Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[C:14](=[O:33])[N:15]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][C:19]([CH3:24])=[CH:18][CH:17]=2)=O)C>C1(C)C=CC=CC=1.O>[CH:1]1([NH:7][C:11]([C:13]2[C:14](=[O:33])[N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][C:19]([CH3:24])=[CH:18][CH:17]=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)c1c(O)c2cc(C)ccc2n(Cc2ccc(F)cc2)c1=O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)c(O)c(C(=O)NC1CCCCC1)c(=O)n2Cc1ccc(F)cc1
Yield: 92.2 %

Procedure:
Cyclohexylamine (3.22 mL, 28.14 mmol) was added to a solution of Compound 16 (5.0 g, 14.07 mmol) in toluene (50 mL) and refluxed for 4 h. The solution was cooled and the solvent was evaporated under vacuum. The residue obtained was suspended in water, briefly sonicated, and filtered. The crude product was recrystallized by ether to yield 5.3 g (93%) of yellow solids. M.P. 156° C. 1H NMR (DMSO-d6): δ 1.24 (m, 1H), 1.37 (m, 4H), 1.57 (m, 1H), 1.68 (m, 2H), 1.88 (m, 2H), 2.36 (s, 3H), 3.87 (m, 1H), 5.49 (s, 2H), 7.11 (m, 2H), 7.22 (m, 2H), 7.36 (d, J=8.7 Hz, 1H), 7.51 (dd, J=1.6, 8.7 Hz, 1H), 7.90 (d, J=1.6 Hz, 1H), 10.39 (s, 1H). EIMS m/z 409 (M+1), 431 (M+23).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.[O:27]=[C:28]1[C:33](C(Cl)=O)=[CH:32][CH:31]=[C:30]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[O:29]1.[N:42]1[C:51]2[C:46](=[CH:47][C:48]([NH2:52])=[CH:49][CH:50]=2)[CH:45]=[CH:44][CH:43]=1>>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][O:14][N:13]=[C:11]2[CH2:12][N:8]([C:6]([C:33]3[C:28](=[O:27])[O:29][C:30]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:31][CH:32]=3)=[O:7])[C@H:9]([C:24]([NH:52][C:48]3[CH:47]=[C:46]4[C:51](=[CH:50][CH:49]=3)[N:42]=[CH:43][CH:44]=[CH:45]4)=[O:26])[CH2:10]2)=[CH:21][CH:20]=1
Reactant: CCCCCc1ccc(C(=O)Cl)c(=O)o1
Reactant: COc1ccc(CON=C2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)cc1
Reactant: Nc1ccc2ncccc2c1
Product: CCCCCc1ccc(C(=O)N2CC(=NOCc3ccc(OC)cc3)C[C@H]2C(=O)Nc2ccc3ncccc3c2)c(=O)o1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and 6-quinolinamine the title compound was obtained in 61% purity by LC/MS. MS(ESI+): m/z=583.4.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)([O-:3])=[O:2].[NH2:18][CH2:19][CH2:20][S:21][CH2:22][C:23]1[C:28]([Br:29])=[CH:27][CH:26]=[CH:25][N:24]=1>>[N+:1]([CH:4]=[C:5]([NH:18][CH2:19][CH2:20][S:21][CH2:22][C:23]1[C:28]([Br:29])=[CH:27][CH:26]=[CH:25][N:24]=1)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)([O-:3])=[O:2]
Reactant: NCCSCc1ncccc1Br
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1nccs1
Product: O=[N+]([O-])C=C(NCCSCc1nccs1)NCCSCc1ncccc1Br

Procedure:
Reaction of 1-nitro-2-methylthio-2-[2-(2-thiazolylmethylthio)ethylamino]ethylene with 2-[(2-aminoethyl)thiomethyl]-3-bromopyridine according to the process of Example 1(a)(ii) yields the title compound.
Reaction SMILES: F[C:2]1(F)CC1CN1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O.F[C:23]1[CH:44]=[CH:43][C:26]([CH2:27][N:28]2[C:32](=[O:33])[N:31]([C:34]3[S:35][C:36]([C:40]([OH:42])=O)=[C:37]([CH3:39])[N:38]=3)[CH:30]=[N:29]2)=[CH:25][CH:24]=1.[CH:45]([C:48]1[S:49][CH:50]=[C:51]([CH2:53][NH2:54])[N:52]=1)([CH3:47])[CH3:46]>>[CH:45]([C:48]1[S:49][CH:50]=[C:51]([CH2:53][NH:54][C:40]([C:36]2[S:35][C:34]([N:31]3[C:32](=[O:33])[N:28]([CH2:27][C:26]4[CH:25]=[CH:24][C:23]([CH3:2])=[CH:44][CH:43]=4)[N:29]=[CH:30]3)=[N:38][C:37]=2[CH3:39])=[O:42])[N:52]=1)([CH3:47])[CH3:46]
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: Cc1nc(N2CCN(CC3CC3(F)F)C2=O)sc1C(=O)O
Reactant: CC(C)c1nc(CN)cs1
Product: Cc1ccc(Cn2ncn(-c3nc(C)c(C(=O)NCc4csc(C(C)C)n4)s3)c2=O)cc1
Yield: 61 %

Procedure:
Following the procedure as describe in Example 16, making variations as required to replace 2-(3-((2,2-difluorocyclopropyl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid to react with (2-isopropylthiazol-4-yl)methanamine, the title compound was obtained as a colourless solid in 61% yield: mp 151-153° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.81 (t, J=5.8 Hz, 1H), 8.73 (s, 1H), 7.33-7.30 (m, 2H), 7.20 (s, 1H), 7.19-7.13 (m, 2H), 4.97 (s, 2H), 4.44 (d, J=6.0 Hz, 2H), 3.63-3.53 (m, 1H), 2.54 (s, 3H), 1.28 (d, J=6.0 Hz, 6H); 13C NMR (75 MHz, DMSO-d6) δ 177.3, 162.2 (d), 161.3, 153.6, 151.8, 151.4, 150.2, 132.7 (d), 132.5, 130.4 (d), 123.0, 115.9, 114.1, 48.2, 42.3, 32.9, 23.3, 17.4; MS (ES+) m/z 472.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[OH-].[K+].I[CH3:14].O>CN(C=O)C>[CH3:14][N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ccc2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To room temperature solution of 5-chloroindole (4.97 g) in dry DMF (40 mL) was added potassium hydroxide pellets (2.76 g) and stirred 1 h until most of the solid dissolved. The resulting mixture was cooled to 0° C. in an ice bath and iodomethane (2.45 mL) was added dropwise and later stirred overnight at room temperature under argon. The reaction mixture was poured into water and extracted twice with ETOAc. The combined ETOAc portions were combined, washed with water, dried over magnesium sulfate, concentrated, and flash chromatographed with 10% ETOAc/Hexane to give 1-methyl-5-chloroindole as a pink liquid (5.43 g).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:27])[C:9]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([OH:26])=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].C1C=[CH:30][C:31]2N(O)N=[N:34][C:32]=2C=1.C(Cl)CCl.[CH3:42][N:43](C=O)C>>[C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:27])[C:9]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([N:43]([CH2:30][CH2:31][C:32]#[N:34])[CH3:42])=[O:26])=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: On1nnc2ccccc21
Reactant: CN(C)C=O
Reactant: CC1(C)c2cc(OCC(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Solvent: ClCCCl
Product: CN(CCC#N)C(=O)COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(3-Cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yloxy)-acetic acid (Compound A8-7, 30 mg, 0.083 mmol), N-methyl-3-aminopropionitrile (14 mg, 2 eq.) and HOBt (30 mg, 3 eq.) were dissolved in 0.5 ml DMF, added with EDC (48 mg, 3 eq.), and stirred at room temperature overnight. Thereafter, the solvent was removed under reduced pressure and the resulting residues were purified by preparative TLC to obtain the title compound (7 mg).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.[Si:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[CH:25][C:24]=1[CH2:32][CH3:33])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].[F:34][C:35]([F:44])([F:43])[C:36](N1C=CN=C1)=[O:37]>C1COCC1>[Si:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH2:30][C:36](=[O:37])[C:35]([F:44])([F:43])[F:34])=[CH:25][C:24]=1[CH2:32][CH3:33])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17]
Reactant: O=C(n1ccnc1)C(F)(F)F
Reactant: CCc1cc(C(C)=O)ccc1O[Si](C)(C)C(C)(C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(C(=O)CC(=O)C(F)(F)F)ccc1O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a stirred solution of 1,1,1,3,3,3-hexamethyldisilazane (1.79 g, 11.1 mmol) in THF (37 ml) was added n-butyl lithium (1.52 M solution in hexane; 7.3 ml, 11.1 mmol) dropwise at 0° C. and the mixture was stirred at 0° c. for 30 minutes, then cooled at −78° C. A solution of 1-(4-[[tert-butyl(dimethyl)silyl]oxy]-3-ethylphenyl)-1-ethanone (2.57 g, 9.23 mmol) in THF (40 ml) was added dropwise, and the mixture was stirred at −78° c. for 1 hour. 1-(Trifluoroacetyl)imidazole (2.0 g, 12.2 mmol) was added, and the mixture was stirred at −78° c. for 3 hours, and quenched with water. The reaction mixture was warmed up to room temperature, and diluted with ethyl acetate. The whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was used for next reaction without further purification. (3.45 g, 99% yield).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH:5]([C:10]([OH:12])=[O:11])[CH2:4]1.[CH:13](N(C(C)C)CC)(C)C.[I-].[Na+].Cl.ClC[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>CC#N.C(Cl)Cl>[O:9]=[C:6]1[CH2:7][CH2:8][N:3]([CH2:2][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH2:4][CH:5]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: CCN(C(C)C)C(C)C
Reactant: CN1CCC(=O)C(C(=O)O)C1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: COC(=O)C1CN(Cc2cccnc2)CCC1=O
Reaction time: 1 h
Yield: 100 %

Procedure:
0.200 g (1.034 mmol) of 1-methyl-4-oxopiperidine-3-carboxylate hydrochloride (commercially available, ABCR), 0.54 mL (3.102 mmol) of diisopropylethylamine, 0.155 g (1.034 mmol) of sodium iodide and 0.170 g (1.034 mmol) of 3-(chloromethyl)pyridine hydrochloride were stirred at 80° C. in 5.0 mL of anhydrous CH3CN. The reaction was monitored by HPLC and UPLC-MS. After 1 h at 80° C., the insoluble inorganic materials were filtered off and the filtrate was concentrated in vacuo to give a yellowish residue. This residue was dissolved in CH2Cl2, washed with brine, H2O, dried over Na2SO4 and concentrated in vacuo to give pure methyl 4-oxo-1-(pyridin-3-ylmethyl)piperidine-3-carboxylate (0.257 g, 1.034 mmol, quantitative yield). The product was used for the next step without further manipulation.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:25])[CH2:6][N:7]1[C:11]([CH2:12][CH3:13])=[C:10]([O:14][C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[CH:16]=2)[C:9]([CH2:23][CH3:24])=[N:8]1>O1CCCC1>[Cl:22][C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([Cl:21])[CH:18]=1)[O:14][C:10]1[C:9]([CH2:23][CH3:24])=[N:8][N:7]([CH2:6][C:5]([OH:25])=[O:4])[C:11]=1[CH2:12][CH3:13]
Reactant: CCc1nn(CC(=O)OC)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1nn(CC(=O)O)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Yield: 78 %

Procedure:
Aqueous sodium hydroxide solution (1N, 6.2 ml, 6.2 mmol) was added dropwise to a stirred solution of the ester (2 g, 5.6 mmol) of Example 9 in tetrahydrofuran (20 ml) at 0° C. After 1 hour the solvent was removed under reduced pressure and aqueous hydrochloric acid (20 ml) was added with vigorous stirring. The resulting white precipitate was collected by filtration, washed with ether (3×30 ml) and dried in a vacuum pistol at 60° C./10 mmHg to afford the title compound as a white solid (1.5 g), m.p. 157-158° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[N:14][C:15](Cl)=[N:16][CH:17]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[F:19][C:20]1[C:25]([F:26])=[C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH2:1]([O:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[N:14][C:15]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[C:25]([F:26])[C:20]=3[F:19])=[N:16][CH:17]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCCc1ccc(B(O)O)c(F)c1F
Reactant: CCCCOc1ccc(-c2cnc(Cl)nc2)cn1
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: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCCCCCCCc1ccc(-c2ncc(-c3ccc(OCCCC)nc3)cn2)c(F)c1F
Yield: 46.3 %

Procedure:
The reaction of 2 mmol of 5-(6-butoxypyridin-3-yl)-2-chloropyrimidine, 2.2 mmol of 2,3-difluoro-4-octylphenylboronic acid, 4 mmol of sodium carbonate and 0.02 mmol of tetrakis(triphenylphosphine)palladium(0) in 10 ml of toluene, 5 ml of ethanol and 5 ml of water is carried out analogously to the procedure indicated for Example 1a). The crude product is separated off by column chromatography on silica gel 60 using heptane/ethyl acetate 9:1 (v/v) as eluent and is recrystallized from acetonitrile, giving 0.42 g (46%) of colorless crystals, X 84 SC 73 SA 162 I.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][NH:20][CH:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].[CH2:44]([Cl:46])[Cl:45]>C(O)(=O)C>[NH3:1].[CH2:44]([Cl:46])[Cl:45].[CH3:19][N:20]([CH:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1)[CH2:15][C:14]1[CH:17]=[CH:18][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:12][CH:13]=1
Reactant: O=Cc1ccc(OCCCN2CCCCC2)cc1
Reactant: CNC1CCN(C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1CCC(N(C)Cc2ccc(OCCCN3CCCCC3)cc2)CC1
Product: N
Reaction time: 16 h

Procedure:
A solution of the product of Example 9 (227 mg), methyl-(1-methyl-piperidin-4-yl)-amine (118 mg), and acetic acid (0.06 mL) in DCM (3 mL) was treated with sodium triacetoxyborohydride (290 mg). After 16 h, the resulting mixture was treated with 10% sodium hydroxide (5 mL) and extracted with DCM (3×10 mL). The combined organic phases were dried (sodium sulfate) and evaporated. Chromatography of the residue (1-5% 2 M methanolic ammonia/DCM) gave the title compound as a colorless oil (270 mg). 1H NMR (400 MHz, CDCl3): 7.19 (d, J=8.6 Hz, 2H), 6.83 (d, J=8.6 Hz, 2H), 3.98 (t, J=6.3 Hz, 2H), 3.49 (s, 2H), 2.90 (m, 2H), 2.78 (m, 2H), 2.46 (m, 2H), 2.43-2.35 (m, 4H), 2.26 (s, 3H), 2.17 (s, 3H), 2.00-1.87 (m, 5H), 1.78 (m, 2H), 1.68 (m, 2H), 1.61-1.54 (m, 4H), 1.47-1.40 (m, 2H).
Reaction SMILES: [Cl-].[NH4+:2].Br[C@@H:4]1[C@H:8]2OC[C@H:11]([C:12]3C=C(C)C=CC=3S([O-])(=O)=O)[C@@H:7]2[O:6][CH2:5]1.N.C[OH:25]>O.CC(O)C.[Zn]>[NH2:2][CH2:12][C@H:11]([C@@H:7]1[CH:8]=[CH:4][CH2:5][O:6]1)[OH:25]
Reactant: [NH4+]
Reactant: CO
Reactant: Cc1ccc(S(=O)(=O)[O-])c([C@H]2CO[C@H]3[C@H]2OC[C@@H]3Br)c1
Agent: N
Agent: [Cl-]
Agent: [Zn]
Solvent: CC(C)O
Solvent: O
Product: NC[C@@H](O)[C@@H]1C=CCO1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
A solution of ammonium chloride (600 mg, 11.2 mmol) in water (7.5 mL) was added to a solution of bromotosylate (47) (3.0 g, 8.26 mmol) in propan-2-ol (15 mL) under argon. Zinc dust (600 mg, 9.2 mmol) was then added in portions over 4 minutes and the mixture was stirred for 16 hours before filtering the suspension through celite in vacuo. The filter cake was washed with diethyl ether (60 mL). Hydrochloric acid (1M, 60 mL) was added to the filtrate then the organic phase separated. The aqueous layer was extracted with diethyl ether (60 mL) then the combined organic phase was washed with brine (60 mL), then dried (MgSO4), filtered and reduced in vacuo. The residue was dissolved in ammonium hydroxide (18 mL) and a solution of ammonia in propan-2-ol (12 mL, 2.0M, 24 mmol), then divided into two equal portions and heated in sealed tubes at 75° C. for 16 hours. The mixtures were combined using methanol then the solvents were removed in vacuo. The residue was azeotroped with diethyl ether (3×10 mL) to obtain (R)-2-amino-1-((S)-2,5-dihydrofuran-2-yl)ethanol which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:39]=[N:40][C:41]([CH3:45])=[CH:42][C:43]=2[CH3:44])[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:39]=[N:40][C:41]([CH3:45])=[CH:42][C:43]=2[CH3:44])[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1cc(C)c(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cnc(C)cc3C)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J8) (240 mg, 0.75 mmol) and 3-[3-(4,6-dimethyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K32) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (350 mg, 82%).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6]1)=O.C([NH2:19])=O.C[O-].[Na+].[Na]>CN(C=O)C.CO.C(O)(C)C>[CH2:10]([N:7]1[CH2:8][CH2:9][CH:5]([C:3]([NH2:19])=[O:2])[CH2:6]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)C1CCN(Cc2ccccc2)C1
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: NC(=O)C1CCN(Cc2ccccc2)C1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a mixture of 4.4 g 1-benzyl-pyrrolidine-3-carboxylic acid methyl ester (M. J. Kornet, P. A. Thio, S. E. Tan, J. Organic Chemistry, 33:3637–3639(1968) and 3 g formamide in 10 mL of anhydrous DMF heated to 100° C., a solution of sodium methoxide, from 0.33 g of sodium dissolved in methanol, was added dropwise over 20 minutes. After stirring for 1 h at 100° C., the mixture was allowed to cool to room temperature and added to 100 mL of isopropanol. The mixture was concentrated to dryness. The residue was triturated with 200 mL of chloroform, filtered and concentrated to dryness under reduced pressure. The resulting oil was fairly homogeneous by TLC (development with 90:10 chloroform saturated with ammonia:methanol):
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=O)[NH:8][C:7]2=O)([O-:3])=[O:2].CN1CCN(C)C1=O.P(Cl)(Cl)([Cl:26])=O.C(N(CC)CC)C.[CH:36]1([NH2:41])[CH2:40][CH2:39][CH2:38][CH2:37]1>O>[Cl:26][C:9]1[N:8]=[C:7]([NH:41][CH:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=1
Reactant: NC1CCCC1
Reactant: O=c1[nH]c(=O)c2cc([N+](=O)[O-])ccc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CN1CCN(C)C1=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc2nc(Cl)nc(NC3CCCC3)c2c1
Reaction time: 0.5 h
Yield: 35.8 %

Procedure:
To 300 mg (1.45 mmol) of 6-nitroquinazoline-2,4 (1H,3H)-dione were added 1 ml of 1,3-dimethyl-2-imidazolidinone and 1.23 g (8.05 mmol) of phosphorus oxychloride, and the resulting mixture was subjected to heating under reflux for 3 hours. After phosphorus oxychloride was removed in vacuo, the mixture was dissolved in 3 ml of acetonitrile, followed by addition of 4.05 ml (29.00 mmol) of triethylamine and 0.89 ml (8.70 mmol) of cyclopentylamine and stirring under ice cooling for 30 minutes. To the reaction solution was added water, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 152 mg (yield: 35.9%) of the title compound.
Reaction SMILES: [CH2:1]([O:3]/[CH:4]=[CH:5]\Br)[CH3:2].C([Li])(C)(C)C.Cl[Sn:13]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17].C([O-])(O)=O.[Na+]>C(OCC)C.CCCCC>[CH2:1]([O:3]/[CH:4]=[CH:5]\[Sn:13]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:14][CH2:15][CH2:16][CH3:17])[CH3:2]
Reactant: CCO/C=C\Br
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: CCCCC
Solvent: CCOCC
Product: CCCC[Sn](/C=C\OCC)(CCCC)CCCC
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
(Ref. Wollenberg, R. H.; Albizati, K. F.; Peries, R. J. Am. Chem. Soc. 1977, 99, 22, 7365-7367.) To a −78° C. solution of (Z)-2-ethoxy-1-bromoethene (5.0 mL, 46.8 mmol) in diethyl ether (160 mL) was added a 1.7 M solution of tert-butyl lithium in pentane (55 mL), dropwise over 20 min. This pale yellow solution was stirred at −78° C. for 40 min, and then chloro-tri-n-butylstannane (13.3 mL, 49.0 mmol) was added, dropwise over 7 minutes. The resulting reaction mixture was allowed to warm slowly. Once the cooling bath had reached −30° C., saturated aq. NaHCO3 (150 mL) was added, and the cooling bath was removed. This mixture was stirred for 15 minutes, and then the layers were separated. The aq. layer was extracted with diethyl ether (2×50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to afford (Z)-2-ethoxy-1-tri-n-butylstannanylethene.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[Br:16].CS[N:19]=[C:20]=O.[CH2:22](N)[CH2:23][NH2:24]>>[Br:16][C:3]1[CH:4]=[C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:6]=[CH:7][C:2]=1[NH:1][C:20]1[NH:19][CH2:22][CH2:23][N:24]=1
Reactant: CC1CC(=O)NN=C1c1ccc(N)c(Br)c1
Reactant: NCCN
Reactant: CSN=C=O
Product: CC1CC(=O)NN=C1c1ccc(NC2=NCCN2)c(Br)c1

Procedure:
Using 6-(4-amino-3-bromophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone and methylthioisocyanate, the reaction was carried out in the same manner as described in Example 1(b) to the corresponding methylisothiuronium salt which was then reacted with ethylenediamine in the same manner as described in Example 1(c) to afford the above-identified compound. M.P. 265°-267° C. (with decomp.).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][N:14]1[C:18]([S:19][CH3:20])=[CH:17][C:16]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[N:15]1.I[CH2:27][CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CCCCCC>[CH3:13][N:14]1[C:18]([S:19][CH3:20])=[CH:17][C:16]([CH:21]([CH2:27][CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:22]([O:24][CH3:25])=[O:23])=[N:15]1
Reactant: ICC1CCOCC1
Reactant: COC(=O)Cc1cc(SC)n(C)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: COC(=O)C(CC1CCOCC1)c1cc(SC)n(C)n1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 36.9 %

Procedure:
To a solution of diisopropylamine (4.0 mL) in tetrahydrofuran (60 mL) was slowly added 1.6M hexane solution (16.1 ml) of n-butyllithium at −70° C. under a nitrogen atmosphere. The reaction mixture was stirred at −70° C. for 15 min, and a solution of methyl [1-methyl-5-(methylsulfanyl)-1H-pyrazol-3-yl]acetate (4.68 g) in tetrahydrofuran (5 mL) was slowly added thereto. The reaction mixture was stirred at −70° C. for 15 min, and 4-(iodomethyl)tetrahydro-2H-pyran (5.80 g) was added thereto. The mixture was stirred overnight at room temperature. To the reaction mixture was added 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (2.57 g, yield 37%) as a pale-yellow oil from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 299 (MH+).