Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.FC1C([C:27]([F:30])([F:29])[F:28])=C(C2CCN(C(C3C4CCNCC=4NN=3)=O)CC2)C=C(F)C=1.BrCCC(F)(F)F.[F:38][C:39]1[C:40]([C:67]([F:70])([F:69])[F:68])=[C:41]([CH:46]2[CH2:51][CH2:50][N:49]([C:52]([C:54]3[C:58]4[CH2:59][N:60]([CH2:63][CH2:64]OC)[CH2:61][CH2:62][C:57]=4[NH:56][N:55]=3)=[O:53])[CH2:48][CH2:47]2)[CH:42]=[C:43]([F:45])[CH:44]=1>>[F:38][C:39]1[C:40]([C:67]([F:70])([F:69])[F:68])=[C:41]([CH:46]2[CH2:51][CH2:50][N:49]([C:52]([C:54]3[C:58]4[CH2:59][N:60]([CH2:63][CH2:64][C:27]([F:30])([F:29])[F:28])[CH2:61][CH2:62][C:57]=4[NH:56][N:55]=3)=[O:53])[CH2:48][CH2:47]2)[CH:42]=[C:43]([F:45])[CH:44]=1
Reactant: COCCN1CCc2[nH]nc(C(=O)N3CCC(c4cc(F)cc(F)c4C(F)(F)F)CC3)c2C1
Reactant: O=C(c1n[nH]c2c1CCNC2)N1CCC(c2cc(F)cc(F)c2C(F)(F)F)CC1
Agent: Cl
Agent: FC(F)(F)CCBr
Product: O=C(c1n[nH]c2c1CN(CCC(F)(F)F)CC2)N1CCC(c2cc(F)cc(F)c2C(F)(F)F)CC1

Procedure:
Following general procedure GP-G2, (4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone hydrochloride (60) and 3-bromo-1,1,1-trifluoropropane were converted to (4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(2-methoxyethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone as a white solid (41 mg, 51%): 1H NMR (500 MHz, DMSO-d6) δ 12.83 (m, 1H), 7.43 (m, 2H), 5.12 (m, 1H), 4.67 (m, 1H), 3.53 (m, 2H), 2.50-3.12 (m, 11H), 1.68 (m, 4H); ESI MS m/z 511 [M+H].
Reaction SMILES: OO.FC(F)(F)C(O)=[O:6].[C:10]([C:12]1[C:16]([S:17][C:18]([F:21])([F:20])[F:19])=[C:15]([CH3:22])[N:14]([C:23]2[C:28]([Cl:29])=[CH:27][C:26]([C:30]([F:33])([F:32])[F:31])=[CH:25][C:24]=2[Cl:34])[N:13]=1)#[N:11]>>[C:10]([C:12]1[C:16]([S:17]([C:18]([F:20])([F:19])[F:21])=[O:6])=[C:15]([CH3:22])[N:14]([C:23]2[C:28]([Cl:29])=[CH:27][C:26]([C:30]([F:32])([F:33])[F:31])=[CH:25][C:24]=2[Cl:34])[N:13]=1)#[N:11]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1c(SC(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: OO
Product: Cc1c(S(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 8 h
Yield: 83 %

Procedure:
A 30 wt % aqueous solution of hydrogen peroxide (29 μL) was added to a trifluoroacetic acid solution of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-methyl-4-trifluoromethylthiopyrazole (116 mg) described in Example 1. The reaction mixture was stirred overnight whereupon solvent was evaporated under reduced pressure to give a residue that was purified by chromatography (SiO2, heptane/EA) to afford the title compound as a white solid (100 mg, 83%). MS (ES): M/Z [M+NH4]=453. 1H NMR: (400 MHz, DMSO-d6): 2.35 (s, 3H) and 8.41 (s, 2H). 19F NMR (376 MHz, DMSO-d6): −62.01 (s, 3F) and −74.18 (s, 3F).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13](/[C:17](=C\C(C)C)/[C:18]([CH3:24])([CH3:23])[C:19]([O:21]C)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CS(C)=O.[OH-:33].[Na+]>CO>[CH2:10]([O:33][CH:17]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:18]([CH3:24])([CH3:23])[C:19]([OH:21])=[O:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [OH-]
Reactant: COC(=O)C(C)(C)/C(=C/C(C)C)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: CC(C)(C(=O)O)C(OCc1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 8 h

Procedure:
(E)-Methyl 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethylhex-3-enoate (52 mg, 0.123 mmol) was dissolved in MeOH (5 mL) and DMSO (5 mL) and treated with 1 M NaOH (5 mL) at 100° C. After stirring overnight, the MeOH was removed in vacuo, the residue acidified with sat KH2PO4 to pH 4-5 and extracted with EtOAc×3. The organic layer was dried with MgSO4, filtered, concentrated in vacuo to give 3-(benzyloxy)-3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2-dimethylpropanoic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@H:4]([CH:5]=[C:6]([Cl:8])[F:7])[C@@H:3]1[C:9]([OH:11])=[O:10].[CH3:13][C:14]1([CH3:26])[C@H:16]([CH:17](O)[C:18](Cl)([Cl:20])[Cl:19])[C@@H:15]1[C:23]([OH:25])=[O:24]>>[CH3:1][C:2]1([CH3:12])[C@H:4]([CH:5]=[C:6]([Cl:8])[F:7])[C@@H:3]1[C:9]([OH:11])=[O:10].[CH3:13][C:14]1([CH3:26])[C@H:16]([CH:17]=[C:18]([Cl:20])[Cl:19])[C@@H:15]1[C:23]([OH:25])=[O:24]
Reactant: CC1(C)[C@H](C(O)C(Cl)(Cl)Cl)[C@@H]1C(=O)O
Agent: CC1(C)[C@H](C=C(F)Cl)[C@@H]1C(=O)O
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)O

Procedure:
The process of claim 3 wherein the lactone is the lactone of 1R, cis 2,2-dimethyl-3-(1'hydroxy-2',2',2'-trichloroethyl)-cyclopropane-1-carboxylic acid to obtain 1R, cis2,2-dimethyl-3-(2',2'-dichlorovinyl)-cyclopropane-1-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]([S:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25])=[C:3]=[C:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C:18](=[CH:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.C1C[O:35][CH2:34]C1.C[O-].[Na+]>CO>[Cl:1][CH:2]([S:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25])[C:3]([O:35][CH3:34])=[C:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C:18](=[CH:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=C=C(Cl)S(=O)c3ccccc3)CC[C@@H]12
Reactant: C1CCOC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=C1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@]12C)C(Cl)S(=O)c1ccccc1

Procedure:
21-Chloro-21-(phenylsulfinyl)pregna-4,9(11),17(20),20-tetraen-3-one, (V, Example 2, 100 mg) and THF (1 ml) are slurried and cooled to 0°-5° under nitrogen. Sodium methoxide in methanol (25%, 0.05 ml) is added with stirring. The mixture is stirred 1 hr and then quenched with water (10 ml). The mixture is extracted with ethyl acetate (2×15 ml). The organic extracts are combined, backwashed with water (10 ml), dried over sodium sulfate and concentrated under reduced pressure to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:5]=2[S:4][CH:3]=1.C1C(=O)N([Br:19])C(=O)C1.O>C(Cl)Cl>[Br:19][C:3]1[S:4][C:5]2[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1csc2c1C(=O)CCC2
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClCCl
Product: Cc1c(Br)sc2c1C(=O)CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
To a stirred solution of 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzothiophene (500 mg, 3.01 mmol) in CH2Cl2 (15 mL) was added NBS (536 mg, 3.01 mmol) at room temperature, and the mixture stirred for 3 hours at room temperature. The reaction mixture was poured into water (50 mL) and the whole was extracted with diethyl ether (100 mL). The organic layer was washed with water (100 mL×2), brine, dried over MgSO4, and concentrated in vacuo to provide the title product (686 mg, 93% yield).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[C:21]([O:25][C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:32][CH:31]=1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: CC(C)(C)OC(=O)NCc1ccc(B(O)O)cc1
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(CNC(=O)OC(C)(C)C)cc3)ccn2c1=O
Yield: 107.5 %

Procedure:
Methyl 8-(4-(((tert-butoxycarbonyl)-amino)-methyl)-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (500 mg, 1.71 mmol) and (4-(((tert-butoxycarbonyl)-amino)-methyl)-phenyl)-boronic acid (516 mg, 2.06 mmol). Purification by flash silica column chromatography (CH2Cl2:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (850 mg, 100%). ESI-MS m/z: 485 (M+Na)+, 463 (M+H)+.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]1(=O)[C:15]2[C:10](=[CH:11][N:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][NH:7]1>ClC1C=CC=CC=1>[Cl:3][C:6]1[C:15]2[C:10](=[CH:11][N:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][N:7]=1
Reactant: O=c1[nH]ccc2cnccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: Clc1ccccc1
Product: Clc1nccc2cnccc12
Temperature: 100 °C

Procedure:
Under stirring, 184 ml (2.00 mol) phosphorus oxychloride was added slowly to a suspension of 146 g (1.00 mol) 2,6-naphthyridine-1(2H)-one in 1500 ml chlorobenzene at room temperature. The reaction mixture was heated to 100° C., stirred at this temperature for 16 hours and then cooled to room temperature. The solids were filtered off, washed with chlorobenzene and dried under vacuum. The residue was taken up in 1.5 l ice-cold water, 350 ml 50% aqueous sodium hydroxide solution to reach a pH value of 7-8. The precipitate thus formed was filtered off, washed with water and dried under vacuum yielding 1-chloro-[2,6]naphthyridine as brown crystals; HPLC/MS (A): 1.62 min, [M+H] 165.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N-:13]=[N+:14]=[N-:15].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.O>[N:13]([C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1)=[N+:14]=[N-:15]
Reactant: Fc1cccc2c(Cl)ccnc12
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: [N-]=[N+]=Nc1ccnc2c(F)cccc12
Yield: 93.2 %

Procedure:
A mixture of 2.08 g (0.0114 mol) of 4-chloro-8-fluoroquinoline, 1.12 g (0.0172 mol) of sodium azide, and 4.10 g ((0.0127 mol) of tetrabutyl ammonium bromide in 70 mL of dichloromethane and 25 mL of water was refluxed overnight. The layers were then separated and the organic layer was washed once with water, passed through phase separating paper, and concentrated to an oil, which was triturated with ether. The solid was filtered and the filtrate was concentrated to give 2.0 g of the title product.
Reaction SMILES: O(C=C)S(C(F)(F)F)(=O)=O.C(B(CC)[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)C.FC(F)(F)S(O[C:28]1[C@:29]2([CH2:46][CH2:45][C@H:44]3[C@@H:34]([CH2:35][CH:36]=[C:37]4[C@:42]3([CH3:43])[CH2:41][CH2:40][C@H:39]([O:47][C:48](=[O:50])[CH3:49])[CH2:38]4)[C@@H:31]2[CH2:32][CH:33]=1)[CH3:30])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>O.C(OCC)(=O)C.O1CCCC1>[CH3:49][C:48]([O:47][C@@H:39]1[CH2:38][C:37]2[C@@:42]([CH3:43])([C@@H:44]3[C@@H:34]([CH2:35][CH:36]=2)[C@@H:31]2[CH2:32][CH:33]=[C:28]([C:14]4[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=4)[C@@:29]2([CH3:30])[CH2:46][CH2:45]3)[CH2:41][CH2:40]1)=[O:50]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(OS(=O)(=O)C(F)(F)F)=CC[C@@H]32)C1
Reactant: CCB(CC)c1cccnc1
Agent: C=COS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(c4cccnc4)=CC[C@@H]32)C1
Temperature: 25 °C

Procedure:
Trifluoromethanesulphonic anhydride (235 g) is dropped into a solution of prasterone acetate (250 g) in methylene chloride (5 L), maintaining the temperature between −5° C. and 0° C., and anhydrous sodium carbonate (80 g) is added in portions. The mixture is stirred for 4 h at 0-5° C. Cold water (2.5 L) is added and the organic phase is separated and washed with a 10% sodium chloride aqueous solution. The mixture is treated with decolourising carbon (120 g), and then concentrated under vacuum to obtain an oily residue (about 355 g). The vinyl triflate thus obtained is taken up with tetrahydrofuran (3.0 L), and diethyl(3-pyridyl)borane (100 g), bis(triphenylphosphine)palladium II chloride (3.3 g) and a 2M sodium carbonate aqueous solution (900 mL) are loaded in succession in an inert gas environment. The resulting mixture is refluxed for about 1 h, then cooled to room temperature, and ethyl acetate (2.5 L) and water (2.5 L) are added. The aqueous phase is back-extracted with ethyl acetate (1.4 L), and the combined organic phases are treated with decolourising carbon (about 100 g), and then concentrated under vacuum to obtain crude abiraterone acetate as an oil (304 g; purity about 92%; assay 52%).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:25])[C:9]4[CH:21]=[CH:20][C:19]([C:22]([OH:24])=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH3:16][C:11]1([CH3:17])[C:12]2[NH:13][C:14]3[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:15]=3)[C:7]=2[C:8](=[O:25])[C:9]2[CH:21]=[CH:20][C:19]([C:22]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:24])=[CH:18][C:10]1=2
Reactant: C1COCCN1
Reactant: CC1(C)c2cc(C(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)c2cc(C(=O)N3CCOCC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
To the tetrahydrofuran (1 ml) solution of 3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-carboxylic acid (Compound B2-28, 15 mg, 0.045 mmol), morpholine (6 μl, 1.5 eq.), hexafluorophosphoric acid uronium 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethylmethane aminium (HATU) (26 mg, 1.5 eq.), and N,N-diisopropylethylamine (24 μl, 3.0 eq.) were added and the mixture was stirred at room temperature for 3 hr. The reaction solution was filtered to remove insoluble matters and the residues obtained after concentration under reduced pressure were purified by high performance liquid chromatography to obtain the title compound (11 mg, 55%).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7]([CH:9]([CH3:13])[C:10]([OH:12])=O)=[O:8])=[CH:4][CH:3]=1.[NH2:16][CH:17]1[C:35](=[O:36])[N:19]2[C:20]([C:32]([OH:34])=[O:33])=[C:21]([CH:24]([S:26][C:27]3[NH:31][N:30]=[N:29][N:28]=3)[CH3:25])[CH2:22][S:23][C@H:18]12>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][S:7]([CH:9]([CH3:13])[C:10]([NH:16][CH:17]2[C:35](=[O:36])[N:19]3[C:20]([C:32]([OH:34])=[O:33])=[C:21]([CH:24]([S:26][C:27]4[NH:28][N:29]=[N:30][N:31]=4)[CH3:25])[CH2:22][S:23][C@H:18]23)=[O:12])=[O:8])=[CH:14][CH:15]=1
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CC(C(=O)O)S(=O)Cc1ccc(O)cc1
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)C(C)S(=O)Cc3ccc(O)cc3)[C@H]2SC1

Procedure:
456 mg. of 2-(p-hydroxybenzylsulfinyl)propionic acid and 7-amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 291 mg. of 7-[2-(p-hydroxybenzylsulfinyl)propionamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid were obtained.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:20][CH3:21])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:8]=1[N+:17]([O-])=O>C(O)C.[Pd]>[CH3:21][O:20][CH:3]([O:2][CH3:1])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:8]=1[NH2:17]
Reactant: COc1cc(CNCC(OC)OC)c([N+](=O)[O-])cc1OC
Agent: [Pd]
Solvent: CCO
Product: COc1cc(N)c(CNCC(OC)OC)cc1OC

Procedure:
1.2 g of N-(2,2-dimethoxyethyl)-2-nitro-4,5-dimethoxybenzylamine are dissolved in 20 ml of ethanol, and then hydrogenated at room temperature and at normal pressure, in the presence of 300 mg of palladium catalyst (10% on carbon). After filtering off the catalyst and evaporating the filtrate, the heading compound remains as an almost colourless oil, which is used in the next stage (e) without further purification.
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([NH:9][C:10]([N:12]3[CH2:17][CH2:16][C:15](=[CH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:14][CH2:13]3)=[O:11])[S:8][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[NH4+]>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:37]1[CH:38]=[CH:39][CH:40]=[C:35]([C:2]2[CH:26]=[CH:25][C:5]3[N:6]=[C:7]([NH:9][C:10]([N:12]4[CH2:17][CH2:16][C:15](=[CH:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=5)[CH2:14][CH2:13]4)=[O:11])[S:8][C:4]=3[CH:3]=2)[CH:36]=1
Reactant: O=C(Nc1nc2ccc(Br)cc2s1)N1CCC(=Cc2ccccn2)CC1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Product: O=C(Nc1nc2ccc(-c3cccnc3)cc2s1)N1CCC(=Cc2ccccn2)CC1
Reaction time: 16 h
Yield: 53 %

Procedure:
The compound (50 mg, 116 μmol) obtained in Example 1 and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (119 mg, 580 μmol) were dissolved in dimethoxyethane (3 mL), under a nitrogen atmosphere, a 2N sodium carbonate aqueous solution (350 μL, 700 μmol) and tetrakis(triphenylphosphine)palladium(0) (26.8 mg, 23.2 μmol) were added thereto, followed by stirring for 16 hours while heating under reflux. A saturated ammonium chloride aqueous solution was added to the resulting mixture to stop the reaction, and after extraction with ethyl acetate, the extract was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The desiccant was filtered off, and the residue obtained by evaporation under reduced pressure was purified using medium pressure flash column chromatography (silica gel; methanol:chloroform=1:25), thereby giving the title compound (26.3 mg, 53%) as an amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:12]([OH:14])=[O:13])[C:9]([OH:11])=[O:10].S(Cl)(Cl)=O.[N+:19]([C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1)([O-:21])=[O:20]>C1(C)C=CC=CC=1.CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:9]([O:11][C:25]1[CH:26]=[CH:27][C:22]([N+:19]([O-:21])=[O:20])=[CH:23][CH:24]=1)=[O:10])[C:12]([O:14][C:25]1[CH:26]=[CH:27][C:22]([N+:19]([O-:21])=[O:20])=[CH:23][CH:24]=1)=[O:13]
Reactant: O=C(O)C(C(=O)O)c1ccccc1F
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)C(C(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccccc1F
Temperature: 30 °C
Yield: 77.7 %

Procedure:
To a 1 L flask was added toluene (500 mL), 2-(2-fluorophenyl)propanedioic acid (100 g, 0.479 moles) and N,N-dimethylformamide (6.92 g) at 25° C. under a nitrogen atmosphere. The reaction mixture was initially heated to 30° C. and thionyl chloride (127.53 g, 1.071 moles) was added dropwise over a period of 20 minutes at 25-30° C. After the addition, the reaction mixture was heated to 48-50° C. and this temperature maintained for 3.5 hours. Toluene (300 mL) was then added to the reaction mixture in one portion, followed by the addition of solid 4-nitrophenol (148.09 g total, 1.064 moles) in ten portions over a period of 15 minutes. After the addition, the reaction mixture was maintained at 49-55° C. for 1.5 hours. The reaction mixture was then concentrated under reduced pressure at 40-45° C. to remove toluene. The resulting residue was triturated using cold methanol (300 mL, approximately 5° C.) to yield an off-white solid which was isolated by filtration, washed with cold methanol (2×150 mL, approximately 5° C.) and dried under reduced pressure at 45° C. to give the title compound (163.8 g, 71.6%).
Reaction SMILES: NC1(C2C=CC(C3C(C4C=CC=CC=4)=CC4N(CCC#N)C(=O)COC=4N=3)=CC=2)CCC1.C(OC(=O)[NH:39][C:40]1([C:44]2[CH:49]=[CH:48][C:47]([C:50]3[C:51]([C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)=[CH:52][C:53]4[NH:58][C:57](=[O:59])[CH:56]([CH3:60])[O:55][C:54]=4[N:61]=3)=[CH:46][CH:45]=2)[CH2:43][CH2:42][CH2:41]1)(C)(C)C>>[NH2:39][C:40]1([C:44]2[CH:45]=[CH:46][C:47]([C:50]3[C:51]([C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)=[CH:52][C:53]4[NH:58][C:57](=[O:59])[CH:56]([CH3:60])[O:55][C:54]=4[N:61]=3)=[CH:48][CH:49]=2)[CH2:41][CH2:42][CH2:43]1
Reactant: CC1Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2NC1=O
Agent: N#CCCN1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Product: CC1Oc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc2NC1=O
Yield: 94.1 %

Procedure:
Following the procedure for 3-(6-(4-(1-aminocyclobutyl)phenyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)propanenitrile, tert-butyl(1-(4-(3-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (25 mg, 0.051 mmol) was reacted to afford the title compound (18.5 mg). 1H NMR (500 MHz, CD3OD): 7.37-7.42 (m, 4H), 7.34 (s, 1H), 7.28-7.30 (m, 3H), 7.18-7.20 (m, 2H), 5.03 (q, 1H), 2.73-2.79 (m, 2H), 2.56-2.60 (m, 2H), 2.20-2.26 (m, 1H), 1.96-1.99 (m, 1H), 1.65 (d, 3H). LCMS (Method D): RT=0.73 min, M+H+=386.2
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([CH3:15])[C:10](=O)[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.Cl.[CH3:18][NH:19][C:20]([NH2:22])=[NH:21].C([O-])([O-])=O.[Cs+].[Cs+].O>CC1OCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:15])=[C:10]([CH:11]([CH3:13])[CH3:12])[N:22]=[C:20]([NH:19][CH3:18])[N:21]=2)=[CH:4][CH:3]=1
Reactant: CNC(=N)N
Reactant: CC(C)C(=O)C(C)C(=O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC1CCCO1
Solvent: O
Product: CNc1nc(-c2ccc(F)cc2)c(C)c(C(C)C)n1
Temperature: 40 °C
Reaction time: 10 h

Procedure:
A mixture of 1-(4-fluorophenyl)-2,4-dimethylpentane-1,3-dione (MDK, 1.00 g, 4.5 mmol), N-methyl guanidine hydrochloride salt (0.49 g, 4.5 mmol) and Cs2CO3 (2.61 g, 8.0 mmol) in MeTHF (10 mL) was stirred at 40° C. for 10 h. The resulting suspension was cooled down to room temperature. Water (10 mL) and MeTHF (10 mL) were added. Layers were separated and the water layer was back-extracted with MeTHF (10 mL). The combined MeTHF fractions were washed with brine (20 mL) and dried over magnesium sulphate. Then, approximately 90% of the solvent was evaporated under reduced pressure and methanol (5 mL) was added to the resulting oily residue. White crystalline precipitate was collected by filtration, washed with ice-cold methanol (5 mL) and dried to afford the pyrimidine derivative CMDK (1.1 g, 92%) as pale yellow solid.
Reaction SMILES: [CH3:1][CH:2]([C:7]([O:9]C)=O)[C:3](OC)=[O:4].[NH2:11][C:12]1[NH:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=1.C[O-].[Na+]>CO>[OH:9][C:7]1[N:16]2[N:15]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:13]=[C:12]2[NH:11][C:3](=[O:4])[C:2]=1[CH3:1]
Reactant: Nc1cc(-c2ccccc2)n[nH]1
Reactant: COC(=O)C(C)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(O)n2nc(-c3ccccc3)cc2[nH]c1=O
Temperature: 75 °C
Yield: 126.3 %

Procedure:
To a solution of dimethyl methylmalonate (1.30 mL, 9.80 mmol) and 5-amino-3-phenylpyrazole (1.50 g, 9.42 mmol) in methanol (11 mL) is added 25% sodium methoxide in methanol (6.04 mL, 26.4 mmol). The reaction mixture is heated at 75° C. for 48 hr. The precipitate was collected in a Buchner funnel and washed with dichloromethane to provide 7-hydroxy-6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-5(4H)-one (2.87 g, yield 95%). LCMS: (AA) M+1 242; 1H NMR (400 MHz, DMSO) δ 10.39 (s, 1H), 7.92-7.86 (m, 2H), 7.41-7.33 (m, 2H), 7.32-7.26 (m, 1H), 5.92 (s, 1H), 1.75 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[N:12]2)=[S:10])=[CH:4][CH:3]=1.I[CH3:33]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]=[C:9]([S:10][CH3:33])[N:11]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:26][CH:27]=3)=[N:12]2)=[CH:6][CH:7]=1
Reactant: CI
Reactant: FC(F)(F)c1ccc(C2=NN(C(=S)Nc3ccc(Cl)cc3)CC2c2ccccc2)cc1
Product: CSC(=Nc1ccc(Cl)cc1)N1CC(c2ccccc2)C(c2ccc(C(F)(F)F)cc2)=N1
Reaction time: 8 h

Procedure:
A mixture of 0.54 g of the compound from Step C and 0.1 mL of iodomethane were stirred overnight after which time the precipitated solids were filtered and dried. This product was suspended in 2 mL of chloroform and 2 mL of 5% aqueous sodium bicarbonate was added. After stirring overnight the layers were separated and the chloroform extracts dried over magnesium sulfate and concentrated to afford 0.12 g of the title compound as a yellow oil.