Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5](=[O:38])[NH:6][C:7](=[O:37])[N:8]([CH:36]=1)[C@@H:9]1[O:35][C@H:13]([CH2:14][O:15]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C@@H:11]([OH:12])[CH2:10]1.Cl[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1>CS(C)=O>[F:3][C:4]1[C:5](=[O:38])[NH:6][C:7](=[O:37])[N:8]([CH:36]=1)[C@@H:9]1[O:35][C@H:13]([CH2:14][OH:15])[C@@H:11]([O:12][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[CH2:10]1
Reactant: Clc1ccccn1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](Oc3ccccn3)[C@@H](CO)O2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A 0.30 g quantity of sodium hydride (60%, dispersion in mineral oil) was added to a solution of 2.00 g of 2'-deoxy-5-fluoro-5'-O-trityluridine in 10 ml of dimethyl sulfoxide. The mixture was stirred at room temperature for 30 minutes. To the mixture was added 0.46 ml of 2-chloropyridine. Then the mixture was stirred at 80° C. for 3 hours. The solvent was distilled off and the residue was dissolved in 50 ml of ethyl acetate and 30 ml of water. The solution was made into a weak acidic solution by addition of 6N-hydrochloric acid. The ethyl acetate layer was separated, washed with water and concentrated. The residue was dissolved with heating in 20 ml of 80% acetic acid. The solution was left to stand at 80° C. for 1 hour and concentrated. The residue was dissolved in 50 ml of ethyl acetate, and the solution was washed with water, dried on anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography using 1% methanol-chloroform as an eluent, giving 1.06 g of 2'-deoxy-5-fluoro-3'-O-(2-pyridyl)uridine in a yield of 80%.
Reaction SMILES: [H-].[Na+].[C:3]([NH:10][NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]>CN(C=O)C>[C:3]([N:10]1[CH2:18][CH2:17][CH2:16][CH2:15][N:11]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CC(C)(C)OC(=O)NNC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCCN1C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
1.5 g (37.5 mmol) of 60% sodium hydride in oil was suspended in 50 mL of DMF to which was added 5.0 g (18.7 mmol) of 1-Boc-2-Cbz-hydrazine dissolved in 20 mL of dry DMF slowly over 30 minutes. The reaction mixture was stirred for 1 hour until H2 evolution had ceased. To this mixture was added 2.24 mL (18.77 mmol) of 1,4-dibromobutane neat. The reaction mixture was stirred at room temperature over 3 days. The mixture was concentrated in vacuo and the residue was suspended in 150 mL of EtOAc. The mixture was washed with water twice, 5% citric acid twice, saturated aqueous NaHCO3 solution , water and brine. The solution was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography over silica gel eluting with 30% EtOAc/hexanes to give the desired product as a white solid. 1H-NMR (CDCl3, 400 MHz):1.45 (bs, 9H); 1.62 (bm, 4H); 2.90 (bs, 2H); 4.15 (bm, 2H); 5.00-5.30 (m, 2H); 7.20-7.40 (bm, 5H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([CH3:11])[CH:9]=[N:8][C:5]2=[N:6][CH:7]=1.[NH2:12][C:13]1[C:22]2[C:17](=[C:18](Br)[C:19]([CH3:23])=[CH:20][CH:21]=2)[N:16]=[N:15][C:14]=1[C:25]([NH2:27])=[O:26]>>[NH2:12][C:13]1[C:22]2[C:17](=[C:18]([C:2]3[CH:3]=[C:4]4[N:10]([CH3:11])[CH:9]=[N:8][C:5]4=[N:6][CH:7]=3)[C:19]([CH3:23])=[CH:20][CH:21]=2)[N:16]=[N:15][C:14]=1[C:25]([NH2:27])=[O:26]
Reactant: Cn1cnc2ncc(Br)cc21
Reactant: Cc1ccc2c(N)c(C(N)=O)nnc2c1Br
Product: Cc1ccc2c(N)c(C(N)=O)nnc2c1-c1cnc2ncn(C)c2c1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 96 using 6-bromo-1-methyl-1H-imidazo[4,5-b]pyridine and 4-amino-8-bromo-7-methylcinnoline-3-carboxamide. 1H NMR (400 MHz, CD3OD) δ ppm 2.37 (s, 3 H), 3.98 (s, 3 H), 7.76 (d, J=9.09 Hz, 1 H), 8.09 (d, J=1.77 Hz, 1 H), 8.29 (d, J=8.59 Hz, 1 H), 8.39 (d, J=2.02 Hz, 1H), 8.47 (s, 1 H); ESI-MS m/z [M+H]+ 334.2.
Reaction SMILES: C([S:4][CH2:5][CH:6]([S:18][CH3:19])[C:7]([N:9]1[CH2:16][C:15](=[O:17])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=O)C.N>>[SH:4][CH2:5][CH:6]([S:18][CH3:19])[C:7]([N:9]1[CH2:16][C:15](=[O:17])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8]
Reactant: CSC(CSC(C)=O)C(=O)N1CC(=O)C[C@H]1C(=O)O
Agent: N
Product: CSC(CS)C(=O)N1CC(=O)C[C@H]1C(=O)O

Procedure:
The product from part (c) is hydrolyzed with concentrated ammonia according to the procedure of Example 2 to yield 1-(3-mercapto-2-methylthio-1-oxopropyl)-4-oxo-L-proline.
Reaction SMILES: I[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[N:5]=[CH:4][CH:3]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[C:16]([F:23])[C:15]=1[F:24].C([O-])([O-])=O.[Na+].[Na+]>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>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[N:5]=[CH:4][CH:3]=2)=[C:16]([F:23])[C:15]=1[F:24]
Reactant: OB(O)c1ccc(Br)c(F)c1F
Reactant: COC(=O)c1c(I)ccnc1C
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: O
Solvent: C1COCCO1
Product: COC(=O)c1c(-c2ccc(Br)c(F)c2F)ccnc1C
Temperature: 110 °C
Yield: 43.8 %

Procedure:
In a microwave vessel, methyl 4-iodo-2-methylnicotinate (1.00 g, 3.61 mmol) was taken in a mixture of 1,4-dioxane (18 mL) and water (2 mL) under inert atmosphere. (4-bromo-2,3-difluorophenyl)boronic acid (1.03 g, 4.33 mmol) and Na2CO3 (765 mg, 7.22 mmol) were added to the reaction mixture and degassed for 5 minutes. Pd(Ph3P)4 (83 mg, 0.072 mmol) was added to the reaction mixture and heated in microwave at 110° C. for 90 min. The reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (200 mL). The organic phase was washed with brine (2×100 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (gradient of ethyl acetate and petroleum ether) to afford methyl 4-(4-bromo-2,3-difluorophenyl)-2-methylnicotinate (540 mg, 1.58 mmol, 44% yield) as a yellow liquid. LC/MS (ESI) m/e 344.0 [(M+2H)+, calcd for C14H12BrF2NO2 344.1]; LC/MS retention time (method C): tR=2.48 min.
Reaction SMILES: [C:1]([O:5]C)(=O)[CH:2]=[CH2:3].[CH2:7]([NH2:10])[CH2:8][NH2:9].C[O:12][C:13](=O)[CH2:14][CH2:15][NH:16][CH2:17][CH2:18][NH2:19]>O>[NH:9]1[CH2:3][CH2:2][C:1](=[O:5])[NH:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][C:13](=[O:12])[NH:10][CH2:7][CH2:8]1
Reactant: COC(=O)CCNCCN
Reactant: C=CC(=O)OC
Reactant: NCCN
Solvent: O
Product: O=C1CCNCCNC(=O)CCNCCN1
Reaction time: 4 h

Procedure:
Methyl acrylate (344 g, 4.0 moles) was added dropwise into neat ethylenediamine (240 g, 4.0 moles) while stirring. Addition was conducted at such a rate that the reaction temperature did not exceed 45° C. Addition time was 4.0 hours. The crude colorless product, N-(2-aminoethyl)-β-alanine methyl ester (580 g), was dissolved in deionized water to give a concentration of about 25 weight percent. Allowing the solution to stand at room temperature for 2-3 days caused a white solid product to slowly precipitate. The product was obtained as a fine white powder, m.p. 198° C.-199° C. Spectral analysis confirmed the product's structure as
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[NH:7]1[C:8]2[C:4](=[CH:3][CH:2]=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:11]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13]
Reactant: C1CCNCC1
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Product: O=C(c1cc2ccccc2[nH]1)N1CCCCC1
Yield: 92 %

Procedure:
Treat 1H-indole-2-carboxylic acid 3 (X═H, 750 mg, 4.66 mmol) with piperidine (3.0 equiv., 1.4 mL, 13.98 mmol) as described in General Synthetic Procedure VIa to afford 1H-indol-2yl-piperidin-1-yl-methanone 8 (X═H, R4=piperidin-1-yl; 979 mg, 92%) as a white solid, mp 161-162° C. 1H NMR (DMSO-d6) δ 11.5 (s, 1H), 7.6 (d, 1H), 7.4 (d, 1H), 7.2 (t, 1H), 7.1 (t, 1H), 6.7 (s, 1H), 3.7 (m, 4H), 1.7-1.5 (m, 6H). Treat 1H-indol-2yl-piperidin-1-yl-methanone (456 mg, 2.0 mmol) with phenyldisulfide (480 mg, 2.2 mmol) as described in General Synthetic Procedure VIIa to afford the title compound Ix (440 mg, 65%) as an opaque oil. 1H NMR (DMSO-d6) δ 12.1 (brs, 1H), 7.5 (d, 1H), 7.4 (d, 1H), 7.3-7.1 (m, 3H), 7.1-7.0 (m, 4H), 6.7 (s, 1H), 3.6 (m, 2H), 3.4 (s, 8H), 3.2 (m, 2H), 1.8 (m, 4H), 1.4 (m, 2H). m/z=337 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([N:18]=[N+:19]=[N-:20])[CH2:12]2)=[C:4]([NH:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[N:3]=1>C(OCC)(=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([N:18]=[N+:19]=[N-:20])[CH2:12]2)=[C:4]([N:21]2[CH2:22][CH2:23][CH2:25][CH2:24]2)[N:3]=1
Reactant: [N-]=[N+]=N[C@H]1C[C@H](n2cnc3c(NCC4CC4)nc(N)nc32)O[C@@H]1CO
Solvent: CCOC(C)=O
Product: [N-]=[N+]=N[C@H]1C[C@H](n2cnc3c(N4CCCC4)nc(N)nc32)O[C@@H]1CO
Yield: 52 %

Procedure:
The title compound was prepared in a manner analogous to the preparation of 2-Amino-9-(3-azido-2,3-dideoxy-β-D-erythropentofuranosyl)-6-cyclopropylmethylamino-9H-purine (Example 15b). The reaction was worked up in an analogous manner except the combined ethyl acetate fractions were back washed with 150 mL of 1M potassium carbonate two times prior to chromatography. The product was isolated in 52% yield, 0.360 g, mp=180°-183°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([C:32]#[N:33])=[CH:31][C:18]3=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>CCO.[Ni]>[NH2:33][CH2:32][C:30]1[CH:29]=[CH:28][C:19]2[O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:17](=[CH:16][CH2:15][CH2:14][N:11]3[CH2:12][CH2:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)([OH:34])[CH2:9][CH2:10]3)[C:18]=2[CH:31]=1
Reactant: N#Cc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1ccccc1CO2
Agent: [Ni]
Solvent: CCO
Product: NCc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1ccccc1CO2
Reaction time: 2 h
Yield: 33.9 %

Procedure:
To a solution of 4-(4-chlorophenyl)-1-[3-(2-cyano-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)propyl]piperidin-4-ol (380 mg) in EtOH (20 ml) were added Raney nickel (50% slurry in water, 60 mg), and the mixture was hydrogenated at 15 psi for 2 hours. The mixture was filtered through the celite and distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with dichloromethane-methanol-aqueous ammonium (95:5:1) to give the titled compound (130 mg).
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:23]=[C:22]([NH:24][CH2:25][C@H:26]3[O:31][CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]3)[C:21]3[C:16](=[N:17][CH:18]=[CH:19][N:20]=3)[CH:15]=2)=[CH:10][CH:9]=1)(=[O:4])=[O:3]>Cl.CC(=O)OCC>[CH3:1][S:2]([CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:23]=[C:22]([NH:24][CH2:25][C@H:26]3[O:31][CH2:30][CH2:29][NH:28][CH2:27]3)[C:21]3[C:16](=[N:17][CH:18]=[CH:19][N:20]=3)[CH:15]=2)=[CH:12][CH:13]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CNc2nc(-c3ccc(OCCS(C)(=O)=O)cc3)cc3nccnc23)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)CCOc1ccc(-c2cc3nccnc3c(NC[C@@H]3CNCCO3)n2)cc1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
(R)-tert-butyl 2-((7-(4-(2-(methylsulfonyl)ethoxy)phenyl)pyrido[4,3-b]pyrazin-5-ylamino)methyl)morpholine-4-carboxylate (76 mg, 0.14 mmol) was dissolved in a solution of HCl/EA (5 N, 5 mL) and stirred for 4 hours at 20° C. The reaction was concentrated and washed with sat. NaHCO3, water and brine, concentrated and purified on TLC (CH2Cl2:MeOH=5:1) to give yellow solid. MS (m/z): 444 (M+H)+
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4](=[O:17])[C:5]2[CH:16]=[CH:15][C:14]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[C:6]=2[O:7][CH:8]=1.O.O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].O>C(O)(=O)C>[CH:2]([C:3]1[C:4](=[O:17])[C:5]2[CH:16]=[CH:15][C:14]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[C:6]=2[O:7][CH:8]=1)=[O:1]
Reactant: O=c1c(CO)coc2c3c(ccc12)CCCC3
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1coc2c3c(ccc2c1=O)CCCC3
Temperature: 60 °C

Procedure:
This compound is prepared by adding a mixture of 23.0 g (0.1 mole) of 3-(hydroxymethyl)-7,8,9,10-tetrahydro-4H-naphtho-[1,2-b]pyran-4-one and 150 ml of glacial acetic acid to a solution of 29.8 g (0.1 mole) of sodium dichromate dihydrate in 150 ml of glacial acetic acid, keeping the temperature at about 50°C with cooling. After the initial exotherm, the reaction is heated at 60°C for one-half hour, water (1-liter) is added, and the mixture is heated at 75°C for about one-half hour to generate a precipitate. The cooled mixture is filtered and the crude product is purified by dissolving in methylene chloride and filtering through a layer of silica gel. The aldehyde is obtained by removal of solvent from the filtrate. ##SPC32##
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[OH:26][NH:27][C:28](=N)[C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1>>[CH:23]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:26][N:27]=[C:28]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[N:2]=3)[CH2:8][CH2:7]2)[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Reactant: N=C(NO)c1ccncc1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2nc(-c3ccncc3)no2)CC1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and N-hydroxy-isonicotinamidine following a procedure analogous to that described in Example 1. LC (method 6): tR=1.51 min; Mass spectrum (ESI+): m/z=457 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3I)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]([OH:25])([C:23]#[CH:24])[CH:21]=[CH2:22]>C(N(CC)CC)C.CN(C)C=O.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.[Cu]I>[Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:22]#[C:21][C:20]([OH:25])([CH3:19])[CH:23]=[CH2:24])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(I)ncn2-c2cccc(Cl)c2C1=O
Reactant: C#CC(C)(O)C=C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CC(C)(O)C#Cc1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Yield: 63.5 %

Procedure:
7.47 g (20 mmol) of 7-chloro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one, 2.88 g (30 mmol) of 3-methyl-1-penten-4-yn-3-ol, 110 mg of bis(triphenylphosphine)-palladium(II) dichloride and 35 mg of copper(I) iodide were heated to boiling under reflux for 12 hours in 60 ml of triethylamine and 30 ml of dimethyl-formamide. The reaction mixture was evaporated and the residue was chromatographed on silica gel while eluting with ethyl acetate. By recrystallization of the residue from acetonitrile there was obtained 4.34 g (63%) of 7-chloro-4,5-dihydro-3-(3-hydroxy-3-methyl-4-penten-1-ynyl)-5-methyl-6H-imidazo[1,5-a][1,4-]benzodiazepin-6-one of melting point 185-187°.
Reaction SMILES: [CH3:1][C:2]([OH:13])([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3]C.[CH3:14]C(O)(CCCCCCC)CCC>>[CH3:3][C:2]([OH:13])([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:14])[CH3:1]
Reactant: CCCCCCCC(C)(O)CCC
Reactant: CCCCCCCCC(C)(O)CC
Product: CCCCCCCCCC(C)(C)O

Procedure:
3-methyl-3-undecanol; 4-methyl-4-undecanol;
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Sn](CCCC)(CCCC)[C:45]([O:47]CC)=[CH2:46])CCC>O1CCOCC1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[C:45]([C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1)(=[O:47])[CH3:46]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
A mixture of tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (5.0 g, 14.6 mmol), palladium diacetate (240 mg, 1.46 mmol), triphenylphosphine (376 mg, 2.92 mmol) and tributyl(1-ethoxyvinyl)stannane (5.3 mL, 16.1 mL) in dioxane (100 mL) was degassed with nitrogen for three times, and the reaction mixture was stirred at 80° C. overnight. The reaction was cooled to RT and diluted with THF (100 mL), followed by the addition of 2 N HCl (100 mL). The mixture was stirred at RT for 30 mins, and LCMS showed the reaction was completed. The reaction mixture was diluted with ethyl acetate (200 mL). The organic phase was separated, washed with water (3×100 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography to afford the title compound (3.0 g, 67%). MS (ES+) C15H22N4O3 requires: 306. found: 251 [M−56+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[N:21]1([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[CH:25]=[CH:24][CH:23]=[N:22]1.C([O-])(=O)C.[NH4+].C(O)C>C(OCC)C>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:29]([C:28]3[CH:31]=[CH:32][CH:33]=[C:26]([N:21]4[CH:25]=[CH:24][CH:23]=[N:22]4)[CH:27]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1cccc(-n2cccn2)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCO
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4cccc(-n5cccn5)c4)nc23)[C@H]2C=C[C@@H]1C2
Temperature: 80 °C

Procedure:
(1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50.00 mg, 0.1702 mmol), 3-Pyrazol-1-yl-benzaldehyde (32.2 mg, 0.187 mmol), and Ammonium acetate (26.2 mg, 0.340 mmol) were combined in Ethanol (2.21 mL, 37.8 mmol) in a reaction tube and heated at 80° C. overnight. Upon cooling, a precipitate formed. Reaction was diluted with 3 ml ethyl ether and cooled in an ice/water bath. The resulting solid was filtered, washed with cold ether and dried under hi-vacuum. Product is a white solid. Yield: 41.35 mg (54%) of the title compound. (300 MHz, DMSO-d6) 13.39 (s, 1H), 8.68 (s, 1H), 8.53 (s, 1H), 8.06 (d, J=7.6 Hz, 1H), 7.98 (s, 1H), 7.93 (d, J=8 Hz, 1H), 7.81 (m, 2H), 7.67 (t, J=16 Hz, 8 Hz, 1H), 7.32 (d, J=8 Hz, 1H), 7.25 (s, 1H), 6.62 (s, 1H), 6.53 (s, 1H), 6.39 (s, 1H), 5.15 (t, J=17 Hz, J=9 Hz, 1H), 2.89 (d, J=17 Hz, 2H), 2.63 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.39 (d, J=8 Hz, 1H). MS=446 (M+H), HPLC: 2.51 min. (G Method)
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C@@H:3]1[CH2:7][N:6]([C:8]2[C:12]([N+:13]([O-])=O)=[CH:11][N:10]([CH3:16])[N:9]=2)[C:5](=[O:17])[CH2:4]1>[C].[Pd].CO>[NH2:13][C:12]1[C:8]([N:6]2[CH2:7][C@@H:3]([N:2]([CH3:1])[CH3:18])[CH2:4][C:5]2=[O:17])=[N:9][N:10]([CH3:16])[CH:11]=1
Reactant: CN(C)[C@H]1CC(=O)N(c2nn(C)cc2[N+](=O)[O-])C1
Agent: [Pd]
Solvent: CO
Product: CN(C)[C@H]1CC(=O)N(c2nn(C)cc2N)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
A mixture of (4S)-4-(dimethylamino)-1-(1-methyl-4-nitro-1H-pyrazol-3-yl)pyrrolidin-2-one (69.9 mg), 10% palladium-carbon (24.9 mg) and methanol (1.38 mL) was stirred at room temperature for 1 hr under hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (55.6 mg).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Br:25]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:25])[N:6]2[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: BrBr
Reactant: Nc1nc(NC2CCCCC2)nc2c1ncn2Cc1ccccc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Nc1nc(NC2CCCCC2)nc2c1nc(Br)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
6-Amino-9-benzyl-2-cyclohexylaminopurine (100 mg, 0.31 mmol) and bromine (0.5 ml) were dissolved in 50 ml of methylene chloride and the solution was stirred at room temperature for 1 hour. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on sodium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (105 mg, yield 84%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][C:9](=[O:19])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][C:25]([CH2:32][CH3:33])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(=O)([O-])[O-].[Ag+2].CN(C)C=O>[CH2:32]([C:25]([CH3:31])([CH2:24][CH2:23][CH2:22][CH2:21][O:19][C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:10]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:33]
Reactant: O=c1cc(-c2ccccc2)cc(-c2ccccc2)[nH]1
Reactant: CCOC(=O)C(C)(CC)CCCCBr
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(CC)CCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1
Temperature: 100 °C

Procedure:
The procedure in Example 5 is followed but using 4,6-diphenyl-2-pyridinone (3 g), ethyl 6-bromo-2-ethyl-2-methylhexanoate (6.44 g) [prepared according to the method of K. E. MOELLER, Brenstoff-Chem., 47, 10 (1966)], silver carbonate (1.68 g) and dimethylformamide (110 cc). The reaction mixture is heated at 100° C. for 121 hours. The product is purified by chromatography under pressure on silica gel (30-60 mm; eluent: n-hexane-ethyl acetate 9-1).(yellow oil)
Reaction SMILES: [C:1]([OH:6])(=O)[CH:2]([CH3:4])[CH3:3].[NH2:7][CH:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1>>[OH:14][CH:11]1[CH2:12][CH2:13][CH:8]([NH:7][C:1](=[O:6])[CH:2]([CH3:4])[CH3:3])[CH2:9][CH2:10]1
Reactant: CC(C)C(=O)O
Reactant: NC1CCC(O)CC1
Product: CC(C)C(=O)NC1CCC(O)CC1

Procedure:
Prepared as in Example 24a from isobutyric acid and 4-aminocyclohexanol as a colorless oil (44%). MS 186 (MH+).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:29])[C:15]2[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=2[CH:18]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4c(C)cccc4C)c3O2)cc1
Product: CNCC1Cc2cc(Cl)cc(-c3c(C)cccc3C)c2O1

Procedure:
The title compound was prepared (0.155 g, 62%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.333 g, 0.74 mmol) and methylamine (0.231 g, 7.4 mmol). mp 229-231° C.