Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][C:5]2[C:6]([CH:21]=1)=[N:7][C:8]1[N:9]([NH:19][CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[CH3:23][CH:24]1[CH2:29][NH:28][CH2:27][CH2:26][NH:25]1>N1C=CC=CC=1>[F:22][C:3]1[C:2]([N:28]2[CH2:27][CH2:26][NH:25][CH:24]([CH3:23])[CH2:29]2)=[CH:21][C:6]2=[N:7][C:8]3[N:9]([NH:19][CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=3[CH:14]=[C:5]2[CH:4]=1
Reactant: CNn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reactant: CC1CNCCN1
Solvent: c1ccncc1
Product: CNn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNC(C)C4)cc3nc21

Procedure:
7-Fluoro-1-methylamino-8-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under the conditions of Reference Example 5 but starting from 3.2 g of 8-chloro-7-fluoro-1-methylamino-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 4 g of 2-methylpiperazine in 40 cm3 of pyridine. The crude product obtained is taken up in 30 cm3 of water and 7 cm3 of 2N aqueous potassium hydroxide solution. A very small amount of insoluble matter is removed by filtration through diatomaceous silica. The filtrate is washed with twice 20 cm3 of diethyl ether and the product is then precipitated by adding 3.5 cm3 of 4N methanesulphonic acid. The precipitate obtained is drained and washed with 3 times 20 cm3 of water and 3 times 20 cm3 of ethanol 2.2 g of 7-fluoro-1-methylamino-8-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a deep yellow solid melting at 343°-345° C., solvated by 3.7% of water.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([CH:19]=[O:20])[CH:3]=1.Cl([O-])=[O:22].[Na+].CC(=CC)C.P([O-])([O-])(O)=O.[Na+].[Na+].Cl>C(O)(C)(C)C.O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([OH:22])=[O:20])[CH:3]=1
Reactant: COc1c(Cl)ccc(-c2nc(C=O)cc(N)c2F)c1F
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: Cl
Agent: O=P([O-])([O-])O
Solvent: O
Solvent: CC(C)(C)O
Product: COc1c(Cl)ccc(-c2nc(C(=O)O)cc(N)c2F)c1F
Temperature: 80 °C

Procedure:
In a typical reaction, 4-amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinaldehyde is oxidized with an excess of sodium chlorite, between 20-30 equivalents of 2-methyl-2-butene and about 5 equivalents of disodium hydrogen phosphate in a t-butanol/water mixture. The mixture is heated at about 80° C. until the reaction is complete. After cooling, the mixture is treated with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer is separated and dried. The solvent is evaporated to provide crude 4-amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinic acid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]([CH3:18])[CH:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[NH:11][C:10]([CH3:17])([CH3:16])[CH2:9]2)=[N:4][N:3]=1.[CH3:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([CH:25]=[CH:26][CH:27]=[N:28]2)=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].Cl.O1CCOCC1>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.C(COC)OC.O>[CH3:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([CH:25]=[CH:26][CH:27]=[N:28]2)=[CH:23][C:22]=1[C:2]1[S:6][C:5]([N:7]([CH3:18])[CH:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[NH:11][C:10]([CH3:17])([CH3:16])[CH2:9]2)=[N:4][N:3]=1
Reactant: COc1cc2ncccc2cc1B(O)O
Reactant: CN(c1nnc(Br)s1)C1CC(C)(C)NC(C)(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: COCCOC
Solvent: O
Product: COc1cc2ncccc2cc1-c1nnc(N(C)C2CC(C)(C)NC(C)(C)C2)s1
Temperature: 140 °C
Yield: 84.2 %

Procedure:
In a microwave tube, a mixture of 5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (Intermediate 4) (100 mg, 0.300 mmol), (7-methoxyquinolin-6-yl)boronic acid (˜50% by weight, 171 mg, 0.420 mmol) and sodium carbonate (95 mg, 0.90 mmol) in 3:1 dimethoxyethane/water (2.5 mL) was degassed with a dry stream of nitrogen for five minutes. Tetrakis(triphenylphosphine)palladium(0) (34.7 mg, 0.030 mmol) was added and the mixture heated in a microwave at 140° C. for 30 min. The mixture was diluted with water and extracted with DCM (6×). HCl in dioxane (1 M, 1.2 mL, 1.2 mmol) was added and the solution concentrated to dryness. SCX purification (2 g column, 7 M ammonia in MeOH elution) provided a brown residue which was further purified by flash column chromatography (12 g silica gel, 1-17% 1.4 N ammonia in MeOH gradient in DCM over 30 column volumes) to provide 5-(7-methoxyquinolin-6-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine as a yellow solid (104 mg, 84%). MS=412.3 (M+1), Rt=0.45 min [Method D]. 1H NMR (400 MHz, METHANOL-d4) ppm 8.83 (dd, J=4.3, 1.8 Hz, 1H), 8.71 (s, 1H), 8.42 (d, J=8.1 Hz, 1H), 7.57 (s, 1H), 7.48 (dd, J=8.3, 4.3 Hz, 1H), 4.43-4.57 (m, 1H), 4.16 (s, 3H), 3.11 (s, 3H), 1.81 (dd, J=12.6, 3.0 Hz, 2H), 1.58 (t, J=12.4 Hz, 2H), 1.37 (s, 6H), 1.25 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:31])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([N+:24]([O-])=O)[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:27][CH:28]([F:30])[F:29])=[CH:13][CH:12]=1)=[O:10].[Cl-].[NH4+]>[Zn].C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:31])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH2:24])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:27][CH:28]([F:29])[F:30])=[CH:13][CH:12]=1)=[O:10]
Reactant: O=C(Nc1c(Cl)cncc1Cl)c1ccc(OC(F)F)c2oc3ccc([N+](=O)[O-])cc3c12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Product: Nc1ccc2oc3c(OC(F)F)ccc(C(=O)Nc4c(Cl)cncc4Cl)c3c2c1
Temperature: 95 °C

Procedure:
Third, N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-aminodibenzo[b,d]furan-1-carboxamide was prepared by reacting N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide (prepared using the procedure of Example 4) with zinc. In particular, to a 250 mL 2-necked round bottom flask was added N′-(3,5-dichloropyrid-4-yl)-4-difluoro methoxy-8-nitro-dibenzo[b,d]furan-1-carboxamide (1.00 g, 2.14 mmol), sat.aq. ammonium chloride (30.0 mL), ethanol (10.0 mL) and zinc (0.84 g, 12.82 mmol). The reaction mixture was heated to 95° C. over the weekend. The solvent was removed in vacuo, DMF (14 mL) was added to the residue and heated to 50-55° C. until dissolution. The hot solution was filtered, washed with DMF (4 mL) and poured onto water (100 mL). The precipitate was filtered, washed with water (20 mL) and dried in a vacuum oven to yield the amine as a pale yellow solid (0.73 g, 79.4%). Purity 86.31% by HPLC.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][NH:7][C:8](=[O:17])[C:9]1[CH:14]=[C:13]([I:15])[CH:12]=[CH:11][C:10]=1[NH2:16])[CH3:2].FC(F)(F)C(O)=O.CN1C2C=CC(C#CCCCN)=CC=2C(=O)N(CCC(O)=O)CC1=O.N1C(C)=CC=CC=1C.Cl[CH:60]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][NH:7][C:8](=[O:17])[C:9]1[CH:14]=[C:13]([I:15])[CH:12]=[CH:11][C:10]=1[NH:16][CH:60]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[CH3:2]
Reactant: ClC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CCNC(=O)c1cc(I)ccc1N
Agent: CN1C(=O)CN(CCC(=O)O)C(=O)c2cc(C#CCCCN)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)c1cc(I)ccc1NC(c1ccccc1)c1ccccc1
Temperature: 50 °C
Yield: 56.2 %

Procedure:
A magnetically stirred solution of 1.1 gram of N-(2-amino-5-iodobenzoyl)-b-alanine ethyl ester (3.1 mmol), prepared by the method shown in part (b) of Example 1, 0.48 mL of 2,6-lutidine (4.1 mmol), 1.2 grams of chlorodiphenylmethane (4.7 mmol), and 10 mL of dimethylformamide was heated to 50° C. for 1 hour. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The resulting oil was dissolved in 35 mL of methylene chloride and washed with 2×50 mL 10% citric acid, 1×50 mL water, dried over sodium sulfate, decanted and concentrated in vacuo. The resulting oil was further purified by column chromatography, using silica gel, eluting with a solvent gradient of 10/90 ethyl acetate/hexane to 25/75 ethyl acetate/hexane (TLC, SiO2, 1:1 EtOAc/hexane, Rf =0.82, uv positive) to yield 0.92 gram (56%) of N-(2-diphenylmethylamino-5-iodobenzoyl)-b-alanine ethyl ester. 1H NMR (CDCl3, dTMS) 8.40 (1H, d, 3JHH =5 Hz, NHCHAr2), 7.56 (1H, d, 3JHH =2 Hz, ArH o-CON), 7.18-7.36 (11H, m, 4JHH =2 Hz, ArH Ph, ArH p-CON), 6.73 (1H, t, 3JHH =6 Hz, NHCH2), 6.29 (1H, d, 3JHH =9 Hz, ArH m-CON), 5.52 (1H, d, 3JHH =5 Hz, CHNH), 4.15 (2H, q, 3JHH =7 Hz, OCH2), 3.61 (2H, q, 3JHH =6 Hz, CH2NH), 2.58 (2H, t, 3JHH =6 Hz, CH2CO), 1.25 (3H, t, 3JHH =6 Hz, CH3CH2O).
Reaction SMILES: C(=[N:14][C:15]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:22]2[C:17](=[CH:18][C:19]([S:32][C:33]3[CH:34]=[C:35]([C:39]4([C:45]#[N:46])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)[CH:36]=[CH:37][CH:38]=3)=[CH:20][CH:21]=2)[N:16]=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.NO.C([O-])(=O)C.[K+]>CO>[NH2:14][C:15]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:22]2[C:17](=[CH:18][C:19]([S:32][C:33]3[CH:34]=[C:35]([C:39]4([C:45]#[N:46])[CH2:40][CH2:41][O:42][CH2:43][CH2:44]4)[CH:36]=[CH:37][CH:38]=3)=[CH:20][CH:21]=2)[N:16]=1
Reactant: N#CC1(c2cccc(Sc3ccc4c(-c5ccc(F)cc5)cc(N=C(c5ccccc5)c5ccccc5)nc4c3)c2)CCOCC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: CO
Product: N#CC1(c2cccc(Sc3ccc4c(-c5ccc(F)cc5)cc(N)nc4c3)c2)CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3d (300 mg, 0.48 mmol), hydroxylamine hydrochloride (67 mg, 0.97 mmol), and potassium acetate (92 mg, 0.97 mmol) was dissolved in MeOH (10 mL) and stirred overnight at room temperature. The reaction was concentrated and purified by silica gel chromatography (30% EtOAc in hexanes) to obtain the desired product, 3e.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:10]([C:13]#[N:14])[C:11]#[N:12].[OH-].[Na+].S(OC)(O[CH3:21])(=O)=O>O>[CH3:21][N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1][C:2]1=[C:10]([C:13]#[N:14])[C:11]#[N:12]
Reactant: N#CC(C#N)=C1Nc2ccccc2O1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1C(=C(C#N)C#N)Oc2ccccc21
Reaction time: 1 h

Procedure:
9.15 g. (0.05 M) of 2-benzoxazolinylidene-malononitrile and 16.0 g. (0.4 M) of sodium hydroxide are dissolved in 500 ml. of water. The solution is brought to 5° C. while stirring and, over a period of 1 hour, 25.2 g. (0.2 M) of dimethyl sulfate are added dropwise. The resulting crystals are filtered off under suction, washed with water and dried to obtain 3-methyl-benzoxazolinylidene-malononitrile of melting point 198°-200° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:16][C:17]1[CH:18]=[C:19]([CH:24]=[C:25]([CH2:27][N:28]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH:26]=1)[C:20]([O:22]C)=[O:21])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[OH-].[Na+].CO.CCOC(C)=O.Cl>CO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]([CH2:16][C:17]1[CH:18]=[C:19]([CH:24]=[C:25]([CH2:27][N:28]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[CH:26]=1)[C:20]([OH:22])=[O:21])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: COC(=O)c1cc(CN(Cc2ccccn2)Cc2ccccn2)cc(CN(Cc2ccccn2)Cc2ccccn2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(CN(Cc2ccccn2)Cc2ccccn2)cc(CN(Cc2ccccn2)Cc2ccccn2)c1
Temperature: 0 °C

Procedure:
Methyl 3,5-bis[[bis(2-pyridylmethyl)amino]methyl]benzoate (1 g, 1.8 mmol) was dissolved in MeOH (50 mL) and 10% solution of NaOH (5 mL) was added. The reaction mixture was refluxed for 2 h (reaction progress was monitored by TLC, Al2O3, MeOH/AcOEt 1:9 (v/v)). The reaction mixture was cooled to 0° C. followed by the addition of 10M HCl until pH=2 was reached followed by solvent evaporation under reduced pressure. Obtained yellow oily suspension was redissolved in water (50 mL) and TEA (3.6 g, 36 mmol) was added dropwise. Aqueous solution was extracted with DCM (2×50 mL) and organic layers were combined, evaporated and dried under high vacuum to obtain a product as a viscous oil. Yield: 1.1 g (95%). 1H NMR (500 MHz, CDCl3) δ 8.50 (m, 3H), 7.99 (d, J=1.3 Hz, 2H), 7.66 (d, J=8.7 Hz, 1H), 7.59 (m, 8H), 7.11 (m, 4H), 3.82 (s, 8H), 3.70 (s, 4H), 3.06 (q, J=7.3 Hz, 6H), 1.29 (t, J=7.3 Hz, 9H). 13C NMR (101 MHz, CDCl3) δ 170.2, 159.4, 148.9, 148.6, 138.8, 136.6, 136.5, 133.4, 132.7, 129.1, 122.9, 122.0, 77.3, 76.7, 60.1, 59.8, 58.5, 45.0, 8.5.
Reaction SMILES: CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[NH:20]1[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]1.Br[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH:39]([F:41])[F:40])=[CH:34][CH:33]=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[F:40][CH:39]([F:41])[O:38][C:35]1[CH:36]=[CH:37][C:32]([N:20]2[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]2)=[CH:33][CH:34]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: FC(F)Oc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1CCN(c2ccc(OC(F)F)cc2)CC1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
Sodium tert-butoxide (2.29 g, 23.8 mmol), palladium(II) acetate (428 mg, 1.91 mmol), and tri-tert-butylphosphine (370 μL, 1.52 mmol) were added to a solution of ethyl piperidine-4-carboxylate (3.52 mL, 22.9 mmol) and 1-bromo-4-(difluoromethoxy)benzene (4.25 g, 19.1 mmol) in toluene (122 mL), and the mixture was stirred at 80° C. for 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The obtained organic layer was washed with brine and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elute: hexane/ethyl acetate=100/0-90/10] to obtain the title compound (3.17 g, yield: 56%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[CH3:36][N:37]1[CH2:42][CH2:41][CH:40]([NH2:43])[CH2:39][CH2:38]1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:43][CH:40]3[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: CN1CCC(N)CC1
Reactant: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(NC2CCN(C)CC2)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 81.9 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide (20 mg, 0.04 mmol) in THF (3 mL) was added 1-methyl-4-piperidinamine (20 mg, 0.176 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM [90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (18 mg, 82%). LC-MS m/z 550 (M+H)+; 1H-NMR (MeOD) δ 1.26 (d, 6H), 1.48 (m, 2H), 1.88 (m, 4H), 2.24 (s, 3H), 2.29 (s, 3H), 2.75 (m, 2H), 3.18 (m, 1H), 4.09 (s, 2H), 4.23 (m, 1H), 7.15 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H), 7.69 (s, 1H), 7.85 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15]C(=O)C)[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[N:21]([CH3:23])[CH3:22].[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH2:15])[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[N:21]([CH3:23])[CH3:22]
Reactant: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(N(C)C)c3)cc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)c1cc(-c2ccc3nc(N)sc3c2)cnc1Cl
Temperature: 60 °C

Procedure:
To a mixture of N-(6-(6-chloro-5-(dimethylamino)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (160 mg, 461 μmol) in MeOH (10 mL) was added NaOH (1000 μL, 5000 μmol). The mixture was heated to 60° C. for 5.5 h. The reaction mixture was neutralized with HCl (5 N, 1 mL), filtered and the solid was washed with H2O (3×2 mL) and air dried (140 mg). MS (ESI, POS. ION) M/Z: calc'd for C14H13ClN4S: 304.5. found: 305.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.83 (s, 6H) 7.42 (s, 1H) 7.53-7.77 (m, 4H) 8.10 (s, 1H) 8.29 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:32])[CH:10]([C:12]2[CH:13]=[C:14]([C:29](O)=[O:30])[CH:15]=[C:16]3[C:21]=2[O:20][C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:18][C:17]3=[O:28])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.CN1CCOCC1.[NH:40]1[CH2:45][CH2:44][CH:43]([OH:46])[CH2:42][CH2:41]1>CN1C(=O)CCC1>[F:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:32])[CH:10]([C:12]2[CH:13]=[C:14]([C:29]([N:40]3[CH2:45][CH2:44][CH:43]([OH:46])[CH2:42][CH2:41]3)=[O:30])[CH:15]=[C:16]3[C:21]=2[O:20][C:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:18][C:17]3=[O:28])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1cc(F)cc(F)c1
Reactant: OC1CCNCC1
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Product: CC(c1cc(C(=O)N2CCC(O)CC2)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1cc(F)cc(F)c1
Temperature: 23 °C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (113 mg, 0.35 mmol) was added to a stirred solution of 8-(1-((3,5-difluorophenyl)(methyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (130 mg, 0.29 mmol), 4-methylmorpholine (0.080 mL, 0.73 mmol) and piperidin-4-ol (36 mg, 0.35 mmol) dissolved in NMP (1.2 mL). The resulting solution was stirred at 23° C. for 2 hrs. The reaction mixture was purified by preparative HPLC using a Waters SunFire system. The fractions containing the desired compound were evaporated, triturated with ether and dried to afford 8-(1-((3,5-difluorophenyl)(methyl)amino)ethyl)-6-(4-hydroxypiperidine-1-carbonyl)-2-morpholino-4H-chromen-4-one (90 mg, 58%) as a white solid. Mass Spectrum: M+H+ 528. NMR Spectrum (DMSOd6 at 323° K): 1.38 (bs, 2H), 1.57 (d, 3H), 1.75 (bs, 2H), 2.66 (s, 3H), 3.23-3.30 (m, 2H), 3.30-3.38 (m, 2H), 3.61 (m, 4H), 3.65 (bs, 4H), 3.71-3.79 (m, 1H), 4.66 (d, 1H), 5.52 (s, 1H), 5.54 (q, 1H), 6.36 (t, 1H), 6.50 (d, 2H), 7.62 (d, 1H), 7.87 (d, 1H).
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([CH2:26][O:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:14][CH:11]1OC)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=C[C@H]([C@H]([C@H](CO)O)O)O.C(OC(=O)C)(=O)C.[C:53]([OH:56])(=[O:55])[CH3:54].S(=O)(=O)(O)O>O>[C:53]([O:56][CH:11]1[O:14][C@@H:15]([CH2:26][O:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:10]1[O:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:55])[CH3:54]
Reactant: COC1O[C@@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Reactant: CC(=O)O
Agent: O=C[C@@H](O)[C@@H](O)[C@@H](O)CO
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)OC1O[C@@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1

Procedure:
5.37 g of crude 2,3,5-tri-O-benzoyl-1-O-methyl-L-ribofuranose synthesized from L-ribose (1.0 g; 6.66 mmol) in accordance with the method described in Helvetica Chimica Acta 1959, (121), 1171-1173p was added to a 100-ml flask. Thereafter, acetic anhydride (3.73 ml; 5.95 equivalents) and acetic acid (1.60 ml; 2.80 equivalents) were added thereto. The obtained mixture was cooled on ice, and thereafter, concentrated sulfuric acid (530 μl; 1.5 equivalents) was slowly added dropwise thereto. After completion of the reaction for 30 minutes, cold water (50 ml) was slowly added dropwise to the reaction solution, and an upper aqueous layer was separated. The precipitated semi-oily solid was dried under reduced pressure. Thus, 3.97 g of crude 1-O-acetyl-2,3,5-tri-O-benzoyl-L-ribofuranose was obtained in the form of a light yellow oily solid. The obtained solid was analyzed by HPLC. As a result, the ratio of α-/β-anomers in the crude 1-O-acetyl-2,3,5-tri-O-benzoyl-L-ribofuranose was 35/65, and the reaction yield of the β-anomer from the total 3 steps was 56%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:26]=[C:25]3[C:17]([C:18]4[CH:19]=[C:20](Br)[CH:21]=[C:22]([C:27]([NH2:29])=[O:28])[C:23]=4[NH:24]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]1([CH3:40])[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>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(Cl)Cl.COCCOC>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:26]=[C:25]3[C:17]([C:18]4[CH:19]=[C:20]([C:33]5[CH:32]=[C:31]([CH3:40])[CH:36]=[CH:35][CH:34]=5)[CH:21]=[C:22]([C:27]([NH2:29])=[O:28])[C:23]=4[NH:24]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1cc(Br)cc2c1[nH]c1cc(N3CCN(Cc4ccccc4)CC3)ccc12
Reactant: Cc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1cccc(-c2cc(C(N)=O)c3[nH]c4cc(N5CCN(Cc6ccccc6)CC5)ccc4c3c2)c1
Temperature: 100 °C

Procedure:
7-(4-Benzylpiperazin-1-yl)-3-bromo-9H-carbazole-1-carboxamide (100 mg, 0.216 mmol), m-tolylboronic acid (58.7 mg, 0.432 mmol), PdCl2(dppf)-CH2Cl2 adduct (17.62 mg, 0.022 mmol), and Na2CO3 (2M) (0.432 mL, 0.863 mmol) were mixed with DME (4 mL) in a sealed microwave vial. The mixture was flushed with N2 and heated at 100° C. in an oil bath for 4 hrs. The mixture was purified using preparative HPLC to give titled product. MS (ESI) m/z 475.12 (M+H)+. 1H NMR (DMSO-d6) δ ppm 11.07 (s, 1H), 8.44 (s, 1H), 8.28 (s, 1H), 8.12 (s, 1H), 8.02 (d, 1H, J=8.6), 7.69 (s, 1H), 7.65 (d, 1H, J=7.0), 7.47(s, 1H), 7.36 (m, 5H), 7.28 (m, 1H), 7.21 (s, 1H), 7.16 (d, 1H, J=7.9), 6.90 (dd, 1H, J=8.5, 2.1), 3.56 (s, 2H), 3.22 (bm, 4H), 2.57 (bm, 4H), 2.42 (s, 3H).