Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[NH2:1][C@H:2]([CH2:3][C:4]([OH:6])=[O:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC(CC(=O)O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: N[C@H](CC(=O)O)c1ccccc1
Temperature: 10 °C
Reaction time: 0.67 h

Procedure:
(±)-3-Amino-3-phenylpropanoic acid (2.378 g, 14.4 mmol), 2.0 ml of acetic acid, and 236 mg (2.88 mmol) of anhydrous sodium acetate were charged into a 30-ml two-necked round-bottomed flask equipped with a stirrer and a calcium chloride tube and cooled down to a temperature not higher than 10° C. using an ice bath. Acetic anhydride (4 ml, 42.8 mmol) cooled to a temperature of not higher than 10° C. was added dropwise to the solution, and the mixture was stirred for 40 minutes at that temperature and then stirred for 80 minutes at room temperature.
Reaction SMILES: [CH2:1]([O:3][CH:4]([N:6]1[C:10]2[S:11][C:12]([C:14]([O:16]CC)=[O:15])=[CH:13][C:9]=2[C:8]([NH:19][C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[N:7]1)[CH3:5])[CH3:2].[OH-].[Na+]>O1CCCC1>[CH2:1]([O:3][CH:4]([N:6]1[C:10]2[S:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:9]=2[C:8]([NH:19][C:20](=[O:29])[C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)=[N:7]1)[CH3:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(NC(=O)c3ccc(OC)cc3)nn(C(C)OCC)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(C)n1nc(NC(=O)c2ccc(OC)cc2)c2cc(C(=O)O)sc21

Procedure:
Ethyl 3-bromo-1-(1-ethoxyethyl)-1H-thieno[2,3-c]pyrazole-5-carboxylate (10 g, 28 mmol), 4-methoxybenzamide (7.39 g, 48 mmol, 1.7 eq.), copper(I)iodide (0.548 g, 2.88 mmol, 0.1 eq.), preground tripotassium phosphate (18.34 g, 86 mmol, 3 eq.) and 180 mL of anhydrous dioxane degassed beforehand with argon are introduced into a 500 mL round-bottomed flask under argon. 0.306 mL (2.88 mmol, 0.1 eq.) of N,N′-dimethylethylenediamine is added to this suspension by syringe. The reaction mixture is then heated to a temperature in the region of 110° C. for a period of 24 hours. The dioxane is then evaporated off under vacuum and the residue is diluted with ethyl acetate (300 mL) and 150 mL of water. The organic phase is washed once with 100 mL of water and is then dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue is purified by chromatography on silica gel, eluting with an ethyl acetate/heptane mixture (1:1). The pale yellow oil obtained after purification corresponds to ethyl 1-(1-ethoxyethyl)-3-(4-methoxybenzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylate (7.41 g, 64%). The combined aqueous phases are acidified with 5 N hydrochloric acid to pH 5-6. A thick precipitate appears, which is extracted with (2×100 mL) of ethyl acetate. The organic phase is in turn dried over magnesium sulfate and concentrated to dryness under reduced pressure. The white solid obtained after evaporation is triturated in a heptane/dimethyl ether mixture (1:1). After filtration, 1-(1-ethoxyethyl)-3-(4-methoxybenzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid is obtained in the form of a white solid (1.27 g, 11%). The ethyl 1-(1-ethoxyethyl)-3-(4-methoxybenzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylate is subjected to saponification using 50 mL of tetrahydrofuran and 20 mL of 5 N sodium hydroxide at a temperature in the region of 50° C. for 5 hours. The tetrahydrofuran is then evaporated off, the aqueous phase is diluted with 150 mL of water and the pH is adjusted to 3-4 with 5 N hydrochloric acid. The white precipitate obtained is filtered off and washed with water, and then dried under vacuum at a temperature in the region of 60° C. 7.04 g of 1-(1-ethoxyethyl)-3-(4-methoxybenzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid are thus obtained, i.e. 98%, which product is used directly in the following step.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([NH2:12])=O)[CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:22]2)=CC=1>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10](=[S:22])[NH2:12])[CH:3]=1
Reactant: NC(=O)c1cc(Cl)c(Cl)c(Cl)n1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: NC(=S)c1cc(Cl)c(Cl)c(Cl)n1
Yield: 58.7 %

Procedure:
A mixture of 4, 5, 6-trichloropyridine-2-carboxamide (10.4 g, 46 mmol) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's Reagent, 22.0 g, 54 mmol) in toluene (150 mL) was heated under reflux for two hours. The reaction mixture was cooled, diluted with water (250 mL) and extracted with ethyl acetate (2×150 mL). The organic phase was dried (Na2SO4) and concentrated. The residue was purified by column chromatography (20% ethyl acetate in hexanes) to give 4, 5, 6-trichloropyridine-2-carbothioamide (6.5 g, 27 mmol): mp 168-169° C.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]([CH3:12])([OH:11])[CH3:10])[C:6]=1[CH3:7].C1COCC1.C([Mg]Cl)(C)C.CO[B:25]1[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]1.[NH4+].[Cl-]>>[CH3:10][C:9]([OH:11])([CH3:12])[CH2:8][N:5]1[C:6]([CH3:7])=[C:2]([B:25]2[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]2)[CH:3]=[N:4]1
Reactant: Cc1c(I)cnn1CC(C)(C)O
Reactant: COB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1CC(C)(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-(4-iodo-5-methyl-1H-pyrazol-1-yl)-2-methylpropan-2-ol (150.0 mg, 0.5355 mmol) in THF (8 mL, 100 mmol) was added 2 M isopropylmagnesium chloride in THF (0.80 mL, 1.6 mmol) at 0° C., and the reaction was allowed to warm to rt over 30 min. 2-Methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.35 mL, 2.1 mmol) was then added, and the mixture was stirred at rt overnight. Sat. NH4Cl was added to quench, and the organic solvent was removed in vacuo. The material was extracted with DCM and water, and the organic layer was concentrated in vacuo to afford the title compound as a white solid. The material was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:8]Br)=[N:4][CH:5]=[CH:6][CH:7]=1.C(O)C.O.[C-:14]#[N:15].[Na+]>ClCCl>[Br:1][C:2]1[C:3]([CH2:8][C:14]#[N:15])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ncccc1Br
Reactant: [C-]#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: N#CCc1ncccc1Br
Reaction time: 0.5 h

Procedure:
The above pyridine (5.13 g, 20.4 mmol) was stirred in 50.1 mL of a 5.6:1 solution of ethanol:deionized water. To this mixture was added sodium cyanide (1.20 g, 24.5 mmol), which was stirred for 2 hours and 30 minutes. The reaction mixture was diluted with dichloromethane (100 mL), washed with water (3×100 mL), and partitioned between water and dichloromethane. The organic layer was dried over sodium sulfate, filtered, concentrated, and subjected to silica gel chromatography eluting with 5-30% EtOAc in hexanes to yield (3-bromopyridin-2-yl)acetonitrile.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[C@@H:21]([OH:25])[CH2:22][CH2:23][OH:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]([Si:30](Cl)([CH3:32])[CH3:31])([CH3:29])([CH3:28])[CH3:27].N1C=CN=C1.O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:15])[CH3:16])[CH2:10][C@H:9]1[C@@H:21]([OH:25])[CH2:22][CH2:23][O:24][Si:30]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:32])[CH3:31])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1[C@@H](O)CCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1[C@@H](O)CCO[Si](C)(C)C(C)(C)C
Yield: 92 %

Procedure:
To a solution of (2S,4R)-1-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-[(S)-1,3-dihydroxypropyl]pyrrolidine (16.95 g, 45.2 mmol) in methylene chloride (200 ml) were successively added tert-butylchlorodimethylsilane (6.81 g, 45.2 mmol), 4-N,N-dimethylaminopyridine (0.55 g, 4.5 mmol) and imidazole (3.08 g, 45.2 mmol) in a nitrogen atmosphere under cooling with ice under stirring. The mixture was stirred at room temperature for 1 h. Then, the reaction solution was poured into water (200 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was subjected to silica gel column chromatography (Wakogel™ C-300, heptane-ethyl acetate=9:1→4:1) to give (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-[(S)-3-tert-butyldimethylsiloxy-1-hydroxypropyl]pyrrolidine (20.36 g, yield: 92.0%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([F:37])=[C:8]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[C:26]4[C:21](=[C:22]([F:32])[CH:23]=[CH:24][C:25]=4[O:27][C:28]([F:31])([F:30])[F:29])[N:20]([CH2:33][CH2:34][O:35][CH3:36])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH:9]=1.[NH:38]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C@H:39]([C:43]([NH:45][CH2:46][C:47](O)=[O:48])=[O:44])[CH:40]([CH3:42])[CH3:41].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[C:53]([O:52][C:50](=[O:51])[NH:38][C@H:39]([C:43](=[O:44])[NH:45][CH2:46][C:47](=[O:48])[NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([F:37])=[C:8]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[C:26]4[C:21](=[C:22]([F:32])[CH:23]=[CH:24][C:25]=4[O:27][C:28]([F:31])([F:29])[F:30])[N:20]([CH2:33][CH2:34][O:35][CH3:36])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH:9]=1)[CH:40]([CH3:41])[CH3:42])([CH3:54])([CH3:56])[CH3:55]
Reactant: COCCn1cc(C(=O)N2CCC(c3cc(CN)ccc3F)CC2)c2c(OC(F)(F)F)ccc(F)c21
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COCCn1cc(C(=O)N2CCC(c3cc(CNC(=O)CNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)ccc3F)CC2)c2c(OC(F)(F)F)ccc(F)c21
Yield: 94.7 %

Procedure:
A solution of [4-(5-aminomethyl-2-fluoro-phenyl)-piperidin-1-yl]-[7-fluoro-1-(2-methoxy-ethyl)-4-trifluoromethoxy-1H-indol-3-yl]-methanone hydrochloride (0.3 g, 0.55 mmol), BOC-Val-GlyOH (0.18 g, 0.66 mmol), EDCI (0.126 g, 0.66 mmol), HOBT (0.224 g, 1.65 mmol), and Et3N (0.23 ml, 1.65 mmol) in DMF (15 mL) was stirred at room temperature overnight. The reaction mixture was poured into EtOAc and the organic layer washed with water and brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give the crude product. Purification by flash chromatography on SiO2 eluting with 3% MeOH/CH2Cl2 provided the desired product (0.4 g, 95%). 1H NMR (300 MHz, CDCl3) δ 7.4 (s, 1H), 7.1 (m, 2H), 7.0-6.8 (m, 3H), 6.7 (bs, 1H), 5.1 (bs, 1H), 4.5-4.3 (m, 4H), 4.1-3.7 (m, 6H), 3.35 (s, 3H), 3.1 (m, 3H), 2.1 (m, 1H), 1.8-1.6 (m, 6H), 1.4 (s, 9H), 0.9 (m, 6H). MS m/z: [M+H]+=768.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+](=[C:17]([C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=1)[C:18]([O:20][CH3:21])=[O:19])=[N-]>CCCCCCCCCCCCC1C=CC(S(N2[C@@H](C(O)=O)CCC2)(=O)=O)=CC=1.CCCCCCCCCCCCC1C=CC(S(N2[C@@H](C(O)=O)CCC2)(=O)=O)=CC=1.CCCCCCCCCCCCC1C=CC(S(N2[C@@H](C(O)=O)CCC2)(=O)=O)=CC=1.CCCCCCCCCCCCC1C=CC(S(N2[C@@H](C(O)=O)CCC2)(=O)=O)=CC=1.[Rh].[Rh]>[CH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:22]=1[C@:17]1([C:18]([O:20][CH3:21])=[O:19])[CH2:8][C:7]1([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)C(=[N+]=[N-])c1ccc2ccccc2c1
Reactant: C=C(c1ccccc1)c1ccccc1
Agent: [Rh]
Agent: CCCCCCCCCCCCc1ccc(S(=O)(=O)N2CCC[C@@H]2C(=O)O)cc1
Product: COC(=O)[C@@]1(c2ccc3ccccc3c2)CC1(c1ccccc1)c1ccccc1
Yield: 74 %

Procedure:
To a flame-dried round bottom flask kept under a dry atmosphere of argon, was added Rh2(R-DOSP)4 (0.01 equiv., 474 mg), 1,1-diphenylethlyene (2.32 equiv., 10.5 g, 58 mmol), and dry degassed pentane (100 mL). A solution of freshly prepared methyl 2-diazo-2-(naphthalen-2-yl)acetate (1.0 equiv., 5.65 g, 25 mmol) in dry, degassed pentane (250 mL) was added to the former solution drop-wise over 3 hours at −40° C. The mixture was allowed to stir overnight to room temperature, and then concentrated in vacuo. The crude material was purified using flash column chromatography eluting with a 40:1 mixture of hexanes/ethyl acetate to provide the desired product as a white solid (7.0 g, 74% yield, >99% ee). mp: 138-139° C.; [α]20D −347.9° (c=1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.74-7.71 (m, 1H), 7.50-7.36 (m, 4H), 7.24-7.22 (m, 1H), 7.06-7.04 (m, 2H), 6.96-6.86 (m, 3H), 3.38 (s, 3H), 2.79 (d, J=5.6 Hz, 1H), 2.57 (d, J=5.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 171.4, 141.9, 139.4, 133.6, 132.8, 132.3, 130.4, 130.2, 129.9, 128.7, 128.3, 127.7, 127.6, 127.5, 126.9, 126.7, 126.1, 125.8, 125.6, 141.9, 139.4, 133.6, 132.8, 132.2, 130.4, 130.2, 129.9, 128.7, 128.3, 127.7, 127.6, 127.5, 126.9, 126.7, 126.1, 125.8, 125.6, 52.2, 44.5, 43.2, 23.1; IR (neat): 3057, 3024, 2947, 1724, 1433, 1215; HRMS (APCI) calcd for C27H23O2 (M+H)+ 379.16926. found 379.16952; HPLC (ODH, 0.5% isopropanol in hexane, 1.0 mL/min, 1 mg/mL, 30 min, UV 254 nm) retention times of 8.6 min (major) and 9.6 min (minor), >99% ee.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[O:28])[C:10]([NH:12][CH:13]2[C:26](=[O:27])[N:15]3[C:16]([C:23]([OH:25])=[O:24])=[C:17]([CH2:20][S:21][CH3:22])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.C(=O)(O)[O-].[Na+]>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[O:28])[C:10]([NH:12][CH:13]2[C:26](=[O:27])[N:15]3[C:16]([C:23]([OH:25])=[O:24])=[C:17]([CH2:20][S:21][CH3:22])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CSCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=O)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CSCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.1 %

Procedure:
A mixture of 7-[(2-formamidothiazol-4-yl)-glyoxylamido]-3-methylthiomethyl-3-cephem-4-carboxylic acid (3.0 g) and conc. hydrochloric acid (3 ml) in methanol (50 ml) was stirred at ambient temperature for 2 hours. The reaction mixture was adjusted to pH 5-6 with an aqueous solution of sodium bicarbonate and then concentrated under reduced pressure. The precipitated crystals in the concentrate were collected by filtration to give 7-[(2-aminothiazol-4-yl)glyoxylamido]-3-methylthiomethyl-3-cephem-4-carboxylic acid (1.1 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9](Cl)=[O:10])=[CH:5][CH:4]=1.[CH3:14][CH2:15][O:16][C:17]([C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=1)=[O:18].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([C:17]([O:16][CH2:15][CH3:14])=[O:18])=[CH:24][CH:23]=2)=[O:10])=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COc1ccc(C=CC(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)C=Cc2ccc(OC)cc2)cc1
Reaction time: 19 h

Procedure:
To a solution of 10 g. of p-methoxycinnamoyl chloride in 200 ml. of dichloromethane is slowly added a solution of 0.24 g. of benzocaine and 7.1 ml. of triethylamine in 200 ml. of dichloromethane. The mixture is stirred for 19 hours, then the organic layer is washed with 200 ml. of 10% hydrochloric acid followed by 200 ml. of brine, dried over magnesium sulfate, and condensed to a solid. This solid is crystallized from 100 ml. of ethanol, giving 10.6 g. of the desired product as yellow crystals, m.p. 163°-165.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[F:12][C:13]1[CH:14]=[CH:15][C:16]([O:31][CH3:32])=[C:17]([C:19]2([CH2:22][C:23]([OH:30])([C:26]([F:29])([F:28])[F:27])[CH:24]=O)[CH2:21][CH2:20]2)[CH:18]=1.C(O)(=O)C.CCCCCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[N:7]1[C:8]2[C:3](=[C:2]([N:1]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])([OH:30])[CH2:22][C:19]3([C:17]4[CH:18]=[C:13]([F:12])[CH:14]=[CH:15][C:16]=4[O:31][CH3:32])[CH2:21][CH2:20]3)[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(F)cc1C1(CC(O)(C=O)C(F)(F)F)CC1
Reactant: Nc1cccc2ncccc12
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(F)cc1C1(CC(O)(C=Nc2cccc3ncccc23)C(F)(F)F)CC1
Reaction time: 6 h

Procedure:
Analogously to Example 37, 362 mg (2.5 mmol) of 5-aminoquinoline is reacted with 640 mg (2.09 mmol) of 3-[1-(5-fluoro-2-methoxyphenyl)cycloprop-1-yl]-2-hydroxy-2-(trifluoromethyl)propanal and 2.80 ml of concentrated acetic acid in 19 ml of toluene. After 6 hours, the chromatography is carried out on silica gel with hexane-ethyl acetate (0-100%), and 810 mg (90% of theory) of the product is obtained.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:34](=[O:37])[CH2:35][CH3:36])[CH2:32][CH2:33]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(CC)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f48) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][N:12]([CH3:27])[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([CH:25]=O)=[CH:19]2.N1CCCCC1>C(O)C>[CH3:11][N:12]([CH3:27])[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([CH:25]=[C:3]1[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]1=[O:10])=[CH:19]2
Reactant: CN(C)CCOc1ccc2[nH]c(C=O)cc2c1
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CN(C)CCOc1ccc2[nH]c(C=C3C(=O)Nc4ccccc43)cc2c1
Temperature: 100 °C
Yield: 80.9 %

Procedure:
A mixture of oxindole (28 mg, 0.216 mmol), 5-(2-dimethylamino-ethoxy)-1H-indole-2-carbaldehyde (50 mg, 0.21 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 59 mg (79%) of the title compound as an orange solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.Cl.[CH2:21]1[C:29]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[CH2:23][NH:22]1>>[CH2:21]1[C:29]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[CH2:23][N:22]1[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1
Reactant: c1cc2c(cn1)CNC2
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Agent: Cl
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3Cc4ccncc4C3)n2)c1

Procedure:
B49 was prepared following the general procedure reported for B10 using A1 and 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine hydrochloride; yield: 139.0 mg (36%), brown amorphous solid. 1H NMR (400 MHz, d6-DMSO, 300K) δ 4.27 (s, 2H), 4.92 (s, 2H), 4.97 and 4.99 (2 s, 2H), 6.87 and 6.88 (2 s, 2H), 7.01 (d, J=7.5 Hz, 1H), 7.30 (t, J=7.9 Hz, 1H), 7.59-7.72 (m, 2H), 7.98 (bs, 1H), 8.31 (d, J=1.4 Hz, 1H), 8.62 (t, J=6.0 Hz, 1H), 8.76 (d, J=5.7 Hz, 1H), 9.82 (s, 1H). MS (ES) C17H17N7O2S requires: 383. found: 384 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]2)[CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([N:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[CH:36]=2)O1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:23][C:12]1[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10][N:9]([CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:35]3[CH:40]=[CH:39][N:38]=[C:37]([N:41]4[CH2:42][CH2:43][NH:44][CH2:45][CH2:46]4)[CH:36]=3)[CH:3]=2)[C:14](=[O:15])[C:13]=1[C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17]
Reactant: CC(C)c1nn(Cc2cccc(Br)c2)c(=O)c(C(=O)NCC(=O)O)c1O
Reactant: CC1(C)OB(c2ccnc(N3CCNCC3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)c1nn(Cc2cccc(-c3ccnc(N4CCNCC4)c3)c2)c(=O)c(C(=O)NCC(=O)O)c1O
Yield: 46.6 %

Procedure:
To a 5 mL microwave tube was added N-{[2-[(3-bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (example 79, 31 mg, 0.073 mmol), 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (21.13 mg, 0.073 mmol), potassium carbonate (30.3 mg, 0.219 mmol), and tetrakis(triphenylphosphine)palladium (0) (2.53 mg, 2.192 μmol) in 1,4-Dioxane (1.5 ml) and Water (0.500 ml). The mixture was irradiated at 100° C. for 20 minutes. The reaction mixture was diluted with water (3 ml) and acidified with 1N HCl. The mixture was then filtered to remove residual salts and purified by HPLC chromatography (ODS silica, gradient 10-75% acetonitrile/water (0.1% TFA)). The title compound, N-{[5-hydroxy-6-(1-methylethyl)-3-oxo-2-({3-[2-(1-piperazinyl)-4-pyridinyl]phenyl}methyl)-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (22 mg, 0.034 mmol, 46.2% yield), was obtained as a white solid tfa salt. 1H NMR (400 MHz, DMSO-d6) d ppm 15.88 (s, 1 H), 12.90 (br. s., 1H), 10.17 (t, J=5.81 Hz, 1H), 8.75 (br. s., 2H), 8.22 (d, J=5.56 Hz, 1H), 7.72 (s, 1H), 7.70 (d, J=8.59 Hz, 1H), 7.48 (t, J=7.71 Hz, 1H), 7.35 (d, J=7.58 Hz, 1H), 7.14 (s, 1H), 7.01 (dd, J=5.31, 1.01 Hz, 1H), 5.34 (s, 2H), 4.09 (d, J=5.56 Hz, 2H), 3.75-3.84 (m, 4H), 3.13-3.27 (m, 5H), 1.21 (d, J=6.82 Hz, 6H). MS (ES+) m/e 507 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].Cl[C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1>C(#N)C>[CH3:1][N:2]([C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[CH:16][N:15]=1)[CH2:3][CH2:4][NH:5][CH3:6]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CNCCNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNCCN(C)c1ncccc1[N+](=O)[O-]

Procedure:
To a solution of N,N'-dimethylethylenediamine (3.2 ml) and potassium carbonate (830 mg) in acetonitrile (15 ml) stirred at 20°-25° under a nitrogen atmosphere is added a solution of 2-chloro-3-nitropyridine (500 mg) in acetonitrile (10 ml) over one hour. The mixture is concentrated under reduced pressure and partitioned between methylene chloride (75 ml) and water (25 ml). The phases are separated and the aqueous phase is extracted with methylene chloride (25 ml) and the total organics are dried with saline and sodium sulfate. Concentration under reduced pressure gives the title compound, NMR (CDCl3) 8.29, 8.10, 6.69, 3.85, 2.90, 2.88 and 2.46δ.