Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][N:9]2[N:12]=[CH:13][C:14]([CH:15]=O)=[C:8]2[N:7]=1)[CH:2]([CH3:4])[CH3:3].[NH:17]1[CH2:23][C:21](=[O:22])[NH:20][C:18]1=[O:19].N1CCCCC1>C(#N)C>[CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][N:9]2[N:12]=[CH:13][C:14]([CH:15]=[C:23]3[NH:17][C:18](=[O:19])[NH:20][C:21]3=[O:22])=[C:8]2[N:7]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: O=C1CNC(=O)N1
Reactant: CC(C)CNc1ccn2ncc(C=O)c2n1
Solvent: C1CCNCC1
Solvent: CC#N
Product: CC(C)CNc1ccn2ncc(C=C3NC(=O)NC3=O)c2n1
Temperature: 70 °C

Procedure:
To 5-(isobutylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (24 mg, 0.110 mmol) in acetonitrile was added hydantoin (11 mg, 0.110 mmol) and piperidine (11 μL, 0.110 mmol). The reaction was heated at 70° C. for 48 hr. The reaction was cooled to room temperature and the solid formed was isolated by filtration to yield 5-((5-(isobutylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=301)
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([O:20][CH3:21])=[C:15](B(O)O)[CH:16]=1>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:20][CH3:21])=[C:13]([C:2]2[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=2)[CH:12]=1
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: N#Cc1cccc(I)c1
Product: COc1ccc(Cl)cc1-c1cccc(C#N)c1

Procedure:
The subtitle compound was prepared by the method of example 1 step (ii) using 3-iodobenzonitrile and 5-chloro-2-methoxyphenyl boronic acid. Yield 0.465 g
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[NH:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[CH2:18][N:19]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][NH:38][CH:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH3:40])[CH:32]=1)[CH:20]1[C:29]2[N:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[NH:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[CH2:18][N:19]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][N:38]([CH:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH3:40])[CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:32]=1)[CH:20]1[C:29]2[N:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:23][CH2:22][CH2:21]1
Reactant: O=Cc1ccccn1
Reactant: CC(NCc1cccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)c1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(c1ccccc1)N(Cc1cccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)c1)Cc1ccccn1
Yield: 50 %

Procedure:
Using general procedure B: Reaction of Pyridine-2-carbaldehyde (22 mg, 0.20 mmol, (1H-Benzimidazol-2-ylmethyl)-{3-[(1-phenyl-ethylamino)-methyl]-benzyl}-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (101 mg, 0.20 mmol) and sodium triacetoxyborohydride (58 mg, 0.26 mmol) in CH2Cl2 (2 mL) at room temperature under N2 for 20 h, followed by purification of the crude material by chromatography on silica gel (2:2:96 CH3OH—NH3 H2O—CH2Cl2) afforded the title compound (60 mg, 50%) as a white foam.
Reaction SMILES: [CH2:1]([O:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][NH2:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:17](OC)(=[O:22])[CH2:18][C:19]([CH3:21])=O>>[CH2:1]([O:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:22])[CH2:18][C:19]([CH3:21])=[N:16][CH2:15][CH2:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOCCCNCCN
Reactant: COC(=O)CC(C)=O
Product: CCCCCCCCOCCCN1CCN=C(C)CC1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 230.1 g (1 mole) of N-octoxypropylethylenediamine and 116.1 g (1 mole) of methyl acetoacetate. At 140° to 145° C., 18 g of water and 32 g of ethanol were distilled off to obtain 4-octoxypropyl-7-methyl-3,6-dihydro-2H-1,4-diazepin-5-one.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([CH2:56]O)[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44].C(OC(N=NC(OCC)=O)=O)C>C1(C)C=CC=CC=1.C1COCC1>[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][CH:53]([CH2:56][O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:17](=[O:18])[C:16]4[C:15]5[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=5)[NH:9][C:8]=4[C:7]([CH3:21])([CH3:22])[C:6]=3[CH:23]=2)[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.8 %

Procedure:
Under nitrogen atmosphere, 3-cyano-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound A6, 85 mg, 0.28 mmol) and triphenylphosphine (150 mg, 2 eq.) were added with THF (2 ml), and then further added dropwise with 4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (120 mg, 2 eq.) and 2.19 N toluene solution of diethyl azodicarboxylic acid (0.26 mL, 2 eq.). The resultant was stirred at room temperature for 12 hr under nitrogen atmosphere. The residues obtained after concentrating the reaction solution under reduced pressure were purified by silica gel column chromatography (ethyl acetate/dichloromethane) to obtain 4-(3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (white powder, 120 mg).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[Na+].[CH2:8]([N:15]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:16][C:17]([C:19]1[CH:27]=[C:23]([C:24]([NH-:26])=[O:25])[C:22]([OH:28])=[CH:21][CH:20]=1)=[O:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[CH2:29]([N:15]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:16][C:17]([C:19]1[CH:20]=[CH:21][C:22]([O:28][CH2:2][CH:3]([OH:6])[CH2:4][OH:5])=[C:23]([CH:27]=1)[C:24]([NH2:26])=[O:25])=[O:18])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: OCC(O)CCl
Reactant: [NH-]C(=O)c1cc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)ccc1O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: NC(=O)c1cc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)ccc1OCC(O)CO
Reaction time: 6 h

Procedure:
3-Chloropropane-1,2-diol (2.65 g) was added to a refluxing suspension of 5-(N,N-dibenzylglycyl)salicylamide sodium salt (10.0 g) in toluene (100 ml) and heating was continued for 6 hours. The mixture was cooled and filtered and the filtrate was evaporated. The residue was crystallised twice from ethanol to give the required product m.p. 169°-173°.
Reaction SMILES: [NH3:1].[C:2]([OH:9])(=[O:8])/[CH:3]=[CH:4]\[C:5]([OH:7])=[O:6]>O>[NH2:1][CH:3]([C:2]([OH:9])=[O:8])[CH2:4][C:5]([OH:7])=[O:6]
Reactant: N
Reactant: O=C(O)/C=C\C(=O)O
Solvent: O
Product: NC(CC(=O)O)C(=O)O
Yield: 95.7 %

Procedure:
The mother liquor and the washing water from Example 11 are combined. Then water and ammonia are added until 2780 ml of a 20% strength aqueous solution with a pH of 10.5 are obtained. This solution is reacted as described in Example 9 and subsequently concentrated as in Example 10. 1453 ml of a bottom product remain. D,L-aspartic acid is then precipitated as described in Example 11 by adding 323 g (2.78 mol) of maleic acid. Drying results in 382 g (2.87 mol) of D,L-aspartic acid, corresponding to a yield of 95.7% based on the amount of maleic acid added in Example 11.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH3:12].[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15].[Cl-].[Li+]>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.C1(C)C=CC=CC=1>[CH3:12][C:3]1[C:4]2[CH2:8][O:7][C:6](=[O:9])[C:5]=2[CH:10]=[CH:11][C:2]=1[CH2:15][CH:14]=[CH2:13]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1c(Br)ccc2c1COC2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: C=CCc1ccc2c(c1C)COC2=O

Procedure:
To a flask charged with 5-bromo-4-methyl-2-benzofuran-1(3H)-one (320 mg, 1.409 mmol) and a stir bar was added allyl tri-n-butyltin (0.655 ml, 2.11 mmol), Pd(PPh3)4 (244 mg, 0.211 mmol), lithium chloride (179 mg, 4.23 mmol), and toluene (15 mL). The reaction was purged with nitrogen 2 times then was heated at reflux for 4 hours. The product was separated by silica gel chromatography to give 4-methyl-5-prop-2-en-1-yl-2-benzofuran-1(3H)-one.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([CH3:14])[CH:8]=1)[C:5]#[N:6].O.[NH2:17]N>C(O)C>[CH3:13][C:11]1[CH:12]=[C:7]([C:4]2[CH:5]=[N:6][NH:2][C:3]=2[NH2:17])[CH:8]=[C:9]([CH3:14])[N:10]=1
Reactant: NN
Reactant: Cc1cc(C(C#N)=CN(C)C)cc(C)n1
Solvent: CCO
Solvent: O
Product: Cc1cc(-c2cn[nH]c2N)cc(C)n1
Yield: 39 %

Procedure:
To stirred solution of 3-dimethylamino-2-(2,6-dimethyl-pyridin-4-yl)-acrylonitrile (2.2 g, 10.9 mmol) in ethanol (22 ml) was added at room temperature hydrazine monohydrate (1.17 ml, 24.1 mmol), the reaction mixture was heated under reflux conditions for 23 h and evaporated. Purification by column chromatography on silica gel (dichloromethane/methanol/NH4OH 80:10:1) and crystallization from diethyl ether yielded 4-(2,6-dimethyl-pyridin-4-yl)-2H-pyrazol-3-ylamine (0.8 g, 39%) as a light brown solid. MS (ISP) 189.3 [(M+H)+]; mp 222° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13](/[CH:17]=[C:18]4/[C:19](=[O:30])[N:20]([CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[C:21](=[O:23])[S:22]/4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:33]([F:36])([F:35])[F:34])[CH:4]=1.[CH2:37](I)[CH3:38]>>[CH2:37]([N:27]1[CH2:28][CH2:29][CH:24]([N:20]2[C:19](=[O:30])/[C:18](=[CH:17]/[C:13]3[CH:12]=[C:11]4[C:16](=[CH:15][CH:14]=3)[N:8]([CH2:7][C:6]3[CH:31]=[CH:32][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[C:33]([F:35])([F:36])[F:34])[N:9]=[CH:10]4)/[S:22][C:21]2=[O:23])[CH2:25][CH2:26]1)[CH3:38]
Reactant: COc1ccc(Cn2ncc3cc(/C=C4\SC(=O)N(C5CCNCC5)C4=O)ccc32)c(C(F)(F)F)c1
Reactant: CCI
Product: CCN1CCC(N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(OC)cc4C(F)(F)F)c3)C2=O)CC1

Procedure:
(5Z)-3-(1-Ethylpiperidin-4-yl)-5-({1-[4-methoxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-methoxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-piperidin-4-yl-1,3-thiazolidine-2,4-dione (Example 26) and ethyl iodide following General Procedure S.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][NH:7][C:8]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])=[O:11])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br:30][CH2:31][C:32](Br)=[O:33].O>C(Cl)(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][N:7]([C:8]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])=[O:11])[C:32](=[O:33])[CH2:31][Br:30])(=[O:3])[CH3:2]
Reactant: O=C(Br)CBr
Reactant: CC(=O)OCCNc1ccc(Cl)cc1C(=O)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)OCCN(C(=O)CBr)c1ccc(Cl)cc1C(=O)c1ccccc1F

Procedure:
A mixture of 2.5g (0.0074 M) of 2-(2-acetoxyethylamino)-5-chloro-2'-fluorobenzophenone and 5g (0.0362 M) of potassium carbonate in 25 ml of dry chloroform was treated with 2.0g (0.0096 M) of bromoacetyl bromide over a 20 minute period with stirring. The mixture was stirred for 1 hour at room temperature when 25 ml of water was added, and the chloroform layer was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness. The residual oil was dissolved in 10 ml of benzene, and chromatographed over 100g of Florisil. Elution with 1 l. of benzene gave 0.2g of an oil and elution with 1.5 l. of ether and 1 l. of ethyl acetate gave 1.8g and 1.0g, respectively of a colorless oil which were combined and recrystallized from a mixture of dichloromethane and petroleum ether to give the above named product as white prisms, m.p. 84°-88°.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Br:25][C:26]1[CH:34]=[CH:33][C:29]([CH2:30][O:31][NH2:32])=[CH:28][CH:27]=1.CC([O-])=O.[Na+]>CCO>[Br:25][C:26]1[CH:34]=[CH:33][C:29]([CH2:30][O:31][N:32]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[NH:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])=[CH:28][CH:27]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: NOCc1ccc(Br)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=S(=O)(Nc1ccc(Cl)cc1C(=NOCc1ccc(Br)cc1)c1ccccc1)C(F)(F)F
Yield: 37.6 %

Procedure:
A solution of N-(2-benzoyl-4-chlorophenyl)trifluoromethanesulfonamide 25 (370 mg, 1.02 mmol), O-(4-bromobenzyl)hydroxylamine hydrochloride (270 mg, 1.13 mmol) and anhydrous NaOAc (90 mg, 1.10 mmol) in EtOH (20 mL) was stirred for 15 hours at RT. The reaction mixture was concentrated under vacuum and the residue filtered through a pad of silica (eluting with CH2Cl2/PE, 3:2). Purification by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:9) afforded N-{2-[(4-bromobenzyloxyimino)phenylmethyl]-4-chlorophenyl}trifluoromethanesulfonamide 64 (210 mg, 38%), as a yellow solid. M.p. 55-56° C. 1H n.m.r. (200 MHz, CDCl3) δ 11.32, br s, 1H, 7.66, d, J=9.0 Hz, 1H, 7.55-7.48, m, 5H, 7.33-7.20, m, 5H, 6.88, d, J=2.4 Hz, 1H, 5.11, s, 2H.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]2[N:18]([C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[CH2:17][CH2:16][N:6]2[C:7]=1[C:8](O)([CH2:12][CH2:13][CH3:14])[CH2:9][CH2:10][CH3:11])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[N:4]=[C:5]2[N:18]([C:19]3[C:20]([CH3:27])=[CH:21][C:22]([CH3:26])=[CH:23][C:24]=3[CH3:25])[CH2:17][CH2:16][N:6]2[C:7]=1[C:8]([CH2:12][CH2:13][CH3:14])=[CH:9][CH2:10][CH3:11])[CH3:2]
Reactant: CCCC(O)(CCC)c1c(CC)nc2n1CCN2c1c(C)cc(C)cc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC=C(CCC)c1c(CC)nc2n1CCN2c1c(C)cc(C)cc1C
Temperature: 25 °C

Procedure:
A mixture of 4-[2-ethyl-7-(2,4,6-trimethyl-phenyl)-6,7-dihydro-5H-imidazo[1,2-a]imidazol-3-yl]-heptan-4-ol (0.0444 g, 0.000120 mol) and p-toluenesulfonic acid-H2O (15 mole %) in toluene (3 mL) was heated at reflux for 1 h. Upon cooling to room temperature, the solvent was evaporated under reduced pressure, and the residue was partitioned between ether and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated to give the desired product in quantitative yield. LC-MS indicated the presence of two regioisomers in an approximate ratio of 2:1. LC/MS: tR=1.52 min. and 1.63 min., (MH+)=352.28.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([CH3:20])[CH2:9][C:10]1[O:14][N:13]=[C:12]([C:15]([O:17]CC)=[O:16])[CH:11]=1.O.[OH-].[Li+]>C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([CH3:20])[CH2:9][C:10]1[O:14][N:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=1
Reactant: CCOC(=O)c1cc(CC(C)OC2CCCCO2)on1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(Cc1cc(C(=O)O)no1)OC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 5-(2-(tetrahydro-2H-pyran-2-yloxy)propyl)isoxazole-3-carboxylate (1.87 g, 6.60 mmol) was dissolved in THF (20 ml). Lithium hydroxide monohydrate 1 M (6.60 ml) was added and the resulting mixture was stirred for overnight at RT. Next day more lithium hydroxide monohydrate 1 M (3.3 ml+13.20 ml) was added and the mixture was again stirred overnight. THF was evaporated, water was added and pH was adjusted to 4 with citric acid solution. The mixture was extracted four times with ethyl acetate and the combined organic phases dried and evaporated. LC-MS: [M+1]=256.27.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:6]3[N:14]([CH2:15][C:16]4([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17]4)[C:13]([CH2:22][O:23][CH2:24][CH3:25])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:38].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:38][C:8]1[C:7]2[N:12]=[C:13]([CH2:22][O:23][CH2:24][CH3:25])[N:14]([CH2:15][C:16]3([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[C:5]2[N:4]=[CH:3][C:2]([Br:1])=[CH:11][C:10]=2[N:9]=1
Reactant: CCOCc1nc2cnc3cc(Br)cnc3c2n1CC1(O)CCCC1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3cc(Br)cnc3c2n1CC1(O)CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
mCBPA (21 g of about 50% pure material, 61 mmol) was added to a solution of 1-{[7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]methyl}cyclopentanol (18.89 g, 46.6 mmol) in chloroform (190 mL), and the reaction was stirred for one hour at room temperature. Additional mCPBA (11 g) was added, and the reaction was stirred for an additional 30 minutes. Concentrated ammonium hydroxide (40 mL) was added slowly followed by p-toluenesulfonyl chloride (9.32 g, 48.9 mmol). The reaction was stirred for one hour at room temperature, and additional chloroform (600 mL) was added. The reaction was stirred for one additional hour, and additional p-toluenesulfonyl chloride (4.45 g, 23.3 mmol) and ammonium hydroxide (10 mL) were added. After the reaction mixture was stirred for an additional 1.5 hours, it was filtered to remove a precipitate. The filtrate layers were separated, and the organic phase was washed with saturated aqueous sodium bicarbonate (2×200 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue (25.86 g) was triturated with acetonitrile at 98° C., and a solid impurity was removed by filtration. The acetonitrile was removed under reduced pressure, and the residue was dissolved in chloroform. The resulting solution was washed with 1% aqueous sodium carbonate, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with 98.5:1.5 chloroform:methanol) and then triturated with acetonitrile at 98° C., isolated by filtration at room temperature, and dried in a vacuum oven at 110° C. over two nights to provide 4.83 g of 1-{[4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]methyl}cyclopentanol as a white solid, mp 166-167.5° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([CH:44]=[CH:45][C:46]=1[O:47][CH3:48])[CH2:17][C:18]1[NH:23][C:22](=[O:24])[C:21]([CH:25]([NH:28][C:29](=[O:43])[CH:30]([CH:40]([OH:42])[CH3:41])[CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:26][CH3:27])=[N:20][N:19]=1)[CH3:12].C(N(C(C)C)C(C)C)C>>[C:40]([CH:30]([CH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:29]([NH:28][CH:25]([C:21]1[C:22](=[O:24])[NH:23][C:18]([CH2:17][C:16]2[CH:44]=[CH:45][C:46]([O:47][CH3:48])=[C:14]([O:13][CH2:11][CH3:12])[CH:15]=2)=[N:19][N:20]=1)[CH2:26][CH3:27])=[O:43])(=[O:42])[CH3:41]
Reactant: CCOc1cc(Cc2nnc(C(CC)NC(=O)C(CCCc3ccccc3)C(C)O)c(=O)[nH]2)ccc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCOc1cc(Cc2nnc(C(CC)NC(=O)C(CCCc3ccccc3)C(C)=O)c(=O)[nH]2)ccc1OC

Procedure:
Analogously to Example 40A, 12.9 mg (0.10 mmol) of oxalyl chloride, 9.91 mg (0.13 mmol) of dimethyl sulphoxide, 43.0 mg (0.08 mmol) of N-{1-[3-(3-ethoxy-4-methoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}2-(1-hydroxyethyl)-5-phenylpentanamide and 32.8 mg (0.25 mmol) of N-ethyldiisopropylamine are reacted to give 2-acetyl-N-{1-[3-(3-ethoxy-4-methoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}-5-phenylpentanamide.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([O:15][CH2:16][CH:17]=O)[CH2:11][CH:12]=[CH:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].Cl.[NH2:25][OH:26]>C(O)C>[CH2:1]([O:8][CH2:9][C@H:10]([O:15][CH2:16][CH:17]=[N:25][OH:26])[CH2:11][CH:12]=[CH:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC=CC[C@H](COCc1ccccc1)OCC=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC=CC[C@H](COCc1ccccc1)OCC=NO
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a mixture of {[(2R)-1-(benzyloxy)hex-4-en-2-yl]oxy}acetaldehyde (C14) (207 g, ≦0.63 mol) and sodium acetate (342 g, 4.17 mol) in aqueous ethanol (2:1 ethanol/water, 2.1 L) was added hydroxylamine hydrochloride (207 g, 2.98 mol). The reaction mixture was stirred at 60° C. for 18 hours, then concentrated in vacuo and extracted with ethyl acetate (2.0 L). The combined organic layers were dried over sodium sulfate, filtered, concentrated under reduced pressure and purified by chromatography on silica gel (Eluent: ethyl acetate in petroleum ether) to afford the product as a brown oil. By 1H NMR, this was assigned as a mixture of geometric isomers at both the oxime and olefin functional groups. Yield: 117 g, 0.444 mol, 70% over three steps. 1H NMR (400 MHz, CDCl3), characteristic peaks: δ [7.42-7.48 (m) and 6.88-6.92 (m), total 1H], 7.20-7.36 (m, 5H), 5.29-5.61 (m, 2H), [4.48-4.54 (m) and 4.41-4.45 (m), total 3H], 2.13-2.32 (m, 2H), 1.54-1.65 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C[Al](C)C.CCCCCCC.C[O:21][C:22]([C:24]1[C:29]([NH:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[N:28][CH:27]=[CH:26][N:25]=1)=O>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:22]([C:24]2[C:29]([NH:30][C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)=[N:28][CH:27]=[CH:26][N:25]=2)=[O:21])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1nccnc1Nc1cccnc1
Reactant: Nc1cccc(Cl)c1
Agent: C[Al](C)C
Solvent: CCCCCCC
Solvent: C1COCCO1
Product: O=C(Nc1cccc(Cl)c1)c1nccnc1Nc1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Chloroaniline (140 mg, 1.1 mmol) was dissolved in 4 mL dioxane and trimethylaluminium-solution 2M in heptane (0.55 mL, 1.1 mmol) was added. The solution was stirred for 1 hr at room temperature and 3-(pyridin-3-ylamino)-pyrazine-2-carboxylic acid methyl ester (127 mg, 0.55 mmol) was added. The reaction mixture was stirred for 2 hrs at 80° C., cooled and quenched with 0.5 mL water. Sodium sulfate was added, stirred for 10 minutes, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethyl acetate 1:2->0:100 gradient) and the desired product was obtained as a yellow solid (13 mg, 7.2%), MS: m/e=326.2 (M+H+).
Reaction SMILES: C([O:8][C:9](=[O:27])[C@H:10]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:11][C:12]([N:14]1[CH2:19][CH2:18][S:17][CH2:16][CH2:15]1)=[O:13])C1C=CC=CC=1.[OH-].[Na+]>CO.O>[S:17]1[CH2:18][CH2:19][N:14]([C:12]([NH:11][C@H:10]([C:9]([OH:27])=[O:8])[CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:13])[CH2:15][CH2:16]1
Reactant: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)NC(=O)N1CCSCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)[C@H](Cc1ccccc1)NC(=O)N1CCSCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a solution of N-thiomorpholinocarbonyl-L-phenylalanine benzyl ester (526 mg) in a mixture of methanol (10 ml) and water (10 ml) which was cooled to 0° C., was added lN sodium hydroxide solution (4 ml). The mixture was stirred at the same temperature for 1 hour. After evaporation of methanol, remaining aqueous solution was washed with diethyl ether, acidified to pH 2.5 with 3N hydrochloric acid and extracted with ethyl acetate (30 ml×3). The extract was washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure to give N-thiomorpholinocarbonyl-L-phenylalanine (382 mg) as an oil.