Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][C:4](=[O:12])[NH:3]1.[N:13]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[N:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[C:25]([O:24][C:22]([N:13]([C:6]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][C:4](=[O:12])[NH:3][C:2]1=[O:1])[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Reactant: CCOC(=O)C1CC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.1 %

Procedure:
To a solution of ethyl 2,5-dioxopyrrolidine-3-carboxylate (2.96 g) in ethyl acetate (25 ml) were added di-tert-butyl azodicarboxylate (4.19 g) and then potassium carbonate (4.78 g) at room temperature. After this reaction mixture was stirred at room temperature for 15 minutes, the resulting mixture was filtered through a Celite pad and the filtrate was concentrated. The residue was purified by a flash column chromatography (hexane:ethyl acetate=3:1) to give ethyl 3-[N,N′-bis(tert-butyloxycarbonyl)hydrazino]-2,5-dioxopyrrolidine-3-carboxy late (5.77 g, 83%) as amorphous.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH2:14][C:15]3[CH:28]=[CH:27][C:18]4[CH:19]=[C:20]([C:22]([O:24]CC)=[O:23])[S:21][C:17]=4[CH:16]=3)=[N:11][N:10]=2)=[CH:5][CH:4]=1.[OH-].[K+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][C:12]([CH2:14][C:15]3[CH:28]=[CH:27][C:18]4[CH:19]=[C:20]([C:22]([OH:24])=[O:23])[S:21][C:17]=4[CH:16]=3)=[N:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cc2ccc(Cc3nnc(-c4ccc(OC)cc4)o3)cc2s1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(-c2nnc(Cc3ccc4cc(C(=O)O)sc4c3)o2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of ethyl 6-{[5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl]methyl}-1-benzothiophene-2-carboxylate (70 mg, 0.18 mmol) in THF (2.5 mL) was treated with 1M KOH solution (0.89 mL, 0.89 mmol) and stirred at ambient temperature for 12 hours. The reaction was partitioned between 1M HCl and ethyl acetate. The organics were dried over sodium sulfate, filtered and evaporated to give the title compound as a white solid. LC/MS (EI): cal'd 367.0 (MH+), exp 367.0 (MH+).
Reaction SMILES: Cl.[C:2]([C:5]1[S:34][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[C:15]([O:20][C@H:21]4[CH2:26][CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]4)=[N:16][CH:17]=[CH:18][CH:19]=3)[C:7]=2[C:6]=1[CH3:35])(=[O:4])[NH2:3]>O1CCOCC1.CO>[CH3:35][C:6]1[C:7]2[C:12]([NH:13][C:14]3[C:15]([O:20][C@H:21]4[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]4)=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:11][CH:10]=[N:9][C:8]=2[S:34][C:5]=1[C:2]([NH2:3])=[O:4]
Reactant: Cc1c(C(N)=O)sc2ncnc(Nc3cccnc3O[C@H]3CCCN(C(=O)OC(C)(C)C)C3)c12
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1c(C(N)=O)sc2ncnc(Nc3cccnc3O[C@H]3CCCNC3)c12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
HCl in Dioxane (4M; 4 ml) was added into a solution of (S)-tert-butyl 3-(3-(6-carbamoyl-5-methylthieno[2,3-d]pyrimidin-4-ylamino)pyridin-2-yloxy)piperidine-1-carboxylate (250 mg) in Methanol (8 ml). The reaction was stirred at room temperature for 1.5 h. The solution was purified by chromatography.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([OH:14])=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:15][CH3:16])[CH:8]=2)[CH:3]=1.S(Cl)(Cl)=O.C1C=CC2C(=CC=CC=2C(O)=O)C=1.OC1C(C(Cl)=O)=CC2C(=CC=C(OC)C=2)C=1.[NH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(N(CC)C1C=CC=CC=1)C>C(Cl)Cl.CN(C)C=O>[OH:1][C:2]1[C:11]([C:12]([NH:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:14])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:15][CH3:16])[CH:8]=2)[CH:3]=1
Reactant: COc1ccc2cc(O)c(C(=O)O)cc2c1
Reactant: Nc1ccccc1
Agent: COc1ccc2cc(O)c(C(=O)Cl)cc2c1
Agent: O=C(O)c1cccc2ccccc12
Solvent: CCN(CC)c1ccccc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1ccc2cc(O)c(C(=O)Nc3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59 %

Procedure:
2-hydroxy-6-methoxy-3-naphthoic acid (10 g, 0.045 moles) and thionyl chloride (6 g, 0.05 moles) are placed inside a 250 ml three-neck flask containing about 100 ml of methylene chloride. The mixture is stirred and brought to reflux under a nitrogen atmosphere. A catalytic amount of dimethylformamide is added. After about 20 minutes, all of the naphthoic acid is reacted and goes into solution. The solution is cooled to room temperature, and transferred to a 250 ml pressure equalizing funnel. The resulting 2-hydroxy-6-methoxy-3-napthoic acid chloride is then added to a 50 ml methylene chloride solution containing 5.6 g of aniline and 8 g of N,N-diethylaniline. The mixture is heated to reflux for about another 3 hours. After being cooled to room temperature, the mixture is filtered and washed with methanol, yielding 9.1 grams of a crude product after vacuum drying. The crude product is then purified by recrystallization from a mixture of dimethylformamide and methanol, affording 7.8 grams of a creamy while solid, 2-hydroxy-6-methoxy-3-naphthanilide (about 59%), having a melting point of 230° C. and an IR(KBr) of about 1640 cm-1 (amide C=O).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([N:6]=[N:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)=[N:4][N:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O)C>O>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:2]2[N:10]3[C:5]([N:6]=[N:7][C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=43)=[N:4][N:3]=2)[CH2:18][CH2:17]1
Reactant: Brc1nnc2nnc3ccccc3n12
Reactant: CN1CCNCC1
Solvent: CCO
Solvent: O
Product: CN1CCN(c2nnc3nnc4ccccc4n23)CC1
Yield: 70 %

Procedure:
A mixture of 12.0 g (0.048 mole) of 1-bromo-s-triazolo[3,4-c]benzo-as-triazine, 40 ml of N-methyl-piperazine and 80 ml of ethanol is refluxed for 2 hours. The solution is poured into water and the product is extracted mit methylene chloride. The solvent is evaporated from the extract and the residue is recrystallized from benzene. 9.7 g (70%) of 1-(N-methyl-piperazino)-s-triazolo[3,4-c]benzo-as-triazine are obtained; m.p.: 162°-163° C. This product is added to a suspension of 12 g (0.068 moles) of sodium dithionite in 100 ml of water, and reduced into the respective dihydro compound under argon atmosphere. The separated precipitate is filtered off, dried, admixed with 50 ml of propionic anhydride, and the mixture is heated at 120° to 125° C. for 2 hours. The reaction mixture is cooled and the separated product is filtered off. 12.3 g (67.0%) of the title compound are obtained; m.p.: 173°-175° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][NH2:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl-].[CH:28]1([S:31](C2CC2)(=[O:33])=[O:32])[CH2:30][CH2:29]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:19][NH:20][S:31]([CH:28]4[CH2:30][CH2:29]4)(=[O:33])=[O:32])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: NC[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: O=S(=O)(C1CC1)C1CC1
Agent: [Cl-]
Product: O=S(=O)(NC[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1)C1CC1

Procedure:
Prepared according to the procedure described for Example 1 from [(1S)-1-[1-(4-fluorophenyl)indazol-5-yl]oxy-1-phenyl-ethan-2-amine (41a, 31 mg, 0.09 mmol) cyclopropylsulphone chloride (28 μl, 0.27 mmol). Yield: 22 mg (54%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:13]=[CH:14][C:15]([Cl:21])=[C:16]([CH:20]=1)[C:17]([OH:19])=[O:18].C([O-])([O-])=O.[Na+].[Na+].O>C(O)C.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.CN(C=O)C>[Cl:21][C:15]1[CH:14]=[CH:13][C:12]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[CH:20][C:16]=1[C:17]([OH:19])=[O:18]
Reactant: OB(O)c1cccc(F)c1
Reactant: O=C(O)c1cc(Br)ccc1Cl
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: CCO
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cc(-c2cccc(F)c2)ccc1Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
A solution of 3-fluorophenyl boronic acid (500 mg, 3.5 mmol, 1.2 eq), 5-bromo-2-chlorobenzoic acid (700 mg, 3.0 mmol, 1.0 eq), Pd(PPh3)4 (687 mg, 0.60 mmol, 0.2 eq) and Na2CO3 (2.52 g, 24 mmol, 8.0 eq) in a mixture of ethanol (5 mL), H2O (5 mL) and DMF (20 mL) was stirred at 100° C. under N2 overnight. The reaction was quenched by addition of diluted HCl (to pH 3) and the aqueous phase was extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4) filtered and evaporated in vacuo. The residue was purified by chromatography (petroleum ether:EtOAc 20:1 to 1:1) to give the title compound as a white solid (500 mg, 67%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].FC(F)(F)C(O)=O.[Cl:29][C:30]1[CH:31]=[N:32][C:33]2[NH:34][C:35]3[CH:36]=[N:37][CH:38]=C(C=3)[CH2:40][CH2:41][C:42]3[CH:50]=[C:46]([NH:47][C:48]=1[N:49]=2)[CH:45]=[CH:44][C:43]=3[NH:51][CH2:52][CH2:53][CH:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1.[C:61]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=1[S:69](Cl)(=[O:71])=[O:70])#[N:62]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[Cl:29][C:30]1[CH:31]=[N:32][C:33]2[NH:34][C:35]3[CH:36]=[N:37][CH:38]=[C:3]([CH:2]=3)[CH2:40][CH2:41][C:42]3[CH:50]=[C:46]([NH:47][C:48]=1[N:49]=2)[CH:45]=[CH:44][C:43]=3[NH:51][CH2:52][CH2:53][CH:54]1[CH2:55][CH2:56][N:57]([S:69]([C:64]2[CH:65]=[CH:66][CH:67]=[CH:68][C:63]=2[C:61]#[N:62])(=[O:71])=[O:70])[CH2:58][CH2:59]1
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Reactant: Clc1cnc2nc1Nc1ccc(NCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccccc1S(=O)(=O)N1CCC(CCNc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 60 %

Procedure:
The desired compound was prepared according to the procedure of Example D20, step A, using 6-chloro-N-(2-piperidin-4-ylethyl)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tetrakis(trifluoroacetate) and 2-cyanobenzenesulfonyl chloride as the starting materials in 60% yield. LCMS for C31H32ClN8O2S (M+H)+: m/z=615.2.
Reaction SMILES: CC(C)C([O:5][C@@H:6]1[C@@H:10]([CH2:11][O:12]C(=O)C(C)C)[O:9][C@@H:8]([N:18]2[C:22]3[N:23]=[C:24]([NH:29]C=O)[N:25]=[C:26]([O:27]C)[C:21]=3[C:20]([Cl:32])=[C:19]2[Cl:33])[CH2:7]1)=O.CC(O)=O>[OH-].[Na+]>[NH2:29][C:24]1[NH:25][C:26](=[O:27])[C:21]2[C:20]([Cl:32])=[C:19]([Cl:33])[N:18]([C@@H:8]3[O:9][C@H:10]([CH2:11][OH:12])[C@@H:6]([OH:5])[CH2:7]3)[C:22]=2[N:23]=1
Reactant: COc1nc(NC=O)nc2c1c(Cl)c(Cl)n2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1nc2c(c(Cl)c(Cl)n2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Yield: 95.5 %

Procedure:
A suspension of compound (49) (200 mg, 0.4 mmol) in 2N aq. NaOH (8 ml) is boiled under reflux for 3 h. After the solution has been neutralized with conc. AcOH, the reaction product is filtered, washed with water and dried. Colorless crystals (128 mg, 96%) are obtained after crystallizing from CH3CN. 1H-NMR ([D6] DMSO): δ=2.22 (m, Hα—C(2′)), 2.92 (m, Hβ—C(2′)), 3.52 (m, H—C(5′)), 3.72 (m, H—C(4′)), 4.33 (m, H—C(3′)), 4.81 (t, 5′-OH), 5.22 (d, 3′-OH), 6.35 (dd, H—C(1′)), 6.46 (br., NH2), 10.75 (s, NH).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][C:12]1[CH:13]=[C:14]([C:29]2[S:33][C:32]([C:34]3([C:44]#[N:45])[CH2:43][CH2:42][C:37]4([O:41][CH2:40][CH2:39][O:38]4)[CH2:36][CH2:35]3)=[N:31][CH:30]=2)[CH:15]=[C:16]([NH:18][C:19]2[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=2)[CH:17]=1.CC(C[AlH]CC(C)C)C>>[NH2:45][CH2:44][C:34]1([C:32]2[S:33][C:29]([C:14]3[CH:15]=[C:16]([NH:18][C:19]4[N:24]=[C:23]([C:25]([F:26])([F:28])[F:27])[CH:22]=[CH:21][N:20]=4)[CH:17]=[C:12]([CH3:11])[CH:13]=3)=[CH:30][N:31]=2)[CH2:43][CH2:42][C:37]2([O:38][CH2:39][CH2:40][O:41]2)[CH2:36][CH2:35]1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(C#N)CCC4(CC3)OCCO4)s2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: [H-]
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(CN)CCC4(CC3)OCCO4)s2)c1
Temperature: -10 °C
Reaction time: 1 h
Yield: 38.6 %

Procedure:
Diisobutylaluminum hydride (1M in Hexanes, 0.239 ml, 0.239 mmol, 1.2 equiv) was added to a solution of 8-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-dioxaspiro[4.5]decane-8-carbonitrile (100 mg, 0.20 mmol) at −10° C. and the resulting cloudy mixture was stirred at −10° C. for 1 h. A second addition of DIBAL (1M in Hexanes, 0.239 ml, 0.239 mmol, 1.2 equiv) was made at −10° C. and the reaction was allowed to slowly warm to 23° C. and then stir for 4 days. The reaction was quenched with 1:1:3 mixture of water:aqueous 6N NaOH and the particulate matter was removed via filtration. The remaining filtrate was partitioned between EtOAc (2×55 ml) and water (65 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated to afford N-(3-{2-[8-(aminomethyl)-1,4-dioxaspiro[4.5]dec-8-yl]-1,3-thiazol-5-yl}-5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2-amine (39 mg, 39%), as an off-white solid. MS ESI: [M+H]+ m/z 506.1. 1H NMR (500 MHz, CDCl3) δ 8.66 (d, J=4.6 Hz, 1H), 7.93 (s, 1H), 7.45 (bs, 1H), 7.28 (s, 1H), 7.08-7.04 (m, 2H), 4.06-3.95 (m, 6H), 2.51-2.35 (m, 7H), 1.95-1.71 (m, 4H).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([CH3:11])[CH2:9][N:8]([C:12]2[C:17]([NH2:18])=[CH:16][N:15]=[C:14]3[CH:19]([O:22]C(=O)C)[CH2:20][CH2:21][C:13]=23)[CH2:7][C@H:6]1[NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(=O)C.[F:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=1[C:42]1[N:47]=[C:46]([C:48](O)=[O:49])[CH:45]=[CH:44][C:43]=1[F:51].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>[OH-].[Na+].CO.CN(C=O)C>[F:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=1[C:42]1[N:47]=[C:46]([C:48]([NH:18][C:17]2[C:12]([N:8]3[CH2:9][C@H:10]([CH3:11])[C@@H:5]([OH:4])[C@H:6]([NH:26][C:27](=[O:28])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[CH2:7]3)=[C:13]3[CH2:21][CH2:20][CH:19]([OH:22])[C:14]3=[N:15][CH:16]=2)=[O:49])[CH:45]=[CH:44][C:43]=1[F:51]
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C)[C@@H](OC(C)=O)[C@H](NC(=O)OC(C)(C)C)C1
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cccc2F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: C[C@H]1CN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCC3O)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (3R,4R,5S)-1-[7-(acetyloxy)-3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-4-yl acetate (11 mg, 0.024 mmol), 6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (9.0 mg, 0.036 mmol), HATU (33 mg, 0.086 mmol), DMF (0.090 mL) and DIPEA (23 mg, 0.18 mmol) was stirred at room temperature for 16 h. The reaction mixture was diluted with 1 M NaOH (1.0 mL) and MeOH (1.0 mL) and the mixture was stirred at room temperature for a further 1 h, and then concentrated under reduced pressure. After concentrating under reduced pressure, the aqueous layer was extracted with DCM three times. The combined organic extract was dried, filtered and concentrated under reduced pressure to give a crude product, which was further purified by preparative LCMS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the sub-title compound as a colorless gum. LCMS calc. for C31H35F3N5O5 (M+H)+: m/z=614.3. Found: 614.2.
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.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.C(O)C>N1C=CC=CC=1>[F:22][C:3]1[C:2]([N:33]2[CH2:32][CH2:31][N:30]([C:27]3[CH:26]=[CH:25][C:24]([F:23])=[CH:29][CH:28]=3)[CH2:35][CH2:34]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: Fc1ccc(N2CCNCC2)cc1
Solvent: CCO
Solvent: c1ccncc1
Product: CNn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCN(c5ccc(F)cc5)CC4)cc3nc21
Yield: 28.7 %

Procedure:
7-Fluoro-8-[4-(4-fluorophenyl)piperazin-1-yl]-1-methylamino-4-oxo-1,4-dihydrobenzo[b][1,8]naph-thyridine-3-carboxylic acid was prepared under the conditions of Example 2, but from 3.2 g of 8-chloro-7-fluoro-1-methylamino-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 9 g of 4-(4-fluorophenyl)piperazine in 30 cm3 of pyridine for 28 hours. After concentrating the reaction mixture to dryness under reduced pressure (20 kPa) at approximately 60° C., the residue was taken up twice in 30 cm3 of ethanol and concentrated under reduced pressure under the above conditions. The solid was taken up into 50 cm3 of water and 10 cm3 of 30% aqueous potassium hydroxide solution. 20 cm3 of water and approximately 10 cm3 of 10% acetic acid were added to the precipitate formed. The suspension was extracted 3 times with 50 cm3 of trichloromethane. The trichloromethane was concentrated under reduced pressure (20 kPa) and the solid obtained was taken up in 2 times 20 cm3 of ethanol. After crystallizing once from 42 cm3 and then recrystallizing once from 15 cm3 of dimethylformamide, 1.33 g of 7-fluoro-8-[4-(4-fluorophenyl)piperazin-1-yl]-1-methylamino-4-oxo-1,4-dihydrobenzo[b][1,8]naph-thyridine-3-carboxylic acid were obtained in the form of a brown solid melting at about 304-305° C.
Reaction SMILES: C([O-])C.[CH3:4][O:5][C:6]1[C:7]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)=[C:8]2[C:13](=[C:14]([N:16]3[C:20](=[O:21])[C:19]4=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]4[C:17]3=[O:26])[CH:15]=1)[NH:12][C:11](=O)[CH:10]=[C:9]2[CH3:28].O=P(Cl)(Cl)[Cl:42]>C(Cl)(Cl)Cl>[Cl:42][C:11]1[CH:10]=[C:9]([CH3:28])[C:8]2[C:13](=[C:14]([N:16]3[C:17](=[O:26])[C:18]4=[CH:25][CH:24]=[CH:23][CH:22]=[C:19]4[C:20]3=[O:21])[CH:15]=[C:6]([O:5][CH3:4])[C:7]=2[O:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:38])([F:37])[F:39])[CH:31]=2)[N:12]=1
Reactant: COc1cc(N2C(=O)c3ccccc3C2=O)c2[nH]c(=O)cc(C)c2c1Oc1cccc(C(F)(F)F)c1
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[O-]
Solvent: ClC(Cl)Cl
Product: COc1cc(N2C(=O)c3ccccc3C2=O)c2nc(Cl)cc(C)c2c1Oc1cccc(C(F)(F)F)c1

Procedure:
From 6-Methoxy-4-methyl-8-phthalimido-5-(3-trifluoromethylphenoxy)quinoline-2-one Ethanolate (IV): A solution of 6-methoxy-4-methyl-8-phthalimido-5-(3-trifluoromethylphenoxy)quinoline-2-one ethanolate (1 g, 1.85 mmol) in CHCl3 (10 mL) was treated with POCl3 (1.5 mL, 2.5 g, 16.4 mmol) as described above to give, after recrystallization from EtOH, 0.3 g (32%) of title compound, mp 225°-227° C. Further recrystallization from EtOH raised the mp to 227°-229° C. [mixed mp with material prepared in A) 226°-229° C⟧
Reaction SMILES: [C:1]1([C:15]([OH:16])=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=[C:6]([N+:7]([O-:9])=[O:8])[CH:5]=1)[N+:2]([O-:4])=[O:3].[NH2:17][CH2:18][C:19](=O)[CH2:20][CH:21]([C:24]1[CH:29]=[CH:28][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=1)[CH2:22][CH3:23].[NH2:35][NH:36][C:37]([NH2:39])=[O:38].[ClH:40]>CCO>[ClH:40].[C:11]1([C:15]([OH:16])=[C:1]([N+:2]([O-:4])=[O:3])[CH:5]=[C:6]([N+:7]([O-:9])=[O:8])[CH:10]=1)[N+:12]([O-:14])=[O:13].[NH2:17][CH2:18][C:19](=[N:35][NH:36][C:37]([NH2:39])=[O:38])[CH2:20][CH:21]([C:24]1[CH:29]=[CH:28][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=1)[CH2:22][CH3:23]
Reactant: NNC(N)=O
Reactant: CCC(CC(=O)CN)c1ccc(C(=O)OC)cc1
Agent: Cl
Agent: O=[N+]([O-])c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Solvent: CCO
Product: CCC(CC(CN)=NNC(N)=O)c1ccc(C(=O)OC)cc1

Procedure:
A mixture of the amino ketone picrate ((9) 6.4 g, 0.133 mol), semicarbazide.HCl (2.6 g, 0.023 mol) and 190 ml of 70% EtOH was stirred at room temperature for 90 hours. The solid was collected and washed with 70% EtOH, and the filtrate was evaporated and similarly retreated with 1.27 g of semicarbazide.HCl in 75 ml of 70% EtOH to afford 0.76 g of yellow crystals (10), mp 200°-201° C. The original solid above was treated with 225 ml of warm EtOH and the insoluble portion collected to give 2.67 g, ml 196°-197° C. The combined mother liquors were evaporated and retreated with 0.84 g of semicarbazide.HCl in 61 ml of 70% EtOH to afford another 1.66 g of (10), mp 200°-201° C., for a total yield of (10) of 5.09 (71%).
Reaction SMILES: [H-].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]([O-])=[O:18])[CH:13]=[N:14]2)=[CH:9][CH:8]=1.O>O1CCCC1>[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([CH2:17][OH:18])[CH:13]=[N:14]2)=[CH:9][CH:8]=1
Reactant: O=C([O-])c1cnc2cc(-c3cccs3)ccc2c1
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cnc2cc(-c3cccs3)ccc2c1
Reaction time: 0.5 h
Yield: 56.9 %

Procedure:
Diisobutylalminium hydride (1M in toluene, 7.2 ml) was added dropwise to a stirred solution of 7-(2-thienyl)-3-quinolinecarboxylate (500 mg) in tetrahydrofuran (30 m) at 0° C. After stirring for 30 min, the reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried (MgSO4), and concentrated. The residue was purified by silica gel column chromatography. From the fraction eluted with ethyl acetate-hexane (1:2, v/v) 7-(2-thienyl)-3-quinolylmethanol (270 mg, 63%) was obtained. Recrystallization from ethyl acetate-hexane gave yellow prisms, 143-144° C.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][C:8]1[CH:9]=C(C(O)=O)[NH:11][C:12]=1[C:13]([O:15][CH3:16])=[O:14].CN(C=O)C>C(Cl)Cl>[Cl:7][C:8]1[CH:9]=[C:1]([C:2]([Cl:4])=[O:3])[NH:11][C:12]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)c1[nH]c(C(=O)O)cc1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1[nH]c(C(=O)Cl)cc1Cl
Reaction time: 8 h

Procedure:
Oxalyl chloride (0.430 mL, 4.91 mmol) was added to a solution of 4-chloro-5-[(methyloxy)carbonyl]-1H-pyrrole-2-carboxylic acid (0.500 g, 2.45 mmol) in DCM (50 mL). DMF (9.51 μl, 0.123 mmol) was added to the reaction mixture and the resulting suspension was stirred overnight. The solvent was evaporated to afford the title compound as a crude product (0.804 g) which was used with no further purification. 1H NMR (400 MHz, CDCl3) δ ppm 11.02 (s, 1H), 7.11 (d, 1H), 3.97 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([N:15]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[C:16]2[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:18]=[C:19]3[C:24]=2[CH:23]=[CH:22][CH:21]=[CH:20]3)=[O:14])=[C:8]([F:37])[CH:7]=1.[OH-].[Li+]>C(OC(C)=O)(C)C.[Cl-].[Na+].O>[CH:31]1([N:15]([C:16]2[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:18]=[C:19]3[C:24]=2[CH:23]=[CH:22][CH:21]=[CH:20]3)[C:13](=[O:14])[NH:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:38])=[O:2])=[CH:7][C:8]=2[F:37])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: COC(=O)COc1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccccc2)C2CCCCC2)c(F)c1
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)C
Product: O=C(O)COc1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccccc2)C2CCCCC2)c(F)c1

Procedure:
In analogy to the procedure described in example 2.2, {4-[3-cyclohexyl-3-(2-phenyl-2H-indazol-3-yl)-ureido]-3-fluoro-phenoxy}-acetic acid methyl ester was treated with 1 N aqueous lithium hydroxide solution in THF/MeOH 1/1 for 1 h at 60° C. to give the title compound as off-white solid. MS: m/e=501.0 [M−H−].