Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:5]([CH:6]=O)[C:4]=1[OH:15].Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+]>C(O)C.O>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:5]([CH:6]=[N:19][OH:20])[C:4]=1[OH:15]
Reactant: CC(C)(C)c1cc(C=O)c(O)c(C(F)(F)F)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(C=NO)c(O)c(C(F)(F)F)c1

Procedure:
0.05 moles of the aldehyde from Step A, 0.12 moles of hydroxylamine hydrochloride and sodium acetate (0.12 moles) are dissolved in a mixture of ethanol (100 ml.) and water (30 ml.). The reaction mixture is refluxed for 2 hours, cooled and water added until no more precipitate forms. The solid that separates is crystallized from ethanol to yield 3-trifluoromethyl-5-tert-butyl salicylaldehyde oxime.
Reaction SMILES: [Br:1][C:2]1[C:13](=[O:14])[N:12]([CH2:15][CH3:16])[C:5]2[N:6]=[C:7]([S:10][CH3:11])[N:8]=[CH:9][C:4]=2[CH:3]=1.ClC1C=CC=C(C(OO)=[O:25])C=1>ClCCl>[Br:1][C:2]1[C:13](=[O:14])[N:12]([CH2:15][CH3:16])[C:5]2[N:6]=[C:7]([S:10]([CH3:11])=[O:25])[N:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCn1c(=O)c(Br)cc2cnc(SC)nc21
Solvent: ClCCl
Product: CCn1c(=O)c(Br)cc2cnc(S(C)=O)nc21
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To a solution of 6-bromo-8-ethyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (3, 0.96 g, 3.19 mmol) in dichloromethane (40 mL) was added 3-chloroperbenzoic acid (77%, 0.68 g, 3.04 mmol) in dichloromethane (10 mL) at 0-5° C. and the mixture was stirred at 0-5° C. for 1 h. The reaction mixture was washed with 10% sodium bicarbonate solution (1×20 mL) and in water (1×20 mL). The organic layer was dried over sodium sulfate, filtered and evaporated. The title compound was obtained as a pale yellow solid (0.98 g, 3.10 mmol, 97%). ESMS m/z 316 (M+H)+.
Reaction SMILES: Br[C:2]1=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[O:10][CH2:11][CH2:12][CH:13]=[CH2:14].C1CCN2C(=NCCC2)CC1.CCOC(C)=O.Cl>CS(C)=O>[CH2:11]([O:10][CH:9]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]#[C:2]1)[CH2:12][CH:13]=[CH2:14]
Reactant: C=CCCOC1CCCCCC=C1Br
Agent: C=CCCOC1CCCCC/C=C\1Br
Agent: Cl
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: C=CCCOC1C#CCCCCC1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 87.2 %

Procedure:
The compound 2 (2.04 g, 7.8 mmol) is dissolved in anhydrous DMSO (10 ml) and heated to 60° C. DBU (2.3 ml, 2 eq.) is added and the solution is stirred for 15 min. before adding further DBU (4.6 ml, 4 eq.) and again stirring for 15 min. Finally, DBU (4.6 ml, 4 eq.) is added a final time and the solution is stirred at 60° C. overnight and subsequently left to return to ambient temperature. 150 ml of AcOEt are added to this solution and extraction is carried out with HCl (1M). When the pH becomes basic, the organic phase is washed with water to neutrality. The extracted phase is dried over MgSO4, filtered and purified by flash chromatography (cyclohexane/AcOEt 99:1) in order to produce the compound 3 (1.22 g, 6.8 mmol, 87%), a colorless liquid.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[N:16]([CH:19]([F:21])[F:20])[C:15]([CH3:22])=[N:14]2)=[C:9]([F:23])[CH:8]=1.[Br:24]Br>>[Cl:6][C:7]1[C:12]([Br:24])=[CH:11][C:10]([N:13]2[C:17](=[O:18])[N:16]([CH:19]([F:20])[F:21])[C:15]([CH3:22])=[N:14]2)=[C:9]([F:23])[CH:8]=1
Reactant: BrBr
Reactant: Cc1nn(-c2ccc(Cl)cc2F)c(=O)n1C(F)F
Agent: O=S(=O)(O)O
Product: Cc1nn(-c2cc(Br)c(Cl)cc2F)c(=O)n1C(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a 250 mL roundbottom flask equipped with a mechanical stirrer and a thermometer was added 6 mL of 20% fuming sulfuric acid (oleum) (% wt/vol. triazole to solvent—23.3%), 1.4 grams (0.0051 mole—1.0 equiv.) of 1-(4-chloro-2-fluorophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole, and 0.85 gram (0.0053 mole—1.03 equiv.) of bromine crystals. The reaction mixture stirred at ambient temperature for two hours. After this time TLC analysis of the reaction mixture indicated that the reaction was almost complete. The reaction mixture was stirred at ambient temperature for an additional 16 hours. At the conclusion of this period a second TLC analysis of the reaction mixture indicated the reaction was essentially completed. The reaction mixture was poured into 300 grams of ice, and the resulting mixture was extracted with two 50 mL portions of methylene chloride. The organic extracts were combined and washed with an aqueous 10% potassium carbonate solution, an aqueous 5% sodium bisulfite solution, and an aqueous saturated sodium chloride solution. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure yielding a white solid, which was dried to a constant weight, yielding 1.6 grams of 1-(4-chloro-2-fluoro-5-bromophenyl)-4-difluoromethyl4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazole (90.1 % yield) . The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:14]([F:27])[CH:13]=1.N1C=CC=CC=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>[OH-].[Na+]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)=[C:14]([F:27])[CH:13]=1)[C:34](=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(Br)c(NCc2ccc(OCCN3CCCCC3)c(F)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: COc1ccc(Br)c(N(Cc2ccc(OCCN3CCCCC3)c(F)c2)C(C)=O)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of (2-bromo-5-methoxyphenyl)[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl]amine (690 mg), pyridine (2 ml) and acetic anhydride (2 ml) was stirred for 4 hours at 80° C. The reaction mixture was diluted with an aqueous solution of 1N sodium hydroxide, extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (530 mg).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:18])[C:16]=3[N:17]=2)[CH:5]=[CH:4][N:3]=1.Cl.[OH-:20].[Na+]>O1CCOCC1>[NH2:18][C:15]1[C:16]2[N:17]=[C:8]([C:6]3[CH:5]=[CH:4][NH:3][C:2](=[O:20])[CH:7]=3)[CH:9]=[CH:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: [OH-]
Reactant: Nc1ncnc2ccc(-c3ccnc(F)c3)nc12
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1ncnc2ccc(-c3cc[nH]c(=O)c3)nc12
Temperature: 80 °C
Yield: 60 %

Procedure:
6-(2-fluoro-4-pyridyl)pyrido[3,2-d]pyrimidin-4-amine (50 mg, 0.21 mmol) 1 was treated with hydrogen chloride (4 mol/L) in 1,4-dioxane. The mixture was heated to 80° C. for 1 hour. Cooled to room temperature and basified with 4 N NaOH. Yellow precipitate was collected, and purified with Prep HPLC, 30 mg of 4-(4-aminopyrido[3,2-d]pyrimidin-6-yl)pyridin-2(1H)-one 2 was obtained (yield 60%). LC/MS (ESI+): m/z 240 (M+H). 1H NMR (400 MHz, DMSO) δ 8.39 (d, J=8.7 Hz, 1H), 8.18 (s, 1H), 8.15 (d, J=8.6 Hz, 1H), 7.52 (d, J=6.9 Hz, 1H), 7.11 (d, J=1.6 Hz, 1H), 7.00 (dd, J=6.9, 1.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[H-].[Na+].[Cl:13][C:14]1[CH:19]=[C:18](Cl)[N:17]=[CH:16][N:15]=1.O>CN(C=O)C>[Cl:1][C:2]1[N:6]([C:18]2[CH:19]=[C:14]([Cl:13])[N:15]=[CH:16][N:17]=2)[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Clc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1cc(-n2c(Cl)nc3ccccc32)ncn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To the solution of 2-Chloro-1H-benzoimidazole (3.0 g, 19.67 mmol) in 10 mL DMF at 0° C. under argon atmosphere is added with sodium hydride (60% dispersion in mineral oil, 1.18 g, 29.5 mmol) portion wise. After 20 minutes, 4,6-dichloro-pyrimidine (3.3 g, 22.1 mmol) is added. The resulting reaction mixture is allowed to warm to room temperature and stirred overnight. The reaction mixture is treated with 120 mL water and extracted three times with 100 mL dichloromethane. The organic extracts are washed with brine and dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (0% EtOAc/hexanes to 20% EtOAc/hexanes gradient), affords the title compound as a white powder: Rf=0.35 (20% EtOAc/hexanes); 1H NMR 400 MHz (DMSO-d6) δ 9.26 (s, 1H), 8.25 (s, 1H), 7.80-7.72 (m, 2H), 7.43-7.37 (m, 2H); MS m/z 265.1 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][CH:5]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][N:7]=[N+:8]=[N-:9].[Li+].[OH-]>C1COCC1>[N:7]([CH2:6][CH:5]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:4][C:3]([OH:18])=[O:2])=[N+:8]=[N-:9]
Reactant: COC(=O)CC(CN=[N+]=[N-])NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(CN=[N+]=[N-])CC(=O)O

Procedure:
DL-4-azido-3-tert-butoxycarbonylamino-butyric acid methyl ester (450 mg, 1.74 mmol) was dissolved in THF (12 mL) and hydrolized by adding an aqueous solution of LiOH (393 mg).
Reaction SMILES: [C:1](=O)([O:43]C1C=CC([N+]([O-])=O)=CC=1)[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([NH:31][C:32]([O:34][C@@H:35]2[C@H:42]3[C@H:38]([O:39][CH2:40][CH2:41]3)[O:37][CH2:36]2)=[O:33])[C@H:11]([OH:30])[CH2:12][N:13]([S:18]([C:21]2[CH:29]=[CH:28][C:24]3[O:25][CH2:26][O:27][C:23]=3[CH:22]=2)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:5][CH:4]=1.[N:54]1([CH2:59][CH2:60][NH2:61])[CH:58]=[CH:57][N:56]=[CH:55]1>O1CCOCC1.C(OCC)(=O)C>[O:25]1[C:24]2[CH:28]=[CH:29][C:21]([S:18]([N:13]([CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:12][C@@H:11]([OH:30])[C@@H:10]([NH:31][C:32](=[O:33])[O:34][C@@H:35]3[C@H:42]4[C@H:38]([O:39][CH2:40][CH2:41]4)[O:37][CH2:36]3)[CH2:9][C:6]3[CH:5]=[CH:4][C:3]([O:2][C:1]([NH:61][CH2:60][CH2:59][N:54]4[CH:58]=[CH:57][N:56]=[CH:55]4)=[O:43])=[CH:8][CH:7]=3)(=[O:20])=[O:19])=[CH:22][C:23]=2[O:27][CH2:26]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: NCCn1ccnc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OC(=O)NCCn2ccnc2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
To a solution of 4-{(2S,3R)-2-({[(3R,3aS,6aR)-Hexahydrofuro [2,3-b]furan-3-yloxy]carbonyl}amino)-4-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-3-hydroxybutyl}phenyl 4-nitrophenyl carbonate (50 mg, 0.07 mmol) in 1,4-dioxane (1 mL) was added 2-(1H-imidazol-1-yl)ethanamine (50 mg, 0.45 mmol, Synthetic Communications 1991, 21, 535-544) and the mixture was stirred at ambient temperature for 30 min. The mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate/water (4×), dried (sodium sulfate), evaporated and purified by chromatography (silica gel, dichloromethane/2M ethanolic ammonia, 93:7) to provide the title compound as a white solid (25 mg). 1H NMR (DMSO-d6): δ 0.78 (3H, d), 0.82 (3H, d), 1.2 (1H, dd), 1.4 (1H, quintuplet), 1.9-2.0 (1H, m), 2.4 (1H, t), 2.55-2.80 (3H, m), 2.9-3.0 (2H, m), 3.3-3.4 (3H, m), 3.5-3.6 (4H, m), 3.7 (1H, t), 3.8 (1H, dd), 4.03-4.07 (2H, m), 4.8 (1H, dt), 0.505 (1H, d), 5.5 (1H, d), 6.18 (2H, s), 6.87 (1H, s), 6.9 (2H, d), 7.05 (1H, d), 7.15 (1H, s), 7.2 (2H, d), 7.23 (1H, s), 7.25-7.30 (2H, m), 7.6 (1H, s), 7.8 (1H, t); MS: 730 (MH+)
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:8]=2[O:7][CH2:6][CH2:5]1.[C:20]1([C:26]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([SH:31])[C:27]([F:30])([F:29])[F:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([C:26]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([S:31][CH2:2][CH2:3][N:4]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:8]=3[O:7][CH2:6][CH2:5]2)[C:27]([F:28])([F:29])[F:30])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: FC(F)(F)C(S)(c1ccccc1)c1ccccc1
Reactant: COC(=O)COc1cccc2c1OCCN2CCO
Product: COC(=O)COc1cccc2c1OCCN2CCSC(c1ccccc1)(c1ccccc1)C(F)(F)F
Yield: 84.6 %

Procedure:
The same process as Example 1 was repeated except that methyl (4-(2-hydroxyethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate (375 mg) and 1,1-diphenyl-2,2,2-trifluoroethanethiol (385 mg). were used to obtain the object compound (614 mg, yield 85%).
Reaction SMILES: C([N:18]([CH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1)[CH2:19][C:20]([OH:22])=[O:21])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.[NH2:32][C@H:33]([C:37]([O:39][CH2:40][CH:41]=[CH2:42])=[O:38])[CH:34]([CH3:36])[CH3:35].CN(C=O)C.N1CCCCC1>C(Cl)Cl>[CH:23]1([NH:18][CH2:19][C:20]([OH:22])=[O:21])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1.[NH2:32][C@H:33]([C:37]([O:39][CH2:40][CH:41]=[CH2:42])=[O:38])[CH:34]([CH3:36])[CH3:35]
Reactant: O=C(O)CN(C(=O)OCC1c2ccccc2-c2ccccc21)C1CCc2ccccc21
Agent: C=CCOC(=O)[C@@H](N)C(C)C
Solvent: ClCCl
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: O=C(O)CNC1CCc2ccccc21
Reaction time: 0.75 h

Procedure:
Fmoc-Indanylglycine-Val-OAllyl (0.758 g, 1.31 mmol) was solvated in CH2Cl2 (5 mL) and DMF (1.8 mL) followed by dropwise addition of piperidine (1.05 mL, 8.1 eq) over 30 seconds. After 45 min, the mixture was subjected to extraction CH2Cl2/brine (30/15 mL) and saturated NH4Cl (5 mL). The organic layer was dried over MgSO4, concentrates and purified by silica using a gradient of MeOH/CH2Cl2 (0 to 5%) to get 0.45 g of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][C:20]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[O:21])=[CH:13][CH:12]=2)=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8].[C:33]([CH2:41][CH2:42][C:43](O)=O)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH3:9][C:5]1[N:4]=[C:3]2[N:10]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19][C:20]([NH:22][S:23]([C:26]4[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=4)(=[O:25])=[O:24])=[O:21])=[CH:13][CH:12]=3)[C:43]([CH2:42][CH2:41][C:33](=[O:40])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[N:1][C:2]2=[C:7]([CH3:8])[CH:6]=1
Reactant: O=C(O)CCC(=O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(Nc3nc(C)cc(C)c3N)cc2)cc1
Product: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3c(CCC(=O)c4ccccc4)nc4c(C)cc(C)nc43)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 241 from N-{[(2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethyl)amino]carbonyl}-4-methylbenzenesulfonamide (step 4 of Example 162) and 3-benzoylpropionic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[CH:5]2.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:18][CH2:17][C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[O:14][CH3:13])[CH:6]=[CH:5]2
Reactant: COc1ccccc1CN
Reactant: Clc1ccc2cc(Br)ccc2n1
Product: COc1ccccc1CNc1ccc2cc(Br)ccc2n1

Procedure:
(6-Bromo-quinolin-2-yl)-(2-methoxy-benzyl)-amine was prepared from 6-bromo-2-chloroquinoline and 2-methoxybenzylamine as described in example 2 step A.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].S(=O)(=O)(O)[OH:11].[Cr](O)(O)(=O)=O>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]=[O:11]
Reactant: Cc1cc(F)ccc1Cl
Reactant: O=S(=O)(O)O
Agent: O=[Cr](=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: O=Cc1cc(F)ccc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-5-fluorotoluene (5.0 g) in acetic anhydride (40 ml) was added dropwise under ice-cooling concentrated sulfuric acid (40 ml), and then added dropwise a solution of anhydrous chromic acid (9.3 g) in acetic anhydride (40 ml) for 2 hours. The mixture was stirred at the same temperature for 1 hour, poured into ice-water and extracted with diethylether. The organic layer was washed with sodium carbonate solution, water and saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in tetrahydrofuran (10 ml). To the mixture were added water (4 ml) and concentrated sulfuric acid (4 ml), and the mixture was stirred at 100° C. for 30 minutes and cooled. The reaction solution was extracted with ethyl acetate. The organic layer was washed with sodium carbonate solution, water and saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give the residue, which was subjected to silica gel column chromatography to give 2-chloro-5-fluorobenzaldehyde (1.6 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]=[C:10]([CH2:12]OS(C)(=O)=O)[O:9][N:8]=2)=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>C(#N)C>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([CH2:12][C:10]2[O:9][N:8]=[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[N:11]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CS(=O)(=O)OCc1nc(-c2ccncc2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(Cc2nc(-c3ccncc3)no2)CC1

Procedure:
Methanesulfonic acid 3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl ester (Preparation 12, 56 mg, 0.22 mmol) and potassium carbonate (30 mg, 0.22 mmol) were added to a solution of piperazine-1-carboxylic acid tert-butyl ester (37 mg, 0.2 mmol) in acetonitrile (4 ml). The stirred mixture was heated under reflux for 18 h, the solvent removed and the residue dissolved in EtOAc-water (90:10, 50 ml). The organic phase was separated, washed with brine, dried (MgSO4) and the solvent removed to give a residue which was purified by flash chromatography (IH-EtOAc, 4:1), affording the title compound: RT=3.26 min; m/z (ES+)=346.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=O)=[CH:4][CH:3]=1.COCC(O)C.S1C=CC=C1>[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(F)cc1
Agent: [Pd]
Solvent: COCC(C)O
Solvent: c1ccsc1
Product: O=C(O)c1ccccc1Cc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
In a hydrogenation flask was added 2-(4-fluoro-benzoyl)-benzoic acid, propylene glycol monomethyl ether (1 L/mol) and Pd/C 10% wet (15 g/mol). Hydrogenation was performed at 50° C. over 18 hours. Thiophene (0.3 kg/mol) was added and the catalyst was filtered off. The filtrate was heated up to 80° C. and water (1.12 L/mol) was added at that temperature. The mixture was heated up to reflux, then cooled down to 25° C. and stirred at that temperature during 1 hour. The precipitate was filtered off, washed with water (1 L/mol) and dried at 50° C. during 18 hours. Active yield: 83%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.C(O)=O.CN(C)C=O>CC1C=CC(C(C)C)=CC=1.CC1C=CC(S([N-][C@H]([C@@H](N)C2C=CC=CC=2)C2C=CC=CC=2)(=O)=O)=CC=1.[Cl-].[Ru+2].O>[N+:10]([CH2:9][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[OH:13])([O-:12])=[O:11]
Reactant: Cc1ccc(C(=O)C[N+](=O)[O-])cc1
Agent: [Ru+2]
Agent: Cc1ccc(S(=O)(=O)[N-][C@@H](c2ccccc2)[C@@H](N)c2ccccc2)cc1
Agent: [Cl-]
Solvent: O
Solvent: O=CO
Solvent: CCN(CC)CC
Product: Cc1ccc(C(O)C[N+](=O)[O-])cc1
Reaction time: 16 h

Procedure:
A 50 ml Schlenk flask was charged with 1.075 g (6.0 mmol) of 1-(4-methylphenyl)-2-nitroethanone, 2.01 ml (14.4 mmol) of triethylamine, 1.36 ml (36.0 mmol) of formic acid, 6 ml of dimethylformamide (DMF), and 38.2 mg (0.06 mmol, S/C=100) of RuCl[(S,S)-Tsdpen](p-cymene) under an atmosphere of argon, and stirring was carried out at 30° C. for 16 hours. The reaction solution was poured into water and extracted with ether, and the organic layer was washed with saturated brine and then dried with anhydrous sodium sulfate. After removing the drying agent, the solvent was distilled off, and the oil so obtained was purified by silica gel column chromatography (eluant; n-hexane:ethyl acetate=9:1) to give 0.60 g of optically active 2-nitro-1-(4-methylphenyl)ethanol.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[CH:15]=[C:16]([Br:20])[C:17]([OH:19])=[CH:18][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+].Cl>CO>[Br:20][C:16]1[C:17]([OH:19])=[CH:18][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH:12]([CH3:14])[CH3:13])[C:9]=2[CH:15]=1
Reactant: CC(C)C1CN(C(=O)C(F)(F)F)CCc2cc(O)c(Br)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C1CNCCc2cc(O)c(Br)cc21
Reaction time: 3 h
Yield: 97.3 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-7-hydroxy-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.018 g, 0.047 mmol) in methanol (1 mL) was treated with 15% aqueous NaOH (1 mL), and stirred for 3 hours at 50 C. The product mixture was brought to pH 7-8 with 10% aqueous HCl, extracted three times with EtOAc (50 mL), dried with MgSO4, and concentrated to give 0.013 g of a white solid. 1H NMR (400 MHz, CD3OD) d 7.10 (s, 1H), 6.60 (s, 1H), 3.30 (m, 1H), 3.2-3.0 (m, 2H), 2.78 (m, 1H), 2.7-2.5 (m, 2H), 2.3-2.1 (m, 2H), 1.05 (d, 3H), 0.73 (d, 3H). MS calculated for C13H18BrNO+H: 284, observed: 284.
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:6]=2[CH2:5][CH2:4]1)[CH3:2].Cl[C:16]1[N:21]=[C:20]([NH:22][CH2:23][CH:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH3:25])[C:19]([Cl:31])=[CH:18][N:17]=1.Cl.O1CCOCC1>CC(O)C>[Cl:31][C:19]1[C:20]([NH:22][CH2:23][CH:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH3:25])=[N:21][C:16]([NH:14][C:11]2[CH:12]=[CH:13][C:6]3[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:9][CH2:8][C:7]=3[CH:10]=2)=[N:17][CH:18]=1
Reactant: CC(CNc1nc(Cl)ncc1Cl)NS(C)(=O)=O
Reactant: CCN1CCc2ccc(N)cc2CC1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(NCC(C)NS(C)(=O)=O)n3)cc2CC1
Temperature: 140 °C
Yield: 21.8 %

Procedure:
3-Ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (86.7 mg, 0.456 mmol, 1.0 eq) and N-[2-(2,5-dichloro-pyrimidin-4-ylamino)-1-methyl-ethyl]-methanesulfonamide (150 mg, 0.502 mmol, 1.1 eq) were dissolved in IPA (3 mL). 4.0 M HCl in dioxane (126 μL, 0.502 mmol, 1.1 eq) was added and the reaction was heated at 140° C. in a microwave for 90 minutes. The reaction was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 (20 mL) and washed with sat. NaHCO3 (20 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by amine capped silica gel chromatography using a gradient of 0-100% EtOAc/hex as the eluting solvent to obtain N-{2-[5-chloro-2-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-1-methyl-ethyl}-methanesulfonamide as a white foam (45 mg, 22%). LCMS (m/e) 453 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.95 (s, 1H), 7.32 (d, 1H, J=8.6 Hz), 7.06 (d, 1H, J=8.2 Hz), 6.93 (s, 1H), 5.72-5.62 (m, 1H), 5.41-5.31 (m, 1H), 3.81-3.65 (m, 2H), 3.55-3.43 (m, 1H), 2.99-2.86 (m, 4H), 2.90 (s, 3H), 2.74-2.60 (m, 4H), 2.60 (q, 2H, J=6.9 Hz), 1.32 (d, 3H, J=6.6 Hz), 1.12 (t, 3H, J=6.9 Hz).