Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1.Cl>O1CCCC1.O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH2:19][C:3]([O:7][CH2:8][CH3:9])=[O:10])=[CH:14][CH:13]=1
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(=O)c1ccc(F)cc1
Reaction time: 6 h
Yield: 95.6 %

Procedure:
(Step 1) To 1.3 L (liters) of dry tetrahydrofuran (THF) was added 162 g of 60% sodium hydride (NaH) and 342 g of diethyl carbonate. To this mixture was added a solution of 200 g p-fluoroacetophenone in 440 ml dry THF dropwise over about 1 hour while refluxing, followed by 6 hours of refluxing. This reaction mixture was cooled, poured into iced water, neutralized with concentrated hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate (MgSO4), and concentrated. The residue was distilled under reduced pressure to provide 291 g of ethyl 3-(4-fluorophenyl)-3-oxopropionate as pale yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]2[CH2:26][C:25]3[N:27]4[C:18](=[CH:19][N:20]=[C:21]4[CH:22]=[CH:23][CH:24]=3)[C:17]2=[O:28])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:29]>C(O)C>[ClH:29].[ClH:29].[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]2[CH2:26][C:25]3[N:27]4[C:18](=[CH:19][N:20]=[C:21]4[CH:22]=[CH:23][CH:24]=3)[C:17]2=[O:28])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN2Cc3cccc4ncc(n34)C2=O)CC1
Agent: Cl
Solvent: CCO
Product: O=C1c2cnc3cccc(n23)CN1CCC1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a solution prepared by dissolving 2.88 g (7.49 mM) of 4,5-dihydro-4-[2-(1-tert-butoxycarbonylpiperidin-4-yl)ethan-1-yl]-3H-1,4,8b-triazaacenaphthylen-3-one in 30 ml of ethanol was added 6.25 ml (74.9 mM) of 12N-hydrochloric acid and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the precipitate was recovered by filtration. The precipitate was rinsed with small amounts of ethanol and ether to provide 2.13 g (yield 79.8%) of the title compound as light-yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([CH3:12])[CH:6]=1.C([O-])(O)=O.[Na+].Br[C:32]1[CH:37]=[CH:36][N:35]([CH2:38][CH2:39][CH2:40][CH3:41])[C:34](=[O:42])[C:33]=1[C:43]#[N:44]>O1CCOCC1.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>[CH2:38]([N:35]1[CH:36]=[CH:37][C:32]([C:15]2[CH:14]=[CH:13][C:3]([O:4][C:5]3[CH:6]=[C:7]([CH3:12])[N:8]=[C:9]([CH3:11])[CH:10]=3)=[C:2]([F:1])[CH:16]=2)=[C:33]([C:43]#[N:44])[C:34]1=[O:42])[CH2:39][CH2:40][CH3:41]
Reactant: Cc1cc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2F)cc(C)n1
Reactant: CCCCn1ccc(Br)c(C#N)c1=O
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
Product: CCCCn1ccc(-c2ccc(Oc3cc(C)nc(C)c3)c(F)c2)c(C#N)c1=O

Procedure:
To a solution of intermediate 20 (1.078 mmol) in 1,4-dioxane (6 ml) and a saturated solution of NaHCO3 (5 ml) was added intermediate 6 (0.25 g, 0.979 mmol). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.113 mg, 0.098 mmol). The reaction was then microwaved in a sealed tube at 150° C. for 10 minutes. The resulting cooled reaction mixture was filtered through a pad of diatomaceous earth and the pad of diatomaceous earth was washed with EtOAc. The combined filtrates were washed with water and the organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude reaction mixture was then purified by column chromatography (silica gel; DCM to DCM/MeOH up to 2% as eluent). The desired fractions were collected and evaporated in vacuo to yield compound 7 that was precipitated from diethylether (0.225 g, 59%).
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].Cl[CH2:6][C:7]([NH:9][C:10]([CH3:17])([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:8]>O.CO.[Pd]>[NH2:1][CH2:6][C:7]([NH:9][C:10]([CH3:17])([CH3:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:8]
Reactant: CCCCCC(C)(C)NC(=O)CCl
Reactant: [N-]=[N+]=[N-]
Agent: [Pd]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCC(C)(C)NC(=O)CN

Procedure:
A solution of sodium azide (6.7 g, 103 m mol) in water (56 ml) and methanol(104 ml) was treated with 2-chloro-N-(1,1-dimethylhexyl)acetamide (16.5 g, 80 m mol) and the mixture was refluxed for 5 hours. After cooling, the mixture was extracted with 40-60 petrol (3×200 ml), the extracts were dried over magnesium sulphate and evaporated under reduced pressure to give crude 2-azido-N-(1,1-dimethylhexyl)acetamide as a pale yellow oil.This oil was dissolved in methanol (200 ml) and hydrogenated over 10% palladium on charcoal (3.2 g) at atmospheric pressure and room temperaturefor 24 hours. The mixture was filtered and the filtrate evaporated to give a crude oil (13.6 g) which was distilled to give 2-amino-N-(1,1-dimethylhexyl)acetamide as a colourless oil, b.p. 88°-90° C. at 0.05 mm Hg.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([C:16]3[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22]([O:24]C)=O)=[CH:18][CH:17]=3)=[O:15])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[NH3:28]>CO>[N:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]([C:16]3[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22]([NH2:28])=[O:24])=[CH:18][CH:17]=3)=[O:15])[CH2:11][CH2:12]2)=[CH:5][CH:6]=1
Reactant: COC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Reactant: N
Solvent: CO
Product: NC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Reaction time: 48 h

Procedure:
A solution of the product of Example 1 (200 mg) in methanol (10 ml), prepared under argon, was cooled to 4° C. and saturated with dry ammonia gas, then sealed in a pressure bottle and kept for 2 days. The orange crystals which formed, after filtration and washing with a little methanol, gave the title compound, 140 mg: m.p. 247° to 248° C.; NMR (d6DMSO)δ8.16(2H,d), 7.99(2H,d), 7.55(1H,bs), 7.37(1H,bs), 7.02(2H,d), 6.81(2H,d), 4.54(2H,s), 3.85(2H,s), 3.33(4H,t), 2.60(4H,t); m/e 355 (M+H)+ ; calculated for C19H22N4O3 : C, 64.4; H, 6.3; N, 15.8. found: C, 64.4; H, 6.4; N, 15.6%.
Reaction SMILES: [C:1](=[O:23])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N+:11]=[N-:12])=[CH:6][CH:5]=1.Cl.[C:25]([NH:42][C@H:43]([C:49]([OH:51])=[O:50])[CH2:44][CH2:45][CH2:46][CH2:47][NH2:48])([O:27][CH2:28][CH:29]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:26].C(=O)(O)[O-].[Na+].Cl>CN(C=O)C>[CH:31]1[C:30]2[CH:29]([CH2:28][O:27][C:25]([NH:42][C@@H:43]([CH2:44][CH2:45][CH2:46][CH2:47][NH:48][C:1]([O:2][CH2:3][C:4]3[CH:5]=[CH:6][C:7]([N:10]=[N+:11]=[N-:12])=[CH:8][CH:9]=3)=[O:23])[C:49]([OH:51])=[O:50])=[O:26])[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]=2[CH:34]=[CH:33][CH:32]=1
Reactant: [N-]=[N+]=Nc1ccc(COC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1ccc(COC(=O)NCCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
4-Azidobenzyl (4-nitrophenyl) carbonate synthesized by the method described in the literature (Bioconjugate Chem. 2008, 19, 714) (Compound tk32) (3.46 g, 11.0 mmol) was added to a suspension of Fmoc-lysine hydrochloride (Compound tk31) (4.9 g, 12.10 mmol) and sodium bicarbonate (2.77 g, 33.0 mmol) in DMF (22 mL) under ice-cooling. The reaction mixture was stirred at 25° C. for 8 hours and 1 N hydrochloric acid was then added, followed by extraction with ethyl acetate. The organic phase was washed with brine three times and dried over sodium sulfate. Following concentration under reduced pressure, the resulting residue was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-6-((((4-azidobenzyl)oxy)carbonyl)amino)hexanoic acid (Compound SP661) (5.5 g, 92%).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:12][C@@H:11]([NH:13][C:14]([C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]=3[OH:26])=[O:15])[CH2:10][C@H:9]2[C:27]([OH:29])=[O:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.[CH2:35](O)[CH3:36]>>[CH2:35]([O:28][C:27]([C@@H:9]1[CH2:10][C@H:11]([NH:13][C:14]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[OH:26])=[O:15])[CH2:12][N:8]1[CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:29])[CH3:36]
Reactant: O=C(N[C@H]1C[C@@H](C(=O)O)N(CC2CCCCC2)C1)c1ccc2ccccc2c1O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1CC1CCCCC1
Temperature: 95 °C
Reaction time: 14 h
Yield: 52.3 %

Procedure:
To a stirred solution of (2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid (50 mg, 0.13 mmol) in ethanol (3 mL) was added conc. sulfuric acid (0.1 mL) and the reaction mixture was stirred at 95° C. for 14 h. The reaction mixture was then concentrated under vacuum, diluted with water, extracted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (using 5% EtOAc in hexane as eluent) to give (2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid ethyl ester (28 mg, 52.3% yield) as a blue sticky liquid. MS calcd. for C25H33N2O4 [(M+H)+] 425.0, obsd. 425.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:18][C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22](O)=[O:23])[C:5]([NH:8][C:9]2[S:10][C:11]3[C:16]([N:17]=2)=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:6][CH:7]=1.[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][NH2:32].Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.O.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([S:18][C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([NH:32][CH2:31][CH2:30][N:29]([CH3:33])[CH3:28])=[O:23])[C:5]([NH:8][C:9]2[S:10][C:11]3[C:16]([N:17]=2)=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:6][CH:7]=1
Reactant: CN(C)CCN
Reactant: O=C(O)c1cccc(Sc2cc(Br)cnc2Nc2nc3cccnc3s2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCNC(=O)c1cccc(Sc2cc(Br)cnc2Nc2nc3cccnc3s2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 33.3 %

Procedure:
3-(5-bromo-2-(thiazolo[5,4-b]pyridin-2-ylamino)pyridin-3-ylthio)benzoic acid (0.080 g, 0.17 mmol) and N1,N1-dimethylethane-1,2-diamine (0.020 g, 0.23 mmol) were dissolved in DMF. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.037 g, 0.19 mmol) and HOBT-H2O (0.029 g, 0.19 mmol) were then added. N,N-Diisopropylethylamine (0.034 mL, 0.19 mmol) was added last. The reaction was stirred at ambient temperature for 2 days. The material was diluted with water and the solid was filtered and recrystallized in EtOAc/hexanes to afford the title compound (0.030 g, 33% yield) as a white solid. 1H NMR (CDCl3) δ 2.25 (s, 6H), 2.50 (t, 2H), 3.46-3.51 (m, 2H), 6.91 (bs, 1H), 7.28-7.37 (m, 3H), 7.62 (d, 1H), 7.68 (s, 1H), 7.86 (d, 1H), 7.97 (s, 1H), 8.41 (d, 1H), 8.48 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11](O)=O)=[CH:5][CH:4]=1)#[N:2].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:21](=[O:31])[C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH3:29])=[C:24]([NH2:30])[CH:23]=1>ClCCl.CO>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:21]([C:22]1[CH:27]=[CH:26][C:25]2[N:28]([CH3:29])[C:11]([CH2:10][NH:9][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)=[N:30][C:24]=2[CH:23]=1)=[O:31]
Reactant: CCOC(=O)CCN(C(=O)c1ccc(NC)c(N)c1)c1ccccn1
Reactant: N#Cc1ccc(NCC(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccccn1
Yield: 61 %

Procedure:
Prepared analogously to Example 25c from N-(4-cyanophenyl)glycine and 3-amino-4-methylaminobenzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide. Yield: 61% of theory; Rf value: 0.62 (silica gel; dichloromethane/methanol=19:1).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:9]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[N:36]1[CH:41]=[CH:40][CH:39]=[C:38](B(O)O)[CH:37]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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]>[Cl:8][C:6]1[CH:7]=[C:2]([C:38]2[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=2)[C:3]2[N:4]([C:9]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[N:11]=2)[N:5]=1
Reactant: OB(O)c1cccnc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(Br)cc(Cl)nn4c3-c3ccccc3)cc2)CCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(-c5cccnc5)cc(Cl)nn4c3-c3ccccc3)cc2)CCC1
Reaction time: 0.5 h
Yield: 31 %

Procedure:
A mixture of tert-butyl {1-[4-(8-bromo-6-chloro-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-7.1 (0.15 g, 0.27 mmol), 3-pyridineboronic acid (0.040 g, 0.33 mmol, 1.2 equiv.), 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (0.022 g, 0.03 mmol, 0.1 equiv.), Na2CO3 (0.086 g, 0.81 mmol, 3.0 equiv.), in dioxane (2.9 mL) and water (0.4 mL) was bubbled with Ar, then placed under an argon atmosphere and was irradiated in a microwave apparatus at 105° C. for 90 min. The reaction mixture was then added to a mixture of water (10 mL), a saturated aqueous NH4Cl solution (10 mL) and CH2Cl2 (20 mL). The resulting mixture was stirred strongly for 30 minutes. The organic phase was separated, dried (Na2SO4 anh), and concentrated under reduced pressure. The resulting material was purified using MPLC (Biotage Isolera; Snap 10 g cartridge, 100% hexane 2.0 min, gradient to 80% hexane/20% EtOAc 1.0 min, 80% hexane/20% EtOAc 3.0 min, gradient to 50% hexane/50% EtOAc 2.5 min, 50% hexane/50% EtOAc 3.5 min, gradient to 100% EtOAc 3.0 min, 100% EtOAc 4.8 min) to give tert-butyl (1-{4-[6-chloro-3-phenyl-8-(pyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate (0.046 g, 31%):
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:33][C:34]#[C:35][CH3:36])[C:4]([C:11]([N:13]([CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)[NH:14]C(OC(C)(C)C)=O)=[O:12])=[C:5]([C:7]([O:9]C)=O)[N:6]=1.Cl>C(OCC)(=O)C.O1CCOCC1>[CH2:33]([N:3]1[C:4]2[C:11](=[O:12])[N:13]([CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)[NH:14][C:7](=[O:9])[C:5]=2[N:6]=[C:2]1[Cl:1])[C:34]#[C:35][CH3:36]
Reactant: CC#CCn1c(Cl)nc(C(=O)OC)c1C(=O)N(Cc1ccc2ccccc2n1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC#CCn1c(Cl)nc2c(=O)[nH]n(Cc3ccc4ccccc4n3)c(=O)c21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
2.80 g methyl 2-chloro-5-[N′-tert-butoxycarbonyl-N-(quinolin-2-ylmethyl)-hydrazinocarbonyl]-1-(but-2-ynyl)-1H-imidazol-4-carboxylate are dissolved in 50 ml of ethyl acetate. Then 1.5 ml of 4 M hydrochloric acid in dioxane are added, and the solution is stirred for 2 h at 50° C. Then the solution is cooled to ambient temperature, the precipitate formed is separated off, washed with ethyl acetate and diethyl ether and dried in the drying cupboard at 50° C.
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:10].N([CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=C=O>O1CCOCC1>[O:10]=[C:2]1[NH:3][C:4]2=[N:5][CH:6]=[CH:7][CH:8]=[C:9]2[O:1]1.[CH2:19]1[CH2:18][CH2:17][CH2:16][CH:15]([CH2:14][C:2]([NH2:3])=[O:1])[CH2:20]1
Reactant: O=C=NCC1CCCCC1
Agent: O=c1[nH]c2ncccc2o1
Solvent: C1COCCO1
Product: NC(=O)CC1CCCCC1

Procedure:
100 mg (0.735 mmol) of 3H-oxazolo[4,5-b]pyridin-2-one were reacted in analogy to Example 1 with 102 mg (0.735 mmol) of isocyanatomethylcyclohexane in dioxane at 80° C. Yield: 43 mg (21%), M+H+: 276.13.
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)Cl.[C:21]([N:26]=[C:27]=[O:28])(=[O:25])[C:22]([CH3:24])=[CH2:23]>ClCCCl>[C:21]([NH:26][C:27](=[O:28])[O:8][CH:7]([C:9](=[O:10])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:25])[C:22]([CH3:24])=[CH2:23]
Reactant: C=C(C)C(=O)N=C=O
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: C=C(C)C(=O)NC(=O)OC(C(=O)c1ccccc1)c1ccccc1
Yield: 102.1 %

Procedure:
Into a three-necked flask purged with nitrogen gas, benzoin (2.12 g; 10 mmol) was charged, and chloroform (30 ml) was added thereto. To the resultant solution, a solution of methacryloyl isocyanate (1.11 g; 10 mmol) in 1,2-dichloroethane (7 g) was dropwise added in 5 minutes under nitrogen stream while stirring. Chloroform and 1,2-dichloroethane were removed by evaporation under reduced pressure to give benzoylbenzyl N-methacryloylcarbamate (3.3 g), which was recrysallized from a mixture of benzene and chloroform to give colorless transparent plates. M.P., 161°-163° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:11]([OH:13])=O)=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.S(Cl)([Cl:16])=O>>[CH3:1][C:2]1[S:3][C:4]([C:11]([Cl:16])=[O:13])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1
Reactant: Cc1nc(C(F)(F)F)c(C(=O)O)s1
Reactant: O=S(Cl)Cl
Product: Cc1nc(C(F)(F)F)c(C(=O)Cl)s1
Reaction time: 2 h

Procedure:
0.50 g of 2-methyl-4-trifluoromethylthiazole-5-carboxylic acid was added to 5 ml of thionyl chloride and reaction was carried out for 2 hours under reflux. After the reaction, the reaction mixture was concentrated to obtain 0.54 g of 2-methyl-4-trifluoromethylthiazole-5-carbonyl chloride.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:24]3[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:31][C@@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.O>[O:17]([C:14]1[CH:13]=[CH:12][C:11]([C:10]2[C:3]3[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([C@H:24]3[CH2:25][CH2:26][C@@H:27]([NH:31][C@@H:32]4[CH2:36][CH2:35][NH:34][CH2:33]4)[CH2:28][CH2:29]3)[CH:9]=2)=[CH:16][CH:15]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(=O)CC1
Reactant: N[C@@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2[C@H]1CC[C@@H](N[C@@H]2CCNC2)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexanone (1.00 g, 2.51 mmol), (3R)-(+)-3-aminopyrrolidine (0.65 g, 7.5 mmol), and acetic acid (0.43 mL, 7.5 mmol) in 1,2-dichloroethane (50 mL) was stirred at ambient temperature under an atmosphere of nitrogen for 45 minutes. Sodium triacetoxyborohydride (0.691 g, 3.26 mmol) was added and the mixture stirred at ambient temperature for 15 hours. Water (50 mL) and sodium bicarbonate (1.35 g, 16.1 mmol) were added and the mixture was stirred for 45 minutes. The reaction mixture was transferred to a separatory funnel and the organic layer was separated. The organic portion was dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure to yield an oily brown solid. The compound was purified by flash chromatography on silica gel (1 L 10% MeOH in CH2Cl2, then 1 L 20% MeOH in CH2Cl2, followed by 500 mL 30% MeOH in CH2Cl2) to yield cis-5-(4-phenoxyphenyl)-7-{4-[(3R)tetrahydro-1H-3-pyrrolylamino]cyclohexyl}-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a beige solid (0.285 g, 0.608 mmol): 1H NMR (d6 DMSO, 400 MHz): δ H 8.13(1H, s), 7.39-7.49(5H, m), 7.07-7.17(5H, m), 6.09(2H, bs), 4.65 (1H, m), 3.29-3.35 (3H, m), 2.63-2.67(2H, m), 1.94-2.51(8H, m), 1.46-1.80(4H, m); RP-HPLC (Delta Pak C18, 5,μm, 300 A, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 20 min, 1 mL/min) Rt 12.59 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]([CH3:11])[S:6][C:7]=1[C:8]([OH:10])=O.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][C:45]=1[CH3:46])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[N:33]=1>CN(C)C=O.CN(C)C(=O)C>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:43]=[CH:44][C:45]([CH3:46])=[C:24]([NH:23][C:8]([C:7]5[S:6][C:5]([CH3:11])=[N:4][C:3]=5[O:2][CH3:1])=[O:10])[CH:25]=4)=[N:33][N:32]3[CH:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: COc1nc(C)sc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: COc1nc(C)sc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1C
Yield: 54.5 %

Procedure:
In the same manner as in Example 259 and using 4-methoxy-2-methyl-1,3-thiazole-5-carboxylic acid (120 mg, 0.70 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (120 μL, 1.4 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.46 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (120 mg, 53%) was obtained as a white solid.
Reaction SMILES: [C:1]1(=O)[N:5]2[C:6]3[C:11]([NH:12][C:13](=O)[C@@H:4]2[CH2:3][CH2:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[N+:16]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])#[C-:17]>>[C:18]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[N:16]=[CH:17][N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]3[CH:1]=[CH:2][CH2:3][C@H:4]3[C:13]=12
Reactant: [C-]#[N+]CC(=O)OC(C)(C)C
Reactant: O=C1Nc2ccccc2N2C(=O)CC[C@@H]12
Product: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CC=CN1c1ccccc1-2

Procedure:
Following the general procedure of EXAMPLE 30 and making non-critical variations but starting with (S)-3,3a-dihydropyrrolo[1,2-a]quinoxaline-1,4(2H,5H)-dione (intermediate formed in EXAMPLE 282, 0.638 g) and tert-butyl isocyanoacetate (0.621 g), the title compound is obtained, mp 202°-207° (decomp); MS (m/z) at 325; IR (mineral oil) 1719, 1363, 1700, 1507, 1161, 1293 cm-1 ; NMR (CDCl3) 1.64, 2.25-2.40, 2.55-2.81, 3.31-3.41, 5.26, 7.23-7.29, 7.33, 7.52, 8.06, 8.34 δ; [α]D =-248° (0.96, methanol).
Reaction SMILES: [CH3:1][N:2]([C:4]([CH2:6][C:7]1[CH:28]=[CH:27][C:26]2[C:12]3[NH:13][C:14](=[O:25])[C:15]4[N:16]([CH:17]=[C:18]([C:20]([O:22]CC)=[O:21])[N:19]=4)[C:11]=3[CH2:10][C:9]=2[CH:8]=1)=[O:5])[CH3:3].O1CCOCC1.[OH-].[Na+]>O>[CH3:1][N:2]([C:4]([CH2:6][C:7]1[CH:28]=[CH:27][C:26]2[C:12]3[NH:13][C:14](=[O:25])[C:15]4[N:16]([CH:17]=[C:18]([C:20]([OH:22])=[O:21])[N:19]=4)[C:11]=3[CH2:10][C:9]=2[CH:8]=1)=[O:5])[CH3:3]
Reactant: CCOC(=O)c1cn2c3c([nH]c(=O)c2n1)-c1ccc(CC(=O)N(C)C)cc1C3
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CN(C)C(=O)Cc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nc(C(=O)O)cn12
Yield: 72 %

Procedure:
The preparation is carried out as in Example 25 but from 0.3 g of ethyl 8-(N,N-dimethylaminocarbonylmethyl)-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylate, 15 ml of dioxane, 15 ml of water and 2.3 ml of 1N sodium hydroxide solution. 0.2 g of 8-(N,N-dimethylaminocarbonylmethyl)-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylic acid is obtained in the form of an ochre solid melting above 260° C. (Analysis C18H16N4O4 ; % Calculated C: 61.36, H: 4.58, N: 15.90, O: 18.16; % Found C: 61.1, H: 4.5, N: 15.6, O: 18.0).