Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=1.[NH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:25]1([NH:24][C:21]([C:18]2[N:19]=[N:20][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:16][CH:17]=2)=[O:23])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: NN1CCOCC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)nn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NN2CCOCC2)nn1
Yield: 37 %

Procedure:
To a stirred solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (215 mg, 0.69 mmol) in DMF (5 mL) at room temperature under argon was added N-aminomorpholine (78 mg, 0.76 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (244 mg, 0.76 mmol) and N,N-diisopropylethylamine (446 mg, 3.4 mmol). After 15 h the reaction mixture was concentrated, diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica, dichloromethane:methanol 1:0 to 97.5:2.5) afforded the title compound (101 mg, 37%) as a white gum. MS: m/e=396.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12](Cl)=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)#[N:24].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:28]2[CH:29]=[CH:30][C:25]([C:23]#[N:24])=[CH:26][CH:27]=2)=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: O=c1c(Cl)c(-c2ccc(Cl)cc2)cnn1Cc1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2c(-c3ccc(Cl)cc3)cnn(Cc3ccccc3)c2=O)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 45.9 %

Procedure:
To a sealed tube was added 2-benzyl-4-chloro-5-(4-chlorophenyl)pyridazin-3(2H)-one (3.31 gm, 110.0 mmol), 4-cyanophenyl boronic acid (2.94 gm, 20 mmol), Pd(dppf)Cl2 dichloromethane complex (0.817 gm, 1.0 mmol), potassium phosphate (6.36 gm, 30 mmol) and THF (10 ml). The reaction solution was degassed with argon for 5 min and then sealed in a reaction tube. The reaction was then heated to 90° C. and keeped at this temperature for 4 hrs. The reaction was then cooled to rt and diluted with EtOAc (50 ml). The reaction mixture was then poured into a separatory funnel and the layers were separated. The organic layer was washed with water (20 ml) and saturated aqueous NaCl (20 ml). The organic layer was then slurried with MgSO4 to remove excess water, filtered and concentrated to give the crude product. The crude product was purified using an automated column chromatography system (ISCO, 330 gm silica gel) eluting with a gradient of 0-70% EtOAc/Hex to give 3.65 gm (92% yield) 4-(2-benzyl-5-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazin-4-yl)benzonitrile. HPLC retention time (method B) 3.81 min; LCMS (M+H)=398.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12](=[O:18])[CH2:13][C:14](=[O:17])[CH2:15][CH3:16].[CH:19](OCC)(OCC)[O:20][CH2:21][CH3:22].C(OC(=O)C)(=O)C>>[Cl:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12](=[O:18])[C:13](=[CH:19][O:20][CH2:21][CH3:22])[C:14](=[O:17])[CH2:15][CH3:16]
Reactant: CCC(=O)CC(=O)c1ccc(S(C)(=O)=O)cc1Cl
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)CC)C(=O)c1ccc(S(C)(=O)=O)cc1Cl
Yield: 85.9 %

Procedure:
A mixture of 1-[2-chloro-4-(methylsulphonyl)phenyl]pentan-1,3-dione (7.0 g), triethyl orthoformate (7.2 g) and acetic anhydride was stirred and heated at reflux for 4 hours. The mixture was cooled and evaporated to dryness. Toluene was added to the residue and then re-evaporated to give 1-[2-chloro-4-(methylsulphonyl)phenyl]-2-ethoxymethylenepentan-1,3-dione (7.18 g) as a sticky orange solid which was not purified further.
Reaction SMILES: CO[C:3](=O)[CH2:4][CH2:5][CH2:6][C:7]1[O:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[N:11]=1.BrCC(C1C=CC=CC=1[N+]([O-])=O)=O.[CH2:35]([O:37][C:38](=[O:47])[CH2:39]CCCCC(=O)N)[CH3:36]>>[CH2:35]([O:37][C:38](=[O:47])[CH2:39][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[O:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[N:11]=1)[CH3:36]
Reactant: COC(=O)CCCc1nc(-c2ccccc2[N+](=O)[O-])co1
Reactant: CCOC(=O)CCCCCC(N)=O
Agent: O=C(CBr)c1ccccc1[N+](=O)[O-]
Product: CCOC(=O)CCCCCc1nc(-c2ccccc2[N+](=O)[O-])co1
Yield: 26 %

Procedure:
Using a method similar to the procedure described for the preparation of 4-[4-(2-nitro-phenyl)-oxazol-2-yl]-butyric acid methyl ester; reaction of 2-bromo-2′-nitroacetophenone (8.9 g, 36.5 mmol) with 6-carbamoyl-hexanoic acid ethyl ester (9.1 g, 48.7 mmol) gives 6-[4-(2-nitro-phenyl)-oxazol-2-yl]-hexanoic acid ethyl ester (3.19 g, 26%). MS (ES): (M+1)+ 333.2, 334.4 m/z.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH:8]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][Si](C(C)(C)C)(C)C)=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CO.O1CCCC1.C(OCC)C>[C:1]([O:5][C:6](=[O:32])[NH:7][CH:8]([C:25]1[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1)c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(O)cc1)c1ccc(Cl)cc1

Procedure:
To a solution of 1.37 g (2.88 mmol) rac-[2-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-1-(4-chloro-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester in 30 ml methanol were added at ambient temperature 3.45 ml (3.45 mmol) 1M tetrabutylammonium fluoride in tetrahydrofuran. After 10 min the reaction mixture was diluted with diethyl ether, the solution washed twice with sodium bicarbonate solution and once with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by flash-chromatography over silica gel with a heptane/ethyl acetate gradient of 0 to 80% ethyl acetate. The purified title compound was triturated in di-isopropyl ether, filtered, dried and obtained as colorless solid: MS (ISN): 360.2 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[N:13][C:14]([C:15]([O:17]CC)=O)=[C:7]1[N:6]=[C:5]2[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C[CH:27](C)[CH2:28][C:29](=[N:31]O)[NH2:30].[H-].[Na+].[C:36](O)(=O)C>CN(C=O)C.ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[N:13][C:14]([C:15]3[O:17][N:31]=[C:29]([CH:28]([CH3:36])[CH3:27])[N:30]=3)=[C:7]1[N:6]=[C:5]2[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: CCOC(=O)c1ncn2c1nc(N1CCOCC1)c1cc(F)ccc12
Reactant: CC(=O)O
Reactant: CC(C)CC(N)=NO
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)c1noc(-c2ncn3c2nc(N2CCOCC2)c2cc(F)ccc23)n1
Temperature: 25 °C

Procedure:
A mixture of ethyl 7-fluoro-5-morpholino-imidazo[1,5-a]quinazoline-3-carboxylate (1.6 g), 2-methyl-1-propanecarboxamide oxime (2.4 g), crushed 4 Å molecular sieves (3.5 g), and sodium hydride (0.14 g, 80% in mineral oil) in 20 ml of dry DMF was stirred at ambient temperature. After 1 hour an additional amount of the carboxamide oxime (2.4 g) and sodium hydride suspension (0.14 g) was added, and the mixture was stirred for one more hour. Glacial acetic acid (2 ml) and dichloromethane (50 ml) were added, and after the precipitated product had dissolved the sieves were removed by filtration through celite. The filtrate was evaporated and the residue was triturated with 100 ml of water. The undissolved material was collected by filtration, dried and treated with 25 ml of acetone. Yellow crystals precipitated and were filtered off and dried. Yield 0.47 g, m.p. 262°-264° C.
Reaction SMILES: C(O[C:4]1(O[Si](C)(C)C)[CH2:6][CH2:5]1)C.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:17][CH:18]=1.O.[BH3-]C#N.[Na+]>C1COCC1.C(O)(=O)C>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:20][CH2:21][N:22]([CH:4]3[CH2:5][CH2:6]3)[CH2:23][CH2:24]2)=[N:17][CH:18]=1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: Brc1ccc(N2CCNCC2)nc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: Brc1ccc(N2CCN(C3CC3)CC2)nc1
Temperature: 25 °C

Procedure:
[(1-Ethoxy-cyclopropyl)oxy]trimethylsilane (26 mL, 129.3 mmol) was added to a solution of 1-(5-bromopyridin-2-yl)-piperazine (15 g, 62.0 mmol) in THF (120 mL). Water (24 mL), acetic acid (11 mL), and 1 M NaCNBH3 in THF (90 mL, 90 mmol) were added to the reaction mixture, which was then heated at reflux temperature for 3 hours. The resulting solution was cooled to rt and evaporated to dryness in vacuo. The residue was dissolved in a mixture of dichloromethane (200 mL) and water (50 mL) and 4 N sodium hydroxide (20 mL) was added to pH 8-9. The organic phase was isolated and the aqueous phase was extracted with further dichloromethane (100 mL). The combined organic phases were evaporated to dryness in vacuo and the residue was purified on a silica gel column (gradient: from 5% ethyl acetate in heptane to 100% ethyl acetate over 40 min.). This afforded 13.1 g (75%) of 1-(5-bromopyridin-2-yl)-4-cyclopropylpiperazine.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:47])[CH:10]([NH:12][C:13](=[O:46])[CH:14]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:36][CH:35]=1)[CH:15]=[P:16]([CH:18]([NH:21][C:22]([O:24][CH:25]([O:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH3:26])=[O:23])[CH2:19]O)=[O:17])[CH3:11])[C:2]1C=CC=CC=1.Cl.C([O:51]C(=O)[C@H](C)N)C>>[CH2:1]([O:8][C:9](=[O:47])[CH:10]([NH:12][C:13](=[O:46])[CH:14]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[CH:36][CH:35]=1)[CH2:15][P:16]([OH:51])([CH:18]([NH:21][C:22]([O:24][CH:25]([O:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH3:26])=[O:23])[CH3:19])=[O:17])[CH3:11])[CH3:2]
Reactant: CCOC(=O)[C@H](C)N
Reactant: CC(OC(=O)NC(CO)[P+]([O-])=CC(Cc1ccc(-c2ccccc2)cc1)C(=O)NC(C)C(=O)OCc1ccccc1)OC(=O)C(C)C
Agent: Cl
Product: CCOC(=O)C(C)NC(=O)C(Cc1ccc(-c2ccccc2)cc1)CP(=O)(O)C(C)NC(=O)OC(C)OC(=O)C(C)C

Procedure:
The compound from example 3 (500 mg) is coupled under the conditions in step 4 of example 3 with alanine ethyl ester hydrochloride (152 mg). The crude product obtained is chromatographed on silica gel using the 7:3:0.2 CH2Cl2/MeOH/AcOH mixture. White solid, 530 mg (88%).
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:18])[CH2:7][CH:8]([C:12]2[CH2:13][O:14][CH2:15][CH2:16][CH:17]=2)[CH2:9][C:10]=1[OH:11])(=[O:4])[CH2:2][CH3:3].ClC1C=CC=C(C(OO)=[O:27])C=1>ClCCl>[C:1]([C:5]1[C:10](=[O:11])[CH2:9][CH:8]([C:12]23[O:27][CH:17]2[CH2:16][CH2:15][O:14][CH2:13]3)[CH2:7][C:6]=1[OH:18])(=[O:4])[CH2:2][CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCC(=O)C1=C(O)CC(C2=CCCOC2)CC1=O
Solvent: ClCCl
Product: CCC(=O)C1=C(O)CC(C23COCCC2O3)CC1=O

Procedure:
14.8 parts by weight of 2-propionyl-5-(5,6-dihydro-2H-pyran-3-yl)-3-hydroxy-2-cyclohexen-1-one are dissolved in 100 parts by volume of dichloromethane, and m-chloroperbenzoic acid is added at room temperature, and the reaction is monitored by means of thin layer chromatography. After the reaction has ended, the precipitated m-chlorobenzoic acid is filtered off, the filtrate is washed twice with semiconcentrated sodium bicarbonate solution and water and dried over sodium sulfate, and the solvent is distilled off under reduced pressure to leave 2-propionyl-5-(3,4-epoxy-tetrahydropyran-3-yl)-3-hydroxy-2-cyclohexen-1-one (compound No. 30).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].[I:24][C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:28]1[CH:29]=[CH:30][C:25]([I:24])=[CH:26][CH:27]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(C)c(Cl)c1
Reactant: Ic1ccc(I)cc1
Product: Cc1ccc(C(NC(=O)OC(C)(C)C)C(=O)c2ccc(I)cc2)cc1Cl

Procedure:
The title compound was prepared from rac-[(3-chloro-4-methyl-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 4) and 1,4-di-iodobenzene in analogy to Example 1a): MS (ISN): 484.2 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([F:27])[CH:18]=2)([NH2:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[F:28][C:29]([F:34])([F:33])[C@@H:30]1[CH2:32][O:31]1>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:16][CH2:32][C@@H:30]([OH:31])[C:29]([F:34])([F:33])[F:28])([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:20]=[C:19]([F:27])[CH:18]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: FC(F)(F)[C@@H]1CO1
Reactant: N[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Solvent: CC#N
Product: O[C@H](CN[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1)C(F)(F)F
Temperature: 140 °C
Yield: 64 %

Procedure:
(S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenyl ethanamine (0.148 g, 0.376 mmol, prepared as described in Procedures 5, 6 and 7) was dissolved in anhydrous acetonitrile (1 mL). (S)-2-(trifluoromethyl)oxirane (approximate 85:15 ratio of R to S) (0.20 mL, excess) was added to the solution in a microwave vial followed by Yb(OSO2CF3)3 (0.020 g, mmol). The sealed vial was heated to 140° C. for 20 mins in the microwave. The reaction mixture was taken from the reaction vial via syringe and injected directly onto a silica gel ISCO cartridge column (40 g). The product eluted at 8 minutes with a gradient of 0-50% EtOAc in hexanes over 18 minutes and flow rate of 40 mL/min, (0.122 mg, 64% yield). The crude NMR of this material showed an 85:15 ratio of R to S at the hydroxy centre. The material was further purified on a Chiral cell AD column with 5% IPA in hexane as the mobile phase yielding 0.068 g of (R)-3-((S)-1-(5-chloropyridin-2-yl)-1-(3fluoro-5-(trifluoromethyl)phenyl)-2-phenylethylamino)-1,1,1-trifluoropropan-2-ol as a colorless oil and a further 0.044 g of mixed fractions. LCMS: 2.06 min [M+1] 507.2 (2 min gradient, MeOH/H2O 0.1% TFA); HPLC: 7.88 min (8 min gradient, MeOH/H2O 0.2% PPA Purity 100%; NMR: 400 MHz 1H (CDCl3) 8.42 ppm, 1H, d, J=2.2 Hz; 7.55 ppm, 1H, dd, J=8.36 and J=2.64 Hz; 7.30 ppm, 1H, s; 7.13 ppm, 3H, m; 7.08 ppm, 2H, m; 6.57 ppm, 2H, d, J=7.04 Hz; 3.85 ppm, IH, m; 3.76 ppm, 1H, d, J=12.2 Hz; 3.50 ppm, 1H, d, J=12.2 Hz; 2.78 ppm, 1H, dd, J=6.12 and 12.0 Hz; 2.64 ppm, 1H, dd, J=3.96 and J=12.2 Hz.
Reaction SMILES: [CH2:1]1[C:4]2([CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][CH2:6][O:5]2)[CH2:3][NH:2]1.Br[CH2:18][CH2:19][C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][OH:28])[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[OH:28][CH2:27][CH2:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][CH2:18][N:2]1[CH2:3][C:4]2([CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][CH2:6][O:5]2)[CH2:1]1
Reactant: OCCc1cccc(CCBr)c1
Reactant: CC(C)(C)OC(=O)N1CCOC2(CNC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCOC2(CN(CCc3cccc(CCO)c3)C2)C1
Temperature: 60 °C

Procedure:
A mixture of tert-butyl 5-oxa-2,8-diazaspiro[3.5]nonane-8-carboxylate (0.49 g) (example 176 step c), 2-(3-(2-bromoethyl)phenyl)ethanol (0.738 g) [Organometallics 2002, 21(20), 4217] and potassium carbonate (1.187 g) in acetonitrile (30 mL) and water (0.5 mL) was heated at 60° C. for 24 hours. The mixture was cooled to RT and filtered. The solvent was passed through a 10 g SCX cartridge and further acetonitrile then eluted through. The cartridge was then eluted with a 10% solution of 880 ammonia in acetonitrile (80 mL) to bring off product. The solvents were evaporated under reduced pressure and the residue was diluted with acetonitrile and then evaporated to dryness to afford the subtitled compound. Yield 0.610 g.
Reaction SMILES: [S:1]([N:5]=[C:6]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)OC1C=CC=CC=1)(=[O:4])(=[O:3])[NH2:2].[Br:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25]>C(#N)C>[Br:21][C:22]1[CH:23]=[C:24]([NH:25][C:6](=[N:5][S:1](=[O:3])(=[O:4])[NH2:2])[O:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: NS(=O)(=O)N=C(Oc1ccccc1)Oc1ccccc1
Reactant: Nc1cccc(Br)c1
Solvent: CC#N
Product: NS(=O)(=O)N=C(Nc1cccc(Br)c1)Oc1ccccc1
Temperature: 70 °C

Procedure:
Diphenyl sulfamoylcarbonimidate, from step A, (0.05 g, 0.17 mmol) and 3-bromoaniline (18 μl, 0.17 mmol) were dissolved in acetonitrile (0.5 ml) and heated to 70° C. for 12 hours. The reaction was concentrated under vacuum to afford phenyl N-3-bromophenyl-N′-sulfamoylcarbamimidate, which was carried on crude to the next reaction.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[F:13])[CH2:4]1.C(N([CH2:35][CH3:36])CC)C.C=O.[C:39](O[BH-](OC(=O)C)OC(=O)C)(=[O:41])C.[Na+]>CO.O1CCCC1.C(#N)C>[Cl:14][C:11]1[C:12]([F:13])=[C:7]([CH:5]2[CH2:4][N:3]([CH:36]3[CH2:35][O:41][CH2:39]3)[CH2:6]2)[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]2[C:21]3=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]3[C:19]([CH3:27])=[N:18]2)[CH3:16])[CH:10]=1
Reactant: CCN(CC)CC
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1C1CNC1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C2COC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.5 %

Procedure:
To a mixture of 1-[1-(3-azetidin-3-yl-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (19 mg, 0.041 mmol racemic intermediate from Example 67, Step 1) and triethylamine (28 μL, 0.20 mmol) in methanol (0.1 mL)/acetonitrile (0.1 mL)/tetrahydrofuran (0.1 mL) was added 37% formaldehyde (15 μL, 0.20 mmol), followed by sodium triacetoxyborohydride (22 mg, 0.10 mmol). The resulting mixture was stirred overnight at room temperature. The mixture was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (1.2 mg, 6.3%). The product was isolated as a racemic mixture. LCMS calculated for C19H23ClFN6O (M+H)+: m/z=405.2; Found: 405.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:13]([CH3:14])=[CH:12][C:11](Cl)=[CH:10][CH:9]1[CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Li+].[Li+].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:13]([CH3:14])=[CH:12][CH2:11][CH2:10][CH:9]1[CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: [H][H]
Reactant: CC1=CC(Cl)=CC(C2CCCC2)N1C(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CO
Product: CC1=CCCC(C2CCCC2)N1C(=O)OC(C)(C)C

Procedure:
To a stirred solution of 1-(tert-Butoxycarbonyl)-4-chloro-6-methyl-2-cyclopentyl-1,2-dihydropyridine (2.54 g, 8.53 mmol) in 175 mL of MeOH at 0° C. was added of lithium carbonate (0.63 g, 8.53 mmol) followed by 5% Pd/C. The mixture was placed under a positive pressure of hydrogen gas from a balloon, and the reaction progress was monitored by removing aliquots with a syringe, concentrating the aliquot in vacuo, and examining its 1H NMR spectrum. Upon completion, the mixture was filtered through Celite and evaporated. The residue was dissolved in ether (100 mL) and water (50 mL) was added, and the aqueous phase was extracted twice with ether. The combined organic extracts were washed with 1M NaOH and brine. The organic phase was dried with potassium carbonate, filtered through Celite, and concentrated in vacuo to give the crude product. Purification by column chromatography (silica gel, 5% EtOAc in hexanes) afforded 1.14 g (52%) as a clear oil that was homogeneous by TLC analysis. 1H NMR (300 MHz) δ 4.87 (br s, 1H), 4.45-4.40 (m, 1H), 2.22, (m, 1H), 2.02 (s, 3H), 1.99-1.91 (m, 2H), 1.82-1.20 (m, 21H).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH2:14])[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1.Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1.CCN(C(C)C)C(C)C>CC(O)C>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH:14][C:23]3[N:31]=[CH:30][N:29]=[C:28]4[C:24]=3[N:25]=[CH:26][N:27]4[CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[CH3:13])[N:9]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:8]=2[CH:21]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 80 °C
Yield: 70 %

Procedure:
To a solution of (S)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (30.7 g, 93.7 mmol) in IPA (300 mL) was added 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (26.9 g, 112.5 mmol) and DIPEA (48 mL, 281.2 mmol) and the reaction mixture heated at 80° C. for 16 h. The reaction mixture was concentrated in vacuo and the residue dissolved in EtOAc (600 mL). The solution was washed with water and the organic fraction separated. The organic fraction was washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-10% methanol in EtOAc) to yield the title compound as a yellow oil (30 g, 70%) 1H NMR 400 MHz (CDCl3) δ 8.25 (1H, s), 7.96 (1H, s), 7.70 (1H, qn, J=4.1 Hz), 7.37-7.58 (5H, m), 6.98-6.82 (1H, m), 6.52-6.66 (1H, m), 5.60-5.77 (2H, m), 4.12-4.19 (1H, m), 3.76 (1H, td, J 11.3, 2.5 Hz), 1.91-2.13 (4H, m), 1.68-1.84 (2H, m), 1.60-1.68 (3H, m)
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[CH:18])=[CH:11][C:10]=1[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]2[CH2:29][CH2:28]2)=[CH:23][CH:22]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:30][C:31]#[N:32].[Na+]>C(O)(=O)C.O.C(OCC)(=O)C>[CH2:1]([N:8]1[C:9]2[C:10](=[CH:11][C:12]([O:15][CH2:16][C:17]#[CH:18])=[CH:13][CH:14]=2)[C:19]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]3[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)=[N:32][C:31]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[O-]
Reactant: C#CCOc1ccc(NCc2ccccc2)c(C(=O)c2ccc(C3CC3)cc2)c1
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C3CC3)cc1)nc(=O)n2Cc1ccccc1

Procedure:
A solution of 460 mg (1.21 mmol) of (2-benzylamino-5-propargyloxyphenyl)-(4-cyclopropyl-phenyl)-methanone (step E) and 118 mg (1.81 mmol) sodium cyanate in 20 ml glacial acetic acid is stirred at rt for 8 h. Then the mixture is diluted with water and ethyl acetate. The layers are separated and the organic phase is washed with water and bicarbonate solution. Chromatography (dichloromethane/MeOH) of the crude product affords a yellow foam. m.p. 112-113° C.