Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]#[C:2]Br.[NH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[NH2:15])[C:8]([O:10]C)=[O:9].N.Cl>O.C(OCC)(=O)C>[NH2:1][C:2]1[NH:15][C:14]2[CH:13]=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=2[N:4]=1
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: N#CBr
Agent: Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1nc2cc(C(=O)O)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
A solution of cyanogen bromide (5.0 mL, 5 M in acetonitrile, 25 mmol) was added to a mixture of methyl 3,4-diaminobenzoate (3.0 g, 18 mmol) in water (50 mL). The reaction was stirred at room temperature overnight. Aqueous ammonia (20 mL) and ethyl acetate (100 mL) were added to the reaction mixture and the layers were separated. The organics were dried over sodium sulfate, filtered, and concentrated. To the crude residue was added 2 N aqueous hydrochloric acid (18 mL, 36.0 mmol) and the mixture was heated at reflux overnight. The reaction was concentrated to give the title compound (2.90 g, 97%). 1H NMR (400 MHz, DMSO-d6, δ): 8.75 (s, 2H), 7.84 (s, 1H), 7.77 (dd, J=1.2, 8.4 Hz, 1H), 7.38 (d, J=8.4 Hz, 1H).
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[CH2:12][N:13]1[CH2:20][CH2:19][C:16]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:17]#[N:18])[CH2:15][CH2:14]1.S(=O)(=O)(O)[OH:29].[OH-].[NH4+]>>[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][C:16]([NH:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:17]([NH2:18])=[O:29])[CH2:19][CH2:20]1
Reactant: O=S(=O)(O)O
Reactant: N#CC1(Nc2ccccc2)CCN(CC2CCc3ccccc3C2O)CC1
Agent: [NH4+]
Agent: [OH-]
Product: NC(=O)C1(Nc2ccccc2)CCN(CC2=Cc3ccccc3CC2)CC1
Temperature: 70 °C

Procedure:
A mixture of 1-[(1,2,3,4-tetrahydro-1-hydroxy-2-naphthalenyl)-methyl]-4-anilino isonipecotonitrile (5.0 g) and 90% sulfuric acid (60.0 g) is heated for 10 minutes at 70° C. The mixture is then stirred at room temperature for an additional hour. The reaction mixture is poured into ice-water, basified with ammonium hydroxide, and extracted with chloroform. Concentration of the dried chloroform solution followed by trituration with benzene yields the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[NH:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[Na+].[Na+].Br[C:31]1[CH:36]=[CH:35][N:34]([CH2:37][CH:38]2[CH2:40][CH2:39]2)[C:33](=[O:41])[C:32]=1[C:42]#[N:43]>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:38]1([CH2:37][N:34]2[CH:35]=[CH:36][C:31]([C:6]3[CH:5]=[CH:4][C:3]([NH:17][CH:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)=[C:2]([Cl:1])[CH:7]=3)=[C:32]([C:42]#[N:43])[C:33]2=[O:41])[CH2:39][CH2:40]1
Reactant: CC1(C)OB(c2ccc(NC3CCOCC3)c(Cl)c2)OC1(C)C
Reactant: N#Cc1c(Br)ccn(CC2CC2)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: N#Cc1c(-c2ccc(NC3CCOCC3)c(Cl)c2)ccn(CC2CC2)c1=O
Yield: 15.8 %

Procedure:
To a solution of intermediate 16 (0.57 g, 1.7 mmol) in 1,4-dioxane (2 ml) and a saturated solution of Na2CO3 (2 ml) was added intermediate 8 (0.43 g, 1.7 mmol). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.19 mg, 0.17 mmol). The reaction was then microwaved in a sealed tube at 150° C. for 10 minutes. The resulting cooled reaction mixture was then diluted with EtOAc and filtered through a pad of diatomaceous earth. The filtrate was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude reaction mixture was then purified by column chromatography (silica gel; DCM to DCM/EtOAc up to 30% as eluent). The desired fractions were collected and evaporated in vacuo to yield compound 2 (0.103 g, 16%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([O:32][CH2:33][O:34][CH3:35])[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:31][CH2:30][CH:29]([O:32][CH2:33][O:34][CH3:35])[CH2:28][CH2:27]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Reactant: COCOC1CCN(c2ccc(N)cc2C#N)CC1
Product: COCOC1CCN(c2ccc(NC(=O)c3cnn(-c4ccc(Cl)cc4)c3C)cc2C#N)CC1
Yield: 28.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.62 g) and 5-amino-2-(4-methoxymethoxypiperidin-1-yl) benzonitrile (0.63 g), the title compound (0.33 g) was obtained, melting point: 186–188° C.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12][C@H:11]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][C:32]([I:39])=[N:33][C:34]=2Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:40][C@@H:41]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:42][OH:43]>>[C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12][C@H:11]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][C:32]([I:39])=[N:33][C:34]=2[NH:40][C@@H:41]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:42][OH:43])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Reactant: N[C@H](CO)Cc1ccccc1
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(N[C@H](CO)Cc4ccccc4)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1

Procedure:
Prepared from ((2R,3R,4S,5S)-4-(benzoyloxy)-2-(6-chloro-2-iodo-9H-purin-9-yl)-5-[(ethylamino)carbonyl]-tetrahydro-3-furanyl benzoate (Preparation 19) and (2S)-2-amino-3-phenyl-1-propanol by the same method as Preparation 20. The title compound was obtained as a yellow foam.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[O:36]([CH2:38][C:39](Cl)=[O:40])[CH3:37]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([F:29])[C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:39](=[O:40])[CH2:38][O:36][CH3:37])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:35])[NH:14][C:15]=23)[CH2:33][CH2:34]1
Reactant: COCC(=O)Cl
Reactant: COc1cc(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f23) and commercially available methoxyl-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].N1C=CC=CC=1.[NH2:11][C:12]1[C:17]([OH:18])=[CH:16][C:15]([Cl:19])=[CH:14][N:13]=1>C(Cl)(Cl)Cl>[Cl:19][C:15]1[CH:16]=[C:17]2[O:18][C:1](=[O:2])[NH:11][C:12]2=[N:13][CH:14]=1
Reactant: Nc1ncc(Cl)cc1O
Reactant: O=C(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c2ncc(Cl)cc2o1
Temperature: 25 °C
Yield: 85 %

Procedure:
Phosgene is introduced at 40°-50° C., after the addition of 20 parts of pyridine, into a solution of 10 parts of 2-amino-3-hydroxy-5-chloropyridine in 200 parts of chloroform, and stirring is maintained for one hour at room temperature; the chloroform and the pyridine are evaporated off in a water-jet vacuum, and ice-water is added to the residue. The precipitate is filtered off and dried at 40°-50° C. in vacuo. There are obtained 10 parts of 6-chloro-oxazolo[4,5-b]pyridin-2-(3H)-one (85% of theory), m.p. 184°-186° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[N:16]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:19])=[O:18])=[CH:13][CH:12]=[C:11]([C:35]([F:38])([F:37])[F:36])[CH:10]=2)=[O:5])C.[OH-].[Na+].Cl>CO.C1COCC1>[CH2:28]([N:16]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[C:15]1[C:14]2[C:9](=[CH:10][C:11]([C:35]([F:37])([F:38])[F:36])=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2c(C(=O)O)cnc3cc(C(F)(F)F)ccc23)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.2 %

Procedure:
To a solution of 1.065 g (2.00 mmol) of the product from Example 1 in 4 mL of methanol/THF (1:1) was added 2 mL of 1N sodium hydroxide solution and the resulting mixture was stirred at 25° C. for 18 h. The reaction was then acidified with 1N HCl and extracted with ethyl acetate (200 mL). The organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was triturated with ethyl acetate/hexane (1:9) and filtered to provide 828 mg (82%) of the desired carboxylic acid as a white solid. Electrospray Mass Spec 517.1 (M+H)
Reaction SMILES: Br[C:2]1[C:3]([F:18])=[CH:4][C:5]([F:17])=[C:6]([C@:8]23[CH2:15][O:14][C@H:13]([CH3:16])[C@H:12]2[CH2:11][O:10][NH:9]3)[CH:7]=1.C(O)(=O)C>C1COCC1.[Zn]>[NH2:9][C@@:8]1([C:6]2[CH:7]=[CH:2][C:3]([F:18])=[CH:4][C:5]=2[F:17])[CH2:15][O:14][C@H:13]([CH3:16])[C@H:12]1[CH2:11][OH:10]
Reactant: C[C@H]1OC[C@]2(c3cc(Br)c(F)cc3F)NOC[C@H]12
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@H]1OC[C@@](N)(c2ccc(F)cc2F)[C@@H]1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
(3aR*,4R*,6aS*)-6a-(5-Bromo-2,4-difluorophenyl)-4-methylhexahydro furo[3,4-c]isoxazole (200 mg, 0.62 mmol) was dissolved in THF (10 mL). Zinc dust (0.49 g, 7.50 mmol) was added, followed by acetic acid (143 μl, 2.50 mmol) and the reaction was stirred at room temperature overnight. The reaction was filtered through Celite®, washing with MeOH and the filtrate was concentrated in vacuo. The residue was basified with saturated NaHCO3 and DCM added. The mixture was filtered and the layers separated. The aqueous layer was extracted with DCM (×2) and the combined organics were dried (MgSO4) and concentrated to leave the title compound (120 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].Br[CH2:19][C:20]1([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[O:24][CH2:23][CH2:22][O:21]1.O>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:19][C:20]3([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[O:21][CH2:22][CH2:23][O:24]3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: Fc1ccc(C2(CBr)OCCO2)cc1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC2(c3ccc(F)cc3)OCCO2)C1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (500 mg, 2.2 mmol) was dissolved in 5 mL of NMP. KOH (896 mg, 15 mmol) was added at RT under nitrogen atmosphere and the reaction mixture was stirred for 5 min. 2-Bromomethyl-2-(4-fluorophenyl)-1,3-dioxolane (886 mg, 3.4 mmol) was added and the reaction mixture was heated at 100° C. overnight. Water was added and the product was extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-2% MeOH:DCM.
Reaction SMILES: C(CCCCCCCCCCCCCCCCCO)(C(C(C(F)(F)F)(F)F)(F)F)(F)F.[C:32]([CH2:45][CH:46]([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][OH:68])I)([C:35]([C:38]([C:41]([F:44])([F:43])[F:42])([F:40])[F:39])([F:37])[F:36])([F:34])[F:33].[OH-].[K+].[H][H]>C(O)(=O)C.[Zn]>[C:32]([CH2:45][CH2:46][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][OH:68])([C:35]([C:38]([C:41]([F:42])([F:43])[F:44])([F:40])[F:39])([F:37])[F:36])([F:34])[F:33]
Reactant: [H][H]
Reactant: OCCCCCCCCCCCCCCCCCCCCC(I)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: OCCCCCCCCCCCCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: OCCCCCCCCCCCCCCCCCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
In a similar manner to the synthesis of C4F9(CH2)17OH above, C4F9CH2CHI(CH2)20OH was treated with zinc in glacial acetic acid to afford a mixture of the reduction product alcohols and acetates as well as their corresponding olefins. The mixture was treated essentially as described above with potassium hydroxide to hydrolyze the acetate esters and finally treated with hydrogen to remove the olefinic impurities and recrystallized from hexane. Approximately 16.8 g of white solids C4F9(CH2)22OH was obtained from this process with 98% purity as confirmed by GC/MS.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C@H:9]2[CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][NH:25][C:24]2=[O:29])=[CH:4][C:3]=1[F:30].[H-].[Na+].C1(O[C:40]#[N:41])C=CC=CC=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:10][C@H:9]2[CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:40]#[N:41])[C:24]2=[O:29])=[CH:4][C:3]=1[F:30]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN2CCCNC2=O)C1
Reactant: N#COc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN2CCCN(C#N)C2=O)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.5 %

Procedure:
To a solution of tert-butyl (6R,7R)-7-(4-chloro-3-fluorophenyl)-6-[(2-oxotetrahydropyrimidin-1(2H)-yl)methyl]-1,4-oxazepane-4-carboxylate (260 mg) in DMF (2.9 mL) was added sodium hydride (94.0 mg, 60% in oil) under ice-cooling, and the mixture was stirred at 0° C. for 1 hr, and at room temperature for 1 hr. Then, phenyl cyanate (210 mg) was added, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added distilled water, and the mixture was extracted with ethyl acetate. The obtained extract was washed with distilled water and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (147 mg).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[N:21]1([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][N:33]=2)[CH:29]=O)[CH:25]=[CH:24][CH:23]=[N:22]1>>[N:21]1([C:26]2[CH:27]=[C:28]([CH2:29][N:1]3[CH:2]([C:11]4[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=4[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]3=[O:9])[CH:31]=[CH:32][N:33]=2)[CH:25]=[CH:24][CH:23]=[N:22]1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccnc(-n2cccn2)c1
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1ccnc(-n2cccn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with 2-(1H-pyrazol-1-yl)isonicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.83 min.; [M+H]+: 407.11 g/mol.
Reaction SMILES: Br[C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[Li]CCCC.CN([CH:17]=[O:18])C>C1COCC1>[CH3:8][C:3]1[N:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:17]=[O:18]
Reactant: Cc1ncccc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ncccc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
To a solution of 3-bromo-2-methylpyridine (148; 10 g, 58.1 mmol) in THF (150 mL) was added n-BuLi (2.5 M, 25.6 mL) at −78° C. The reaction mixture was stirred at this temperature for 1 h. DMF (1.30 mL) was then added and the resulting reaction mixture was stirred for 1 h at −78° C. The reaction was quenched by the addition of aq. NH4Cl. Upon warming to room temperature, the mixture was extracted with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography to afford 2-methylnicotinaldehyde 149 (2.18 g, 31%).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:16])[CH:14]=[CH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][O:18][CH2:19][CH2:20][NH2:21]>C(#N)C>[C:1]([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:16])[CH2:14][CH2:15][N:21]([CH2:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[O:16])[CH2:20][CH2:19][O:18][CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Reactant: COCCN
Solvent: CC#N
Product: COCCN(CCC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C)CCC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Yield: 25.7 %

Procedure:
A solution of 1.0 g (4.44 mmol) (R)-1-acryloyl-pyrrolidine-2-carboxylic acid tert-butyl ester and 0.19 ml (2.22 mmol) 2-methoxyethylamine in 25 ml acetonitrile was stirred for 16 h at 80° C. Concentration in vacuo and flash chromatography (gradient: 0-10% MeOH in EtOAc) afforded 300 mg (23%) of the title compound as a light brown oil. MS m/e (%): 526 (M+H+, 100).
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.Cl.[NH:19]1[CH2:22][CH:21]([O:23][CH2:24][C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[CH2:20]1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[O:17]=[C:15]([N:19]1[CH2:22][CH:21]([O:23][CH2:24][C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[CH2:20]1)/[CH:14]=[CH:13]/[C:8]1[CH:7]=[C:6]2[C:11](=[N:10][CH:9]=1)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]2
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: c1csc(COC2CNC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCc2cc(/C=C/C(=O)N3CC(OCc4nccs4)C3)cnc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.6 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (60 mg, 0.24 mmol), DMF (5.8 mL), 2-[(azetidin-3-yloxy)methyl]-1,3-thiazole hydrochloride (99 mg, 0.48 mmol; which may be prepared as described in Step 3), DIPEA (119 μL, 0.72 mmol), DMAP (2.4 mg, 0.02 mmol) and EDAC (56 mg, 0.29 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was precipitated in methanol/water and then filtered. The resulting solid was purified on column chromatography (eluent: 96/4 dichloromethane/MeOH) then triturated in pentane and MeOH to give the title compound (21 mg, 24%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[C:18](=[O:20])[N:17]([CH3:21])[CH2:16]2.C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([O:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[C:18](=[O:20])[N:17]([CH3:21])[CH2:16]3)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CN1Cc2cccc(O)c2C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: CN1Cc2cccc(Oc3nc(Cl)ncc3Cl)c2C1=O
Temperature: 0 °C
Reaction time: 16 h

Procedure:
2,4,5-trichloropyrimidine (0.20 g) and 7-hydroxy-2-methyl-2,3-dihydro-isoindol-1-one are dissolved in DCM (10 mL), cooled to 0° C. and combined with caesium carbonate (0.75 g). The cooling bath is removed and the mixture is stirred for 16 h. For working up the mixture is combined with 10% NaCl solution (100 mL) and extracted three times with 75 mL ethyl acetate. The combined organic phases are dried on magnesium sulphate, filtered off from the desiccant and the solvent is eliminated in vacuo.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11].C([BH3-])#N.[Na+]>>[F:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][NH:3][O:2][CH3:1]
Reactant: CON=Cc1ccccc1F
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONCc1ccccc1F
Yield: 74 %

Procedure:
Reduction of 2-fluorobenzaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of Compound 44-B gave the title hydroxylamine as a clear oil (74% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.52 (3H, s, OCH3), 4.11 (2H, s, NCH2), 5.78 (1H, broad s, NH), 7.05 (1H, m, aromatic), 7.11 (1H, m, aromatic), 7.27 (1H, m, aromatic), 7.38 (1H, m, aromatic). The hydrochloride salt was obtained as a white solid: mp 138–143° C. (dec.). Anal. calcd. for C8H10FNO—HCl: C, 50.14; H, 5.78; N, 7.31. Found: C, 50.37; H, 5.71; N, 7.18.
Reaction SMILES: [CH2:1]([C:9]1[N:10]=[C:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[NH:15][C:14]3[N:22]=[CH:23][CH:24]=[CH:25][C:13]=3[N:12]2[CH:26]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:27]N1C(=O)CCC1=O>C1COCC1>[Br:27][C:26]1[N:12]2[C:13]3[CH:25]=[CH:24][CH:23]=[N:22][C:14]=3[NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:11]2=[N:10][C:9]=1[CH2:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(CCc2cn3c(n2)-c2ccccc2Nc2ncccc2-3)cc1
Solvent: C1CCOC1
Product: Brc1c(CCc2ccccc2)nc2n1-c1cccnc1Nc1ccccc1-2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.7 %

Procedure:
To a solution 2-phenethyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine (0.374 g, 1 eq.) in THF (50 mL) was added N-bromosuccinimide (0.206 g, 1.05 eq.). The reaction was stirred at room temperature for 30 minutes, poured onto water (100 mL) and extracted with dichloromethane (2×100 mL). The organic extracts were combined, washed with brine (1×50 mL) and dried over sodium sulfate. After filtration and concentration under reduced pressure, the crude product, 3-bromo-2-phenethyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine (0.197 g, 42%) was obtained as an orange solid. LCMS: 419 [M+H].
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:12]([S-:14])[CH3:13].[Na+]>CN(C)C=O>[CH2:12]([S:14][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:13]
Reactant: Brc1cnc2ccccc2c1
Reactant: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCSc1cnc2ccccc2c1

Procedure:
3-Ethylthioquinoline is prepared starting from 2.1 g of 3-bromoquinoline and 4.2 g of sodium ethanethiolate in 30 ml of dimethylformamide analogously to Example 52d) and is purified by means of FC over 30 g of silica gel with a 1:2 mixture of diethyl ether and petroleum ether as the mobile phase. This gives the title compound: Rf (F)=0.31.