Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[CH:16]([C:19]1[C:24](/[CH:25]=[CH:26]/[CH:27]=[O:28])=[C:23]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[C:22]([CH2:36][O:37][C:38](=[O:44])[C:39]([CH3:43])([CH3:42])[CH2:40][CH3:41])=[C:21]([CH:45]([CH3:47])[CH3:46])[N:20]=1)([CH3:18])[CH3:17].[Cl-].[NH4+]>O1CCCC1.CCCCCC.[Br-].[Zn+2].[Br-]>[CH:16]([C:19]1[C:24](/[CH:25]=[CH:26]/[CH:27]([OH:28])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH3:8])=[O:6])=[C:23]([C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[C:22]([CH2:36][O:37][C:38](=[O:44])[C:39]([CH3:42])([CH3:43])[CH2:40][CH3:41])=[C:21]([CH:45]([CH3:46])[CH3:47])[N:20]=1)([CH3:17])[CH3:18]
Reactant: COC(=O)CC(C)=O
Reactant: CCC(C)(C)C(=O)OCc1c(C(C)C)nc(C(C)C)c(/C=C/C=O)c1-c1ccc(F)cc1
Agent: [Br-]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(C)(C)C(=O)OCc1c(C(C)C)nc(C(C)C)c(/C=C/C(O)CC(=O)CC(=O)OC)c1-c1ccc(F)cc1
Temperature: -5 °C
Reaction time: 0.25 h

Procedure:
0.15 ml (1.4 mmol) of methyl acetoacetate in 2 ml of absolute tetrahydrofuran is added dropwise under nitrogen to a suspension of 54.6 mg (1.82 mmol) of 80% strength . sodium hydride in 5 ml of absolute tetrahydrofuran at -5° C. After 15 minutes, 0.89 ml (1.4 mmol) of 15% strength butyllithium in n-hexane is added dropwise at the same temperature and after a further 15 minutes 408 mg (1.8 mmol) of dry zinc bromide in 5 ml of absolute tetrahydrofuran are added. The mixture is allowed to stir for a further 15 minutes at -5° C., 400 mg (0.91 mmol) of the compound from Example 68 dissolved in 10 ml of dry tetrahydrofuran are added and the mixture is stirred overnight. Saturated ammonium chloride solution is added to the mixture and it is extracted several times using ether. The organic phase is dried over magnesium sulphate and concentrated in vacuo, and the residue is chromatographed on a column (silica gel 70-230 mesh, using ethyl acetate/petroleum ether 3:7).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[C:16]([O:27][CH2:28][CH2:29][NH2:30])[N:15]=[C:14]([CH3:31])[N:13]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1.[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[C:16]([O:27][CH2:28][CH2:29][NH:30][S:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:40])=[O:39])[N:15]=[C:14]([CH3:31])[N:13]=2)(=[O:9])=[O:10])=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(C)nc1OCCN
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(C)nc1OCCNS(=O)(=O)c1ccccc1

Procedure:
According to the procedure described in Example 4a) 94 mg 5-methyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridine sulfonamide was reacted with benzenesulfonylchloride to give 67.2 mg 5-methyl-N-[6-(2-(benzenesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridine sulfonamide. LC-MS: tR=4.68 min, [M+1]+=586.39, [M−1]−=584.42.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:23]=[CH:22][C:14]2[C:15]([CH3:21])([CH3:20])[O:16][C:17](=[O:19])[NH:18][C:13]=2[CH:12]=1)(=O)=O.[SH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>>[N:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[S:24][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:23]=[CH:22][C:14]2[C:15]([CH3:20])([CH3:21])[O:16][C:17](=[O:19])[NH:18][C:13]=2[CH:12]=1
Reactant: CC1(C)OC(=O)Nc2cc(OCCCCOS(C)(=O)=O)ccc21
Reactant: Sc1ccccn1
Product: CC1(C)OC(=O)Nc2cc(OCCCCSc3ccccn3)ccc21

Procedure:
Prepared analogously to Example 210 from 7-(4-methanesulfonyloxy-butoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 2-mercapto-pyridine.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[N:11][CH:12]=1.C[Si]([C:18]#[N:19])(C)C>C(Cl)Cl.[I-].[Zn+2].[I-]>[OH:1][CH2:6][CH2:5][CH2:4][O:3][CH:2]([C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[N:11][CH:12]=1)[C:18]#[N:19]
Reactant: Cc1ncc(C2OCCCO2)cn1
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Product: Cc1ncc(C(C#N)OCCCO)cn1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To an ice-cold solution of 5-(1,3-dioxan-2-yl)-2-methylpyrimidine (140 mg, 0.78 mmol) in DCM (5.0 ml) was added zinc iodide (124 mg, 0.39 mmol). Trimethylsilyl cyanide (116 mg, 0.155 ml, 1.17 mmol) was added dropwise over a period of 10 minutes. Cooling was removed and the reaction was stirred for 40 hours at room temperature. The mixture was poured into H2O (20 mL) and extracted with DCM (3×20 mL), the combined org. phases were washed with brine, dried over MgSO4 and concetrated in vacuo. The crude product was used for next step without further purification.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=3)[NH:9][CH:8]=2)[CH2:2]1.[Cl:18][CH2:19][CH2:20][N:21]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][C:22]1=[O:32].C(=O)([O-])O.[Na+].Cl>CN(C)C=O.C(O)C>[ClH:18].[O:32]=[C:22]1[N:21]([CH2:20][CH2:19][N:1]2[CH2:5][CH2:4][CH:3]([CH2:6][C:7]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=4)[NH:9][CH:8]=3)[CH2:2]2)[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23]1
Reactant: O=c1[nH]c2ccccc2c(=O)n1CCCl
Reactant: N#Cc1ccc2[nH]cc(CC3CCNC3)c2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]cc(CC3CCN(CCn4c(=O)[nH]c5ccccc5c4=O)C3)c2c1
Reaction time: 6 h

Procedure:
Under an inert atmosphere and at ambient temperature, 47.3 mmol (10 g) of 3-[3-pyrrolidinylmethyl]-1H-indole-5-carbonitrile, 47.3 mmol (9.97 g) of 3-(2-chloroethyl)-2,4-(1H,3H)-quinazolinedione and 47.3 mmol (3.73 g) of sodium hydrogen carbonate are dissolved in 100 ml of dimethylformamide, and stirring is carried out at 100° C. for 6 hours. The reaction mixture is concentrated and the residue is taken up in dichloromethane. The organic phase is washed with water and then with saturated sodium chloride solution, and is dried over magnesium sulphate. Purification is carried out by chromatography on silica using a mixture of dichloromethane/methanol/ammonia 95/5/0.5 as eluant. The compound obtained is converted into the salt by one equivalent of hydrochloric acid in ethanol.
Reaction SMILES: C1C=CC=CC=1.[CH3:7][O:8][C:9]1[CH:21]=[CH:20][C:12]([O:13][CH2:14][CH2:15][CH2:16][C:17](O)=[O:18])=[CH:11][CH:10]=1.S(Cl)([Cl:24])=O>O>[CH3:7][O:8][C:9]1[CH:21]=[CH:20][C:12]([O:13][CH2:14][CH2:15][CH2:16][C:17]([Cl:24])=[O:18])=[CH:11][CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(OCCCC(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(OCCCC(=O)Cl)cc1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
Benzene (70.0 cc) and 14.0 grams of γ-(p-methoxyphenoxy)butyric acid were agitated with water cooling and 5.74 cc of thionyl chloride was added dropwise. Subsequently, the mixture was agitated for 10 minutes at an internal temperature of 60° C. After the reaction had been completed, the reaction mixture was cooled and transferred to a separate flask and the solvent and excess thionyl chloride were removed in a rotary evaporator. γ-(p-Methoxyphenoxy)butyric acid chloride was obtained as white crystals.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:13]\[CH2:14][CH2:15][CH2:16]O)=[CH:8][CH:7]=1>>[Cl:3][CH2:16][CH2:15][CH2:14]/[CH:13]=[C:12](/[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)\[C:9]1[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=1
Reactant: OCCC/C=C(\c1ccc(F)cc1)c1cccnc1
Reactant: O=S(Cl)Cl
Product: Fc1ccc(/C(=C\CCCCl)c2cccnc2)cc1
Reaction time: 2 h
Yield: 94.4 %

Procedure:
160 Parts of thionyl chloride were added dropwise to 10 parts of (E)-5-(4-fluorophenyl)-5-(3-pyridinyl)-4-penten-1-ol while stirring (exothermic reaction, the temperature rose to 45° C.). Upon complete addition, stirring was continued for 2 hours at room temperature. The reaction mixture was evaporated. The residue was taken up in methylbenzene and the solvent was evaporated again. The residue was solidified in 2,2'-oxybixpropane. The product was filtered off and dried, yielding 11.5 parts (94.4%) of (E)-3-[5-chloro-1-(4-fluorophenyl)-1-pentenyl]pyridine hdyrochloride (int. 60).
Reaction SMILES: C([Mg]Cl)(C)C.C1COCC1.I[C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][CH:13]=1.[CH2:19]([O:21][Si:22](OCC)([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])[CH3:20]>CCOCC>[CH2:19]([O:21][Si:22]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])[C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][CH:13]=1)[CH3:20]
Reactant: Ic1ccc(I)cc1
Reactant: CCO[Si](OCC)(OCC)OCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCO[Si](OCC)(OCC)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 44 h
Yield: 61.1 %

Procedure:
Firstly, 2-M i-PrMgCl (24 mL (solvent: THF, 48 mmol) was added dropwise to a mixture of 1,4-diiodobenzene (15 g, 45.6 mmol) and dist. THF (114 mL) at −30° C. Then the resultant mixture was stirred under a nitrogen atmosphere at −30° C. for 5.5 hours to obtain a reaction solution. Subsequently, the reaction solution was added dropwise (3 drops/second) using a cannular into a mixture of tetraethoxysilane (TEOS: 60.6 mL, 272 mmol) and dist. THF (90 mL), which was cooled to −30° C. The resultant mixture was stirred at −30° C. for 1 hour, and then was stirred at room temperature for 44 hours to obtain a reaction mixed solution. Thereafter, the obtained reaction mixed solution was added with ether (100 mL), and then was washed with distilled water (dist. H2O). After that, an aqueous layer was extracted with ether. Then, an organic layer thus collected was washed with sat. NaCl, and was dried with MgSO4. The dried organic layer was filtered and concentrated to obtain a crude product. Subsequently, the obtained crude product was purified by a reduced-pressure distillation process (1.5 mmHg, 120° C.) to obtain 4-(triethoxysilyl)iodobenzene (10.2 g, 61% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][C:12]([C:15](OCC)=[O:16])=[CH:11][N:10]=2)=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[N:10]=[CH:11][C:12]([CH2:15][OH:16])=[CH:13][N:14]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnc(Nc2ccc(Cl)cc2)nc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCc1cnc(Nc2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.3 %

Procedure:
A solution of ethyl 2-(4-chlorophenylamino)pyrimidine-5-carboxylate (0.43 g, 1.548 mmol) in THF (10 mL) was cooled at −78° C. and 1M solution of DIBAL-H (4.65 ml, 4.65 mmol) in toluene was added. The mixture was stirred for 1.5 h while warming to room temperature. The reaction mixture was diluted with THF (20 mL) and quenched with Na2SO4.10H2O followed by a few drops of water. The mixture was stirred at room temperature for 18 h, then filtered through a pad of Celite topped with silica gel. The pad was washed with ethyl acetate and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel using 45-80% ethyl acetate in hexanes. The desired fractions were concentrated to give (2-(4-chlorophenylamino)pyrimidin-5-yl)methanol as a white solid (0.26 g, 71%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.46 (2H, s), 7.53-7.63 (2H, m), 7.28-7.34 (2H, m), 7.17 (1H, br. s.), 4.64 (2H, d, J=5.52 Hz). LCMS: R.T.=3.24 min; [M+H]+=235.97
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([OH:18])[CH2:16][CH3:17])[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>[O-2].[O-2].[Mn+4]>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([C:15](=[O:18])[CH2:16][CH3:17])[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(O)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Agent: [Mn+4]
Agent: [O-2]
Product: CCC(=O)c1cccc(O[Si](C)(C)C(C)(C)C)c1

Procedure:
In a manner analogous to example 1j, by reaction of 45 g (0.17 mol) of 1-[3-(tert-butyldimethylsilanyloxy)phenyl]propan-1-ol with (148 g, 1.7 mol) of manganese dioxide. A yellow oil is obtained (m=45 g, Y=100%).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][C:7]1[S:8][C:9]([CH3:12])=[CH:10][CH:11]=1.[C:13]([O-])(=[O:15])C.[Na+]>CN(C=O)C>[CH3:6][C:7]1[S:8][C:9]([CH3:12])=[CH:10][C:11]=1[CH:13]=[O:15]
Reactant: Cc1ccc(C)s1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc(C=O)c(C)s1
Temperature: 25 °C

Procedure:
To DMF (100 mL) stirred in an ice bath was added POCl3 (25 mL) drop wise followed by the addition of 2,5-dimethyl-thiophene (5 mL). The solution was warmed to room temperature and then was heated at 80° C. overnight. The reaction was cooled to room temperature and was slowly added to ice. Sodium acetate was added to bring the pH to between 5 and 6. The aqueous portion was extracted with ethyl acetate, and the organic portion was dried over sodium sulfate, concentrated under reduced pressure and purified on a silica gel column (eluent: 10:1:hexanes:EtOAc→4:1:hexanes:EtOAc to yield 2,5-dimethyl-thiophene-3-carboxaldehyde (1.5 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](/[CH:10]=[CH:11]/[CH2:12][N:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[C:20]([C:31](=[O:33])[NH2:32])[CH:19]=2)[S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][CH:9]=1)(=[NH:3])[NH2:2].C(O[C:37]1[O:38][CH2:39][CH2:40][N:41]=1)C.O1CC(=O)N=[C-]1.C(N(CC)CC)C.[ClH:55]>CO>[ClH:55].[ClH:55].[C:1]([C:4]1[CH:5]=[C:6](/[CH:10]=[CH:11]/[CH2:12][N:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]3[CH2:30][CH2:29][N:28]([C:37]4[O:38][CH2:39][CH2:40][N:41]=4)[CH2:27][CH2:26]3)=[C:20]([C:31](=[O:33])[NH2:32])[CH:19]=2)[S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][CH:9]=1)(=[NH:2])[NH2:3]
Reactant: CS(=O)(=O)N(C/C=C/c1cccc(C(=N)N)c1)c1ccc(OC2CCNCC2)c(C(N)=O)c1
Reactant: CCOC1=NCCO1
Agent: Cl
Agent: O=C1CO[C-]=N1
Solvent: CCN(CC)CC
Solvent: CO
Product: CS(=O)(=O)N(C/C=C/c1cccc(C(=N)N)c1)c1ccc(OC2CCN(C3=NCCO3)CC2)c(C(N)=O)c1
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of N-[3-(3-amidinophenyl)-2-(E)-propenyl]-N-[3-carbamoyl-4-(piperidin-4-yloxy)phenyl]methanesulfonamide (0.32 g) obtained in example 99(a) in methanol (15 ml) were added successively 2-ethoxy-4,5-dihydrooxazole (0.21 g), which was prepared from 2-oxazolidone according to the method described in Eur. J. Org. Chem., 10, 2645 (1999), and triethylamine (0.56 ml) at room temperature, and the resulting mixture was stirred at room temperature for 2 hours and allowed to stand at room temperature overnight and then evaporated in vacuo. The residue obtained was purified by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: 12% acetonitrile/water). The amorphous solid obtained was dissolved in 1N hydrochloric acid (1.2 ml) and evaporated to dryness in vacuo to afford the title compound (0.15 g, yield: 59%) as a colorless amorphous solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([NH2:13])[CH2:11][NH2:12].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[NH2:12][CH2:11][CH2:10][NH:13][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: NCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: N#Cc1ccc(NCCN)cc1
Temperature: 25 °C

Procedure:
A suspension of 4-fluorobenzonitrile (167 g, 1.38 mol), ethylenediamine (330 g, 5.5 mol) and potassium carbonate (300 g, 2.17 mol) in 2 1 of toluene is refluxed for 6 hours. After cooling to room temperature, the mixture is filtered and rinsed with toluene, and the filtrate is evaporated to give a yellow oil which is crystallized from toluene. The product is filtered off, rinsed with toluene and dried under vacuum at 50° C. to give 200 g of a slightly yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[O:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:28]1[CH2:33][CH2:32][CH2:31][C@@H:30]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:29]1.CCN(C(C)C)C(C)C>CCCCO>[Br:1][C:2]1[C:3]([N:28]2[CH2:33][CH2:32][CH2:31][C@@H:30]([NH:34][C:35]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:41])[CH2:29]2)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[O:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)C1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CN(C(=O)OC(C)(C)C)CCO4)c23)C1
Temperature: 120 °C
Reaction time: 36 h

Procedure:
A mixture of tert-butyl 2-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbamoyl)morpholine-4-carboxylate (660 mg, 1.49 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (1.49 g, 7.44 mmol), and DIEA (1.30 mL, 7.44 mmol) in n-BuOH (6 mL) was stirred at 120° C. for 36 hours. The reaction was then cooled to room temperature and concentrated in vacuo. The crude residue was purified by reverse phase HPLC (0-50% CH3CN/water) to give the separated diastereomers of tert-butyl 2-(5-bromo-4-((R)-3-(tert-butoxycarbonylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-ylcarbamoyl)morpholine-4-carboxylate in the following yields: diastereomer #1 (70 mg, 7.5%) diastereomer #2 (80 mg, 8.6%).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([F:21])[C:14]=1[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[NH:11][N:10]=[C:9]2[NH:22][C:23](=[O:27])[CH2:24][CH2:25][CH3:26].[BrH:28]>O>[Br:28][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([F:21])[C:14]=1[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[NH:11][N:10]=[C:9]2[NH:22][C:23](=[O:27])[CH2:24][CH2:25][CH3:26]
Reactant: Br
Reactant: CCCC(=O)Nc1n[nH]c2c(F)c(N3CCOCC3)c(N)cc12
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCCC(=O)Nc1n[nH]c2c(F)c(N3CCOCC3)c(Br)cc12
Reaction time: 0.75 h

Procedure:
A solution of 213 mg of sodium nitrite in 9 cm3 of water is added dropwise to a suspension, cooled to 5° C., of 900 mg of N-(5-amino-7-fluoro-6-morpholino-1H-indazol-3-yl)butanamide, prepared as previously, in 9 cm3 of water and 0.94 cm3 of 48% hydrobromic acid, and the mixture is stirred at 0° C. This suspension is added portionwise to a refluxing solution of 482 mg of cuprous bromide, 4.5 cm3 of water and 4.5 cm3 of 48% hydrobromic acid. Refluxing is continued for 45 minutes and the reaction medium is then filtered through a sinter funnel, dissolved in 75 cm3 of tetrahydrofuran and purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 15-40 μm; diameter 3 cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.) and the residue is taken up in 10 cm3 of ethyl acetate, filtered off and washed with 2×5 cm3 of ethyl acetate and with 20 cm3 of diisopropyl ether. After filtration and drying (90 Pa; 45° C.), 60 mg of N-(5-bromo-7-fluoro-6-morpholino-1H-indazol-3-yl)butanamide are obtained in the form of white crystals melting at 240° C.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([N:29]3[CH2:34][CH2:33][CH:32]([O:35][C:36]4[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:37]=4[F:44])[CH2:31][CH2:30]3)=[C:20]([NH:25][CH:26]3[CH2:28][CH2:27]3)[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[CH:26]1([NH:25][C:20]2[N:21]=[C:22]3[CH2:23][CH2:24][NH:15][CH2:16][C:17]3=[N:18][C:19]=2[N:29]2[CH2:30][CH2:31][CH:32]([O:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:37]=3[F:44])[CH2:33][CH2:34]2)[CH2:27][CH2:28]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: COc1ccc(OC2CCN(c3nc4c(nc3NC3CC3)CCN(Cc3ccccc3)C4)CC2)c(F)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1ccc(OC2CCN(c3nc4c(nc3NC3CC3)CCNC4)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 6-benzyl-N-cyclopropyl-3-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (5 mg, 8.10 μmol) and Pd(OH)2 on carbon, (20 wt %, 1 mg, 7.12 μmol) in THF (80 μL) was stirred under atmosphere of hydrogen gas (balloon) at rt. After 1 h, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (4.6 mg, 100%) as a yellow film; ESI-MS m/z [M+H]+ 414.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18]([OH:21])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18]([O:21][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:17][N:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncc(O)cn2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncc(OS(C)(=O)=O)cn2)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 93.4 %

Procedure:
To a stirred solution of 4-(5-hydroxy-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.74 g, 2.5 mmol, 1.0 equiv) in dichloromethane (20 mL) were added N-ethyl diisopropylamine (1.09 mL, 0.82 g, 6.3 mmol, 2.5 equiv), followed by methanesulfonyl chloride (0.24 mL, 0.35 g, 3.0 mmol, 1.2 equiv). After stirring for 4 h, the reaction mixture was poured into ice water and extracted twice with dichloromethane. The combined organic layers were washed with water, then dried over MgSO4, filtered and concentrated by evaporation under reduced pressure. The crude product was purified by column chromatography on silica eluting with a gradient of dichloromethane/methanol to give 0.87 g (93%) of the title compound as colorless foam. MS (ISP): 373.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH:12]([CH2:14][OH:15])[O:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[I:8].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][O:15][S:25]([CH3:24])(=[O:27])=[O:26])[O:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1OC(CO)CN1c1ccc(I)c(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
A solution of iodo-alcohol 104 (25.2 g, 74.8 mmol) in methylene chloride (CH2Cl2, 150 mL) was treated with triethylamine (TEA, 15.15 g, 20.9 mL, 150 mmol, 2.0 equiv) at 25° C., and the resulting mixture was cooled to 0-5° C. before methanesulfonyl chloride (MsCl, 10.28 g, 6.95 mL, 89.7 mmol, 1.2 equiv) was dropwise introduced into the reaction mixture at 0-5° C. under N2. The resulting reaction mixture was subsequently stirred at 0-5° C. for 1 h under N2. When TLC and HPLC/MS showed the reaction was complete, the reaction mixture was quenched with H2O (100 mL) and CH2Cl2 (100 mL). The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (100 mL). The combined organic extracts were washed with H2O (2×100 mL) and saturated aqueous NaCl (100 mL), dried over MgSO4, and concentrated in vacuo. The residue was further dried in vacuo to afford the desired (5R)-methanesulfonic acid 3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl ester 105 (30.71 g, 98.9% yield) as an off-white powder. This product was directly used in subsequent reactions without further purification. C11H11FINO5S, LCMS (EI) m/e 416 (M++H).