Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=O)=[CH:6][CH:5]=1)([O-])=O.[CH3:15][CH2:16][O:17]C(C)=O.CCO>O.[CH]Cl.[Pd]>[CH:13]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][C:4]=1[NH:1][C:16](=[O:17])[CH3:15]
Reactant: CCOC(C)=O
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Agent: [CH]Cl
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1ccc2c(c1)CCCC2
Temperature: 20 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
A solution of 7-nitro-3,4-dihydro-1(2H)-naphthalenone (1.67 g, 8.7 mmol) in EtOAc/EtOH (1:1, 150 mL), water (15 mL) and cHCl (2 mL) with Pd/C (5%, 500 mg) was stirred vigorously under H2 (60 psi) for 16 h. The suspension was filtered through Celite, washed with EtOH (4×10 mL) and the organic solvent evaporated. The aqueous residue was partitioned between DCM and dilute aqueous NH3 solution and the organic fraction dried and the solvent evaporated. The residue was dissolved in dioxane (20 mL), and AcO (1.8 mL, 19.2 mmol) was added dropwise to the solution at 0° C. The solution was stirred at 20° C. for 16 h, diluted with water (50 mL), and partitioned between EtOAc and dilute aqueous NH3 solution. The organic fraction was washed with water (3×20 mL), dried and the solvent evaporated to give N-(5,6,7,8-tetrahydro-2-naphthalenyl)acetamide 166 (1.57 g, 95%) as a white solid: 1H NMR δ 7.18-7.25 (m, 2H, H-1, NH), 7.15 (dd, J=8.2, 2.1 Hz, 1H, H-3), 7.00 (d, J=8.2 Hz, 1H, H-4), 2.69-2.77 (m, 4H, 2×CH2), 2.15 (s, 3H, CH3), 1.74-1.80 (m, 4H, 2×CH2). The procedure was repeated a number of times to give N-(5,6,7,8-tetrahydro-2-naphthalenyl)acetamide 166 (10.21 g, 88% overall).
Reaction SMILES: [S:1]1[C:5]([C:6](O)=O)=[CH:4][N:3]=[CH:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)[N:27]=[N:26][C:24]=2C=1.CN1CCOCC1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:46])=CC=1>>[S:46]1[CH:24]=[N:26][N:27]=[C:6]1[C:5]1[S:1][CH:2]=[N:3][CH:4]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cncs1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: CN1CCOCC1
Product: c1ncc(-c2nncs2)s1
Yield: 44 %

Procedure:
The ester or 1,3,4-thiadiazole substituted thiazoles at ring B may be prepared as shown in Scheme 12. Typical conversion of the carboxylic acid 55 to amide functionality via acyl chloride and the following thionation using Lawesson's reagent produce the corresponding thioamide, which is treated with ethyl 2-chloro-2-formylacetate and pyridine in refluxed ethanol to provide the corresponding thiazole-5-carboxylic acid 56 in 35% over four steps. The ester 56 is hydrolysed under basic conditions to generate the corresponding acid. Next, this acid is coupled with formyl hydrazide under conditions of EDCI, HOBt, and NMM. Following cyclization using Lawesson's reagent produced 5-(1,3,4-thiadiazol-2-yl)-thiazole 57 in 44% yield for the four steps.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11].[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]=[C:37]=[O:38].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:19][C:18]1[N:17]=[CH:16][C:15]2[C:20]([C:23]3[CH2:24][CH2:25][N:26]([C:37]([NH:36][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[Cl:29])=[O:38])[CH2:27][CH:28]=3)=[CH:21][O:22][C:14]=2[C:13]=1[O:12][C@@H:10]([C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1])[CH3:11]
Reactant: O=C=Nc1ccccc1Cl
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCN(C(=O)Nc4ccccc4Cl)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 7-[(R)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy]-3-(1,2,3,6-tetrahydropyridin-4-yl)-furo[3,2-c]pyridin-6-ylamine (10.0 mg, 0.0237 mmol), 2-chlorophenylisocyanate (0.00669 g, 0.0436 mmol), DIPEA (0.033 mL, 0.19 mmol) in DMF (1 mL) was stirred at rt for 15 min. Purification by HPLC afforded the title compound as a light yellow solid. 1H NMR (400 MHz, CD3OD): δ=1.89 (d, J=6.6 Hz, 3H), 2.59 (br. s., 2H), 3.78 (t, J=5.8 Hz, 2H), 4.28 (d, J=2.5 Hz, 2H), 6.32 (br. s., 1H), 6.45-6.55 (m, 1H), 7.08-7.17 (m, 1H), 7.18-7.32 (m, 2H), 7.36-7.46 (m, 2H), 7.60 (dd, J=8.1, 1.5 Hz, 1H), 7.69 (s, 1H), 8.23 (br. s., 1H). MS (ES+): m/z 575.03/577.01 (98/100) [MH+]. HPLC: tR=3.63 min (ZQ3, polar—5 min).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([O:9][C:10](=[O:30])[NH:11][C:12]1([C:15]3[CH:20]=[CH:19][C:18](B4OC(C)(C)C(C)(C)O4)=[CH:17][CH:16]=3)[CH2:14][CH2:13]1)[CH2:2]2.Br[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][N:33]=1>>[F:38][C:35]1[CH:36]=[CH:37][C:32]([C:18]2[CH:19]=[CH:20][C:15]([C:12]3([NH:11][C:10](=[O:30])[O:9][C@H:3]4[CH:4]5[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]5)[CH2:2]4)[CH2:14][CH2:13]3)=[CH:16][CH:17]=2)=[N:33][CH:34]=1
Reactant: CC1(C)OB(c2ccc(C3(NC(=O)O[C@@H]4CN5CCC4CC5)CC3)cc2)OC1(C)C
Reactant: Fc1ccc(Br)nc1
Product: O=C(NC1(c2ccc(-c3ccc(F)cn3)cc2)CC1)O[C@@H]1CN2CCC1CC2
Yield: 34 %

Procedure:
Using general procedure E, (S)-quinuclidin-3-yl(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)phenyl)cyclopropyl)carbamate, 2-bromo-5-fluoropyridine and [PdCl2(pddf)]CH2Cl2 gave the title compound as a white solid (34%). 1H NMR (500 MHz, CDCl3) δ 8.51-8.52 (d, J=3.5 Hz, 1H), 7.87-7.85 (d, J=10.5 Hz, 2H), 7.69-7.67 (m, 1H), 7.47-7.42 (m, 1H), 7.32-7.27 (m, 2H), 5.79-5.66 (d, 1H), 4.73-4.71 (t, J=5.0 Hz, 1H), 3.22-3.19 (m, 1H), 2.87-2.61 (m, 5H), 2.01-1.22 (m, 9H) ppm. 13C NMR (125 MHz, CDCl3) δ 160.8, 157.4, 156.1, 153.5, 144.4, 137.8, 136.3, 126.7, 125.7, 124.9, 123.6, 121.1, 71.6, 55.7, 47.4, 46.5, 35.3, 29.7, 25.4, 24.8, 19.4, 18.2 ppm. Purity: >99% LCMS (214 nm & 254 nm); retention time 1.41 min; (M+1) 382.2.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:19]=[CH:18][C:17]2[C:8]3[NH:9][C:10](=[O:16])[C:11]4[N:12]([CH:13]=[CH:14][N:15]=4)[C:7]=3[CH2:6][C:5]=2[CH:4]=1.C(N(CC)CC)C.[C:27]([N:31]=[C:32]=[O:33])([CH3:30])([CH3:29])[CH3:28].CN(C)C=O>O>[C:27]([NH:31][C:32](=[O:33])[NH:2][C:3]1[CH:19]=[CH:18][C:17]2[C:8]3[NH:9][C:10](=[O:16])[C:11]4[N:12]([CH:13]=[CH:14][N:15]=4)[C:7]=3[CH2:6][C:5]=2[CH:4]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)N=C=O
Reactant: Nc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)NC(=O)Nc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12

Procedure:
The preparation is carried out as in Example 7, from 1.2 g of 8-amino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one hydrochloride, 1.8 ml of triethylamine, 2 times 0.6 ml of tert-butyl isocyanate and 25 ml of dimethylformamide. After addition of 100 ml of distilled water to the reaction mixture, the precipitate formed is filtered and recrystallized from dimethylformamide. The solid thus obtained is washed with water, then with ethyl ether and dried under reduced pressure (1 mm Hg, 0.13 kPa) at 80° C. There is obtained 0.31 g of 8-(3-tert-butylureido)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one in the form of a brown solid, the melting point of which is greater than 260° C. (Analysis C18H19N5O2 0.83H2 0.0.03DMF, % calculated C: 64.08, H: 5.68, N: 20.76, % found C: 63.7, H: 5.9, N: 20.6).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH:23]1([CH:26]([NH2:30])[CH:27]2[CH2:29][CH2:28]2)[CH2:25][CH2:24]1>>[CH:23]1([CH:26]([CH:27]2[CH2:29][CH2:28]2)[NH:30][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:21])[CH2:25][CH2:24]1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: NC(C1CC1)C1CC1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NC(C4CC4)C4CC4)cc3)c2)o1

Procedure:
N-Dicyclopropylmethyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and dicyclopropylmethylamine using method I.
Reaction SMILES: [SH:1][C:2]1[N:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4]([CH2:7][OH:8])=[N:5][N:6]=1.[OH-:15].[Na+].Br[CH2:18]C.OO>>[CH3:18][S:1]([C:2]1[N:3]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:4]([CH2:7][OH:8])=[N:5][N:6]=1)=[O:15]
Reactant: [OH-]
Reactant: CCBr
Reactant: OCc1nnc(S)n1-c1ccccc1
Agent: OO
Agent: [Na+]
Product: CS(=O)c1nnc(CO)n1-c1ccccc1

Procedure:
Refer to Chart F. One equivalent of 5-mercapto-4-phenyl-4H-1,2,4-triazole-3-methanol (Formula XXIII of Chart B, R24 is hydroxymethyl, R5 is phenyl, n is zero) is prepared according to Chart B. One equivalent of this compound is treated with sodium hydroxide and bromoethane. This product is then oxidized with aqueous hydrogen peroxide to yield 5-methylsulfinyl-4-phenyl-4H-1,2,4-triazole-3-methanol. This product is further oxidized by treating it with m-chlorobenzoic acid at 25° C. for 24 hrs to yield the titled product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][C:23]1([CH3:43])[C:35]2[CH:34]=[C:33]3[NH:36][C:37]4[C:42]([C:32]3=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:41]N=[CH:39][CH:38]=4.[C:44](P(C(C)(C)C)C(C)(C)C)(C)(C)C>CC1C=CC(C)=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:22][C:23]1([CH3:43])[C:35]2=[CH:34][C:33]3[N:36]([C:2]4[CH:3]=[C:4]([C:8]5[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([C:16]6[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=6)=[O:15])[CH:9]=5)[CH:5]=[CH:6][CH:7]=4)[C:37]4[C:42]([C:32]=3[CH:31]=[C:30]2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:41][CH:44]=[CH:39][CH:38]=4
Reactant: O=C(c1ccccc1)c1cccc(-c2cccc(Br)c2)c1
Reactant: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Reactant: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccncc13
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccc(C)cc1
Product: CC1(C)c2ccccc2-c2cc3c4ccccc4n(-c4cccc(-c5cccc(C(=O)c6ccccc6)c5)c4)c3cc21

Procedure:
15.8 g (47 mmol) of (3′-bromobiphenyl-3-yl)phenylmethanone, 13.36 g (47 mmol) of 10,10-dimethyl-10,12-dihydro-3,12-diazaindeno[2,1-b]fluorene and 29.2 g of Rb2CO3 are suspended in 250 ml of p-xylene. 0.95 g (4.2 mmol) of Pd(OAc)2 and 12.6 ml of a 1 M tri-tert-butylphosphine solution are added to this suspension. The reaction mixture is heated under reflux for 24 h. After cooling, the organic phase is separated off, washed three times with 150 ml of water and subsequently evaporated to dryness. The residue is extracted with hot toluene, recrystallised three times from toluene and finally sublimed in a high vacuum, giving 14.2 g (26.3 mmol), corresponding to 56% of theory. The purity is 99.9%.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.[CH3:18][O:19][C:20]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:21]=1[C:22](N(OC)C)=[O:23]>>[CH3:18][O:19][C:20]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:21]=1[C:22]([C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:23]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: COc1ccc(C(=O)N(C)OC)c(OC)c1
Agent: [Li]CCCC
Product: COc1ccc(C(=O)c2ccc(OC)cc2C(=O)O)c(OC)c1

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with 2,4-dimethoxy-N-methoxy-N-methylbenzamide. It is used in crude form in the following reaction.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:12]([O:19][C:20]([NH:22][CH:23](P(OC)(OC)=O)[C:24]([O:26][CH3:27])=[O:25])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN(C)C(N(C)C)=N>CCOC(C)=O>[CH2:12]([O:19][C:20]([NH:22][C:23](=[C:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[C:24]([O:26][CH3:27])=[O:25])=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CN(C)C(=N)N(C)C
Solvent: CCOC(C)=O
Product: COC(=O)C(NC(=O)OCc1ccccc1)=C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 72 h
Yield: 26.8 %

Procedure:
A solution of 1,4-dioxaspiro[4.5]decan-8-one (15 g, 96 mmol) in EtOAc (150 mL) was added to a solution of methyl 2-(benzyloxycarbonylamino)-2-(dimethoxyphosphoryl)acetate (21.21 g, 64.0 mmol) in 1,1,3,3-tetramethylguanidine (10.45 mL, 83 mmol) and EtOAc (150 mL). The resulting solution was the stirred at ambient temperature for 72 h and then it was diluted with EtOAc (25 mL). The organic layer was washed with 1N HCl (75 mL), H2O (100 mL) and brine (100 mL), dried (MgSO4), filtered and concentrated. The residue was purified via BIOTAGE® (5% to 25% EtOAc/Hexanes; 300 g column). The combined fractions containing the product were then concentrated under vacuum and the residue was re-crystallized from hexanes/EtOAc to give white crystals that corresponded to methyl 2-(benzyloxycarbonylamino)-2-(1,4-dioxaspiro[4.5]decan-8-ylidene)acetate (6.2 g) 1H NMR (400 MHz, CDCl3-d) δ ppm 7.30-7.44 (5 H, m), 6.02 (1 H, br. s.), 5.15 (2 H, s), 3.97 (4 H, s), 3.76 (3 H, br. s.), 2.84-2.92 (2 H, m), 2.47 (2 H, t, J=6.40 Hz), 1.74-1.83 (4 H, m). LC (Cond. OL1): Rt=2.89 min. LC/MS: Anal. Calcd. for [M+Na]+ C19H23NNaO6: 745.21; found: 745.47.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].Cl[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[C:14]([C:21]3[NH:29][C:28]4[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=4[CH:22]=3)[CH:15]=[CH:16][CH:17]=2)[N:12]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C(O)(C(F)(F)F)=O>C1COCC1.CS(C)=O>[CH2:1]([N:3]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[C:14]([C:21]3[NH:29][C:28]4[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=4[CH:22]=3)[CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH3:2]
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Reactant: CCNc1cccnc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CCN(c1cccnc1)c1ccc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1
Reaction time: 0.5 h
Yield: 10.8 %

Procedure:
To a mixture of N-ethylpyridin-3-amine (Enamine, Kiev, Ukraine; 0.164 g, 1.343 mmol) and 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 0.080 g, 0.269 mmol) was added NaHMDS (1.0 M in THF; 1.343 ml, 1.343 mmol). The dark red reaction was stirred for 30 min, then 0.5 mL 1.0 M NaHMDS in THF was added. After 30 min, the reaction was concentrated in vacuo and 2.5 mL DMSO and TFA (0.207 ml, 2.69 mmol) were added. Purified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 5-60% ACN/H2O with 0.1% TFA); product-containing fractions were treated with saturated aq. NaHCO3 and DCM. The organic layer was separated, and the aq. layer was extracted 3×DCM. The combined organic layers were then dried over Na2SO4, filtered, and concentrated in vacuo to give 2-(2-(ethyl(pyridin-3-yl)amino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.011 g, 0.029 mmol, 11% yield) as a solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.97 (1H, br. s), 8.63-8.69 (1H, m), 8.55-8.62 (1H, m), 8.08 (1H, d, J=9.2 Hz), 7.99 (1H, dt, J=7.5, 0.7 Hz), 7.88 (1H, dt, J=8.2, 2.1 Hz), 7.53-7.63 (2H, m), 7.29 (1H, t, J=7.6 Hz), 6.99-7.07 (1H, m), 6.90-6.97 (2H, m), 4.11 (2H, q, J=7.0 Hz), 3.37-3.45 (2H, m), 2.66 (2H, t, J=6.9 Hz), 1.30 (3H, t, J=7.1 Hz). m/z (ESI, +ve) 384.2 (M+H)+.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[C:12]([C:15]1[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[N:19][CH:20]=1)(=[O:14])[CH3:13]>C1COCC1>[F:23][C:21]([F:24])([F:22])[C:18]1[CH:17]=[CH:16][C:15]([C:12]2([CH3:8])[CH2:13][O:14]2)=[CH:20][N:19]=1
Reactant: C[S+](C)C
Reactant: CC(=O)c1ccc(C(F)(F)F)nc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC1(c2ccc(C(F)(F)F)nc2)CO1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents stirred for 10 min. after which the solution of 5-acetyl-2-(trifluoromethyl)pyridine (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. After completion, the reaction mixture is poured in ice water, extracted in diethyl ether, dried over sodium sulfate and concentrated at 25° C. to get the crude product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([C:15]#[N:16])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][CH2:20][CH2:21][NH2:22].CCN(C(C)C)C(C)C>CS(C)=O>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([NH:22][CH2:21][CH2:20][O:19][CH3:18])[C:11]([C:15]#[N:16])=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C#N)cn1
Reactant: COCCN
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCNc1cc(NC(=O)OC(C)(C)C)ncc1C#N
Temperature: 67.5 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl(4-chloro-5-cyanopyridin-2-yl)carbamate (intermediate 288, 9.8 g, 38.6 mmol), 2-methoxyethylamine (5.8 g, 77.3 mmol) and DIPEA (6 g, 46.4 mmol) in DMSO (80 ml) was heated at 65-70° C. for 24 h and monitored by chromatography until complete conversion. The solution was then cooled to room temperature and a white solid precipitated gradually. Water (20 ml) was then added slowly within 1 h. The suspension was stirred for a further 1 h, filtered and dried to give the title compound as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ 9.87 (s, 1H), 8.18 (s, 1H), 7.20 (s, 1H), 6.86 (s, 9H), 3.51 (t, 2H), 3.36 (t, 2H), 3.28 (s, 3H), 1.47 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][O:7][C:8]([C:10]1[CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N+:28]([O-:30])=[O:29])[C:12]([C:18]([O:20]C)=O)=C(C)[NH:14][C:15]=1[CH3:16])=[O:9]>CO>[CH3:6][O:7][C:8]([CH2:10][C:18](/[CH:12]=[CH:11]/[C:22]1[C:23]([N+:28]([O-:30])=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:20])=[O:9].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][O:7][C:8](=[O:9])/[CH:10]=[C:15](\[NH2:14])/[CH3:16]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCc2ccc(OC)c(OC)c2)C1c1ccccc1[N+](=O)[O-]
Solvent: CO
Product: COC(=O)CC(=O)/C=C/c1ccccc1[N+](=O)[O-]
Product: COc1ccc(COC(=O)/C=C(/C)N)cc1OC

Procedure:
Analogously to Example 1 heating a solution of 65 mmols of 2'-nitrobenzylideneacetoacetic acid methyl ester and 75 mmols of β-aminocrotonic acid 3,4-dimethoxybenzyl ester in 120 ml of glycol monomethyl ester for 5 hours gave 2,6-dimethyl-3-methoxycarbonyl-4-(2'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid 3,4-dimethoxybenzyl ester of melting point 149° C (from methanol).
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][N:8]1[C:18](=[O:19])[CH2:17][N:16]=[C:15]([C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)[CH:14]=[C:9]12)[CH3:3].[BH4-].[Na+].[CH2:28]1COCC1>CCOC(C)=O.CCOCC>[CH3:28][O:1][CH:2]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][N:8]1[C:18](=[O:19])[CH2:17][N:16]=[C:15]([C:20]3[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=3)[CH:14]=[C:9]12)[CH3:3]
Reactant: C1CCOC1
Reactant: CC(O)c1cccc2c1CCN1C(=O)CN=C(c3ccn(C)n3)C=C21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(C)c1cccc2c1CCN1C(=O)CN=C(c3ccn(C)n3)C=C21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
9-(1-hydroxyethyl)-2-(1-methyl-1H-pyrazol-3-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one. 47-2. A solution of 47-1 (400 mg, 1.20 mmol) in THF (30 mL) was treated with NaBH4 (23 mg, 0.60 mmol) and the mixture was stirred at RT for 48 h. The mixture was then diluted with AcOEt, and washed with H2O. The org. phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue obtained was purified by flash chroatography (SiO2, DCM to DCM/MeOH 95:5) to afford a yellow oil that was suspended in Et2O. The suspension was filtered and the filter cake was dried on vacuo to give the title compound (145 mg) as a light yellow solid. UPLC-MS: MS 337.3 (M+H+); UPLC rt 0.60 min. 1H NMR (400 MHz, CHLOROFORM-d): δ ppm 1.49 (d, J=6.26 Hz, 3 H); 1.82-1.96 (m, 1 H); 2.86-3.09 (m, 2 H); 3.75-3.99 (m, 2 H); 3.92 (s, 3 H); 4.48 (d, J=12.12 Hz, 2 H); 5.17 (d, J=3.52 Hz, 1 H); 6.82 (br. s., 1 H); 7.19 (s, 1 H); 7.32-7.40 (m, 2 H); 7.61 (d, J=7.82 Hz, 1 H); 7.64 (d, J=7.82 Hz, 1 H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10].C(O)(=O)C.C(N(CC)CC)C.Cl.[CH3:36][O:37][C:38]1[CH:39]=[C:40]([C:44]2([C:47](=N)OCC)[CH2:46][CH2:45]2)[CH:41]=[CH:42][CH:43]=1>CO>[CH3:36][O:37][C:38]1[CH:39]=[C:40]([C:44]2([C:47]3[NH:10][C:9]4=[N:8][C:7]([N:11]5[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]6[CH2:23][CH2:22][CH2:21][CH2:20]6)=[O:18])[CH2:12]5)=[CH:6][CH:5]=[C:4]4[N:3]=3)[CH2:45][CH2:46]2)[CH:41]=[CH:42][CH:43]=1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: CCOC(=N)C1(c2cccc(OC)c2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CO
Product: COc1cccc(C2(c3nc4ccc(N5CCC[C@@H](C(=O)N6CCCC6)C5)nc4[nH]3)CC2)c1
Temperature: 130 °C

Procedure:
To a solution of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (60 mg, 0.17 mmol) in methanol (0.5 mL) and acetic acid (150 μL, 2.7 mmol) was added triethylamine (94 μL, 0.67 mmol) and a solution of ethyl 1-(3-methoxyphenyl)cyclopropanecarbimidate hydrochloride (40 mg, 0.16 mmol) in methanol (0.3 mL). The reaction mixture was heated in a microwave for 45 min at 130° C. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and a saturated aqueous solution of sodium bicarbonate. The organic layer was washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via HPLC to afford the title compound. MS (ESI+) (M+H) 446.3; HPLC retention time 2.3 min (Method A).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3]C=1.SCC[C:11]([OH:13])=[O:12].[CH3:14]C1C=CC2C(=CC=C(C)C=2)C=1.CC(C1C=CC(O)=CC=1)=O>>[CH3:14][O:13][C:11]([CH:5]1[CH2:4][CH2:3][O:7][CH2:1][CH2:6]1)=[O:12]
Reactant: Cc1ccc2cc(C)ccc2c1
Reactant: O=C(O)CCS
Reactant: Oc1ccccc1
Agent: CC(=O)c1ccc(O)cc1
Product: COC(=O)C1CCOCC1
Temperature: 65 °C

Procedure:
A mixture of 94 grams (1.0 mol) of phenol, 5.31 g (0.0500 mol) of 3-mercaptopropionic acid, 10 g of LEWATIT BE ion exchange resin and 1.0 g of 2,6-dimethylnaphthalene (internal standard for liquid chromatography analysis) was heated to about 65° C. in a round bottom flack equipped with a distillation setup, an internal thermometer and a mechanical stirrer. The solution was continuously sparged with nitrogen (using a dip tube) to remove the water. To this mixture was added 11.35 g (0.8336 mol) of 4-hydroxyacetophenone. The mixture was stirred at about 65° C. with the nitrogen sparge for about 8 hrs. The THPE was isolated by precipitation with methylene chloride (4 mL/1 g of reaction mixture) and the yield is given in Table III.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:24]>C(Cl)Cl>[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]([C:13]([F:24])=[O:15])[CH:10]([CH3:12])[CH3:11])([CH3:7])([CH3:6])[CH3:5]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)F
Temperature: -15 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
To an oven-dried, septaed 25 mL round-bottom flask, cooled under an argon atmosphere, and charged with (S)-N-BOC-valine (217.2 mg, 1.00 mmol) was added 2.5 mL CH2Cl2, and pyridine (81 μL, 1.00 mmol). The solution was cooled to −15° C., and to the reaction was added cyanuric fluoride (450 μL, 5.0 mmol). The reaction was stirred at −15° C. for 60 minutes, with the gradual formation of a white precipitate. Without warming, the crude reaction was poured over ice, and immediately extracted twice with CH2Cl2. The combined CH2Cl2 extracts were washed once with ice-cold water, dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford 201.3 mg of 25g as white needles. FTIR (neat) 1847 cm−1.