Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[N:13]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([S:23](Cl)(=[O:25])=[O:24])[C:17]=2[N:16]=[CH:15][CH:14]=1.N1C=CC=CC=1.C(Cl)Cl>CCOC(C)=O>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=1[NH:1][S:23]([C:18]1[C:17]2[N:16]=[CH:15][CH:14]=[N:13][C:22]=2[CH:21]=[CH:20][CH:19]=1)(=[O:24])=[O:25]
Reactant: O=S(=O)(Cl)c1cccc2nccnc12
Reactant: COC(=O)c1ccc(Cl)cc1N
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nccnc12
Yield: 0.1 %

Procedure:
A solution of methyl 2-amino-4-chlorobenzoate (0.33 g, 1.8 mmol), quinoxaline-5-sulfonyl chloride (0.40 g, 1.8 mmol), pyridine (0.71 mL, 8.8 mmol), and DCM (10 mL) was stirred at rt for 16 h. EtOAc (75 mL) was added and the solution was washed with satd. aq. NaHCO3 (50 mL), then dried and concentrated. Chromatographic purification of this residue (EtOAc/hexanes) gave the title compound as a white solid (0.60 mg, 90%). MS (ESI+): mass calcd. for C16H12ClN3O4S, 377.0; m/z found, 378 [M+H]+. 1H NMR (400 MHz, CDCl3): 11.44 (s, 1H), 8.97 (d, J=1.8, 1H), 8.95 (d, J=1.8, 1H), 8.61 (dd, J=7.4, 1.4, 1H), 8.33 (dd, J=8.5, 1.4, 1H), 7.89 (dd, J=8.4, 1.0, 1H), 7.84 (d, J=2.0, 1H), 7.77 (d, J=8.6, 1H), 6.89 (dd, J=8.6, 2.0, 1H), 3.90 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[C:16](=[O:20])[CH2:17][CH2:18][CH3:19].Cl.ClCCN1CCCC1>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][CH2:15][CH2:14]2)[CH:5]=[CH:4][C:3]=1[C:16](=[O:20])[CH2:17][CH2:18][CH3:19]
Reactant: CCCC(=O)c1ccc(OCCN(CC)CC)cc1Cl
Agent: Cl
Agent: ClCCN1CCCC1
Product: CCCC(=O)c1ccc(OCCN2CCCC2)cc1Cl

Procedure:
This compound is prepared by essentially the same procedure as described in Example 1 Step A except that the 2-diethylaminoethyl chloride hydrochloride of Example 1 Step A is replaced by an equimolecular quantity of N-(2-chloroethyl)pyrrolidine hydrochloride. The product is obtained as a pale yellow oil upon distillation in vacuo (0.3 mm.).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH:15]([CH3:17])[CH3:16])=[C:8]2[C:3]=1[C:4](=[O:24])[C:5]([C:21]([OH:23])=[O:22])=[CH:6][N:7]2[CH:18]1[CH2:20][CH2:19]1.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][CH2:32][CH2:33][NH2:34].C(N(CC)CC)C.[NH4+].[Cl-]>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:34][CH2:33][CH2:32][NH:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=2)[C:9]([O:14][CH:15]([CH3:16])[CH3:17])=[C:8]2[C:3]=1[C:4](=[O:24])[C:5]([C:21]([OH:23])=[O:22])=[CH:6][N:7]2[CH:18]1[CH2:19][CH2:20]1
Reactant: NCCNc1ccccn1
Reactant: CC(C)Oc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)Oc1c(NCCNc2ccccn2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
A solution of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-isopropoxy-4-oxoquinoline-3-carboxylic acid (100 mg, 0.296 mmol), N-2-pyridyl-1,2-ethanediamine (60.9 mg, 0.444 mmol) and triethylamine (0.0619 mL, 0.444 mmol) in DMSO (3 mL) was stirred at 100° C. for 8 h. After the reaction mixture was poured into ice-water, NH4Cl was added and stirred for 30 min. The resulting precipitate was collected by filtration in vacuo and washed with water. The crude product was purified by preparative thin layer chromatography (Hexane:EtOAc 1:4) to yield 5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-isopropoxy-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-3-carboxylic acid (80.6 mg, 60%) as a pale yellow amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[N:5][N:6]=1.[CH3:14][N:15]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][N:17]=[C:16]1[CH:23]=O.CCOCC>C(O)(=O)C.C(OC(=O)C)(=O)C.[Cl-].[Cl-].[Zn+2]>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[S:3][C:2]([CH:1]=[CH:23][C:16]3[N:15]([CH3:14])[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][N:17]=3)=[N:6][N:5]=2)=[CH:8][CH:9]=1
Reactant: Cc1nnc(-c2ccc(Cl)cc2)s1
Reactant: Cn1c([N+](=O)[O-])cnc1C=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: Cn1c([N+](=O)[O-])cnc1C=Cc1nnc(-c2ccc(Cl)cc2)s1
Yield: 79.3 %

Procedure:
21 g of 2-methyl-5-(4-chlorophenyl)-1,3,4-thiadiazole and 22.8 g of 1-methyl-5-nitroimidazol-2-carboxaldehyde are heated with 0.5 g of ZnCl2 in a mixture of 100 ml of acetic acid and 50 ml acetic anhydride for 5 hours at reflux temperature. After cooling, ether is added to the reaction mixture, and the precipitated solid is washed with water and recrystallized from dimethylformamide. 27.5 g of product of obtained, corresponding to 77% of the theory. The compound melts at 268° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[O:21][C:20]3[C:11](=[CH:12][C:13]4[CH2:14][C@@H:15]([C:31](O)=[O:32])[N:16]([C@@H:22]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:23][CH3:24])[CH2:17][C:18]=4[CH:19]=3)[N:10]([CH3:34])[C:9]2=[O:35])=[CH:4][CH:3]=1.Cl.[CH3:37][O:38][C:39](=[O:57])[C@@H:40]([NH2:56])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([C:54]#[N:55])=[CH:50][CH:49]=2)=[CH:44][CH:43]=1>>[CH3:37][O:38][C:39](=[O:57])[C@@H:40]([NH:56][C:31]([C@@H:15]1[CH2:14][C:13]2[CH:12]=[C:11]3[C:20]([O:21][C@H:8]([C:5]4[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=4)[C:9](=[O:35])[N:10]3[CH3:34])=[CH:19][C:18]=2[CH2:17][N:16]1[C@@H:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:23][CH3:24])=[O:32])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][C:51]([C:54]#[N:55])=[CH:50][CH:49]=2)=[CH:44][CH:43]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: CC[C@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)N(C)C(=O)[C@@H](c1ccc(O)cc1)O3
Agent: Cl
Product: CC[C@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)OC)N(C)C(=O)[C@@H](c1ccc(O)cc1)O3

Procedure:
(S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester (68 mg) was prepared from (3R,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((R)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylic acid (100 mg) and (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester hydrochloride following general procedure A.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:2][CH2:3][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.4 %

Procedure:
To a solution of indole-6-carboxylic acid methyl ester (20.0 g, 114 mmol) in anhydrous tetrahydrofuran (1.6 L) stirring under nitrogen at room temperature was added carefully lithium aluminum hydride (8.7 g, 230 mmol) while purging with nitrogen. Following this addition, the reaction mixture was stirred at room temperature for 3 hours and was then cooled to 0° C. This mixture was treated sequentially with water (9 mL), 15% sodium hydroxide (9 mL), and additional water (25 mL). The resulting suspension was filtered and the filtrate concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 30%-60% ethyl acetate in hexanes. Fractions containing product were combined and concentrated under reduced pressure to provide 16.0 g (95%) of the desired compound as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]([CH:13]2[CH2:16][CH2:15][CH2:14]2)=[O:12])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:17]([O:20][CH2:21][C:22]1[C:23]([N:31]2[CH2:42][CH2:41][N:40]3[C:33](=[CH:34][C:35]4[CH2:36][C:37]([CH3:44])([CH3:43])[CH2:38][C:39]=43)[C:32]2=[O:45])=[N:24][CH:25]=[CH:26][C:27]=1B(O)O)(=[O:19])[CH3:18].CC([O-])=O.[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[C:17]([O:20][CH2:21][C:22]1[C:23]([N:31]2[CH2:42][CH2:41][N:40]3[C:33](=[CH:34][C:35]4[CH2:36][C:37]([CH3:44])([CH3:43])[CH2:38][C:39]=43)[C:32]2=[O:45])=[N:24][CH:25]=[CH:26][C:27]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]([CH:13]2[CH2:16][CH2:15][CH2:14]2)=[O:12])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: Cn1cc(Br)cc(NC(=O)C2CCC2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(NC(=O)C3CCC3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C
Yield: 44.8 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 101a (230 mg, 0.80 mmol), {3-[(acetyloxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid (320 mg, 0.80 mmol), Pd(dppf)Cl2 (42 mg, 0.050 mmol), NaOAc (82 mg, 1.0 mmol), K3PO4.3H2O (266 mg, 1.0 mmol), water (5 drops) and acetonitrile (6 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 1 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 20:1 dichloromethane/methanol to afford 101b (200 mg, 56%) as a brown solid. MS-ESI: [M+H]+ 558.3
Reaction SMILES: C1COCC1.[CH:6]1([Mg]Br)[CH2:8][CH2:7]1.Br[C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]=1.C(=O)(O)[O-].[Na+]>[Cl-].[Zn+2].[Cl-].Cl[Pd]Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([CH:6]2[CH2:7][CH2:8]2)=[N:13][CH:14]=1
Reactant: Brc1ccc(Br)nc1
Reactant: Br[Mg]C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: Brc1ccc(C2CC2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
0.5M Zinc chloride in THF (5.5 mL, 2.8 mmol) was added to a solution of 0.5M cyclopropylmagnesium bromide in THF (5.5 mL, 2.8 mmol) under argon. The solution was stirred at RT for 2 h at which time a slurry had formed. To this slurry was added in one portion 2,5-dibromopyridine (0.65 g, 2.8 mmol) and PdCl2×dppf (0.041 g, 0.050 mmol). After a few minutes an exotherm was seen and the slurry became thicker, the exotherm subsided and the slurry was stirred at RT overnight. The reaction mixture was poured into saturated sodium bicarbonate solution and extracted with ether. The ether phase was dried, filtered and concentrated, then re-dissolved in DCM and applied to a short plug of silica gel. The gel was washed with DCM and the washings were concentrated. The residue was taken up in ether and washed with 1.0M hydrochloric acid. The acidic water phase was made basic with 2.0M sodium hydroxide and the product was extracted back into ether. The combined ether phases were washed with brine, dried, filtered and concentrated to give 0.28 g (50%) of 5-bromo-2-cyclopropylpyridine as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:30])[N:6]2[CH:22]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[CH3:23].Cl.[F:32][C:33]1([F:37])[CH2:36][NH:35][CH2:34]1>>[F:32][C:33]1([F:37])[CH2:36][N:35]([C:2]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[N:8]=[C:7]3[C:3]=2[NH:4][C:5](=[O:30])[N:6]3[CH:22]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH3:23])[CH2:34]1
Reactant: FC1(F)CNC1
Reactant: CC(c1cccnc1)n1c(=O)[nH]c2c(Cl)nc(-n3cnc4ccc(C#N)cc43)nc21
Agent: Cl
Product: CC(c1cccnc1)n1c(=O)[nH]c2c(N3CC(F)(F)C3)nc(-n3cnc4ccc(C#N)cc43)nc21
Yield: 57 %

Procedure:
White semi-solid. 57% yield. Synthesized from 3-(6-chloro-8-oxo-9-(1-(pyridin-3-yl)ethyl)-8,9-dihydro-7H-purin-2-yl)-3H-benzo[d]imidazole-5-carbonitrile (19 mg, 0.046 mmol) and 3,3-difluoroazetidine hydrochloride (3 equiv.) following the general procedure for displacement reactions of 6-chloropurinones with aliphatic amines. 1H NMR (300 MHz, CD3OD) δ, ppm: 9.27 (s, 1H), 9.20-9.00 (br m, 1H), 8.78 (d, 1H), 8.88-8.77 (m, 1H, overlapping with 8.78 ppm), 8.63 (s, 1H), 8.09 (br s, 1H), 7.88 (d, 1H), 7.67 (d, 1H), 6.13 (q, J=7.1 Hz, 1H), 4.78 (t, 4H), 2.16 (d, J=7.1 Hz, 3H); MS (EI) m/z 474.0 (MH)+.
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:21]=1)=[O:18]>>[CH3:15][CH:16]([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]2[CH2:31][CH2:30][N:29]([CH2:11][C:10]3[CH:13]=[CH:14][C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:8][CH:9]=3)[CH2:28][CH2:27]2)[CH:21]=1)=[O:18]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(N4CCOCC4)cc3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 4-(4-morpholinyl)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 422.5 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH:7]1[CH:12]=CC=C[CH:8]=1>CC(C)=O>[CH3:8][C:7]1([CH3:12])[NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][O:4]1
Reactant: c1ccccc1
Reactant: CC(C)(N)CO
Solvent: CC(C)=O
Product: CC1(C)COC(C)(C)N1
Yield: 57 %

Procedure:
Firstly, the precursor compound (2,2,4,4-tetramethyl-1,3-oxazolidine was prepared. To 237 g (3.0 mole) of 2-amino-2-methyl-1 -propanol, there was added approximately 750 ml of dry benzene containing 174 g (3.0 mole) of acetone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:33]([F:36])([F:35])[F:34])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:31])[C:15]([NH:17][C:18]3[CH:30]=[CH:29][C:21]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:20][CH:19]=3)=[O:16])[C:10](=[O:32])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:33]([F:36])([F:34])[F:35])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:31])[C:15]([NH:17][C:18]3[CH:30]=[CH:29][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=3)=[O:16])[C:10](=[O:32])[CH:9]=2)[CH:7]=1
Reactant: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1ccc(-c2cc(Cl)ccc2C(F)(F)F)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C(=O)Nc1ccc(C(=O)O)cc1)n1ccc(-c2cc(Cl)ccc2C(F)(F)F)cc1=O

Procedure:
104 mg (0.20 mmol) of tert-butyl 4-[(2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}propanoyl)amino]benzoate (racemate) (Example 2.11C) were hydrolysed with TFA according to General Method 2. Yield: 67 mg (73% of theory)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C:8]2[N:13]=[N:12][C:11]([NH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])([CH3:17])[CH3:16])=[N:10][CH:9]=2)[CH:7]=1.[CH3:26][N:27](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.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>[F:25][C:5]1[CH:4]=[CH:3][C:2]([C:26]#[N:27])=[CH:7][C:6]=1[C:8]1[N:13]=[N:12][C:11]([NH:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])([CH3:17])[CH3:16])=[N:10][CH:9]=1
Reactant: CN(C)C=O
Reactant: CC(C)(Nc1ncc(-c2cc(Br)ccc2F)nn1)c1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC(C)(Nc1ncc(-c2cc(C#N)ccc2F)nn1)c1ccccc1F
Temperature: 100 °C

Procedure:
6-(5-Bromo-2-fluorophenyl)-N-(2-(2-fluorophenyl)propan-2-yl)-1,2,4-triazin-3-amine (2.2 g, 5.6 mmol), zinc cyanide (0.72 g, 6.2 mmol), Pd(PPh3)4 (2.9 g, 2.8 mmol), and DMF (20 mL) were combined and heated in a round bottom flask at 100° C. for 2 h. The reaction mixture was diluted with EtOAc and washed with satd. aq. NaHCO3 and brine. The organic layer was dried over sodium sulfate, filtered, concentrated and purified using silica gel chromatography to provide a yellow solid (1.7 g), m/z=352.1 [M+H].
Reaction SMILES: C(OC(N1C[CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[O:31](CCN)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[O:31]([CH2:11][CH2:10][NH:13][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NCCOc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: O=C(NCCOc1ccccc1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 2-phenoxyethylamine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 379 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.93 (1H, br. s.) 10.42 (1H, s) 8.34 (1H, t, J=5.47 Hz) 8.04 (1H, d, J=6.15 Hz) 7.85 (1H, d, J=5.37 Hz) 7.42 (1H, d, J=5.37 Hz) 7.37 (1H, d, J=3.51 Hz) 7.21-7.28 (2H, m) 6.89-6.97 (1H, m) 6.87 (2H, dd, J=8.74, 1.02 Hz) 6.77 (1H, d, J=6.25 Hz) 6.58 (1H, d, J=3.32 Hz) 4.04 (2H, t, J=5.95 Hz) 3.60 (2H, q, J=5.92 Hz)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20].C(OCC)(=O)C>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:11][CH2:10][N:9]2[C:19](=[O:21])[CH3:20])=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Brc1ccc(C2CCN2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 48.7 %

Procedure:
To a mixture of 2-(4-bromophenyl)azetidine (200 mg, 0.808 mmol) and triethylamine (98 mg, 0.97 mmol) in anhydrous dichloromethane (6 mL) was added acetic anhydride (200 mg, 0.97 mmol). The mixture was stirred at rt for 5 hours. The mixture was poured into ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (100 mg, 49% yield) as a yellow oil that was taken on without further purification.
Reaction SMILES: [ClH:1].[O:2]1[C:11]2[CH:10]=[C:9]([CH2:12][NH:13][CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][N:22]4[C:31]5[C:26](=[N:27][C:28]([CH3:33])=[C:29](F)[CH:30]=5)[CH:25]=[CH:24][C:23]4=[O:34])[CH2:16][CH2:15]3)[N:8]=[CH:7][C:6]=2[O:5][CH2:4][CH2:3]1.[C:35](=O)([O-])[OH:36].[Na+]>C(Cl)(Cl)Cl>[ClH:1].[O:2]1[C:11]2[CH:10]=[C:9]([CH2:12][NH:13][CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][N:22]4[C:31]5[C:26](=[N:27][C:28]([CH3:33])=[C:29]([O:36][CH3:35])[CH:30]=5)[CH:25]=[CH:24][C:23]4=[O:34])[CH2:16][CH2:15]3)[N:8]=[CH:7][C:6]=2[O:5][CH2:4][CH2:3]1
Reactant: Cc1nc2ccc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2cc1F
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1cc2c(ccc(=O)n2CCN2CCC(NCc3cc4c(cn3)OCCO4)CC2)nc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 0.16 g of 1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-6-methyl-1,5-naphthyridin-2(1H)-one hydrochloride, chloroform and a saturated aqueous sodium hydrogen carbonate solution were added, the organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the residue, 2.6 mL of methanol and 0.15 mL of a 28% sodium methoxide/methanol solution were added, and the mixture was heated under reflux while stirring for 2 hours. The reaction mixture was cooled to room temperature, thereto were added chloroform and a saturated aqueous sodium hydrogen carbonate solution, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the resultant residue, 1.4 mL of isopropyl alcohol and 93 μL of concentrated hydrochloric acid were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled with ice, and the solid was filtered off to obtain 0.15 g of 1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-6-methyl-1,5-naphthyridin-2(1H)-one hydrochloride as a white solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:26]=[O:27])[C:20]([OH:25])=[C:21]([CH:23]=[O:24])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:16][C:17]1[CH:18]=[C:19]([CH:26]=[O:27])[C:20]([O:25][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:21]([CH:23]=[O:24])[CH:22]=1
Reactant: Cc1cc(C=O)c(O)c(C=O)c1
Reactant: BrCCCCCCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C=O)c(OCCCCCCCCc2ccccc2)c(C=O)c1
Temperature: 80 °C

Procedure:
8-Phenyloctyl bromide (2.69 g, 10 mmol) was added to a stirred mixture of 5-methyl-2-hydroxy-1,3-benzenedicarboxaldehyde (1.64 g, 10 mmol) and anhydrous potassium carbonate (1.38 g, 10 mmol) in dry dimethylformamide (20 ml) at room temperature under nitrogen. The suspension was heated to 80° C. for 3 hours then allowed to cool. Water (40 ml) was added and the mixture extracted with diethyl ether (2×40 ml). The extracts were dried, filtered and evaporated to a yellow solid. Recrystallisation from methanol (25 ml) gave the title product as pale yellow crystals, m.p. 59° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.[C:11]1([NH:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23]Br)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[C:11]1([NH:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23][NH:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(NCCCBr)Nc1ccccc1
Reactant: NCCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(NCCCNCCc1ccc(Cl)cc1)Nc1ccccc1
Temperature: 70 °C
Reaction time: 4.5 h
Yield: 44.4 %

Procedure:
2(4-Chlorophenyl)ethylamine (1.8 g, 12 mmol) was added to a mixture of N-phenylcarbamoyl-3-bromopropylamine (2.5 g, 9.7 mmol) and potassium carbonate (2.6 g, 19 mmol) in CH3CN (50 ml). The mixture was stirred at 70° C. for 4.5 h, and then filtered. The filtrate was concentrated under vacuum to dryness, and the residue was dissolved with chloroform, washed with water, 1N-HCl and brine. The organic layer was dried over sodium sulfate, filtered, and then concentrated under vacuum to dryness. The residue was chromatographed on silica gel (eluting with 2% methanol/chloroform) to afford N-phenylcarbamoyl-N′-[2-(4- chlorophenyl)ethyl]-1,3- diaminopropane (1.43 g, 45%): MS(ES+) m/e 332 M+; 1H NMR (400 MHz, CD3OD) δ 7.35-7.15 (m, 8H), 6.99 (m, 1H), 3.31 (m, 2H), 3.23 (m, 2H), 3.06 (t, J=7.1 Hz, 2H), 3.00 (m, 2H), 1.89 (m, 2H).
Reaction SMILES: [Cl:1][CH2:2][S:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[Cl:14])(=[O:5])=[O:4].[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[Cl:14][C:8]1[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=1[N:6]([S:3]([CH2:2][Cl:1])(=[O:4])=[O:5])[C:15](=[O:17])[CH3:16]
Reactant: O=S(=O)(CCl)Nc1ccc(F)cc1Cl
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N(c1ccc(F)cc1Cl)S(=O)(=O)CCl
Yield: 80 %

Procedure:
77.5 g (0.3 mol) of 1-chloro-N-(2-chloro-4-fluorophenyl)methanesulfonamide were dissolved in 204.2 g (2 mol) of acetic anhydride and refluxed for 4 hours. The excess acetic anhydride was distilled off under reduced pressure at 100° C. To the still hot residue was added ethanol with stirring and the product precipitated (seeding may aid in crystallization). The crude product was filtered off and washed with cold ethanol and dried to yield 72 g (80%) of the title compound as a solid melting at 89-92° C.