Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].F[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[N+:18]([O-:20])=[O:19])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(=O)N1CCN(c2ccc(F)cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Yield: 86.3 %

Procedure:
To a solution of 1-acetylpiperazine (20 g) in acetonitrile (50 ml) were added 2,5-difluoronitrobenzene (25 g) and potassium carbonate (22 g) and the mixture was refluxed under heating at room temperature for 4.5 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give a red oil. The oil was crystallized from ethyl acetate-isopropyl ether to give the title compound (36 g) as a red solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:23][CH:24]=O)[CH2:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:27]1([C:33]2([OH:39])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[BH3-]C#N.[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:23][CH2:24][N:36]2[CH2:37][CH2:38][C:33]([OH:39])([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:34][CH2:35]2)[CH2:10][C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=CCC(CC(=O)N1CCCc2ccccc21)c1ccc(Cl)c(Cl)c1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CC(CCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1)N1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.3 %

Procedure:
1-[3-(3,4-dichlorophenyl)-1,5-dioxopentyl]-1,2,3,4-tetrahydroquinoline (900 mg), in MeOH/THF (1:1, 20 mL) was treated sequentially with molecular sieves 3A (767 mg), 4-phenyl-4-hydroxypiperidine HCl (767 mg) and NaBH3CN (150 mg). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was with quenched with water (20 mL) and diluted with CH2Cl2 (50 mL). The organic layer was separated and the aqueous layer extracted with CH2Cl2 (3×50 mL) The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give the crude oil. Silica gel chromatography eluting with 1-2% MeOH/CH2Cl2 gave the title compound (750 mg). Mass spectrum (FAB): 537.2081.
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([S:39](Cl)(=[O:41])=[O:40])[CH:34]=[CH:35][C:36]=1[O:37][CH3:38]>N.CO>[CH3:29][O:30][C:31]1[CH:32]=[C:33]([S:39]([N:11]2[C:12]3[C:8](=[C:7]4[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]4=[CH:14][CH:13]=3)[CH:9]=[CH:10]2)(=[O:40])=[O:41])[CH:34]=[CH:35][C:36]=1[O:37][CH3:38]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)n2ccc3c4c(ccc32)OCCNC4)cc1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 31.9 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.05 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 3,4-Dimethoxybenzenesulfonyl chloride (24 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (6.2 mg). MS m/z 389 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[SH:9].Br[CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Nc1cc(F)ccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CSc2ccc(F)cc2N)cc1
Yield: 93.9 %

Procedure:
Following General Procedure A, the title compound (873 mg, 94%) was prepared from 2-amino-4-fluorobenzenethiol (456 mg, 3.19 mmol) and methyl 4-(bromomethyl)benzoate (731 mg, 3.19 mmol), K2CO3 (1.32 g, 9.58 mmol) in DMF (20 ml).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[C:4]([F:10])[CH:3]=1.Cl.[CH3:12][O:13][C:14]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[N:20][CH:21]=1)=[O:15].Cl.C(=O)([O-])[O-].[K+].[K+]>>[F:10][C:4]1[CH:3]=[C:2]([C:18]2[CH:19]=[N:20][CH:21]=[C:16]([CH:17]=2)[C:14]([O:13][CH3:12])=[O:15])[CH:7]=[CH:6][C:5]=1[CH:8]=[CH2:9]
Reactant: C=Cc1ccc(Br)cc1F
Reactant: COC(=O)c1cncc(B(O)O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=Cc1ccc(-c2cncc(C(=O)OC)c2)cc1F

Procedure:
2.5 g (11.2 mmol) of 4-bromo-2-fluoro-1-vinylbenzene were reacted according to General Method 1A with 3.2 g (14.5 mmol) of [5-(methoxycarbonyl)pyridin-3-yl]boronic acid hydrochloride. The release of the hydrochloride was achieved by additional addition of 1.70 g (12.3 mmol) of potassium carbonate. Yield: 1.9 g (61% of theory)
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[CH2:10](Br)[CH:11]=[CH2:12]>CN1C(=O)CCC1>[CH2:10]([N:2]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)[CH3:1])[CH:11]=[CH2:12]
Reactant: C=CCBr
Reactant: CNc1cccc(O)c1
Solvent: CN1CCCC1=O
Product: C=CCN(C)c1cccc(O)c1
Temperature: 80 °C
Yield: 137.9 %

Procedure:
To 3-(N-methylamino)phenol (10 g, 80 mmol), dissolved in 80 ml of NMP, was added allyl bromide (9.8 ml, 113 mmol) via syringe. The yellow solution was heated to 80° C. for 4 hours. The reaction mixture was poured into distilled water (200 ml) and saturated aqueous sodium bicarbonate solution was added. Extraction with diethyl ether (3×200 ml), drying over anhydrous magnesium sulfate, filtration and concentration in vacuo yielded 18.0 g of 3-(N-allyl-N-methylamino)phenol as a viscous green tinted oil. Vacuum distillation at I torr (110°-120° C.) yielded 10.5 g (80%) as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:34][CH2:33][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:22][C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26]([OH:28])=[O:27])[C:12]2=[O:32])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(N=[C:42]=[N:43][CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46]C2)CCCCC1.C[C@H](O)CC>CN(C)C1C=CN=CC=1.ClCCl>[CH3:42][N:43]1[CH2:44][CH2:49][CH:48]([O:27][C:26]([C:25]2[CH:24]=[C:23]([CH:31]=[CH:30][CH:29]=2)[CH2:22][N:13]2[C:12](=[O:32])[C:11]3([CH2:33][CH2:34][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]3)[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14]2)=[O:28])[CH2:47][CH2:46]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(Cc1cccc(C(=O)O)c1)CN2c1ccccc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC[C@H](C)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN1CCC(OC(=O)c2cccc(CN3CN(c4ccccc4)C4(CCN(C(=O)OC(C)(C)C)CC4)C3=O)c2)CC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 55.5 %

Procedure:
To a solution of 3-((8-(tert-butoxycarbonyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid (0.15 g, 0.32 mmol), dicyclohexylcarbodiimide (0.079 g, 0.38 mmol) and 4-(dimethylamino)pyridine (0.005 g, 0.038 mmol) in dichloromethane (5 mL), was added (S)-2-butanol (0.037 g, 0.32 mmol). After stirring at room temperature for 60 hours, the reaction mixture was filtered, concentrated in vacuo and isolated by preparatory TLC (10% methanol/dichloromethane) to obtain the title compound (0.1 g, 56%); 1H NMR (DMSO-d6): δ 1.45 (s, 9H), 1.63-1.66 (m, 4H), 1.89 (br, 2H), 2.15-2.23 (m, 5H), 2.43-2.48 (m, 4H), 3.43 (br, 2H), 3.89 (br, 2H), 4.60-4.65 (m, 4H), 4.95-5.00 (m, 1H), 6.67 (d, 2H, J=8.4 Hz), 6.76 (t, 1H, J=7.6 Hz), 7.17 (t, 2H, J=8.4 Hz), 7.52-7.60 (m, 2H), 7.86-7.91 (m, 2H); MS for C32H42N4O5 m/z 563.06 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.Cl[CH2:23][CH2:24][CH2:25][CH2:26][CH:27]=[C:28]([F:30])[F:29]>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]=[C:28]([F:30])[F:29])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: FC(F)=CCCCCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(OCCCCC=C(F)F)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.5 %

Procedure:
Under a nitrogen atmosphere a solution of 2.7 grams (0.0171 mole) of 4-chlorobenzoic acid in 100 ml of acetonitrile was stirred, and 2.6 grams (0.0171 mole) of DBU was added. Upon completion of addition, the reaction mixture was stirred at ambient temperature for 15 minutes, and then 4.0 grams (0.017 mole) of 6-chloro-1,1-difluoro-1-hexene was added. The reaction mixture was then warmed to and stirred at reflux for 18 hours. The reaction mixture was cooled and was washed into a separatory funnel with diethyl ether. The reaction mixture was washed in turn with 50 ml of aqueous 10% hydrochloric acid, 50 ml of aqueous 10% sodium bicarbonate, and 50 ml of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate nd filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished using 5% diethyl ether in hexane. The appropriate fractions were combined and concentrated under reduced pressure yielding 3.9 grams of 6,6-difluoro-5-hexenyl 4-chlorobenzoate. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]1[C:8]([CH3:9])=[C:7]([C:10]([OH:12])=O)[C:6](=[O:13])[N:5]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)C(C)C)(C)C.[C:46]1([C:52]2[O:60][C:59]3[C:54](=[N:55][CH:56]=[CH:57][C:58]=3[O:61][C:62]3[CH:68]=[CH:67][C:65]([NH2:66])=[CH:64][CH:63]=3)[CH:53]=2)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>O1CCOCC1>[C:46]1([C:52]2[O:60][C:59]3[C:54](=[N:55][CH:56]=[CH:57][C:58]=3[O:61][C:62]3[CH:63]=[CH:64][C:65]([NH:66][C:10]([C:7]4[C:6](=[O:13])[N:5]([C:14]5[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:4]([CH2:3][C:2]([OH:1])([CH3:20])[CH3:21])[C:8]=4[CH3:9])=[O:12])=[CH:67][CH:68]=3)[CH:53]=2)[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccccc4)oc23)cc1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1CC(C)(C)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(-c5ccccc5)oc34)cc2)c(=O)n(-c2ccccc2)n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.3 %

Procedure:
To a 10 mL sealed tube with stirbar was added 1-(2-hydroxy-2-methyl-propyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (57.62 mg; 0.20 mmol; 1.20 eq.), and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (63.15 mg; 0.25 mmol; 1.50 eq.). The tube was sealed and flushed with N2. To this mixture was added dioxane (3.00 ml) and N,N-diisopropylethylamine (0.14 ml; 0.83 mmol; 4.00 eq.) and the mixture was stirred at room temperature for 1 h. To the reaction mixture was then added 4-[(2-phenylfuro[3,2-b]pyridin-7-yl)oxy]aniline (50.00 mg; 0.17 mmol; 1.00 eq.) and stirred at room temperature overnight. The reaction mixture was concentrated on a rotary evaporator. The crude mixture was purified by Biotage chromatography (50% EtOAc/hex 10 column vol.; 50-100% 10 column vol.) to afford a beige solid (14 mg, 15%). (HPLC (method F): 88%, RT: 6.27 min); 1H NMR (400 MHz, DMSO-d6) δ [ppm] 10.84 (s, 1H), 8.35 (d, J=5.6, 1H), 7.98-7.90 (m, 2H), 7.73 (d, J=9.0, 2H), 7.70 (s, 1H), 7.60-7.50 (m, 4H), 7.49-7.43 (m, 2H), 7.35 (d, J=7.4, 2H), 7.30 (d, J=9.0, 2H), 6.71 (d, J=5.5, 1H), 4.85 (s, 1H), 3.86 (s, 2H), 2.80 (s, 3H), 0.97 (s, 6H); MS (m/z) 575 [M+H]+, RT: 3.7 min.
Reaction SMILES: [Cl:1][C:2]([Cl:15])([Cl:14])[CH:3]1[NH:8][C:7](=O)[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4]1.[Cl-].[Na+].[S:18](=O)(=[O:21])([OH:20])[OH:19]>>[Cl:1][C:2]([Cl:15])([Cl:14])[CH:3]1[NH:8][CH2:7][C:6]2[CH:10]=[C:11]([S:18]([OH:21])(=[O:20])=[O:19])[CH:12]=[CH:13][C:5]=2[O:4]1
Reactant: O=S(=O)(O)O
Reactant: O=C1NC(C(Cl)(Cl)Cl)Oc2ccccc21
Agent: [Cl-]
Agent: [Na+]
Product: O=S(=O)(O)c1ccc2c(c1)CNC(C(Cl)(Cl)Cl)O2
Temperature: 0 °C

Procedure:
A mixture of 3,4-dihydro-2-trichloromethyl-2H-benzo[e]-[1,3]-oxazin-4-one (10 g.--obtained as described in Example 3) and concentrated sulphuric acid (100 ml.) was heated on a steam bath for 18 hours, and drowned into ice (400 g.). The resulting solution was saturated with sodium chloride and extracted with ethyl acetae (4×100 ml.) The extracts were combined and dried, the solvent was evaporated, and the residue was crystallised from glacial acetic acid to give 3,4-dihydro-2-trichloromethyl-2H-benzo[e]-[1,3]-oxazine-6-sulphonic acid, m.p. > 260° C.
Reaction SMILES: [CH2:1]([C:3]([CH2:16]C)([CH3:15])[CH2:4][C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11](Br)=[CH:10][C:8]=2[N:9]=1)C.[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[CH:19]=[CH2:20].C(N(CC)C(C)C)(C)C>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:16][C:3]([CH3:1])([CH3:15])[CH2:4][C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([CH:20]=[CH:19][C:18]([O:22][CH2:23][CH3:24])=[O:21])=[CH:10][C:8]=2[N:9]=1
Reactant: CCC(C)(CC)Cc1nc2cc(Br)ccc2o1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)C=Cc1ccc2oc(CC(C)(C)C)nc2c1
Temperature: 100 °C
Yield: 98.1 %

Procedure:
A mixture of 2-(2,2-diethylpropyl)-5-bromobenzoxazole (0.60 g, 0.00225 mol), ethyl acrylate (1.08 g, 0.0108 mol), palladium acetate (0.051 g, 0.00023 mol), trintolylphosphine (0.135 g,0.0045 mol) and N,N-diisopropylethylamine (0.585 g, 0.0045 mol) was heated at 100° C. for 6 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic extracts were dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate:dichloromethane 3:97, to give ethyl 3-[2-(2,2-dimethylpropyl)benzoxazol-5-yl]propenoate (0.634 g).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.CCN(CC)CC.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>C(Cl)Cl>[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:6][C@H:3]2[CH2:4][CH2:5][O:1][CH2:2]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: O[C@@H]1CCOC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)O[C@H]2CCOC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a solution of (R)-tetrahydrofuran-3-ol (3 g, 34.1 mmole) and Et3N (6.9 g, 68.2 mmole) in DCM (40 mL) at 0° C. was added 4-methylbenzene-1-sulfonyl chloride (7.2 g, 37.5 mmole). The mixture was stirred at room temperature for 8 h. The mixture was washed with water, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 15% ethyl acetate in hexane) to give the title compound (6.6 g, 80% yield). MS (ESI) m/z: Calc. 242.1 (M+). Found: 243.1 (M++1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23](=[O:38])[C:24]4[C:29]([C:30]=3[C:31]3[S:35][C:34]([CH:36]=[O:37])=[CH:33][CH:32]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([F:18])[CH:12]=3)[C:3]=12.CC(=CC)C.[O-:44]Cl=O.[Na+]>C(O)(C)(C)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23](=[O:38])[C:24]4[C:29]([C:30]=3[C:31]3[S:35][C:34]([C:36]([OH:44])=[O:37])=[CH:33][CH:32]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([F:18])[CH:12]=3)[C:3]=12
Reactant: [O-][Cl+][O-]
Reactant: CC(c1oc(=O)c2ccccc2c1-c1ccc(C=O)s1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(c1oc(=O)c2ccccc2c1-c1ccc(C(=O)O)s1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.9 %

Procedure:
5-(3-(1-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1-oxo-1H-isochromen-4-yl)thiophene-2-carbaldehyde (Intermediate F4, 19 mg, 0.036 mmol) was dissolved in 2-methyl-2-butene (300 μl, 2.83 mmol) and t-Butanol (0.5 ml), then a solution of NaClO2 (32.6 mg, 0.360 mmol) and K2H2PO4 (49.0 mg, 0.360 mmol) in 0.5 mL of water added and the mixture stirred at rt for 2 hrs. The reaction was quenched by the addition of 2M HClaqueous (1 ml) and the crude purified via reverse phase chromatography using a Biotage C18 30 g SNAP with a gradient of water and acetonitrile to give the title compound (8 mg, 40.9%) as white solid.
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([CH:12]3[CH2:14][CH2:13]3)[O:11][C:7]=2[C:6]([C:15](=[CH2:25])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:4]=1[CH3:32])#[N:2].[CH2:33](Br)[CH:34]=[CH2:35].[H-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH2:35]([N:17]([CH2:16][C:15]([C:6]1[C:7]2[O:11][C:10]([CH:12]3[CH2:14][CH2:13]3)=[N:9][C:8]=2[C:3]([C:1]#[N:2])=[C:4]([CH3:32])[C:5]=1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[CH2:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:34]=[CH2:33]
Reactant: C=CCBr
Reactant: C=C(CNC(=O)OC(C)(C)C)c1c(-c2ccccc2)c(C)c(C#N)c2nc(C3CC3)oc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN(CC(=C)c1c(-c2ccccc2)c(C)c(C#N)c2nc(C3CC3)oc12)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
tert-Butyl [2-(4-cyano-2-cyclopropyl-5-methyl-6-phenyl-1,3-benzoxazol-7-yl)prop-2-en-1-yl]carbamate (I-325) (97.0 mg, 0.226 mmol) and allyl bromide (28.7 μl, 0.339 mmol) were dissolved in dimethylformamide (2 ml), then with cooling with ice, sodium hydride (55% w/w) (11.8 mg, 0.271 mmol) was added, followed by stirring for 2 hours with cooling with ice. With cooling with ice, aqueous 10% citric acid solution was added to the reaction liquid, followed by concentration under reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water and saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the residue obtained by concentration was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=2:1, v/v) to obtain the entitled compound (105 mg, 99%) as a colorless oily substance.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:22])([F:21])[C:10]1[CH:20]=[CH:19][C:13]([C:14]([CH2:16][C:17]#[N:18])=[O:15])=[CH:12][CH:11]=1.Cl[C:24](=[N:30]O)[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(O)C>[C:17]([C:16]1[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:30][O:15][C:14]=1[C:13]1[CH:19]=[CH:20][C:10]([C:9]([F:21])([F:22])[F:8])=[CH:11][CH:12]=1)#[N:18]
Reactant: N#CCC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(Cl)=NO
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1noc(-c2ccc(C(F)(F)F)cc2)c1C#N
Reaction time: 0.33 h
Yield: 84.7 %

Procedure:
Triethylamine (0.98 mL, 7.0 mmol) was added to a −5° C. solution of 4-trifluoromethylbenzoylacetonitrile (1.5 g, 7.0 mmol) in ethanol (15 mL) and the mixture was stirred for 20 minutes. A solution of ethyl 2-chloro-2-(hydroxyimino)acetate (1.06 g, 7.0 mmol) in ethanol (5 mL) was added to the reaction over 15 minutes. After stirring at room temperature for 72 hours, the cream-colored solid which formed was collected by filtration, washed with cold water and dried in vacuo to obtain ethyl 4-cyano-5-(4-(trifluoromethyl)phenyl)isoxazole-3-carboxylate (1.84 g, 5.93 mmol).
Reaction SMILES: [N:1]1([C:6]2[CH2:10][CH2:9][C:8](=O)[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C1(C)C=CC=CC=1.N1([Ti](N2CCCC2)(N2CCCC2)N2CCCC2)CCCC1>[N:1]1([C:6]2[CH2:10][CH:9]=[C:8]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1C=C(N2CCCC2)CC1
Agent: C1CCN([Ti](N2CCCC2)(N2CCCC2)N2CCCC2)C1
Solvent: Cc1ccccc1
Product: C1=C(N2CCCC2)C=C(N2CCCC2)C1
Reaction time: 8 h
Yield: 181.3 %

Procedure:
To 2.245 g (14.85 mmol) of 3-(pyrrolidino)-2-cyclopenten-1-one dissolved in 50 mL of toluene was added 2.5 g (7.61 mmol) of the tetrapyrrolidino titanium. The reaction mixture became red with concomitant appearance of precipitate. The reaction mixture was stirred overnight and then filtered giving a dark red solution. Toluene was removed under reduced pressure to give 2.75 g of red crystalline solid. Yield was 90.6 percent. This product was then recrystallized from 60 mL of hexane to give 1.56 g of the desired product as large red-orange crystals.
Reaction SMILES: Cl[CH:2](Cl)[C:3]([CH3:8])(C)[C:4]([OH:6])=[O:5].C([O-])([O-])=O.[Na+].[Na+].C([O-])(=[S:18])C.[K+].C[S:22]([CH3:24])=O>O>[CH3:8][C:3]1([C:4]([OH:6])=[O:5])[CH2:24][S:22][S:18][CH2:2]1
Reactant: CC(C)(C(=O)O)C(Cl)Cl
Reactant: CC([O-])=S
Reactant: CS(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CC1(C(=O)O)CSSC1

Procedure:
8 g of dichloropivalic acid are placed in a 250 ml three-necked flask on which are mounted a condenser and a dropping funnel. The acid is dissolved in 80 ml of water, and 4.6 g of Na2CO3 are slowly added. A solution of 10.7 g of potassium thioacetate is added dropwise, and the reaction medium is brought to reflux. 14.9 g of Na2CO3 are added and the medium is again refluxed. After disappearance of the starting material, 7.3 ml of DMSO are added, followed by refluxing. The dithiolane is obtained after acidification by precipitating and drying the solid under vacuum.
Reaction SMILES: [NH3:1].F[CH:3]1[N:8]=[C:7]([F:9])[N:6]=[C:5]([Cl:10])[N:4]1[O:11][CH:12]([F:14])[F:13]>O1CCCC1>[NH2:1][CH:3]1[N:8]=[C:7]([F:9])[N:6]=[C:5]([Cl:10])[N:4]1[O:11][CH:12]([F:14])[F:13]
Reactant: N
Reactant: FC1=NC(F)N(OC(F)F)C(Cl)=N1
Solvent: C1CCOC1
Product: NC1N=C(F)N=C(Cl)N1OC(F)F
Temperature: 22 °C
Reaction time: 8 h
Yield: 43.2 %

Procedure:
7.8 g (0.46 mol) of ammonia were passed into a mixture of 50.0 g (0.23 mol) of 2,4-difluoro-6-chlorodifluoromethoxy-1,3,5-triazine in 150 ml of tetrahydrofuran in the course of 45 minutes at -70° C., while stirring. Stirring was continued for 2 hours at -70° C. and overnight while warming up to 22° C. The reaction mixture was evaporated down under reduced pressure and the residue was washed with water and dried. The reaction product was then washed onto a silica gel column with methylene chloride and eluted with the same solvent. 21.5 g (43.6% of theory) of 2-amino-4-fluoro-6-chlorodifluoromethoxy-1,3,5-triazine of melting point 131°-133° C. were obtained in fractions 1 to 8.