Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].CS(O[CH2:11][CH2:12][CH2:13][N:14]([C:16]([O:18][CH:19]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]/[CH:46]=[CH:47]\[CH2:48]/[CH:49]=[CH:50]\[CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:17])[CH3:15])(=O)=O>CCO.C(Cl)Cl>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:11][CH2:12][CH2:13][N:14]([CH3:15])[C:16](=[O:17])[O:18][CH:19]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]/[CH:46]=[CH:47]\[CH2:48]/[CH:49]=[CH:50]\[CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH3:2]
Reactant: CCNCC
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(CCCCCCCC/C=C\C/C=C\CCCCC)OC(=O)N(C)CCCOS(C)(=O)=O
Solvent: CCO
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\CCCCCCCCC(CCCCCCCC/C=C\C/C=C\CCCCC)OC(=O)N(C)CCCN(CC)CC
Reaction time: 50 h
Yield: 42 %

Procedure:
A solution of diethylamine (2 mL) in EtOH (10 mL) was treated with 3-((((6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yloxy)carbonyl)(methyl)amino)propyl methanesulfonate (500 mg, 0.7 mmol) in CH2Cl2 (2.5 mL). The solution was stirred (50 h), concentrated and subjected to chromatography (EtOAc) to yield (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl (3-(diethylamino)propyl)(methyl)carbamate (207 mg, 42%) as a pale yellow oil. Rf 0.43 (10% CH3OH—CH2Cl2), 1H NMR (400 MHz, CDCl3, δH) 5.41-5.28 (m, 8H, C═CH×8), 4.79-4.70 (m, 1H, CHO2CNR2), 3.28 (br. s, 2H, CH2NCH3), 2.94-2.83 (br. s, 3H, CO2NCH3), 2.79 (app. t, 4H, bis-allylic CH2×2), 2.52 (q, 4H, N(CH2CH3)2), 2.09-2.01 (m, 8H, CH2HC═C×4), 1.75-1.65 (m 4H, CH2×2), 1.59-1.45 (m, 4H, CH2×2), 1.42-1.22 (m, 36H, CH2×18), 1.15 (t, 6H, N(CH2CH3)2), 0.90 (t, 6H, CH3×2). FW 699.19, C46H86N2O2.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([O:16][CH2:17][CH:18]([F:20])[F:19])[CH2:13][C@H:12]1[C:21]([OH:23])=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:25]>CO.CCOCC>[F:19][CH:18]([F:20])[CH2:17][O:16][C@@H:14]1[CH2:15][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[C@H:12]([C:21]([O:23][CH3:25])=[O:22])[CH2:13]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)[C@@H]1C[C@H](OCC(F)F)CN1C(=O)OCc1ccccc1
Solvent: CCOCC
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](OCC(F)F)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,4S)-1-(benzyloxycarbonyl)-4-(2,2-difluoroethoxy)pyrrolidine-2-carboxylic acid (2.0 g, 6.07 mmol) in MeOH and ether (80 ml) (1:1) was added TMS-diazomethane (4.56 mL, 9.11 mmol) (2.0M solution in ether) dropwise at 0° C. The reaction mixture was stirred at RT for 1 h and concentrated. The residue was used in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH:5]([C:9](=[O:28])[C:10]1[CH:15]=[C:14]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[F:24])[C:13]([O:25][CH3:26])=[CH:12][C:11]=1[F:27])C(=O)C)[CH3:2].O.C([O-])(=O)C.[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:9]([C:10]1[CH:15]=[C:14]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[F:24])[C:13]([O:25][CH3:26])=[CH:12][C:11]=1[F:27])=[O:28])[CH3:2]
Reactant: CCOC(=O)C(C(C)=O)C(=O)c1cc(Cc2cccc(Cl)c2F)c(OC)cc1F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CC(=O)c1cc(Cc2cccc(Cl)c2F)c(OC)cc1F
Temperature: 25 °C

Procedure:
To a solution of 2-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxybenzoyl)-3-oxobutyric acid ethyl ester prepared in Step VI-1 in ethanol were successively added water (5 ml) and sodium acetate (7.87 g) with stirring at room temperature, and the mixture was stirred for 4 days. Water (20 ml) was added to the reaction suspension at 70° C. and, after confirmation of dissolution, the mixture was cooled to room temperature. A seed crystal (10 mg) of the title compound was added and, after stirring for 1 hr, water (75 ml) was added again, and the mixture was stirred for 4 hr. The precipitated crystals were collected by filtration, washed with 50% ethanol (20 ml) and vacuum dried to give 3-(5-(3-chloro-2-fluorobenzyl)-2-fluoro-4-methoxyphenyl)-3-oxopropionic acid ethyl ester (10.3 g, yield 84.5%). This was identified as the title compound by HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@H:18]3[N:23]([CH2:24][C:25](O)=[O:26])[CH2:22][C:21]([CH3:29])([CH3:28])[O:20][CH2:19]3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C([O-])(=O)C.[NH4+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@@H:18]3[CH2:19][O:20][C:21]([CH3:29])([CH3:28])[CH2:22][N:23]3[CH2:24][C:25]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:26])=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: C1COCCN1
Reactant: CC1(C)CN(CC(=O)O)[C@H](C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC1(C)CN(CC(=O)N2CCOCC2)[C@H](C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Yield: 86 %

Procedure:
The desired compound was prepared according to Method F from [(S)-5-(6-Chloro-9H-beta-carbolin-8-ylcarbamoyl)-2,2-dimethyl-morpholin-4-yl]-acetic acid and morpholine in 86% yield. 1H-NMR (300 MHz, DMSO-d6): δ 1.17 (s,3H), 1.30 (s,3H), 2.19 (d,1H), 2.71 (d,1H), 3.03 (d,1H), 3.16 (d,1H), 3.22 (dd,1H), 3.45-3.72 (m,7H), 3.80-3.98 (m, 3H), 7.94 (d,1H), 8.15 (d,1H), 8.21 (d,1H), 8.37 (d,1H), 9.03 (s,1H), 10.35 (s,1H), 11.28 (s,1H). Retention Time (LC, method: ammonium acetate standard): 1.56 min. MS (M+H+): 486.3.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[NH:12][C:11](=O)[N:10]=[CH:9]2.C(Cl)(=O)C([Cl:25])=O>C(Cl)(Cl)Cl.CN(C=O)C>[Cl:25][C:9]1[C:8]2[C:13](=[CH:14][C:15]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=2)[N:12]=[CH:11][N:10]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COCCOc1cc2cnc(=O)[nH]c2cc1OCCOC
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Yield: 97.8 %

Procedure:
To 6,7-bis(2-methoxy-ethoxy)-quinazolone (500 mg, 1.7 mmol), from Preparation 1, in CHCl3 (10 mL) containing one drop of DMF was added oxalylchloride (490 μL, 5.6 mmol) in several portions over 5 minutes. Once foaming ceased the solution was refluxed 1.5 hours. The solvent was removed in vacuo and the residue was dissolved in 1,2-dichloroethane (20 mL) and washed two times with 80 mL saturated aqueous Na2CO3. The organic phase was dried over Na2SO4, and concentrated in vacuo to afford solid title product (520 mg, 92%; M.P. 108°-109° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[C:23]([C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28])#[CH:24]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[NH2:28][C:27]1[CH:26]=[C:25]([C:23]#[C:24][C:2]2[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[N:6][CH:7]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: C#Cc1cccc(N)c1
Reactant: CC(C)(C)OC(=O)Nc1cncc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cncc(C#Cc2cccc(N)c2)c1
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 26.6 %

Procedure:
Into the reaction flask were added tert-butyl (5-bromopyridin-3-yl)carbamate (2.00 g, 7.32 mmol), copper(I) iodide (56 mg, 0.29 mmol), bis(triphenylphosphine)palladium(II) chloride (0.20 g, 0.29 mmol), tetrahydrofuran (20 mL) and triethylamine (1.1 mL, 8.0 mmol). The reaction mixture was stirred under N2 bubbling for 5 min. 3-Ethynylaniline (0.849 g, 7.3 mmol) was then added. The reaction mixture was heated at 50° C. overnight. After removal of the solvent, the residue was treated with EtOAc and water. The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude was purified by silica gel column chromatography to give the desired product as a yellow gel (0.60 g, 49%). LCMS for C14H12N3O2 ([M-(tBu)+H]+H)+: m/z=254.0.
Reaction SMILES: [NH:1]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@@H:2]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].ON1C2C=CC=CC=2N=N1.[CH2:38](N)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C1CCC(N=C=NC2CCCCC2)CC1>O1CCCC1>[NH:1]([C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])[C@@H:2]([C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH:6][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: NCc1ccccc1
Reactant: NC(=O)CC[C@@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(CC[C@@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)NCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 11.4 grams of Z-D-Gln-OBzl and 4.15 grams of 1-hydroxybenzotriazole in 50 ml of absolute tetrahydrofurane are added 3.35 ml of benzylamine and 6.76 grams of DCC. The mixture is stirred for 1 hour at 0° C and 1 hour at room temperature, the precipitate is filtered off with suction and the filtrate is concentrated. The residue is triturated in succession with NaHCO3 solution, 2n-HCl NaHCO3 solution and water, filtered off with suction and washed with water. Yield: 16.2 grams, melting point 144°. For purification recrystallisation from isopropanol is carried out. The product is washed with petroleum ether. Yield: 6 grams, melting point 149°, [α]D20 = -0.1 (c = 1, in glacial acetic acid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11](=[O:16])[C:10]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)=[CH:19][CH:18]=2)=[CH:5][CH:4]=1.Br>C1COCC1.O>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])([CH3:15])[C:11](=[O:16])[C:10]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)=[CH:19][CH:18]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)C(C)(C)O2)cc1
Agent: Br
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OC(c2ccc(O)cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 8.8 %

Procedure:
To a stirred 0° C. solution of 5-(4-methoxyphenyl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (1.0 g, 2.61 mmol) in THF (10 mL), aqueous HBr (908 mg, 5.2 mmol) was added under a nitrogen atmosphere. The reaction mixture was then stirred for 12 h at RT, diluted with water and extracted with hexane (2×50 mL). The organic layers were concentrated in vacuo to afford 5-(4-hydroxyphenyl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (100 mg) as a white solid. 1H NMR (500 MHz, d6-DMSO): δ 10.25 (s, 1H), 8.48 (d, J=7.8 Hz, 1H), 8.16-8.00 (m, 2H), 7.95 (t, J=7.8 Hz, 1H), 7.72 (t, J=7.8 Hz, 1H), 7.63 (t, J=7.2 Hz, 1H), 7.56 (d, J=7.2 Hz, 2H); 7.18 (d, J=7.2 Hz, 2H), 7.12 (d, J=7.2 Hz, 2H), 6.89 (d, J=7.6 Hz, 2H), 5.32 (s, 2H), 1.37 (s, 6H). MS: M+H: m/z=438.2; and LC MS: 88%, (Condition-H).
Reaction SMILES: [CH2:1](OCC)C.[OH-].[K+].CN(N=O)/C(/N)=N/[N+]([O-])=O.[O:18]=[C:19]([CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25]>C(Cl)Cl>[CH3:1][O:25][C:24](=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][C:19](=[O:18])[CH3:27]
Reactant: CCOCC
Reactant: CC(=O)CCCCC(=O)O
Agent: CN(N=O)/C(N)=N/[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)CCCCC(C)=O
Reaction time: 0.17 h

Procedure:
To a rapidly stirred mixture of diethyl ether (175 ml) and 40% KOH (52 ml) at 0° C. was added MNNG (15.4 g, 105 mmol). The mixture was stirred for 10 minutes. The ethereal layer was transferred to a solution of 6-oxo-heptanoic acid 1-1 (5.0 g, 34.68 mmol) and CH2Cl2 at 0° C. The solution was purged with argon for 30 minutes and then concentrated. Flash chromatography (silica, 30–50% EtOAc/hexanes) gave ester 1-2 as a clear oil.
Reaction SMILES: [C:1]1([C:7]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:15][C:14]3[N:13](S(C4C=CC(C)=CC=4)(=O)=O)[N:12]=[C:11]([NH2:26])[C:10]=3[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>ClCCl>[C:1]1([C:7]2([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:15][C:14]3[NH:13][N:12]=[C:11]([NH:26][C:40](=[O:47])[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:10]=3[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)n2nc(N)c3c2CC(c2ccccc2)(c2ccccc2)C=C3)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1n[nH]c2c1C=CC(c1ccccc1)(c1ccccc1)C2)c1ccccc1

Procedure:
But starting with 0.3 g of 6,6-diphenyl-1-(4-toluenesulphonyl)-6,7-dihydro-1H-indazole-3ylamine, 0.095 cm3 of triethylamine and 0.088 cm3 of benzoyl chloride in cm3 of dichloromethane. After flash chromatography on a column of silica [eluent: dichloromethane], 0.14 g of N-(6,6-diphenyl-6,7-dihydro-1H-indazol-3-yl)benzamide is thus obtained in the form of a foam, the characteristics of which are as follows:
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[N+:21]([O-:23])=[O:22])[CH2:10][C@@H:9]1[CH2:24][OH:25])=O)(C)(C)C.[ClH:26]>ClCCl.O1CCOCC1>[ClH:26].[Br:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C@H:11]2[CH2:12][NH:8][C@@H:9]([CH2:24][OH:25])[CH2:10]2)=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](Nc2ccc(Br)cc2[N+](=O)[O-])C[C@@H]1CO
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Br)ccc1N[C@H]1CN[C@@H](CO)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To a solution of (2R,4R)-4-(4-bromo-2-nitro-phenylamino)-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (125.5 g, 0.301 mol) in dichloromethane (400 mL) add 4 N hydrochloric acid in dioxane (800 mL) and stir for 4 h at room temperature. Collect the precipitate by filtration, wash with ether and dry at 20 mm Hg/60° C. to obtain the title compound (105.2 g, 99%). [α]D20−89.6 (c=1.0 in methanol). 1H NMR (400 MHz, DMSO-d6) δ 1.80-1.85 (m, 1H), 2.54-2.59 (m, 1H), 3.43-3.51 (m, 3H), 3.56-3.63 (m, 1H), 3.69-3.72 (m, 2 H), 4.50-4.51 (m, 1H), 5.60 (br s, 1H), 7.10 (d, 1H), 7.65 (dd, 1H), 8.14 (d, 1H), 8.95 (br s, 1H), 9.91 (br s, 1H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[N:9])[C:3]=1[C:10]#[N:11].O.[NH2:13][NH2:14]>C(O)C>[NH2:11][C:10]1[C:3]2[C:4]([C:8]#[N:9])=[CH:5][CH:6]=[CH:7][C:2]=2[NH:14][N:13]=1
Reactant: NN
Reactant: N#Cc1cccc(F)c1C#N
Solvent: CCO
Solvent: O
Product: N#Cc1cccc2[nH]nc(N)c12
Temperature: 70 °C
Yield: 86.9 %

Procedure:
3-Fluoro-1,2-benzenedicarbonitrile (APIN) (5 g, 34.2 mmol) was dissolved in ethanol (80 mL) and hydrazine monohydrate (4.98 mL, 103 mmol) was added to the solution. The reaction was heated at 70° C. overnight. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate (200 mL) and water (200 mL). The organic layer was washed with water (100 mL). The aqueous layers were extracted with ethyl acetate (200 mL). Organic layers were combined, dried over anhydrous magnesium sulfate and evaporated in vacuo to give the title compound (4.7 g, 87%) as a yellow solid. LCMS (System A) RT=0.53 min, ES+ve m/z 159 (M+H)+.
Reaction SMILES: O[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:13])[N:5]=[C:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[N:3]=1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:35]>>[Cl:35][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:13])[N:5]=[C:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[N:3]=1
Reactant: COC(=O)Cc1c(C)nc(Cc2ccc([N+](=O)[O-])cc2)nc1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: COC(=O)Cc1c(C)nc(Cc2ccc([N+](=O)[O-])cc2)nc1Cl
Temperature: 25 °C
Yield: 32.2 %

Procedure:
A solution of methyl [4-hydroxy-6-methyl-2-(4-nitrobenzyl)pyrimidin-5-yl]acetate (1.59 g, 5.0 mmol) and N,N-dimethylaniline (0.56 mL, 4.4 mmol) in POCl3 (2.33 mL, 25 mmol) was refluxed for 14 hours. After cooling to room temperature, the reaction mixture was poured into ice-cold saturated K2CO3. The resulting aqueous layer was extracted with EtOAc and the combined organic extracts was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product thus obtained was chromatographed over silica gel eluting with 20% EtOAc in n-hexane to afford methyl [4-chloro-6-methyl-2-(4-nitrobenzyl)pyrimidin-5-yl]acetate (0.54 g, 32% yield) as a white powder.
Reaction SMILES: [C:1]12([N:11]=[C:12]=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1.CCN(CC)CC>C(Cl)Cl>[C:1]12([NH:11][C:12]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15]3)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: c1ccc2c(c1)CCN2
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC12CC3CC(CC(C3)C1)C2)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 35.7 mg (0.2 mmol) 1-adamantyl isocyanate, 20 mg (0.168 mmol) indoline and 51 mg (0.5 mmol) NEt3 in 2 mL DCM was shaken at room temperature overnight and evaporated to dryness. The residue was taken up in DMF and subjected to column chromatography on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid to yield after evaporation of the product containing fractions 15.2 mg (30%) of the title compound as white solid. MS(m/e): 297.4 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=2)[N:7]=1.[CH3:14]O>S(=O)(=O)(O)O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=2)[N:7]=1
Reactant: CO
Reactant: O=C(O)c1cc2ccc(O)nn2c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc2ccc(O)nn2c1
Temperature: 80 °C

Procedure:
The semi-crude material from above, 2-Hydroxypyrrolo[1,2-b]pyridazine-6-carboxylic acid (100 mg, 0.56 mmol) was dissolved in methanol (5 mL) and concentrated sulfuric acid (2 drops). The solution was heated to 80° C. for 4 hours, and then the solvent evaporated in vacuo. The crude material was used directly in the next step. MS m/z 193.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14](=[NH:17])OC)=[N:6]1.C(O)(=O)C.[Cl-].[NH4+:27]>CO>[F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]([NH2:27])=[NH:17])=[N:6]1
Reactant: COC(=N)c1nn(Cc2ccccc2F)c2ncccc12
Reactant: [NH4+]
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: CO
Product: N=C(N)c1nn(Cc2ccccc2F)c2ncccc12

Procedure:
The above solution of methyl (2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidate from Example 24A in methanol is admixed with 33.76 g (32.19 ml, 562 mmol) of glacial acetic acid and 9.28 g (173 mmol) of ammonium chloride, and the mixture is stirred under reflux overnight. The solvent is evaporated off under reduced pressure, the residue is triturated well with acetone and the precipitated solid is filtered off with suction. The product is added to 2 l of water, the mixture is admixed with stirring with 31.8 g of sodium carbonate and extracted three times with a total of 1 l of ethyl acetate, and the organic phase is dried with magnesium sulphate and concentrated under reduced pressure.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[CH:18]=[CH:19][CH:20]=[N:21]4)[N:13]=[CH:12][C:11]=2[NH2:26])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:28](N)=[O:29].O>CN1CCCC1=O>[C:1]1([C@H:7]([N:9]2[C:10]3[CH:15]=[C:14]([C:16]4[CH:25]=[CH:24][CH:23]=[C:22]5[C:17]=4[CH:18]=[CH:19][CH:20]=[N:21]5)[N:13]=[CH:12][C:11]=3[NH:26][C:28]2=[O:29])[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@@H](Nc1cc(-c2cccc3ncccc23)ncc1N)c1ccccc1
Reactant: NC(N)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: C[C@H](c1ccccc1)n1c(=O)[nH]c2cnc(-c3cccc4ncccc34)cc21
Temperature: 185 °C
Yield: 32.4 %

Procedure:
1-((1R)-1-phenylethyl)-6-(5-quinolyl)-4-imidazolino[4,5-c]pyridine-2-one. ((1R)-1-Phenylethyl)(3-amino-6-(5-quinolyl)(4-pyridyl))amine (150 mg, 0.44 mmol) and urea (52.8 mg, 0.88 mmol) were combined in 1-methylpyrrolidin-2-one (4 mL) and heated at 185° C. for 2 h. Water (10 mL) was added and the crude product was collected by filtration. The product was purified by reverse-phase preparative HPLC (20-95% acetonitrile in water, over 30 min) to give the title compound (52.3 mg, 32.4%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H) 8.91 (dd, J=4.10, 1.56, 1H) 8.39 (d, J=0.78, 1H) 8.33 (ddd, J=8.74, 1.71, 0.88, 1H) 8.05 (d, J=8.49, 1H) 7.80 (dd, J=8.49, 7.13, 1H) 7.59 (dd, J=7.22, 1.37, 1H) 7.41-7.46 (m, 3H) 7.30-7.40 (m, 3H), 5.75 (d, J=7.22, 1H), 4.16 (d, J=0.98, 1H), 1.87 (d, J=7.22, 3H); MS (ESI) m/z 367.0 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([Cl:11])[CH:3]=1.B.C1COCC1.C([O-])([O-])=O.[K+].[K+].O>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([Cl:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(Br)cc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
4-Bromo-2-chlorobenzoic acid (5 g, 21.23 mmol) was dissolved in dry THF (100 mL) and cooled to 0° C. A 1M solution of BH3.THF in THF (31.85 mL, 31.85 mmol) was slowly added. The reaction was stirred overnight, allowing it to gradually reach room temperature. K2CO3 solid (1 g) and H2O (100 mL) were added and the reaction was stirred for 30 minutes. THF was evaporated and residue extracted with EtOAc (30 mL). The organic phase was washed with 1N HCl (3×50 mL), brine (3×50 mL), dried over Na2SO4 and evaporated. The residue was purified by flash column chromatography (30% EtOAc in hexanes) to give the product (2.80 g, 50%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 4.73 (d, J=5.8 Hz, 2H), 7.37 (d, J=8.1 Hz, 1H), 7.42 (dd, J=8.1 Hz, 1.7), 7.52 (d, J=1.7 Hz, 1H)
Reaction SMILES: N1C=CN=C1.[CH3:6][C:7]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])[CH3:8].[CH2:14]([C:16]1[O:17][C:18]([CH2:21][CH2:22][OH:23])=[CH:19][CH:20]=1)[CH3:15]>CN(C=O)C.C(OCC)C>[C:7]([Si:10]([O:23][CH2:22][CH2:21][C:18]1[O:17][C:16]([CH2:14][CH3:15])=[CH:20][CH:19]=1)([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:6]
Reactant: CCc1ccc(CCO)o1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCc1ccc(CCO[Si](C)(C)C(C)(C)C)o1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80 %

Procedure:
Imidazole (255 mg, 3.75 mmol) and TBSCl (414 mg, 2.75 mmol) were added to the solution of 245A (350 mg, 2.5 mmol) in DMF (4 mL). The mixture was stirred at rt for 15 hr and then 100 mg (0.66 mmol) of additional TBSCl was added to drive the reaction to completion. After stirring for an additional hour, the reaction mixture was diluted with diethylether (100 mL) and washed with water (20 mL), 1 N HCl (20 mL), water (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give 509 mg of compound 434A (80.3%) as a yellow oil.