:70]4[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=4)=[CH:54][C:55]4[N:60]([CH2:61][C:62]5[CH:67]=[CH:66][CH:65]=[CH:64][N:63]=5)[C:59](=[O:68])[CH2:58][O:57][C:56]=4[N:69]=3)=[CH:48][CH:47]=2)[CH2:45][CH2:44][CH2:43]1)(C)(C)C>>[NH2:41][C:42]1([C:46]2[CH:47]=[CH:48][C:49]([C:52]3[C:53]([C:70]4[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=4)=[CH:54][C:55]4[N:60]([CH2:61][C:62]5[CH:67]=[CH:66][CH:65]=[CH:64][N:63]=5)[C:59](=[O:68])[CH2:58][O:57][C:56]=4[N:69]=3)=[CH:50][CH:51]=2)[CH2:45][CH2:44][CH2:43]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(Cc3ccccn3)C(=O)CO4)cc2)CCC1
Agent: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(Cc3ncc[nH]3)C(=O)CO4)cc2)CCC1
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(Cc3ccccn3)C(=O)CO4)cc2)CCC1
Yield: 122.5 %

Procedure:
Following the procedure for 1-((1H-imidazol-2-yl)methyl)-6-(4-(1-aminocyclobutyl)phenyl)-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one, tert-butyl(1-(4-(2-oxo-7-phenyl-1-(pyridin-2-ylmethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (16 mg, 0.03 mmol) was reacted to afford the title compound (17 mg, 87%). LCMS (Method A): RT=4.11 min, M-16=446. 1H NMR (500 MHz, MeOD): 8.54 (1H, d), 7.91-7.87 (1H, t), 7.53 (1H, d), 7.42-7.35 (6H, m), 7.26-7.21 (3H, m), 7.04 (2H, d), 5.39 (2H, s), 5.11 (2H, s), 2.77-2.72 (2H, m), 2.59-2.53 (2H, m), 2.25-2.21 (1H, m), 1.98-1.94 (1H, m).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[Cl:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[Cl:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4](=[O:19])[CH2:3][C:2]2([CH3:20])[CH3:1]
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: OB(O)c1cccc(Cl)c1Cl
Product: CC1(C)CC(=O)c2ccc(-c3cccc(Cl)c3Cl)cc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 2,3-dichlorophenyl boronic acid according to the procedure described in example 21. MS (ES) m/z 305.1; HRMS: calcd for C17H14Cl2O+H+, 305.04944; found (ESI, [M+H]+), 305.0504.