Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([CH:16]=[CH:17][CH:18]=1)[C:9]([C:11]1[NH:12][CH:13]=[CH:14][CH:15]=1)=[O:10])([O-:5])=[O:4].[CH2:19](I)[CH3:20].C(OCC)(=O)C>CN(C)C=O>[CH2:19]([N:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9](=[O:10])[C:8]1[CH:16]=[CH:17][CH:18]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=1)[CH3:20]
Reactant: O=C(c1cccc([N+](=O)[O-])c1)c1ccc[nH]1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1cccc1C(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 78.5 %

Procedure:
3.2 g (130 mmol) of 50% sodium hydride were suspended, under nitrogen atmosphere, in 100 ml of anhydrous dimethylformamide. A solution of 12 g (55 mmol) of 2-(3'-nitrobenzoyl)pyrrole, prepared, for example, as described in Preparation 3A, in 50 ml of dimethylformamide was added thereto, at room temperature and under stirring. The resulting mixture was stirred for an additional hour and then treated dropwise with a solution of 11.2 ml (70 mmol) of ethyl iodide in 30 ml of dry dimethylformamide. The reaction mixture was stirred for an additional hour and then poured into 500 ml of ethyl acetate. The organic extract was washed with water (5×250 ml), dried and evaporated in vacuo. Crystallization of the residue from acetone-hexane afforded 10.55 g (78%) of 1-ethyl-2-(3'-nitrobenzoyl)pyrrole, the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])C=O)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(/[CH:32]=[C:33]2/[C:34]([NH:36][C:37]([S:39]/2)=[NH:38])=[O:35])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:3][C:1]([C:5]1[CH:6]=[C:7]([CH:32]=[C:33]2[S:39][C:37](=[NH:38])[NH:36][C:34]2=[O:35])[CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])([CH3:2])[CH3:4]
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(C=C2SC(=N)NC2=O)cc(C(C)(C)C)c1O
Temperature: 0 °C
Yield: 70.7 %

Procedure:
A mixture of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (9.4 g, 0.04 mole), pseudothiohydantoin (4.7 g, 0.0405 mole), sodium acetate (8.3 g, 0.1 mole), and glacial acetic acid (200 mL) is stirred and heated at reflux for 21 hours. The cooled mixture is added to ice-water and the precipitated solid is filtered and washed with water. The solid residue is dissolved in ether and washed successively with water, aqueous sodium bicarbonate solution, and water. The extract is dried and the solvent is removed to give 9.4 g of a residue. The crude product is recrystallized from methanol-ethyl acetate to give 3.8 g (38%) of 5-[[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-2-imino-4-thiazolidinone, (Z)-, mp 277°-279° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[N:10][N:11]3[C:16]=2[CH2:15][CH2:14][CH2:13][N:12]3[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH:5]=[CH:4][N:3]=1.[CH:34]1([NH2:37])[CH2:36][CH2:35]1>C(Cl)(Cl)Cl.O>[CH:34]1([NH:37][C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)=[N:10][N:11]4[C:16]=3[CH2:15][CH2:14][CH2:13][N:12]4[C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH:5]=[CH:4][N:3]=2)[CH2:36][CH2:35]1
Reactant: NC1CC1
Reactant: O=C(OCc1ccccc1)N1CCCc2c(-c3ccnc(Cl)n3)c(-c3ccc(F)cc3)nn21
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(OCc1ccccc1)N1CCCc2c(-c3ccnc(NC4CC4)n3)c(-c3ccc(F)cc3)nn21
Reaction time: 0.08 h

Procedure:
A solution of the phenylmethyl 3-(2-chloro-4-pyrimidinyl)-2-(4-fluorophenyl)-5,6-dihydropyrazolo[1,5-b]pyridazine-7(4H)-carboxylate (i.e. the product of Step C) (464 mg, 1.0 mmol) and cyclopropylamine (1.3 mL, 18.5 mmol) in chloroform (3 mL) was heated at 120° C. in a sealed tube under microwave irradiation for 1 h and then at 160° C. for 5 minutes. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by medium pressure liquid chromatography using 20-100% ethyl acetate in hexanes as eluant to give 240 mg of the title compound as a solid.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[N:9]=[C:10](S(C)=O)[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]([CH3:16])[C:4]1=[O:17])[CH3:2].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:1]([N:3]1[C:8]2[N:9]=[C:10]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]([CH3:16])[C:4]1=[O:17])[CH3:2]
Reactant: Nc1ccccc1
Reactant: CCn1c(=O)c(C)cc2cnc(S(C)=O)nc21
Product: CCn1c(=O)c(C)cc2cnc(Nc3ccccc3)nc21
Temperature: 175 °C
Yield: 15 %

Procedure:
A mixture of 8-ethyl-6-methyl-2-methylsulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (123 mg, 0.49 mmol) and 1 mL of aniline was heated at 175° C. for 20 minutes. The reaction was cooled to room temperature and partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated. Hexane was added to the residue, and the resultant solid was collected by filtration and purified by flash chromatography eluting with ethyl acetate to provide 21 mg (15%) of 8-ethyl-6-methyl-2-phenylamino-8H-pyrido[2,3-d]pyrimidin-7-one, mp 178-180° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[C:33]([OH:35])=[O:34]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]2[C:33]([OH:35])=[O:34])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C(O)C1CCCCN1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CN2CCCCC2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 27.2 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1 g, 2 mmol) was reacted with piperidine-2-carboxylic acid (0.26 g, 2 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.3 g, 27%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]23[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=4)[C:13](=[O:25])[N:12]2[CH2:11][CH2:10][NH:9][CH2:8]3)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Br[CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]>C1COCC1>[C:42]([O:41][C:39]([CH2:38][N:9]1[CH2:8][C:7]2([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Br:1])=[CH:3][CH:4]=3)[N:12]([C:13](=[O:25])[N:14]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)[C:15]2=[O:16])[CH2:11][CH2:10]1)=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)C2(Cc3ccc(Br)cc3)CNCCN12
Reactant: CC(C)(C)OC(=O)CBr
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CN1CCN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)C2(Cc2ccc(Br)cc2)C1
Reaction time: 40 h

Procedure:
To a solution of 6-(4-bromobenzyl)-8-(3,5-dichlorophenyl)-1,4,8-triazabicyclo[4.3.0]nonane-7,9-dione (0.11 g) in THF (5 mL) was added DIEA (0.1 mL) and tert-butyl bromoacetate (0.06 mL). Additional tert-butyl bromoacetate (0.040 mL) was added after 16 hours. After 40 hours, the reaction mixture was concentrated and the residue was diluted with EtOAc and washed with water, NaHCO3, and brine, dried (Na2SO4), filtered, and concentrated. Purification by chromatography (Silica gel: EtOAc/hexane: 1/5, Chromatotron) afforded the titled compound (0.124 g). MS (m/z) 582 (MH+). mp 74.7° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].C([O-])(O)=O.[Na+].Cl[CH2:16][C:17](Cl)=[O:18]>CC(C)CC(=O)C.O>[Br:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][CH2:16][C:17](=[O:18])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Br)ccc1O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=C1COc2ccc(Br)cc2N1
Temperature: 80 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
To a solution of 2-amino-4-bromophenol (25 g, 133.0 mmol), NaHCO3 (22.4 g, 266.0 mmol) in 4-methylpentan-2-one (50 mL) and water (50 mL) at 0° C. was added 2-chloroacetyl chloride (10.0 mL, 200.0 mmol) dropwise. The reaction mixture was stirred at 80° C. for 24 h then cooled to ambient temperature and filtered. The filtrate was washed with water (3×10 mL) and dried over anhydrous Na2SO4. After filtration, the organic phase was evaporated to give 6-bromo-4H-benzo[1,4]oxazin-3-one as a white solid (27 g, 89%). 1H NMR (CDCl3, 400 MHz): δ 8.49 (brs, 1H), 7.08 (dd, J=8.4 Hz, J=2.0 Hz, 1H), 6.93 (d, J=2.0 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 4.61 (s, 2H).
Reaction SMILES: [C@@H:1]1([NH:11][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]3[CH:25]=[C:24]([N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[CH:23]=[CH:22][C:21]=3[NH:32][C:33]([C:35]3[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=3)[C:38](O)=[O:39])=[O:34])[CH:15]=2)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:44][NH:45][CH2:46][CH2:47][CH2:48][N:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1.CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1.O>[CH3:44][N:45]([CH2:46][CH2:47][CH2:48][N:49]1[CH2:50][CH2:51][O:52][CH2:53][CH2:54]1)[C:38](=[O:39])[C:37]1[CH:41]=[CH:42][CH:43]=[C:35]([C:33]([NH:32][C:21]2[CH:22]=[CH:23][C:24]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:25][C:20]=2[C:16]2[CH:15]=[C:14]([C:12](=[O:13])[NH:11][C@@H:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:4][CH2:3][CH2:2]3)[CH:19]=[CH:18][N:17]=2)=[O:34])[CH:36]=1
Reactant: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Reactant: CNCCCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CN(CCCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
A solution of 3-((2-(4-(((S)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzoic acid (150 mg, 0.26 mmol, 1.00 equiv) in dichloromethane (3 mL), N-methyl-3-morpholinopropan-1-amine (42 mg, 0.27 mmol, 1.00 equiv), EDC.HCl (75 mg, 0.39 mmol, 1.50 equiv), 4-dimethylaminopyridine (48 mg, 0.39 mmol, 1.50 equiv). The resulting solution was stirred for 2 h at 25° C. The resulting solution was diluted with 3 mL of water. The resulting solution was extracted with 2×5 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 1×5 mL of water and 2×5 mL of Brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (120 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-3): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (24% CH3CN up to 34% in 6 min); Detector, Waters2545 UvDector 254&220 nm. 97 mg product was obtained. This resulted in 97 mg (35%) of (S)—N1-methyl-N1-(3-morpholinopropyl)-N3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide. Example 126 as a yellow solid. (ES, m/z): 715 [M+H]+ (400 MHz, CD3OD, ppm): 8.91 (s, 1H), 8.73 (d, J=8.8 Hz, 1H), 8.41 (s, 1H), 8.14˜8.09 (m, 3H), 7.873˜7.857 (m, 1H), 7.753˜7.69 (m, 3H), 7.27 (d, J=7.2 Hz, 1H), 7.19˜7.13 (m, 3H), 5.40 (d, J=6.4 Hz, 1H), 4.18 (s, 2H), 3.90˜3.50 (m, 9H), 3.46˜3.17 (m, 5H), 3.07 (s, 3H), 2.89˜2.78 (s, 2H), 2.26˜2.03 (m, 8H), 1.98˜1.81 (m, 4H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]2[C:14]3[NH:21][C:20]([CH3:22])=[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.Cl[CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[C:13]2[C:14]3[N:21]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:20]([CH3:22])=[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc12
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(F)ccc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-(2-cyclopropylmethoxy-5-fluoro-phenyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example D.a3) and commercially available (2-chloromethoxy-ethyl)-trimethyl-silane the title compound is prepared as pale yellow viscous oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([O:11][CH2:12][C:13]([F:14])([F:15])[F:16])[CH:5]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1OCC(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(N)cc1OCC(F)(F)F

Procedure:
4-Nitro-2-(2,2,2-trifluoroethoxy)toluene (2.0 g, 9.0 mmol) from Step 1 above was dissolved in MeOH (20 mL) and shaken with palladium black (100 mg) under 50 psig of hydrogen on a Parr apparatus for 2 h. The catalyst was removed by filtration and the solvent was removed under reduced pressure to give 4-amino-2-(2,2,2-trifluoroethoxy)toluene as a gum.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([C:25]2[CH:26]=[CH:27][C:28]3[C:33]([CH:34]=2)=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:13]=[C:14]([CH2:16][O:17][Si](C(C)(C)C)(C)C)[CH:15]=1)(C(C)(C)C)(C)C.[C:35](Cl)([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)([C:44]1[CH:51]=[CH:50][C:47]([O:48][CH3:49])=[CH:46][CH:45]=1)[C:36]1[CH:43]=[CH:42][C:39]([O:40][CH3:41])=[CH:38][CH:37]=1>C(Cl)(Cl)Cl>[OH:17][CH2:16][C:14]1[CH:13]=[C:12]([C:25]2[C:26]3[C:31](=[CH:32][CH:33]=[CH:28][CH:27]=3)[CH:30]=[CH:29][CH:34]=2)[CH:11]=[C:10]([CH2:9][O:8][C:35]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)([C:44]2[CH:51]=[CH:50][C:47]([O:48][CH3:49])=[CH:46][CH:45]=2)[C:36]2[CH:43]=[CH:42][C:39]([O:40][CH3:41])=[CH:38][CH:37]=2)[CH:15]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(CO[Si](C)(C)C(C)(C)C)cc(-c2ccc3ccccc3c2)c1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(OCc2cc(CO)cc(-c3cccc4ccccc34)c2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 18 h
Yield: 67.8 %

Procedure:
10.3 ml of pyrizine was added to dissolve 0.5448 g of Compound (6) in an Ar atmosphere, and 0.909 g (2.68 mmol, 1.3 eq) of DMTrCl was added. This was agitated for 18 hours in an Ar atmosphere. After extraction with chloroform, the organic layer was washed with H2O, sat. NaHCO3 aq and sat. NaCl aq, and dried by addition of anhydrous NaSO4. The solvent was distilled off under reduced pressure, and 0.4293 g (0.75 mmol, 37%) of Compound (7) was isolated by silica gel chromatography (chloroform only→chloroform:methanol=15:1).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([Br:9])=[CH:5][CH:4]=1.[CH2:10]([O:12][Si:13](OCC)([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])[CH3:11]>C(OCC)C>[Br:9][C:6]1[CH:7]=[CH:8][C:3]([Si:13]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])[O:12][CH2:10][CH3:11])=[CH:4][CH:5]=1
Reactant: CCO[Si](OCC)(OCC)OCC
Reactant: Brc1ccc(Br)cc1
Agent: [Mg]
Solvent: CCOCC
Product: CCO[Si](OCC)(OCC)c1ccc(Br)cc1
Reaction time: 8 h

Procedure:
Freshly activated magnesium (8.5 g, 0.35 mol) was slowly added over a period of four hours to a solution of 1,4-dibromobenzene (80 g, 0.34 mol) in 200 mL of diethylether, keeping the temperature below 30° C. The reaction mixture was stirred for 8 h and then slowly added to a mixture of tetraethoxysilane (100 mL, 0.44 mol) in Et2O (50 mL). The mixture was stirred for 12 h, and unreacted tetraethoxysilane and diethylether were removed in vacuum. The remaining liquid was fractionally distilled through a Vigreux column under reduced pressure to provide 4-bromophenyltriethoxysilane as a clear oil (37 g, 37%, bp 80–90° C. at 250 μHg). 1HNMR(400 MHz, CDCl3): δ 7.56 (4H, dd), 3.89 (6H, q), 1.27 (9H, t). 13CNMR (100 MHz, CDCl3): δ 136.4, 131.1, 58.8, 18.2. GC-MS: 318 (M+).
Reaction SMILES: C([NH:8][C:9]1[C:14]2[O:15][CH2:16][CH2:17][N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:13]=2[CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1>CO.[Pd]>[NH2:8][C:9]1[C:14]2[O:15][CH2:16][CH2:17][N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:13]=2[CH:12]=[CH:11][N:10]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2c1ccnc2NCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCOc2c1ccnc2N
Temperature: 35 °C
Reaction time: 48 h
Yield: 79.1 %

Procedure:
A mixture of tert-butyl 5-(benzylamino)-2,3-dihydropyrido[3,4-b][1,4]oxazine-1-carboxylate (3.6 g, 10.56 mmol) and 10% Pd on carbon (1.12 g, 1.06 mmol) in MeOH (100 mL) was stirred under hydrogen atmosphere (2 L) at 35° C. for 48 h. The mixture was then filtered through Celite and washed with MeOH (3×25 mL). The combined organic layer was concentrated under reduced pressure. The residue was re-dissolved in EtOAc (100 mL) and washed with brine (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered, and the solvent removed under reduced pressure. The residue was purified by reverse phase column chromatography (eluting with 22% acetonitrile in water, with 0.1% NH3H2O) to give tert-butyl 5-amino-2,3-dihydropyrido[3,4-b][1,4]oxazine-1-carboxylate (2.1 g, 79% yield) as a yellow solid. ESI MS: m/z 252 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:8].C([Li])CCC.[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH:28]=[O:29])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>O1CCCC1>[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH:28]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[Cl:8])[OH:29])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=CCC1CCN(Cc2ccccc2)CC1
Reactant: Clc1ccccc1Br
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: OC(CC1CCN(Cc2ccccc2)CC1)c1ccccc1Cl
Temperature: -78 °C
Reaction time: 1 h

Procedure:
After dissolving 1.75 ml of 1-bromo-2-chlorobenzene in 30 ml of tetrahydrofuran, the solution was cooled to −78° C. Next, 5.31 ml of n-butyllithium (2.6 M, n-hexane solution) was added dropwise thereto while stirring and after 1 hour, a solution of 2.50 g of 1-benzylpiperidine-4-acetaldehyde in tetrahydrofuran (10 ml) was added and stirring was continued for 1 hour. After adding water to the reaction solution, the temperature was raised to room temperature and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 2-(1-benzylpiperidin-4-yl)-1-(2-chlorophenyl)ethanol.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)(=[O:4])=[O:3].[CH3:18][NH:19][CH3:20]>C(Cl)Cl>[CH3:18][N:19]([CH3:20])[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)(=[O:4])=[O:3]
Reactant: CCOc1cc(S(=O)(=O)Cl)ccc1C(=O)OC
Reactant: CNC
Solvent: ClCCl
Product: CCOc1cc(S(=O)(=O)N(C)C)ccc1C(=O)OC
Temperature: 0 °C
Reaction time: 16 h
Yield: 40.4 %

Procedure:
Methyl 4-chlorosulfonyl-2-ethoxy-benzoate (1.3 g, 4.55 mmol) was taken up in anhydrous methylene chloride (30 mL) and cooled to 0° C. Dimethylamine (9.1 mL, 18.2 mmol) was added. The reaction mixture was allowed to slowly warm to room temperature and stirred at room temperature for 16 h. The reaction mixture was washed with water, dried over magnesium sulfate and concentrated. Purification of the crude residue by flash column chromatography (silica gel, eluting with 20-50% ethyl acetate in hexanes) gave methyl 4-dimethylsulfamoyl-2-ethoxy-benzoate as a yellow solid (0.528 g, 41%). LC-MS: 288.1 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][C:14]=1[C:23]([F:26])([F:25])[F:24]>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][S:19]([C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[C:14]([C:23]([F:26])([F:24])[F:25])[CH:15]=2)(=[O:21])=[O:20])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: COC(=O)c1nccnc1N
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1nccnc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.7 %

Procedure:
To a solution of 3-amino-pyrazine-2-carboxylic acid methyl ester (153 mg, 1.0 mmol) in 2.0 mL of pyridine was added 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (279 mg, 1.0 mmol) in 1.0 mL of pyridine. The mixture was stirred at room temperature for 16 h, diluted with 15 mL of ethyl acetate, washed twice with 1M HCl (15 mL), dried on MgSO4 and the solvent was evaporated. The product was purified on silica gel column (15% ethyl acetate in hexane) to afford 185 mg of 3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyrazine-2-carboxylic acid methyl ester as white powder. MS: (M+H)/z=396.0.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][N:3]=1.[I-:10].[Na+].C(Cl)(=O)C>C(#N)C>[Br:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([I:10])=[N:3][CH:4]=1
Reactant: [I-]
Reactant: Cc1cc(Br)ncc1Br
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)Cl
Product: Cc1cc(I)ncc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
To a solution of 2,5-dibromo-4-methylpyridine (2 g) in acetonitrile (40 ml) at room temperature under argon were added sodium iodide (4.8 g) then acetyl chloride (0.94 g). After 3 hours stirring at room temperature the white solid formed was filtered off and the filtrate was neutralized with aqueous saturated solution of sodium hydrogenocarbonate. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/cyclohexane) to afford the title product as a brown solid (2.04 g). 1H-NMR (CDCl3, 400 MHz): 8.40 (s, 1H), 7.60 (s, 1H), 2.30 (s, 3H),
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>C1(C)C=CC=CC=1>[C:4]([C:3]1[C:2]([N:1]=[CH:13][N:14]([CH3:16])[CH3:15])=[N:9][C:8]([CH3:10])=[CH:7][CH:6]=1)#[N:5]
Reactant: Cc1ccc(C#N)c(N)n1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(C#N)c(N=CN(C)C)n1
Temperature: 25 °C
Yield: 97.4 %

Procedure:
A solution of the product of Example 10A (10 g, 75.19 mmol) and N,N-Dimethylformamide dimethyl acetal (11 mL, 82.71 mmol) in toluene (100 mL) was heated at reflux for 6 hours. After cooling to room temperature, the solution was concentrated under vacuum to provide the title compound as a yellow solid (13.78 g, 98%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.41 (s, 3H), 3.06 (s, 3H), 3.14 (s, 3H), 6.87 (d, J=7.7 Hz, 1H), 7.89 (d, J=8.1 Hz, 1H), 8.59 (s, 1H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].Br[C:11]1[S:12][C:13]([Br:16])=[CH:14][N:15]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Br:16][C:13]1[S:12][C:11]([N:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]2)=[N:15][CH:14]=1
Reactant: Brc1cnc(Br)s1
Reactant: CC(C)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)N1CCN(c2ncc(Br)s2)CC1
Temperature: 50 °C

Procedure:
In a 50 mL round bottom flask, 1-isopropylpiperazine (224 mg, 1.74 mmol) was dissolved in 4 mL dioxane. 2,5-Dibromothiazole (650 mg, 1.5 eq.) and DIEA (670 mg, 3 eq.) were added and the reaction was heated to 50° C. overnight. Reaction mixture was cooled and extracted using ethyl acetate /brine. The organic layer was concentrated and purified via combiflash to give desired compound. LCMS-ESI+: calc'd for C10H17BrN3S: 290.0 (M+H+); Found: 290.2 (M+H+).