Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]([C@@H:13]1[CH2:15][C@H:14]1[C:16]([OH:18])=O)=[O:12].C(C1NC=CN=1)([C:21]1[NH:22][CH:23]=CN=1)=O.CNC>O1CCCC1>[CH3:21][N:22]([CH3:23])[C:16]([C@@H:14]1[CH2:15][C@H:13]1[C:11]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[NH:7][CH:6]=1)=[O:12])=[O:18]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: O=C(O)[C@@H]1C[C@H]1C(=O)c1c[nH]c2ccc(F)cc12
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)[C@@H]1C[C@H]1C(=O)c1c[nH]c2ccc(F)cc12
Reaction time: 3 h

Procedure:
A solution of trans-2-(5-fluoro-3-indolylcarbonyl)cyclopropanecarboxylic acid (1.5 g, 6 mmol) and carbonyl diimidazole in tetrahydrofuran was stirred for 0.5 hr. A solution of dimethylamine in tetrahydrofuran (3 ml, 2 M solution, 6 mmol) was added and the solution stirred for 3 hr. The solution was concentrated in vacuo and the residue dissolved in ethyl acetate. The organic solution was washed with 1 N HCl and saturated sodium bicarbonate solution. The solution was dried over sodium sulfate and concentrated in vacuo. The residue was triturated with isopropyl ether to give 1.5 g of trans-2-(5-fluoro-3-indolylcarbonyl)cyclopropanecarboxylic acid dimethylamide, mp 239-241° C. LC/MS mw=274; retention time 1.23 min. Mol wt calc1d for C15H15FN2O2: 274.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([OH:13])=O)[S:10][C:5]2=[N:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:48][C:49]1[CH:50]=[C:51]([NH:56][C:57](=[O:69])[C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([C:67]#[N:68])([CH3:66])[CH3:65])[CH:59]=2)[CH:52]=[CH:53][C:54]=1[CH3:55]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([NH:48][C:49]3[CH:50]=[C:51]([NH:56][C:57](=[O:69])[C:58]4[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([C:67]#[N:68])([CH3:65])[CH3:66])[CH:59]=4)[CH:52]=[CH:53][C:54]=3[CH3:55])=[O:13])[S:10][C:5]2=[N:4][CH:3]=1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1N
Reactant: O=C(O)c1cc2nc(Cl)cnc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2nc(Cl)cnc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
A solution of 2-chlorothieno[3,2-b]pyrazine-6-carboxylic acid 23 (350 mg, 1.631 mmol), HATU (744 mg, 1.957 mmol) and DIPEA (0.809 mL, 4.89 mmol) in DMF (8 mL) was stirred for 15 min. N-(3-amino-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide hydrochloride 6 (538 mg, 1.631 mmol) was added and stirred overnight at rt. Quenched in citric acid solution (3%) and the resulting precipitate was collected. Triturating in acetonitrile gave the title compound 2-chloro-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 24 (450 mg, 56%). NMR (400 MHz, DMSO-d6) 1.76 (s, 6H), 2.26 (s, 3H), 7.32 (d, J=8.2 Hz, 1H), 7.58-7.68 (m, 2H), 7.76 (d, J=7.8 Hz, 1H), 7.87 (d, J=1.9, 1H), 7.95 (d, J=7.8 Hz, 1H), 8.05 (s, 1H), 8.49 (s, 1H), 8.89 (s, 1H), 10.38 (s, 1H), 10.59 (s, 1H). (m/z)=490 and 492 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)#[CH:13].N>>[Cl:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: C#Cc1ccc(F)cc1
Reactant: ON=C(Cl)c1cncc(Cl)c1
Agent: N
Product: Fc1ccc(-c2cc(-c3cncc(Cl)c3)no2)cc1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 69B (57 mg, 0.3 mmol) and 1-ethynyl-4-fluorobenzene (Aldrich, 36 mg, 0.3 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.41-7.57 (m, 2H), 7.76 (s, 1H), 7.90-8.05 (m, 2H), 8.43 (t, J=2.2 Hz, 1H), 8.80 (d, J=2.4 Hz, 1H), 9.08 (d, J=1.6 Hz, 1H) ppm; MS (DCI/NH3) m/z 275 (M+H)+, 277 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([C:18]([CH2:21][CH3:22])([CH3:20])[CH3:19])[CH:15]=[C:14]([C:23]([CH2:26][CH3:27])([CH3:25])[CH3:24])[C:13]=1O)([O-:3])=O.[OH-].[Na+].C1C2C(=[O:44])C3C(=CC=CC=3)C=2C=CC=1.N(C1C=CC=CC=1)=NC1C=CC=CC=1>O.C(O)CCC>[OH:44][C:13]1[C:14]([C:23]([CH2:26][CH3:27])([CH3:24])[CH3:25])=[CH:15][C:16]([C:18]([CH2:21][CH3:22])([CH3:19])[CH3:20])=[CH:17][C:12]=1[N:11]1[N+:1]([O-:3])=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:10]1
Reactant: CCC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)CC)c1
Reactant: O=C1c2ccccc2-c2ccccc21
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(N=Nc2ccccc2)cc1
Solvent: CCCCO
Solvent: O
Product: CCC(C)(C)c1cc(-n2nc3ccccc3[n+]2[O-])c(O)c(C(C)(C)CC)c1
Temperature: 65 °C
Reaction time: 4 h

Procedure:
2-nitro-2'-hydroxy-3',5'-di-t-amylazobenzene 25.5 g was added to a mixture of n-butanol 80 g, water 14 g and 97% sodium hydroxide 8.2 g, and the resultant mixture was stirred while raising temperature to 65° C. Thereafter, the mixture was cooled to 50° C., and 9-fluorenone 2.0 g was added to the mixture. The reaction mixture was then heated to 90° C. in one hour, and the mixture was stirred at 90°~96° C. for four hours to effect reaction, thus almost all of the azobenzene having disappeared to produce 2-(2-hydroxy-3,5-di-t-amylphenyl)benzotriazole-N-oxide. Thus, the reaction of Process (b) was finished.
Reaction SMILES: C1C2C(COC(=O)[NH:17][C@H:18]([C:29](=[O:69])[NH:30][C@H:31]([C:58](=[O:68])[NH:59][C:60]3[CH:65]=[CH:64][C:63]([CH2:66][OH:67])=[CH:62][CH:61]=3)[CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37]([C:50]3[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)C3C(=CC=CC=3)C=2C=CC=1.C(NCC)C>C1COCC1>[OH:67][CH2:66][C:63]1[CH:62]=[CH:61][C:60]([NH:59][C:58](=[O:68])[C@@H:31]([NH:30][C:29](=[O:69])[C@@H:18]([NH2:17])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37]([C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:65][CH:64]=1
Reactant: COc1ccc(C(NCCCC[C@H](NC(=O)[C@H](Cc2ccc([N+](=O)[O-])cc2)NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)Nc2ccc(CO)cc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: C1CCOC1
Product: COc1ccc(C(NCCCC[C@H](NC(=O)[C@@H](N)Cc2ccc([N+](=O)[O-])cc2)C(=O)Nc2ccc(CO)cc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.4 %

Procedure:
In a 50 mL round-bottomed flask, the above prepared [(S)-1-((S)-1-(4-hydroxymethyl-phenylcarbamoyl)-5-{[(4-methoxy-phenyl)-diphenyl-methyl]-amino}-pentylcarbamoyl)-2-(4-nitro-phenyl)-ethyl]-carbamic acid 9H-fluoren-9-ylmethyl ester (1.214 g, 1.29 mmol, Eq: 1.001) was combined with THF (19 ml) to give a brown solution. At 0°, diethylamine (1.77 g, 2.49 ml, 24.2 mmol, Eq: 18.70) was added. The reaction was stirred at ambient temperature for 3 h when MS indicated the disappearance of the starting material. All volatiles were evaporated i. V.; ensuing flash chromatography SiO2/0.1% NEt3 in CH2Cl2=>10% MeOH/0.1% NEt3 in CH2Cl2, followed by a second flash chromatography SiO2/5% MeOH/0.1% NEt3 in CH2Cl2 afforded 502 mg of the title compound as light brown foam. MS: expected mass: 715.337, found mass: 715.3362.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[O:25]([C:32]1[N:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][N:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH3:24][N:21]1[CH2:22][CH2:23][N:18]([C@@H:15]2[CH2:16][CH2:17][C@H:12]([N:4]3[C:5]4=[N:6][CH:7]=[N:8][C:9]([NH2:11])=[C:10]4[C:2]([C:35]4[CH:34]=[N:33][C:32]([O:25][C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)=[N:37][CH:36]=4)=[N:3]3)[CH2:13][CH2:14]2)[CH2:19][CH2:20]1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: CC1(C)OB(c2cnc(Oc3ccccc3)nc2)OC1(C)C
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: COCCOC
Solvent: O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4cnc(Oc5ccccc5)nc4)c4c(N)ncnc43)CC2)CC1
Yield: 56.5 %

Procedure:
A mixture of cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate AC) (0.297 g, 0.000674 mol), 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (int AV) (0.221 g, 0.000741 mol), sodium carbonate (0.179 g, 0.001684 mol) in 1,2-dimethoxyethane (10 mL) and water (20 mL) was stirred rapidly and tetrakis(triphenylphosphine)palladium(0) (0.047 g, 0.000040 mol) added. The reaction mixture was stirred 18 hours at 80° C. The solvents were removed in vacuo and the residue was partitioned between ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate (50 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (3×25 mL). The combined organic phases were dried over magnesium sulfate, and the solvent was removed in vacuo. The product was purified by flash column chromatography on silica using dichloromethane/methanol/ammonium hydroxide (95:5:0.5). The solvent was removed in vacuo to give cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-(2-phenoxy-5-pyrimidinyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid (0.185 g, 0.000381 mol): 1H NMR (DMSO-d6, 400 MHz) 8.79 (s, 2H), 8.24 (s, 1H), 7.48 (t, 2H), 7.28 (t, 1H), 7.27 (d, 2H), 4.81 (m, 1H), 1.55-2.56 (m, 20H); TLC (dichloromethane/methanol/ammonium hydroxide=90:10:0.5) Rf 0.23.
Reaction SMILES: [F:1][C:2]([F:19])([O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:27][S:28]([N:16]1[CH2:17][CH2:18][N:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][C:2]([F:1])([F:19])[CH:3]([F:4])[F:5])=[CH:8][CH:9]=2)[CH2:14][CH2:15]1)(=[O:30])=[O:29]
Reactant: FC(F)C(F)(F)Oc1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2ccc(OC(F)(F)C(F)F)cc2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine (10.95 g, 0.04) was dissolved in DCM (500 ml) and triethylamine (18.5 ml, 0.13 mol) was added. The mixture was cooled to 0° C. and methane sulphonyl chloride (7.4 ml, 0.048 mol) added. Allowed to reach ambient temperature and stirred overnight. The reaction mixture washed with water and the organic phase collected, dried over MgSO4, filtered and evaporated to dryness. The residual solid was crystallised from ethanol to yield 1-(methylsulfonyl)-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine as a white solid. Yield 12.3 g (78.5%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]=[C:5]1[CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7][CH2:6]1.[H][H]>[C].[Pd].C(O)C>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH:5]1[CH2:14][CH2:13][C:8]2([O:9][CH2:10][CH2:11][O:12]2)[CH2:7][CH2:6]1
Reactant: COC(=O)C=C1CCC2(CC1)OCCO2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CC1CCC2(CC1)OCCO2
Reaction time: 24 h
Yield: 75.2 %

Procedure:
An ethanol (50 mL) suspension of (1,4-dioxa-spiro[4.5]dec-8-ylidene)-acetic acid methyl ester (6.57 g) obtained in Example (1a) and palladium carbon (10% by weight) was hydrogen-reduced at room temperature for 24 hours. The reaction mixture was filtered and concentrated. The residue was purified by chromatography (hexane/ethyl acetate=5:1) to obtain the title compound (4.99 g, 75%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:27]=[CH:26][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:19])=[O:18])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:2]2[N:27]=[CH:26][C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]4[CH:16]=[CH:15][C:14]([S:17]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)(=[O:19])=[O:18])=[CH:13][CH:12]=4)[C:4]=3[CH:3]=2)[CH2:31][CH2:30]1
Reactant: CN1CCNCC1
Reactant: O=S(=O)(c1ccccc1)c1ccc(Nc2ncnc3cnc(Cl)cc23)cc1
Product: CN1CCN(c2cc3c(Nc4ccc(S(=O)(=O)c5ccccc5)cc4)ncnc3cn2)CC1

Procedure:
Prepared according to Procedure C from 6-chloro-4-(4-phenylsulphonylanilino)pyrido[3,4-d]pyrimidine and 1-methylpiperazine; δH (CDCl3+DMSO) 9.66 (1H,s), 8.91 (1H,s), 8.52 (1H,s), 8.15 (2H, d), 7.88-7.98 (4H,m), 7.48-7.62 (4H,m), 3.66-3.74 (4H,m), 2.52-2.64 (4H,m), 2.38 (3H,s); m/z (M+1)+461.
Reaction SMILES: O1CCOCC1.Cl[C:8]1[C:13]([NH:14][C:15](=[O:24])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][C:17]=2[CH2:22][CH3:23])=[C:12]([NH:25][CH:26]2[CH2:28][CH2:27]2)[N:11]=[CH:10][N:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:35][C:36]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=1B(O)O>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:26]1([NH:25][C:12]2[C:13]([NH:14][C:15](=[O:24])[C:16]3[CH:21]=[CH:20][CH:19]=[N:18][C:17]=3[CH2:22][CH3:23])=[C:8]([C:39]3[CH:38]=[CH:37][C:36]([Cl:35])=[CH:41][C:40]=3[Cl:42])[N:9]=[CH:10][N:11]=2)[CH2:28][CH2:27]1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CCc1ncccc1C(=O)Nc1c(Cl)ncnc1NC1CC1
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: C1COCCO1
Solvent: O
Product: CCc1ncccc1C(=O)Nc1c(NC2CC2)ncnc1-c1ccc(Cl)cc1Cl
Temperature: 90 °C
Reaction time: 3 h

Procedure:
In a test tube which had been dried by heating and preheated to 100° C., the degassed diluent mixture dioxane (2 ml)/water (0.7 ml) was added to N-(4-chloro-6-cyclopropylaminopyrimidin-5-yl)-2-ethylnicotinamide (0.41 mmol), sodium carbonate (3 eq) and 2,4-dichlorophenylboronic acid (2 eq). 5 mol % of tetrakis(triphenylphosphine)palladium(0) were added, and the reaction mixture was stirred at 90° C. for 3 hours. The mixture was then diluted with water and extracted 3× with methylene chloride, and the combined organic phases were washed with aqueous NaHCO3 solution, dried 20 over Na2SO4, filtered and concentrated under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[OH:13].[N+:14]([O-])([OH:16])=[O:15]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([N+:14]([O-:16])=[O:15])=[C:5]2[OH:13]
Reactant: O=c1cc(O)c2cc(Cl)ccc2[nH]1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=c1[nH]c2ccc(Cl)cc2c(O)c1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
A suspension of 6-chloro-4-hydroxycarbostyril (1.82g; 0.0093 mole) in glacial acetic acid (10 ml) was shaken with concentrated nitric acid (2.5 ml; d, 1.42) and the mixture heated on a water bath at 100° C until a clear solution resulted. Cooling of the orange solution gave a bright yellow solid which was filtered, washed well with acetic acid and then ethanol. Drying in vacuo over P2O5NaOH gave analytically pure 6-chloro-4-hydroxy-3-nitrocarbostyril; decomposes 200° C. (Found: C, 45.31; H, 2.31 N, 11.93; Cl, 14.78; C9H5N2CIO4 requires; C, 44.93; H, 2.09; N, 11.64 Cl, 14.74%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:9]=1[F:15])([CH3:4])([CH3:3])[CH3:2].[CH:17](O)=[O:18].C(OC(=O)C)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1>[F:15][C:9]1[CH:10]=[CH:11][C:12]([NH:14][CH:17]=[O:18])=[CH:13][C:8]=1[NH:7][C:6](=[O:16])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: O=CO
Reactant: CC(C)(C)OC(=O)Nc1cc(N)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(NC=O)ccc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl(5-amino-2-fluorophenyl)carbamate (10.0 g, 44.2 mmol) in tetrahydrofuran (60 mL) was added a mixture of formic acid (8.34 mL, 221 mmol) and acetic anhydride (5.01 mL, 53.0 mmol), and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (100 mL), and the mixture was extracted with ethyl acetate (100 mL, 30 mL). The combined organic layer was washed with saturated brine (10 mL), filtered through a silica gel pad, and the filtrate was concentrated under reduced pressure to give tert-butyl [2-fluoro-5-(formylamino)phenyl]carbamate as a brown oil. The obtained compound was used for the next reaction without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][CH2:8][C:9]1[N:10]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:11](=[O:33])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25]1[S:26][CH:27]=[C:28]([C:30]([NH2:32])=O)[N:29]=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].N1C(Cl)=NC(Cl)=NC=1Cl.CN(C)C=O>O>[C:1]([O:5][C:6](=[O:38])[NH:7][CH2:8][C:9]1[N:10]([CH2:34][CH:35]([CH3:36])[CH3:37])[C:11](=[O:33])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25]1[S:26][CH:27]=[C:28]([C:30]#[N:32])[N:29]=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(-c3nc(C(N)=O)cs3)ccc2c1=O
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(-c3nc(C#N)cs3)ccc2c1=O
Yield: 90.7 %

Procedure:
A solution of tert-butyl[6-[4-(aminocarbonyl)-1,3-thiazol-2-yl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.32 g, 0.6 mmol) and cyanuric chloride (0.33 g, 1.8 mmol) in N,N-dimethylformamide (10 mmol) was stirred at 0° C. for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[6-(4-cyano-1,3-thiazol-2-yl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.28 g, 90.3%) as crystals.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=1.[CH2:10]([O:12][C:13]([N:15]=[C:16]=[S:17])=[O:14])[CH3:11].C1(C)C=CC=CC=1>CO>[CH3:8][C:6]1[N:7]=[C:2]2[S:17][C:16]([NH:15][C:13](=[O:14])[O:12][CH2:10][CH3:11])=[N:9][C:3]2=[N:4][CH:5]=1
Reactant: CCOC(=O)N=C=S
Reactant: Cc1cnc(N)c(Br)n1
Solvent: CO
Solvent: Cc1ccccc1
Product: CCOC(=O)Nc1nc2ncc(C)nc2s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.1 %

Procedure:
To 3-bromo-5-methylpyrazin-2-amine (850 mg, 4.52 mmol) was added ethoxycarbonyl isothiocyanate (0.51 mL, 4.52 mmol) followed by toluene (1 mL). The mixture was placed in a preheated 100° C. oil bath, and within a minute, all the solids had dissolved. After 15 min, all had seized to a solid mass. After an additional 15 minutes, methanol (˜5 mL) was added and the mixture refluxed to digest the solids. The mixture was cooled to rt after 5 minutes and the solids collected by filtration, washing with methanol to give ethyl 6-methylthiazolo[5,4-b]pyrazin-2-ylcarbamate (680 mg, 2.85 mmol, 63.1% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.48 (br. s., 1H) 8.48 (s, 1H) 4.30 (q, J=7.03 Hz, 2H) 2.56-2.65 (m, 3H) 1.31 (t, J=7.15 Hz, 3H). MS (LC/MS) R.T.=2.10; [M+H]+=239.17.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[Sn](CCCC)(CCCC)CCCC.Cl[C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][C:39]3[C:48]4[C:43](=[CH:44][C:45]([O:49][CH3:50])=[CH:46][N:47]=4)[N:42]=[CH:41][CH:40]=3)=[CH:34][CH:33]=2)=[N:23][N:22]=1>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]>[CH3:50][O:49][C:45]1[CH:44]=[C:43]2[C:48]([C:39]([O:38][C:35]3[CH:36]=[CH:37][C:32]([NH:31][C:24]4[C:25]5[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=5)[C:21]([C:3]5[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=5)=[N:22][N:23]=4)=[CH:33][CH:34]=3)=[CH:40][CH:41]=[N:42]2)=[N:47][CH:46]=1
Reactant: COc1cnc2c(Oc3ccc(Nc4nnc(Cl)c5ccccc45)cc3)ccnc2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccn1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: COc1cnc2c(Oc3ccc(Nc4nnc(-c5nccn5C)c5ccccc45)cc3)ccnc2c1
Temperature: 100 °C
Yield: 29.4 %

Procedure:
In a nitrogen purged sealed tube was added 1,4-dioxane (1.35 mL), and the solution was purged with nitrogen for 5 minutes, then sealed. 1-Methyl-2-(tributylstannyl)-1H-imidazole (0.311 g, 0.837 mmol), 4-chloro-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amine (0.120 g, 0.279 mmol) were added to the tube, which was then purged with nitrogen and sealed. To the tube was added 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (0.102 mg, 0.140 mmol), and the tube was purged with nitrogen, sealed, and heated to 100° C., while stirring the reaction for 17 hours. The reaction was cooled to RT, and concentrated. The concentrate was purified using reverse phase chromatography, the product fractions were concentrated, extracted into DCM, washed once with sodium carbonate and once with water, upon which the title compound precipitated. The solids were filtered, washed with water, air dried to yield N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)-4-(1-methyl-1H-imidazol-2-yl)phthalazin-1-amine (0.039 g) as light yellow solid. MS [M+H]=476.0; Calc'd 475.5 for C27H21N7O2.
Reaction SMILES: C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[O:32]=[C:33]1[N:37]([CH2:38][C:39]([OH:41])=O)[C:36](=[O:42])[C:35]2([CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)[N:34]1[C:48]1[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=1.[C:55]1([CH:61]([NH2:65])[CH2:62][CH2:63][CH3:64])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1.Cl>CN1C(=O)CCC1>[O:32]=[C:33]1[N:37]([CH2:38][C:39]([NH:65][CH:61]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH2:62][CH2:63][CH3:64])=[O:41])[C:36](=[O:42])[C:35]2([CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)[N:34]1[C:48]1[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=1
Reactant: CCCC(N)c1ccccc1
Reactant: Cc1ccc(N2C(=O)N(CC(=O)O)C(=O)C23CCCCC3)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(NC(=O)CN1C(=O)N(c2ccc(C)cc2)C2(CCCCC2)C1=O)c1ccccc1
Reaction time: 0.33 h

Procedure:
170 μl (0.098 mmol, 0.1 eq.) of N,N-diisopropylethylamine and 204 mg (0.63 mmol, 2 eq.) of TBTU are added to a solution of 100 mg of (2,4-dioxo-1-p-tolyl-1,3-diazaspiro[4.5]dec-3-yl)acetic acid in 30 ml of NMP. The solution is stirred for 20 minutes, and 70 mg (0.47 mmol, 1.5 eq.) of 1-phenylbutylamine (starting material 3) are added. The reaction medium is stirred overnight at room temperature. It is then poured into 1N hydrochloric acid solution and extracted with ethyl acetate. The organic phase is then washed with water, then with 1N sodium hydroxide solution, and then again with water. It is dried over sodium sulfate. The residue is precipitated from dichloromethane and heptane. 2-(2,4-Dioxo-1-p-tolyl-1,3-diazaspiro[4.5]dec-3-yl)-N-(1-phenylbutyl)acetamide is obtained in the form of a white solid.