Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[O:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][NH:14][CH2:13][CH2:12]1>ClCCl>[CH:1]([N:14]1[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:11][CH2:12][CH2:13]1)=[O:2]
Reactant: O=CO
Reactant: c1ccc2c(c1)CNCCO2
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: O=CN1CCOc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 15 ml of formic acid was added dropwise 5 ml of acetic anhydride, and the mixture was stirred for 20 minutes at room temperature. To the mixture was added dropwise a solution of 2.2 g of 2,3,4,5-tetrahydro-1,4-benzoxazepine in 10 ml of dichloromethane, and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was poured into ice-water, then the mixture was subjected to extraction with dichloromethane. The extract was washed successively with a saturated aqueous solution of sodium bicarbonate, and water. The mixture was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 2.6 g of 4-formyl-2,3,4,5-tetrahydro-1,4-benzoxazepine as an oily anhydrous substance.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.Cl[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[OH:29])[CH:24]=O.[ClH:30]>C(Cl)Cl>[Cl:30][C:22]1[CH:21]=[C:28]([OH:29])[CH:27]=[CH:26][C:23]=1[CH2:24][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCNC1
Reactant: O=Cc1ccc(O)c(Cl)c1
Reactant: Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc(CN2CCCC2)c(Cl)c1
Yield: 52 %

Procedure:
NaB(OAc)3H (20 g, 0.094 mol) was added in portions for 15 min to a mixture of pyrrolidine (7.78 mL, 0.11 mol) and 3-chloro-4-hydroxybenzaldehyde (12.5 g, 0.079 mol) in CH2Cl2 (100 mL) under vigorous stirring and cooling with an ice bath in an atmosphere of argon Ar. The mixture was stirred for 20 h and cooled with an ice bath. Concentrated HCl (18 mL) was added. The organic layer was separated and discarded. The aqueous one was alkalized with 10 N NaOH to pH 9 (30 mL) and extracted with chloroform (3×100 mL). The combined extracts were dried with Na2SO4, and evaporated. The residue was purified by chromatography (silica gel 63-100μ, 8 mL, CHCl3/5% i-PrOH to give the title compound (8.07 g, 52%) was obtained as white crystals. LCMS-data: 212 and 214 (M+H)+, (calculated for C11H14NOCl 211.6); 1H NMR (400Mz)-data (DMSO-d6, J, Hz): 9.95 (br s, 1H, OH); 7.20 (d, 1H, Ar, J=2 Hz); 7.00 (dd, 1H, Ar, J1=2 Hz, J2=8.1 Hz); 6.89 (d, 1H, Ar, J=8.1); 3.43 (s, 2H, CH2); 2.35-2.40 (m, 4H); 1.63-1.69 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O.[CH:13](I)([CH3:15])[CH3:14]>CC#N>[CH:13]([C:8]1[C:7]2[C:11](=[CH:12][C:4]([NH2:1])=[CH:5][CH:6]=2)[NH:10][CH:9]=1)([CH3:15])[CH3:14]
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: CC(C)I
Solvent: CC#N
Product: CC(C)c1c[nH]c2cc(N)ccc12

Procedure:
3-Isopropyl-1H-indol-6-ylamine (B-13) was synthesized following the general scheme above starting from 6-nitroindole and isopropyl iodide. Overall yield (17%). HPLC ret. time 2.06 min, 10-99% CH3CN, 5 min run; ESI-MS 175.2 m/z (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[CH:8]=[C:7]([C:9](OCC)(OCC)[CH2:10][NH2:11])[CH:6]=[CH:5][N:4]=1.Cl.[C:20](=[NH:25])(OCC)[CH3:21]>C(O)C>[CH3:18][N:2]([CH3:1])[C:3]1[CH:8]=[C:7]([C:9]2[N:25]=[C:20]([CH3:21])[NH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1
Reactant: CCOC(C)=N
Reactant: CCOC(CN)(OCC)c1ccnc(N(C)C)c1
Agent: Cl
Solvent: CCO
Product: Cc1nc(-c2ccnc(N(C)C)c2)c[nH]1

Procedure:
A mixture of 1.0 g. (4 mmoles) of 2-(2-dimethylamino-4-pyridyl)-2,2-diethoxyethylamine, 500 mg. (4.1 mmoles) of ethyl acetimidate hydrochloride and 15 ml. of ethanol is heated to reflux for 1.5 hours. The mixture is concentrated, and the residue taken up in 10 ml. of concentrated hydrochloric acid. After heating at steam bath temperatures for 1 hour, the cooled acid solution is made basic by the addition of solid sodium carbonate, and the product is extracted with chloroform (3×10 ml.). The combined extracts are dried and concentrated to give the crude product, which is purified further by chromatographing on silica-gel using chloroform-methanol as the eluent.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[O:28][N:27]=[C:26]([CH:29]([CH3:31])[CH3:30])[N:25]=3)[CH2:20][CH2:19]2)=[CH:12][N:11]=1.[OH:32]O>FC(F)(F)C(O)C(F)(F)F>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:9])=[O:32])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[O:28][N:27]=[C:26]([CH:29]([CH3:31])[CH3:30])[N:25]=3)[CH2:20][CH2:19]2)=[CH:12][N:11]=1
Reactant: OO
Reactant: CSc1ccc(-c2ccc(OCC3CCN(c4nc(C(C)C)no4)CC3)cn2)c(F)c1
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: CC(C)c1noc(N2CCC(COc3ccc(-c4ccc(S(C)=O)cc4F)nc3)CC2)n1
Yield: 76.2 %

Procedure:
The title compound (109 g, 76%) was prepared as a white solid from 2-[2-fluoro-4-(methylthio)phenyl]-5-[({1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]pyridine (prepared as in Step 2, 138 g, 312 mmol), 30% H2O2 (aq) (41 mL, 410 mmol) and 1,1,1,3,3,3-hexafluoro-2-propanol (400 mL) in a manner similar to Example 171, Step 3. 1H NMR (400 MHz, CDCl3): δ 8.39 (d, 1H, J=2.8 Hz), 8.13 (t, 1H, J=7.8 Hz), 7.77 (dd, 1H, Ja=8.7 Hz, Jb=1.9 Hz), 7.50 (dd, 1H, Ja=10.4 Hz, Jb=1.6 Hz), 7.43 (dd, 1H, Ja=8.1 Hz, Jb=1.7 Hz), 7.26 (d, 1H, J=3.0 Hz), 4.27-4.16 (m, 2H), 3.92 (d, 2H, J=6.2 Hz), 3.20-3.00 (m, 2H), 2.87 (septet, 1H, J=7.0 Hz), 2.74 (s, 3H), 2.15-2.03 (m, 1H), 2.00-1.90 (m, 2H), 1.52-1.40 (m, 2H), 1.27 (d, 6H, J=7.0 Hz); LRMS (ESI), m/z 459 (M+H).
Reaction SMILES: Br.[CH2:2]([C:4]1[N:5]=[C:6]([C@@H:9]([NH2:20])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[S:7][CH:8]=1)[CH3:3].[C:21]1([CH2:27][C:28](O)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C=O)C.O>[CH2:2]([C:4]1[N:5]=[C:6]([CH:9]([NH:20][C:28](=[O:29])[CH2:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[S:7][CH:8]=1)[CH3:3]
Reactant: O=C(O)Cc1ccccc1
Reactant: CCc1csc([C@@H](N)Cc2ccc([N+](=O)[O-])cc2)n1
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCc1csc(C(Cc2ccc([N+](=O)[O-])cc2)NC(=O)Cc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a solution of 1-(S)-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethyl amine hydrobromide, 3, (0.393 g, 1.1 mmol), phenylacetic acid (0.190 g, 1.4 mmol) and 1-hydroxybenzotriazole (HOBt) (0.094 g, 0.70 mmol) in DMF (10 mL) at 00, is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.268 g, 1.4 mmol) followed by triethylamine (0.60 mL, 4.2 mmol). The mixture is stirred at 0° C. for 30 minutes then at room temperature overnight. The reaction mixture is diluted with water and extracted with EtOAc. The combined organic phase is washed with 1N aqueous HCl, 5% aqueous NaHCO3, water and brine, and dried over Na2SO4. The solvent is removed in vacuo to afford 0.260 g (60% yield) of the desired product which is used without further purification. ESI+ MS 396 (M+1).
Reaction SMILES: C1(N2C(C(F)(F)F)=C(C3ON=C4C5C(CCC=34)=CC(C=C)=CC=5)C=N2)C=CC=CC=1.[I:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)/[C:38](=[N:42]/[OH:43])/[CH2:37][CH2:36][CH2:35]2.[C:44]1([C:50]2[O:54][N:53]=[C:52]([C:55](OC)=O)[C:51]=2[C:59]([F:62])([F:61])[F:60])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[I:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[C:38]1=[N:42][O:43][C:55]([C:52]3[C:51]([C:59]([F:60])([F:61])[F:62])=[C:50]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[O:54][N:53]=3)=[C:37]1[CH2:36][CH2:35]2
Reactant: O/N=C1\CCCc2cc(I)ccc21
Reactant: COC(=O)c1noc(-c2ccccc2)c1C(F)(F)F
Agent: C=Cc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F
Product: FC(F)(F)c1c(-c2onc3c2CCc2cc(I)ccc2-3)noc1-c1ccccc1

Procedure:
The titled compound was prepared using the experimental protocol described for Preparation 89A employing (E)-6-iodo-3,4-dihydronaphthalen-1(2H)-one oxime (121A) and methyl 5-phenyl-4-(trifluoromethyl)isoxazole-3-carboxylate (Intermediate I-5) as starting materials. The compound had an HPLC retention time=4.42 min. (condition C); LC/MS M+1=509.0.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:15]=[C:16]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[CH:17]=[C:18]([CH2:20][P:21]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])=[O:22])[CH:19]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O.O.O.O.[OH-].C[N+](C)(C)C.[CH2:47](Br)[CH:48]=[CH:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>CN(C)C=O>[CH2:47]([O:11][C:10](=[O:12])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:13][C:14]1[CH:15]=[C:16]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[CH:17]=[C:18]([CH2:20][P:21]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])=[O:22])[CH:19]=1)[CH:48]=[CH:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: CCOP(=O)(Cc1cc(CC(NC(=O)OC(C)(C)C)C(=O)O)cc(-c2ccc(Cl)cc2)c1)OCC
Reactant: BrCC=Cc1ccccc1
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1cc(CC(NC(=O)OC(C)(C)C)C(=O)OCC=Cc2ccccc2)cc(-c2ccc(Cl)cc2)c1)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.05 g of the product of step b) in 5 ml dimethylformamide are added 362 mg tetramethylammonium hydroxide pentahydrate. The mixture is stirred at room temperature 1 1/2 hours and then treated with 394 mg cinnamyl bromide. The mixture is stirred at room temperature 17 hours. The mixture is diluted with ice/water (about 50 ml) and extracted with diethyl ether. The extracts are washed with 10 ml aqueous 1N KHCO3 solution, dried (Na2SO4) and evaporated to give the heading compound as an oil.
Reaction SMILES: [N:1]#[C:2]Cl.[C:4]1([CH:11]=[CH:10][CH:9]=[C:7]([OH:8])[CH:6]=1)[OH:5].C([N:14](CC)CC)C>C(O)(C)C>[O-:5][C:2]#[N:1].[O-:8][C:7]#[N:14].[C:4]1([CH:11]=[CH:10][CH:9]=[C:7]([OH:8])[CH:6]=1)[OH:5]
Reactant: CCN(CC)CC
Reactant: N#CCl
Agent: Oc1cccc(O)c1
Solvent: CC(C)O
Product: N#C[O-]

Procedure:
A solution of 271 g (4.4 mols) of cyanogen chloride in 1.1 liter of isopropanol is introduced at 0° to -5° C. into a 3 liter glass vessel equipped with a stirrer and a thermometer. By means of a metering pump, a solution of 220 g (2 mols) of resorcinol and 420 g (4.04 mols) of triethyl amine in 750 ml of isopropanol is introduced with stirring through an inlet pipe projecting below the surface. The pumping rate is adjusted in such a way that the reaction temperature can be kept at -5° C. to +3° C. On completion of the reaction, the crystalline sludge formed is filtered off under suction from the isopropanol. The filter residue is thoroughly stirred with 1.1 liter of water and filtered off under suction again. The residue thus obtained is then thoroughly washed with water and dried in a stream of air at 25° to 30° C. 276 g (86% of the theoretical) of resorcinol dicyanate are obtained in this way. Mp: 81° C., nD90 :1.4980
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[N:6]2)[CH2:2]1.[CH3:28][N:29]([CH3:34])[CH2:30][C:31]([OH:33])=[O:32].Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C.ON1C2N=CC=CC=2N=N1>CN(C)C=O>[C:31]([OH:33])(=[O:32])[CH3:30].[NH2:14][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[N:5]([CH:3]3[CH2:2][N:1]([C:31](=[O:32])[CH2:30][N:29]([CH3:34])[CH3:28])[CH2:4]3)[N:6]=[C:7]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)[C:8]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CNC1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)O
Product: CN(C)CC(=O)N1CC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
A mixture of 1-(3-azetanyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.05 g, 0.00014 mol), 2-(dimethylamino)acetic acid (0.0018 g, 0.000175 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.0034 g, 0.000175 mol), N,N′-diisopropylethylamine (0.033 g, 0.00026 mol) and 1-hydroxy-7-azabenzotriazole (0.019 g, 0.00014 mol) in anhydrous N,N-dimethylformamide (6 mL) was stirred for eighteen hours at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (3 mL) and washed with water (2 mL). The solvent was removed under reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield 1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-2-(dimethylamino)-1-ethanone acetate (0.022 g, 0.00004 mol).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[CH:14]=[CH:13][C:12]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:11][C:10]=3[N:9](COCC[Si](C)(C)C)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2C3C=CC(C4C=CC=CC=4)(C4C=CC=CC=4)CC=3NN2COCC[Si](C)(C)C)C=CC=CC=1.Cl>C(O)C.O>[C:1]1([C:7]2[C:15]3[CH:14]=[CH:13][C:12]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:11][C:10]=3[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccccc2)c2c1CC(c1ccccc1)(c1ccccc1)C=C2
Agent: C[Si](C)(C)CCOCN1NC2=C(C=CC(c3ccccc3)(c3ccccc3)C2)C1c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: C1=CC(c2ccccc2)(c2ccccc2)Cc2[nH]nc(-c3ccccc3)c21
Temperature: 65 °C
Reaction time: 4 h
Yield: 51.5 %

Procedure:
A mixture of 0.16 g of 3,6,6-triphenyl-1-(2-trimethylsilanylethoxymethyl)-6,7-dihydro-1H-indazole and 3,6,6-triphenyl-2-(2-trimethylsilanylethoxymethyl)-6,7-dihydro-1H-indazole is dissolved in 3.4 cm3 of ethanol and 1 cm3 of water, and 3.4 cm3 of an approximately 2N ethanolic solution of hydrogen chloride are then added. The solution is stirred for about 4 hours at a temperature in the region of 65° C. The reaction mixture is concentrated to dryness under reduced pressure (13 kPa). The residue is taken up in 50 cm3 of water, and the pH is brought to about 10 by addition of aqueous 0.1N sodium hydroxide solution. After extraction with three times 50 cm3 of ethyl acetate, the combined organic phases are washed with 50 cm3 of aqueous 0.1N sodium hydroxide solution, 50 cm3 of water and 50 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (13 kPa). After flash chromatography on a column of silica [eluent: dichloromethane], 0.06 g of 3,6,6-triphenyl-6,7-dihydro-1H-indazole is thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [NH2:1][C:2]1[O:3][C@H:4]([C:26]([F:29])([F:28])[F:27])[CH2:5][C@:6]([C:9]2[CH:10]=[C:11]([NH:16]C(=O)C3C=CC(Cl)=CN=3)[CH:12]=[N:13][C:14]=2[F:15])([CH3:8])[N:7]=1.[Cl:30][C:31]1[C:32]([C:39]([OH:41])=O)=[N:33][CH:34]=[C:35]([C:37]#[N:38])[CH:36]=1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1.CO>[NH2:1][C:2]1[O:3][C@H:4]([C:26]([F:27])([F:29])[F:28])[CH2:5][C@:6]([C:9]2[CH:10]=[C:11]([NH:16][C:39](=[O:41])[C:32]3[C:31]([Cl:30])=[CH:36][C:35]([C:37]#[N:38])=[CH:34][N:33]=3)[CH:12]=[N:13][C:14]=2[F:15])([CH3:8])[N:7]=1
Reactant: C[C@@]1(c2cc(NC(=O)c3ccc(Cl)cn3)cnc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Reactant: N#Cc1cnc(C(=O)O)c(Cl)c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@]1(c2cc(NC(=O)c3ncc(C#N)cc3Cl)cnc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 22.2 %

Procedure:
A flask was charged with (4S,6S)-4-(5-amino-2-fluoropyridin-3-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (6a, 0.075 g, 0.257 mmol) and 3-chloro-5-cyanopicolinic acid (Bionet Research, 0.047 g, 0.257 mmol). The solids were dissolved in a mixture of THF (2 mL)/MeOH (1 mL) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (Aldrich, 0.129 g, 0.436 mmol) was added. The reaction was stirred at RT for 25 min. Additional 0.5 equiv. chloro-5-cyanopicolinic acid and 1 equiv. 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride were added. After 1 hour, the reaction was quenched with aqueous saturated sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine and dried over sodium sulfate. The filtrate was concentrated and purified by reversed-phase preparative HPLC using a Phenomenex Gemini column, 10 micron, C18, 110 Å, 100×50 mm, 0.1% TFA in CH3CN/H2O, gradient 10% to 80% over 20 min. The product containing fractions were combined and neutralized with aqueous sodium bicarbonate solution. The free-based product was extracted with DCM. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure to afford the title compound (0.026 g, 0.057 mmol, 22.18% yield) as white solid. MS m/z=457 [M+H]+. Calculated for C18H13ClF4N6O2: 456.8
Reaction SMILES: [O:1]1[C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[O:4][CH2:3][C@@H:2]1[CH2:15]OS(C1C=CC(C)=CC=1)(=O)=O)[N:11]=[CH:10][N:9]=[CH:8]3.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][NH:40][CH2:41][CH:42]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C.C1COCC1>[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][N:40]([CH2:15][CH:2]2[O:1][C:6]3=[C:7]4[C:12](=[CH:13][CH:14]=[C:5]3[O:4][CH2:3]2)[N:11]=[CH:10][N:9]=[CH:8]4)[CH2:41][CH:42]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4ncncc4c3O2)cc1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Fc1ccc2[nH]cc(C3=CCN(CC4COc5ccc6ncncc6c5O4)CC3)c2c1

Procedure:
(2R)-2,3-Dihydro-1,4-dioxino[2,3-f]quinazolin-2-ylmethyl-4-methylbenzenesulfonate (800 mg, 3.7 mmole) was dissolved in a mixture of DMF/THF 1:1 v/v (30 mL) and 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (800 mg, 4 mmole) added, followed by the addition of sodium bicarbonate (1.0 gm, 9.4 mmole) and the mixture was refluxed under nitrogen for 18 hours. The solvent was evaporated under vacuum and the residue partitioned between methylene chloride and water. The organic phase was separated, washed with water and saturated sodium chloride solution, dried over magnesium sulfate and evaporated to a foam. Treatment of this foam with 3% methanol in chloroform yielded 320 mg (35%) of the (S)-enantiomer of the title compound as a yellow crystalline hemihydrate, m.p. 233-235° C.
Reaction SMILES: [O:1]1[C:6]2([CH2:10][CH2:9][NH:8][CH2:7]2)[O:5][CH2:4][CH2:3][CH2:2]1.C([O:13][C:14]([C:16]1[C:25](=[O:26])[C:24]2[C:19](=[C:20]([F:29])[C:21](F)=[C:22]([F:27])[CH:23]=2)[N:18]([CH:30]2[CH2:32][CH2:31]2)[CH:17]=1)=[O:15])C.C(N(CC)CC)C>N1C=CC=CC=1>[CH:30]1([N:18]2[C:19]3[C:24](=[CH:23][C:22]([F:27])=[C:21]([N:8]4[CH2:9][CH2:10][C:6]5([O:5][CH2:4][CH2:3][CH2:2][O:1]5)[CH2:7]4)[C:20]=3[F:29])[C:25](=[O:26])[C:16]([C:14]([OH:15])=[O:13])=[CH:17]2)[CH2:31][CH2:32]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: C1COC2(CCNC2)OC1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC4(C3)OCCCO4)c(F)cc2c1=O

Procedure:
A 0.276 g (1.8 mmol) sample of 1,5-dioxa-8-azaspiro[5.4]decane, from Step 2 Example 14, 0.400 g (1.29 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester (preparation described by K. Grohe, et al., DE 3318145, November 1984) and 0.52 mL (3.7 mmol) of triethylamine and 12 mL of pyridine were heated at 65° C. for 48 hours in dry glassware and under dry nitrogen. The solvent was evaporated and the ester purified by chromatography on a silica gel column using as eluant 0.5% methanol in methylene chloride increasing to 2% methanol in methylene chloride. The solvent was removed to afford 0.218 g of the title compound, which was taken to the next step directly.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([Br:13])[CH:10]=[C:9]([Br:14])[CH:8]=1.[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1>CCCCCC.CCOCC>[Br:14][C:9]1[CH:8]=[C:7]([CH:20]([C:19]2[CH:22]=[CH:23][C:16]([F:15])=[CH:17][CH:18]=2)[OH:21])[CH:12]=[C:11]([Br:13])[CH:10]=1
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: O=Cc1ccc(F)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: OC(c1ccc(F)cc1)c1cc(Br)cc(Br)c1
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
A 2.5M solution of n-butyllithium in hexane (44.0 ml) was added dropwise to a stirred suspension of 1,3,5-tribromobenzene (31.5 g) in dry ether (1000 ml) at -78° C. under an atmosphere of dry nitrogen. The resulting mixture was stirred at this temperature for 30 minutes and the 4-fluorobenzaldehyde (13.65 g) was added dropwise. Stirring at -78° C. was continued for a further 30 minutes and then the reaction was quenched by the addition of water. The temperature was allowed to reach room temperature and the organic layer was separated and dried (MgSO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. The column was eluted with dichloromethane/hexane (1:5), gradually increasing the ratio of solvents to 2:3. The product fractions were combined, evaporated and the residue was triturated with hexane to give the title compound (31.42 g), m.p. 92°-93° C. Found: C,43.75; H,2.43. C13H9Br2OF requires C,43.37; H,2.52%.
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14][N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][CH2:11]2)(=O)=O)=CC=1.[CH:30](=O)[C:31]1[C:32](=[CH:34][CH:35]=[CH:36][CH:37]=1)[OH:33]>[H][H].O=[Pt]=O>[OH:33][C:32]1[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=1[CH2:30][N:16]1[CH2:15][CH2:14][N:13]2[CH2:12][CH2:11][N:10]([CH2:12][CH2:11][NH:10][CH2:18][CH2:17]2)[CH2:18][CH2:17]1
Reactant: [H][H]
Reactant: O=Cc1ccccc1O
Reactant: Cc1ccc(S(=O)(=O)N2CCNCCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: O=[Pt]=O
Product: Oc1ccccc1CN1CCN2CCNCCN(CC2)CC1

Procedure:
From 1,4,7,10-tetrazabicyclo[5.5.2]tetradecane (1.1.20), salicylaldehyde (1.5 equivalents) and H2/PtO2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:35])[C@@H:9]([CH3:34])[C:10]([NH:12][C@@H:13]([CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[C:14]([N:16]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18][C@H:17]1[C:25]([OH:27])=O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[F:60][C:61]1[CH:67]=[CH:66][CH:65]=[C:64]([CH3:68])[C:62]=1[NH2:63].OS([O-])(=O)=O.[K+]>C(Cl)Cl>[F:60][C:61]1[CH:67]=[CH:66][CH:65]=[C:64]([CH3:68])[C:62]=1[NH:63][C:25]([C@H:17]1[N:16]([C:14](=[O:15])[C@@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([N:8]([CH3:35])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH3:34])[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18]1)=[O:27]
Reactant: Cc1cccc(F)c1N
Reactant: C[C@@H](C(=O)N[C@H](C(=O)N1c2ncccc2C[C@H]1C(=O)O)C1CCOCC1)N(C)C(=O)OC(C)(C)C
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(F)c1NC(=O)[C@@H]1Cc2cccnc2N1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C1CCOCC1
Reaction time: 0.08 h
Yield: 41 %

Procedure:
To a solution of (S)-1-((S)-2-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (60 mg, 122 pilot, Eq: 1.00) and diisopropylethylamine (64 μL, 367 μmol, Eq: 3) in DCM (1.8 mL) was added diphenylphosphinic chloride (63.7 mg, 51 μL, 269 μmol, Eq: 2.2). After stirring for 5 min, 2-fluoro-6-methylaniline (18.4 mg, 147 μmol, Eq: 1.2) was added and the resulting solution stirred at rt for 2 d. The reaction mixture was poured into aqueous 0.1 M KHSO4 (20 mL) and the resulting mixture was extracted with EtOAc. The combined organic layers were concentrated in vacuo and the crude material was purified by flash chromatography (silica gel, 4 g, 10% to 50% EtOAc in hexanes) to give tert-butyl (S)-1-((S)-2-((S)-2-(2-fluoro-6-methylphenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylamino)-1-oxopropan-2-yl(methyl)carbamate (30 mg), m/z=598 (M+H).