Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]=[CH:3][CH2:4][SiH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:12]1[O:14][CH2:13]1.[Li]>>[CH:13]([O:14][CH:2]=[CH:3][CH2:4][SiH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH2:12]
Reactant: C1CO1
Reactant: ClC=CC[SiH2]c1ccccc1
Agent: [Li]
Product: C=COC=CC[SiH2]c1ccccc1
Yield: 68 %

Procedure:
Following the procedure of Example 21B, 98 mL (101.33 g, 0.555 mole) of (chloro)vinylmethylphenylsilane was added to the cooled lithium ethenoxide solution prepared in Part A. After work-up and distillation as described in Example 21B, there was obtained 65.21 g (68% yield) of (ethenyloxy)vinylmethylphenylsilane distilling at 78.8°/5.0° mm-80.0°/4.8 mm. The 1H NMR Spectrum (Cl3CD) exhibited resonances at δ=0.50 ppm (CH3 --Si), ~4.1 and 4.5 ppm (CH2 of vinyl on oxygen), a complicated multiline pattern at δ=5.7-6.6 ppm (vinyl group on silicon and the CH of the vinyl group on oxygen) and at δ=7.2-7.7 ppm (C6H5) with the relative intensities consistent with (ethenyloxy)vinylmethylphenylsilane.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[N:8][C:9]([OH:10])=[C:4]2[CH:3]=[N:2]1.[Br:11]Br>O>[Br:11][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[OH:10])[NH:1][N:2]=1
Reactant: BrBr
Reactant: Oc1ncnc2[nH]ncc12
Solvent: O
Product: Oc1ncnc2[nH]nc(Br)c12
Temperature: 91 °C
Yield: 9.5 %

Procedure:
1H-pyrazolo[3,4-d]pyrimidin-4-ol (10 g, 73.5 mmol) was suspended in 700 ml of water. Bromine (10 ml, 194 mmol) was added and the resulting reaction mixture was heated to 91° C. overnight. After cooling on ice-water, the solid was collected by filtration to give 1.508 g of 3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-ol as light yellow solid. 1H NMR (DMSO) 8.06 (s, 1H), 12.25(bs, 1H), 14.06 (bs, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15](O)=[O:16])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:8][C:9]=1[NH:10]2.C(Cl)CCl.C1C=CC2N(O)N=[N:33]C=2C=1.[OH-].[NH4+]>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15](=[O:16])[NH2:33])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:8][C:9]=1[NH:10]2
Reactant: CCOC(=O)C1CCc2c([nH]c3c(C(=O)O)ccc(Br)c23)C1
Reactant: On1nnc2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)C1CCc2c([nH]c3c(C(N)=O)ccc(Br)c23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
A suspension of 5-bromo-2-(ethoxycarbonyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid (Intermediate 46-1, 12.28 g, 33.5 mmol), EDC (7.71 g, 40.2 mmol), and HOBT (6.16 g, 40.2 mmol) in THF-DCM (4:1, 335 mL) was treated with 28% aqueous ammonium hydroxide (7.83 mL, 201 mmol), and the resulting suspension was stirred at rt overnight. The mixture was concentrated and the residue was suspended in water. The precipitate was collected by filtration, washed with water and EtOAc and dried to give ethyl 5-bromo-8-carbamoyl-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylate (8.92 g). The filtrate was concentrated and the residue was suspended in methanol. A solid was collected by filtration, washed with methanol and air dried to afford additional product (0.39 g) for a total of 9.31 g (76%). 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H) 8.02 (br. s., 1H) 7.43 (d, J=8.13 Hz, 1H) 7.39 (br. s., 1H) 7.14 (d, J=8.13 Hz, 1H) 4.02-4.17 (m, 2H) 3.07-3.18 (m, 1H) 2.97-3.06 (m, 1H) 2.86-2.98 (m, 2H) 2.77-2.86 (m, 1H) 2.09-2.19 (m, 1H) 1.72-1.86 (m, 1H) 1.20 (t, J=7.14 Hz, 3H). Mass spectrum m/z 365, 367 (M+H)+.
Reaction SMILES: N#N.[C:3]([O:7][C:8]([NH:10][C@H:11]([C:16]([OH:18])=O)[CH2:12][C:13](=[O:15])[NH2:14])=[O:9])([CH3:6])([CH3:5])[CH3:4].C(N(CC)CC)C.[NH2:26][C@@H:27]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C@H:28]([OH:43])[C:29]([N:31]1[CH2:42][CH2:41][CH2:40][C@H:32]1[C:33]([NH:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:30]>CN(C)C=O>[C:3]([O:7][C:8]([NH:10][C@H:11]([C:16]([NH:26][C@@H:27]([CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[C@H:28]([OH:43])[C:29]([N:31]1[CH2:42][CH2:41][CH2:40][C@H:32]1[C:33]([NH:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:30])=[O:18])[CH2:12][C:13](=[O:15])[NH2:14])=[O:9])([CH3:4])([CH3:5])[CH3:6]
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=O)C(=O)O
Agent: N#N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
15.5 g (43.9 mmol) of the p-nitrophenyl ester of N2 -t-butoxycarbonyl-L-asparagine and 7.33 g (72.3 mmol) of triethylamine were added, whilst ice-cooling, to a solution of 12.7 g (36.6 mmol) of 1-[(2S,3S)-3-amino-2-hydroxy-4-phenylbutyryl]-N-t-butyl-L-prolinamide [prepared as described in step (c) above] in 100 ml of dimethylformamide, and the mixture was stirred overnight at room temperature. At the end of this time, the reaction mixture was poured into ice-water, after which it was extracted with methylene chloride. The organic extract was then washed with a 1N aqueous solution of sodium hydroxide, with a 10% w/v aqueous solution of citric acid and with a saturated aqueous solution of sodium chloride, in that order. The extract was then dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was recrystallized from a mixture of methylene chloride and hexane, to give 17.6 g of the title compound as a colorless powder, melting at 113°-115° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[B:17](OCCCC)([O:23][CH2:24][CH2:25][CH2:26][CH3:27])[O:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[B:17]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])([O:18][CH2:19][CH2:20][CH2:21][CH3:22])[O:16][C:6]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][C:9]([CH3:11])=[CH:8][C:7]=1[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CCCCOB(OCCCC)OCCCC
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Product: CCCCOB(OCCCC)Oc1c(C(C)(C)C)cc(C)cc1C(C)(C)C

Procedure:
In a moisture-protected atmosphere, 2,6-di-tert-butyl-4-methylphenol (1543 g) was heated to 245° C. and while stirring tributyl borate (805.5 g) was slowly added drop by drop. The addition rate was controlled to maintain the reaction temperature at 230°-250° C. and butanol was distilled from the mixture as formed. The distillate was fractionated to separate butanol from tributyl borate and the latter was recycled to the reacting mixture. The reaction mixture was heated at 250°-260° C. until no further distillation was observed.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8](I)[N:7]=1.[CH3:15][O:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([C:24]#[CH:25])=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]([C:25]#[C:24][C:21]2[CH:22]=[CH:23][C:18]([C:17]([O:16][CH3:15])=[O:26])=[CH:19][CH:20]=2)[N:7]=1
Reactant: COC(=O)CCc1nc(I)ccc1O
Reactant: C#Cc1ccc(C(=O)OC)cc1
Product: COC(=O)CCc1nc(C#Cc2ccc(C(=O)OC)cc2)ccc1O
Yield: 59 %

Procedure:
Under the conditions of example 5 A, 6.3 g of 3-(3-hydroxy-6-iodo-2-pyridyl)-propionic acid methyl ester is reacted with 3.28 g of 4-ethinylbenzoic acid methyl ester, worked up, and the crude product is chromatographed on silica gel with hexane/0-50% ethyl acetate. 4.1 g of 3-{3-hydroxy-6-[2-(4-methoxycarbonylphenyl)-ethinyl]-2-pyridyl}-propionic acid methyl ester of melting point 173°-177° C. is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[C:10](Cl)(=[O:13])[CH2:11][CH3:12]>N1C=CC=CC=1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][C:10](=[O:13])[CH2:11][CH3:12]
Reactant: CCC(=O)Cl
Reactant: Oc1cc(F)ccc1F
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCC(=O)Oc1cc(F)ccc1F

Procedure:
At 0° C.-5° C., a solution of 100 g of 2,5-difluorophenol in 66.5 g of pyridine is added dropwise in the course of 2 hours to a solution of 71.2 g of propionic acid chloride in 800 ml of toluene and stirring is then carried out at room temperature for a further hour. The reaction mixture is then diluted with ethyl acetate, washed twice with water and once with saturated sodium chloride solution and the organic phase is separated off, dried with sodium sulfate and concentrated by evaporation in vacuo. The crude product is processed further without further purification.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9][O:10][C:11](=[O:20])[C:12]([CH3:19])([CH3:18])[C:13](=O)[CH2:14][O:15][CH3:16].C([BH3-])#N.[Na+].C(O)(=O)C>CO.CCOC(C)=O>[CH3:9][O:10][C:11](=[O:20])[C:12]([CH3:18])([CH3:19])[CH:13]([NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH2:8])[CH2:14][O:15][CH3:16]
Reactant: COCC(=O)C(C)(C)C(=O)OC
Reactant: Nc1ccccc1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: COCC(Nc1ccccc1N)C(C)(C)C(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.9 %

Procedure:
To a mixture of 1,2-phenylenediamine (900 mg, 8.3 mmol) and 4-methoxy-2,2-dimethyl-3-oxo-butyric acid methyl ester (1.7 g, 9.8 mmol) in MeOH (5 mL) was added sodium cyanoborohydride (700 mg, 11.1 mmol) and acetic acid (1.0 mL). The mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with H2O (75 mL×3). The organic layer was dried over sodium sulfate and concentrated. The resulting residue was purified by CombiFlash with 40% EtOAc in Hexane as the eluent to afford the desired 3-(2-amino-phenylamino)-4-methoxy-2,2-dimethyl-butyric acid methyl ester (550 mg, 25%).
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH:16][C:17]([CH3:31])([C:19]([O:21][CH:22]3[CH2:30]C4C(=CC=CC=4)[CH2:23]3)=[O:20])[CH3:18])=[CH:10][CH:9]=2)[C:6](=[O:32])[CH:5]=[CH:4][C:3]=1[C:33](=[O:42])[C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=1[F:41].[CH3:43]C(C(OC(C)(C)C)=O)(C)N.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.CCOC(C)=O>[NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH:16][C:17]([CH3:31])([C:19]([O:21][C:22]([CH3:30])([CH3:23])[CH3:43])=[O:20])[CH3:18])=[CH:10][CH:9]=2)[C:6](=[O:32])[CH:5]=[CH:4][C:3]=1[C:33](=[O:42])[C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=1[F:41]
Reactant: CC(C)(NCCc1ccc(-n2c(N)c(C(=O)c3ccc(F)cc3F)ccc2=O)cc1)C(=O)OC1Cc2ccccc2C1
Reactant: CC(C)(C)OC(=O)C(C)(C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(C)(C)NCCc1ccc(-n2c(N)c(C(=O)c3ccc(F)cc3F)ccc2=O)cc1
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a solution of Intermediate 2 (180 mg, 0.489 mmol) in THF (3 ml) was added tert-butyl 2-methylalaninate (Intermediate 8) (117 mg, 0.73 mmol), stirred for 30 minutes, and then NaBH(OAc)3 (310 mg, 1.467 mmol). The reaction was stirred for 24 hours, diluted with EtOAc and the organics washed with sat NaHCO3, brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by preparative HPLC to provide the title compound (Intermediate 15) (120 mg, 48% yield).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[NH:5][C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:8]=1.S(OC)(O[CH3:24])(=O)=O>CN(C)C=O>[Cl:3][C:4]1[N:5]([CH3:24])[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:8]=1
Reactant: CCOC(=O)c1[nH]c(Cl)nc1-c1ccccc1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccccc2)nc(Cl)n1C
Temperature: 80 °C

Procedure:
0.6 g of sodium hydride was added to a solution of 7 g (0.028 mol) of ethyl 2-chloro-4-phenylimidazole-5-carboxylate in 25 ml of dimethylformamide. Upon completion of gas evolution, 4.2 g (0.033 mol) of dimethyl sulfate was added and the mixture was heated at 80° C. for 11/2 hours. The dimethylformamide was removed under reduced pressure and the residue was poured into dilute ammonium hydroxide. After extraction with ethyl acetate, drying and removal of the solvent, chromatography on silica gel (developer: ethyl acetate/pentane) gave ethyl 2-chloro-1-methyl-4-phenylimidazole-5-carboxylate (compound no. 2.001) of m.p. 54° to 55° C.
Reaction SMILES: [CH2:1]([C:4]12[CH2:11][O:10][C:7]([CH:12]3[CH2:17][CH2:16][CH2:15][N:14](C(OCC4C=CC=CC=4)=O)[CH2:13]3)([O:8][CH2:9]1)[O:6][CH2:5]2)[CH2:2][CH3:3]>O1CCCC1.[Pd]>[CH2:1]([C:4]12[CH2:5][O:6][C:7]([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)([O:8][CH2:9]1)[O:10][CH2:11]2)[CH2:2][CH3:3]
Reactant: CCCC12COC(C3CCCN(C(=O)OCc4ccccc4)C3)(OC1)OC2
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCC12COC(C3CCCNC3)(OC1)OC2
Yield: 73.3 %

Procedure:
To a solution of benzyl 3-(4-n-propyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)piperidine-1-carboxylate (7.0 g.) in dry tetrahydrofuran (100 ml) under nitrogen, was added 5% palladium on carbon (0.63 g.) and the system was hydrogenated at atmospheric pressure. When the theoretical volume uptake (450 ml) had been achieved the system was purged with nitrogen and the mixture was filtered through celite. The solution was evaporated in vacuo. The resulting solid was recrystallised from hexane. 3-(4-n-Propyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)piperidine (3.3 g.) was obtained as colourless crystals.
Reaction SMILES: C[O-].[Na+].[O:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6](=[O:14])[CH2:5]1.[CH3:15][N:16]([CH3:25])[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1>CN(C=O)C>[CH3:15][N:16]([CH3:25])[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[C:5]2[C:6](=[O:14])[NH:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[O:4]2)=[CH:19][CH:18]=1
Reactant: O=C1COc2ccccc2N1
Reactant: CN(C)c1ccc(C=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)c1ccc(C=C2Oc3ccccc3NC2=O)cc1
Temperature: 25 °C

Procedure:
Sodium methoxide (0.65 g, 0.012 mol) was added in one portion to a mixture of 2H-1,4-benzoxazin-3(4H)-one (1.49 g, 0.01 mol) and 4-dimethylamino benzaldehyde (2.38 g, 0.016 mol) in dry DMF (10 ml). The reaction mixture was refluxed overnight, then cooled to room temperature and poured into crushed ice. The precipitated solid was collected by filtration, washed with water and dried. The crude product was purified by recrystallization from ethanol.
Reaction SMILES: [OH:1][CH:2]([C:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O-:9])=[O:8].[C:24](Br)(Br)(Br)Br.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>>[OH:1][C@@H:2]([C:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:24])=[O:8]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCCCCCCCCC#CC(O)CCCCC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCCCCCCCCCCC#C[C@H](O)CCCCC(=O)OC

Procedure:
This compound was prepared by reaction of 6-(±)-hydroxy-7-eicosynoate (preparative example V) with CBr4 /Ph3P reagent in exactly the same manner as described in preparative example VIII. Note: By use of the corresponding 6-R, and 6-S alcohols (preparative example VI) the optically active (+) and (-) 6-bromo-7-eicosanoates were also obtained
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]([F:38])([F:37])[C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]2[O:14][CH:15]=[C:16]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][N:30]4[CH:34]=[CH:33][N:32]=[C:31]4[CH:35]=[O:36])=[CH:22][CH:21]=3)[N:17]=2)=[CH:7][CH:6]=1.O>CO>[F:37][C:4]([F:3])([F:38])[C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]2[O:14][CH:15]=[C:16]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][N:30]4[CH:34]=[CH:33][N:32]=[C:31]4[CH2:35][OH:36])=[CH:22][CH:21]=3)[N:17]=2)=[CH:7][CH:6]=1
Reactant: O=Cc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
Sodium borohydride (193 mg) was added to a solution of 1-[4-[4-[[2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl]methoxy]phenyl]butyl]-1H-imidazole-2-carbaldehyde (2.30 g) in methanol at 0° C., and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was combined with water and concentrated to give crystals, which were washed with water and recrystallized from ethyl acetate-hexane to give the titled compound (2.16 g) as a colorless crystal powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]2=[N:17][CH:18]=[C:19]([CH:21]=[O:22])[N:20]=[C:15]2[CH:14]=1.[BH4-].[Na+]>O1CCOCC1.CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][OH:22])[N:20]=[C:15]2[CH:14]=1
Reactant: COc1ccc2c(c1)c(-c1cc3nc(C=O)cnc3n1COCC[Si](C)(C)C)cn2C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: COc1ccc2c(c1)c(-c1cc3nc(CO)cnc3n1COCC[Si](C)(C)C)cn2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
6-(5-Methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde (5.03 g, 11.5 mmol, prepared using D from Preparation #C.1. with (E)-styrylboronic acid and E) in 1,4-dioxane (65 mL) and EtOH (13 mL) was treated with NaBH4 (0.436 g, 11.5 mmol) then stirred overnight at rt. The reaction mixture was concentrated under reduced pressure then the residue was partitioned between EtOAc (125 mL) and saturated aqueous NaHCO3 (100 mL). The layers were separated then the aqueous layer was extracted with EtOAc (75 mL). The combined organic layers were extracted with brine (50 mL) then dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The material was purified by flash chromatography on neutral alumina with 8:2 DCM/EtOAc then 7:3 DCM/EtOAc then finally EtOAc to give (6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanol (3.19 g, 63%): LC/MS (Table 2, Method a) Rt=2.76 min; MS m/z 439 (M+H)+.
Reaction SMILES: Cl.C[NH:3]OC.C(N(CC)CC)C.Cl[C:14]1[C:15](Cl)=[N:16][CH:17]=[C:18]([CH:22]=1)[C:19](Cl)=[O:20].O>ClCCl>[C:19]([NH2:3])(=[O:20])[C:18]1[CH:22]=[CH:14][CH:15]=[N:16][CH:17]=1
Reactant: O=C(Cl)c1cnc(Cl)c(Cl)c1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: NC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 167.7 %

Procedure:
N,O-Dimethylhydroxylamine hydrochloride (2.25 g, 0.023 mol) was slurried in dichloromethane (40 mL) and cooled in ice-acetone. Triethylamine (4.7 g, 0.047 mol) was then added dropwise, followed by a solution of 5,6-dichloronicotinoyl chloride (4.5 g, 0.021 mol) in dichloromethane (25 mL). The resultant mixture was allowed to warm to room temperature and stirred for one hour. Water (50 mL) was added and the mixture separated. The organic phase was washed with water, 1M hydrochloric acid, 10% sodium carbonate solution and brine. It was then dried (Na2SO4) and evaporated to dryness to give the desired product (4.3 g, 86%) as a yellow oil which crystallized on standing.
Reaction SMILES: [F:1][C:2]1[C:3]([O:20]C)=[C:4]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27](=[O:33])[NH:28]2.B(Br)(Br)Br>>[OH:17][C:10]1([C:13]([F:15])([F:16])[F:14])[CH2:9][C:8]([CH3:18])([CH3:19])[C:4]2[C:5](=[CH:6][CH:7]=[C:2]([F:1])[C:3]=2[OH:20])[CH:11]1[NH:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27](=[O:33])[NH:28]2
Reactant: Nc1cccc2[nH]c(=O)ccc12
Reactant: COc1c(F)cccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Agent: BrB(Br)Br
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3[nH]c(=O)ccc23)c2ccc(F)c(O)c21
Yield: 18 %

Procedure:
Analogously to Example 2, the corresponding imine is produced starting from 1.0 g of 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal (Example 3) and 520 mg of 5-aminoquinolin-2(1H)-one. 255 mg of the title compound is obtained by reaction of 300 mg of imine with 3.3 ml of BBr3 (1N in dichloromethane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][N:14]=2)[CH:9]=[C:8]([C:16]([O:18]CC)=[O:17])[C:7]1=[O:21].Cl>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][N:14]=2)[CH:9]=[C:8]([C:16]([OH:18])=[O:17])[C:7]1=[O:21]
Reactant: CCOC(=O)c1cc2cccnc2n(Cc2ccccc2OC)c1=O
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccccc1Cn1c(=O)c(C(=O)O)cc2cccnc21
Temperature: 50 °C
Reaction time: 5 h
Yield: 101.4 %

Procedure:
3.00 g (8.90 mmol) of ethyl 1-(2-methoxybenzyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate was dissolved in 1,4-dioxane (90 mL), and 6 N hydrochloric acid (16 mL) was added thereto at room temperature. The resulting mixture was stirred for 5 hours at 50° C., and then the solvent was distilled off under reduced pressure from the reaction mixture. The residue was washed with water and dried, and thus 2.80 g (yield: quantitative) of the title compound was obtained as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([F:14])([F:13])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C:10]([F:13])([F:14])[CH2:11][O:12][S:16]([CH3:15])(=[O:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC(F)(F)COCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC(F)(F)COCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82 %

Procedure:
A solution of 3-benzyloxy-2,2-difluoropropan-1-ol (Compound 59H, 202 mg, 1 mmol) and methanesulfonyl chloride in DCM (3 mL) was cooled to 0° C. and treated with Et3N (0.28 mL, 2 mmol). The reaction mixture was allowed to warm at RT. After 12 h, the reaction mixture was diluted with DCM (5 mL) and washed with aq. K2CO3 (4×5 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give 220 mg (82%) of the title compound as yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.37-7.33 (m, 5H), 4.62 (s, 2H), 4.47 (t, J=12.4 Hz, 2H), 3.74 (t, J=12.4 Hz, 2H), 3.05 (s, 3H).
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[CH2:6][NH:7][C:8]([C:10]1[C:15]([I:16])=[C:14]([NH:17][C:18](=[O:25])[CH:19]([Br:24])[CH2:20][CH2:21][CH2:22]Br)[C:13]([I:26])=[C:12]([C:27]([NH:29][CH2:30][CH:31]([O:37][C:38](=[O:40])[CH3:39])[CH2:32][O:33][C:34](=[O:36])[CH3:35])=[O:28])[C:11]=1[I:41])=[O:9])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.C(OCC)(=O)C>[C:1]([O:4][CH:5]([CH2:42][O:43][C:44](=[O:46])[CH3:45])[CH2:6][NH:7][C:8]([C:10]1[C:15]([I:16])=[C:14]([N:17]2[CH2:22][CH2:21][CH2:20][CH:19]([Br:24])[C:18]2=[O:25])[C:13]([I:26])=[C:12]([C:27]([NH:29][CH2:30][CH:31]([O:37][C:38](=[O:40])[CH3:39])[CH2:32][O:33][C:34](=[O:36])[CH3:35])=[O:28])[C:11]=1[I:41])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(NC(=O)C(Br)CCCBr)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(=O)OCC(CNC(=O)c1c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c(I)c(N2CCCC(Br)C2=O)c1I)OC(C)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.4 %

Procedure:
To a solution of N,N'-bis[2,3-bis(acetyloxy)propyl]-5-[(2,5-dibromo-1-oxopentyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide of example 8a (20.7 g, 18.5 mmol) in N,N-dimethylacetamide (200 ml), was added powdered potassium carbonate (20 g, 92 mmol) and the mixture was stirred at room temperature for 5 hours. The resulting slurry was filtered and the filtrate freed of the solvent to obtain a light brown solid, which was redissolved in ethyl acetate (500 ml). The solution was washed with water (2×50 ml) and saturated aqueous sodium chloride (1×100 ml) and then dried over magnesium sulfate. The solvent was removed in vacuo and the crude product (18.1 g) purified by column chromatography over silica gel to obtain pure N,N'-bis[2,3-bis(acetyloxy)propyl]-5-(3-bromo-2-oxo-1-piperidinyl]-2,4,6-triiodo-1,3-benzenedicarboxamide as a white solid (14.04 g, 80% yield), m.p. 232°-35°.