Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14](=[O:40])[CH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]2[CH:27]=[CH:26][C:25]([NH:28][CH2:29][C@H:30]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH3:31])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1>C1COCC1>[CH3:12][O:13][C:14](=[O:40])[CH2:15][C@H:16]1[CH2:17][CH2:18][C@H:19]([C:22]2[CH:23]=[CH:24][C:25]([N:28]([CH2:29][C@H:30]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:34])[CH3:35])[CH3:31])[C:8]([C:7]3[C:6]([Cl:11])=[N:5][CH:4]=[N:3][C:2]=3[Cl:1])=[O:9])=[CH:26][CH:27]=2)[CH2:20][CH2:21]1
Reactant: O=C(Cl)c1c(Cl)ncnc1Cl
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC[C@@H](C)O[Si](C)(C)C(C)(C)C)cc2)CC1
Solvent: C1CCOC1
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(N(C[C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)c3c(Cl)ncnc3Cl)cc2)CC1

Procedure:
A mixture of 4,6-dichloropyrimidine-5-carbonyl chloride (2.27 g, 10.7 mmol), methyl[trans-4-(4-{[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}propyl]-amino}phenyl)cyclohexyl]acetate (4.50 g, 10.7 mmol), from Step 1, and TEA (2.24 mL, 16.1 mmol) in THF (150 mL) was stirred at room temperature under nitrogen for 14 hours. The reaction mixture was concentrated to remove THF. The residue was diluted with EtOAc (300 mL), washed with water (2×200 mL), dried over MgSO4 and concentrated. The crude material was purified by a 120 g silica gel column eluted with 3-15% EtOAc in heptane to give methyl[trans-4-(4-{[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}propyl][(4,6-dichloropyrimidin-5-yl)carbonyl]amino}phenyl)cyclohexyl]acetate as a colorless oil 4.01 g (63%). m/z=594.2 (M+1). 1H NMR (400 MHz, chloroform-d) δ −0.06 (s, 6H) 0.71 (s, 9H) 0.99-1.14 (m, 2H) 1.25-1.30 (m, 3H) 1.30-1.42 (m, 2H) 1.78 (dd, J=28.30, 11.90 Hz, 5H) 2.20 (d, J=7.03 Hz, 2H) 2.28-2.39 (m, 1H) 3.64 (s, 3H) 3.83-3.97 (m, 2H) 4.04-4.14 (m, 1H) 7.00 (d, J=8.20 Hz, 2H) 7.19 (d, J=8.59 Hz, 2H) 8.53 (s, 1H).
Reaction SMILES: [CH:1]([C:3]1[C:4]([NH:9]C(=O)C(C)(C)C)=[N:5][CH:6]=[CH:7][CH:8]=1)=O.[C:16]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:17][C:18]([O:20]CC)=O.N1CCCC1>C(O)C>[O:20]=[C:18]1[C:17]([C:16]([O:24][CH2:25][CH3:26])=[O:23])=[CH:1][C:3]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:9]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C)C(=O)Nc1ncccc1C=O
Solvent: C1CCNC1
Solvent: CCO
Product: CCOC(=O)c1cc2cccnc2[nH]c1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
6.57 g (32 mmol) of 3-formyl-2-(pivaloylamino)pyridine was dissolved in ethanol (50 mL), and 10.2 g (64 mmol) of diethyl malonate and 1.6 mL (16 mmol) of pyrrolidine were added to the above solution. The resulting mixture was stirred overnight at 100° C. The reaction mixture was cooled to room temperature, and a solid precipitated therefrom was washed with ethanol. Thus, 2.2 g (yield: 32%) of the title compound was obtained as a yellow solid.
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH2:36])=[O:35])=[CH:32][CH:31]=1>>[C:34]([C:33]1[CH:37]=[CH:38][C:30]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([CH2:16][NH:15][CH:12]3[CH2:13][CH2:14][CH:9]([N:8]([CH3:28])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]3)[CH:18]=2)=[CH:31][CH:32]=1)(=[O:35])[NH2:36]
Reactant: NC(=O)c1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(C(N)=O)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 4 (326 mg, 0.83 mmol) is coupled to 4-bromobenzamide (200 mg, 0.99 mmol) using Method B to give the title compound.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:18][C:19]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:22][CH2:21][CH2:20]1>>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][NH:18][C:19]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:22][CH2:21][CH2:20]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1(N)CCC1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Agent: Cl
Product: CCOC(=O)C1(NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)CCC1
Yield: 77 %

Procedure:
Prepared as in Example 12-1b from 3-(tert-butyldimethylsilyloxy)benzaldehyde (Example 12-1c) and ethyl 1-aminocyclobutanecarboxylate hydrochloride. Yield 77%, colorless liquid. MS 364 (MH+).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][C:6]([CH3:13])=[CH:7][C:8]=1[C:9]([O:11][CH3:12])=[O:10].F[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22]>O1CCCC1>[N+:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:3][C:4]1[S:5][C:6]([CH3:13])=[CH:7][C:8]=1[C:9]([O:11][CH3:12])=[O:10])([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COC(=O)c1cc(C)sc1N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)sc1Nc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred suspension of sodium hydride (2 g) in dry tetrahydrofuran (25 mL) under a nitrogen atmosphere was added a solution of methyl 2-amino-5-methylthiophene-3-carboxy-late (4.8 g, 0.028 mol) and 2-fluoronitrobenzene (4.0 g, 0.025 mol) in dry tetrahydrofuran (30 mL). The mixture was stirred at 25° C. for 20 hours, poured onto ice and partitioned between 2N hydrochloric acid and ethyl acetate. The organic extracts were dried over magnesium sulfate, the solvent was evaporated under reduced pressure and the title compound purified by chromatography on silica gel, eluted with toluene, and crystallized from ethanol (4.1 g).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[NH:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:30]1[N:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][N:31]=1>C1COCC1>[CH3:37][O:36][C:34]1[CH:33]=[CH:32][N:31]=[C:30]([N:3]2[C:4]3[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=3[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:2]2=[O:1])[N:35]=1
Reactant: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccccc21
Reactant: COc1ccnc(Cl)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccnc(-n2c(=O)n(CC(=O)OC(C)(C)C)c3ccccc32)n1
Temperature: 130 °C
Reaction time: 0.08 h

Procedure:
A mixture of tert-butyl (2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)acetate (200 mg, 0.806 mmol, described in Intermediate 4) and sodium bis(trimethylsilyl)amide (1.0 M in THF, 1.69 mL, 1.69 mmol) in THF (0.5 mL) was stirred for 5 min, then 2-chloro-4-methoxypyrimidine (583 mg, 4.03 mmol) was added and argon was bubbled through the mixture for 5 min. The reaction mixture was heated at 130° C. for 10 min in a microwave reactor. The cooled mixture was partitioned between CHCl3 (10 mL) and saturated aqueous NaHCO3 (5 mL). The aqueous phase was extracted further with CHCl3 (10 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane::EtOAc—100:0 to 80:20, to give the title compound. MS: m/z=357 (M+1).
Reaction SMILES: [N:1]1([C:7]2[S:8][C:9]3[C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:10]=3[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:21]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=[C:23](O)[CH:22]=1.Cl.CN(C)CCCN=C=NCC>ClCCl>[N+:27]([C:26]1[CH:21]=[CH:22][C:23]([O:17][C:16]([C:15]2[C:9]3[S:8][C:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[N:11][C:10]=3[C:12]([O:19][CH3:20])=[CH:13][CH:14]=2)=[O:18])=[CH:24][CH:25]=1)([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1ccc(C(=O)O)c2sc(N3CCCCC3)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2sc(N3CCCCC3)nc12
Yield: 89.3 %

Procedure:
Starting from 2-(piperidin-1-yl)-4-methoxybenzothiazole-7-carboxylic acid (190 mg), p-nitrophenol (100 mg), and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (150 mg) in dichloromethane (20 ml). Purification by column chromatography (eluent 50% ethylacetate in hexane) yielded the title compound as an off-white solid (240 mg). TLC Rf 0.39 (50% ethyl acetate in hexane).
Reaction SMILES: FC1C=C(C=CC=1F)[CH2:5][N:6]1C=CC=C(C(NCC2C=C(C3C4C(=NC=C(C(N)=O)C=4)NC=3)C=CC=2)=O)[C:7]1=O.[F:39][C:40]1[CH:41]=[C:42]([CH:73]=[CH:74][C:75]=1[F:76])[CH2:43][N:44]1[CH:49]=[CH:48][CH:47]=[C:46]([C:50]([NH:52][CH2:53][C:54]2[CH:55]=[C:56]([C:60]3[C:68]4[C:63](=[N:64][CH:65]=[C:66]([C:69]([OH:71])=O)[CH:67]=4)[NH:62][CH:61]=3)[CH:57]=[CH:58][CH:59]=2)=[O:51])[C:45]1=[O:72].CNC.O1CCCC1>>[CH3:5][N:6]([CH3:7])[C:69]([C:66]1[CH:67]=[C:68]2[C:60]([C:56]3[CH:57]=[CH:58][CH:59]=[C:54]([CH2:53][NH:52][C:50]([C:46]4[C:45](=[O:72])[N:44]([CH2:43][C:42]5[CH:73]=[CH:74][C:75]([F:76])=[C:40]([F:39])[CH:41]=5)[CH:49]=[CH:48][CH:47]=4)=[O:51])[CH:55]=3)=[CH:61][NH:62][C:63]2=[N:64][CH:65]=1)=[O:71]
Reactant: NC(=O)c1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1
Reactant: O=C(O)c1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1

Procedure:
Except where indicated, 3-[3-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid dimethylamide was synthesized as per Example 81, 3-[3-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid amide using 3-[3-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (53 mg, 0.00010 mol) as carboxylic acid and 2.00 M of dimethylamine in tetrahydrofuran (127 uL, 0.254 mmol; Aldrich) as amine, to yield the product. 1H NMR (400 MHz, CDCl3-MeOH-d4) d ppm 8.751 (m, 1H) 8.481 (m, 1H) 8.424 (m, 1H) 7.755 (m, 1H) 7.562 (m, 1H) 7.525 (m, 1H) 7.454-7.379 (m, 2H) 7.342 (m, 1H) 7.138-7.032 (m, 2H) 7.005-6.936 (m, 1H) 6.450 (m, 1H) 5.096 (m, 2H) 4.640 (m, 2H) 3.082 (m, 6H); MS m/z=542.33 M+H.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]([O:20][CH3:21])=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C(N(C(C)C)C(C)C)C.ClC(OC(Cl)C)=O>C(Cl)Cl>[NH:2]1[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]([O:20][CH3:21])=[O:19])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: COC(=O)c1ccc(C2CCN(C)CC2)c2ccccc12
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(C2CCNCC2)c2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
A solution of D9 (0.39 g, 1.4 mmole) in DCM (30 ml) was treated with iPr2EtN (0.26 g, 2 mmole) followed by 1-chloroethyl chloroformate (0.29 g, 2 mmole) and stirred at room temperature for 3 h, then concentrated under vacuum and the residue treated with MeOH (30 ml) and heated under reflux for 1 h. The mixture was allowed to cool and the solid filtered off, washed with Et2O and dried. This was treated with 10% Na2CO3 solution, extracted with DCM and the extract dried and concentrated under vacuum to afford the title compound as a colourless oil (0.33 g, 88%).
Reaction SMILES: [F:1][C:2]1([F:46])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30]([OH:33])=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[C:9]=2[CH:34]([F:45])[C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:53](I)[CH3:54].O>CN(C)C=O>[F:46][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:19])([CH3:20])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:22][CH2:23][N:24]([C:27]4[N:32]=[CH:31][C:30]([O:33][CH2:53][CH3:54])=[CH:29][N:28]=4)[CH2:25][CH2:26]3)[C:9]=2[CH:34]([F:45])[C:35]2[CH:36]=[CH:37][C:38]([C:41]([F:43])([F:42])[F:44])=[CH:39][CH:40]=2)[CH2:6][CH2:7]1
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(O)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a solution of 50 mg (0.077 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Example 4, in 1.0 ml of N,N-dimethylformamide, 75 mg (0.23 mmol) of cesium carbonate and 12 μl (0.15 mmol) of ethyl iodide were added, and the reaction solution was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative thin layer chromatography [n-hexane/ethyl acetate=70/30 (V/V)] to provide 45 mg of the title compound as a white solid (yield: 85%).
Reaction SMILES: C([N:4](CC)[CH:5]([CH3:7])[CH3:6])(C)C.[Br:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([OH:19])=O)=[N:15][CH:16]=1.C1(N)CC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN(C)C=O>C(OCC)(=O)C>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([NH:4][CH:5]2[CH2:7][CH2:6]2)=[O:19])=[N:15][CH:16]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1ccc(Br)cn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N-Diisopropylethylamine (0.69 mL, 0.0040 mol) was added to a mixture of 5-bromopyridine-2-carboxylic acid (400 mg, 0.002 mol), cyclopropylamine (0.16 mL, 0.0024 mol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.1 g, 0.0024 mol) in N,N-dimethylformamide (9.4 mL, 0.12 mol) at 0° C. and the mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed with water and brine successively, dried over sodium sulfate, filtered and concentrated. The product was purified by CombiFlash eluting with CH2Cl2/EtOAc (max.EtOAc 20%). LC-MS: 241.1/243.1 (M+H+)
Reaction SMILES: CS[C:3](SC)=[C:4]1[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:17].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([NH2:30])(=[O:29])=[O:28]>C1(C)C=CC=CC=1>[O:28]=[S:27]1(=[O:29])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[NH:20][C:3]([C:4]2[C:13](=[O:14])[C:12]([CH3:15])([CH3:16])[C:11]3[C:6]([C:5]=2[OH:17])=[CH:7][CH:8]=[CH:9][CH:10]=3)=[N:30]1
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: CSC(SC)=C1C(=O)c2ccccc2C(C)(C)C1=O
Solvent: Cc1ccccc1
Product: CC1(C)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Yield: 14.7 %

Procedure:
A solution of the product of Example 9G (450 mg) and 2-aminobenzenesulfonamide (180 mg, 1.05 mmol) in toluene (10 mL) was stirred at 100° C. for 2.5 hours, cooled to 25° C. and filtered. The filtrate was concentrated in vacuo, and the residue was chromatographed eluting with dichloromethane to give the title compound (57 mg, 15%). 1H NMR (300 MHz, CDCl3): δ 16.77, 16.61 (two s, 1 H), 14.36, 13.98 (two s, 1 H), 8.27 (m, 2 H), 7.99 (d, J=8.09 Hz, 2 H), 7.57 (m, 2 H), 7.31 (m, 2 H), 1.71 (s, 3 H), 1.56 (s, 3 H).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[O-]CC.[Na+].[CH2:20](Br)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].Cl>C(O)C>[C:1]([NH:4][C:5]([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH3:20])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCC(NC(C)=O)(C(=O)OCC)C(=O)OCC
Yield: 71.6 %

Procedure:
Diethyl 2-acetamidomalonate (3.0 g) was dissolved in 50 ml of dry ethanol and 1.13 g of sodium ethoxide was added thereto. A solution of 5.5 g of hexadecyl bromide in 20 ml of ethanol was added thereto at room temprature with stirring. The inside of the reaction vessel was displaced with nitrogen and the mixture was refluxed for about 15 hours. The mixture was neutralized with a 1 N aqueous hydrochloric acid solution and concentrated. The concentrate was purified by silica gel column chromatography to give 4.37 g of diethyl 2-acetamido-2-hexadecylmalonate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:17]=1>>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[N:17]=[C:12]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:13]2[CH:26]=[C:25]([C:27]([F:29])([F:30])[F:28])[S:24][C:14]=2[N:15]=1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3ccccn3)nc2s1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: FC(F)(F)c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-2-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-dichlorobenzylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([N:4]([C:13]1[NH:14][CH2:15][CH2:16][N:17]=1)[C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12])[CH:2]=[CH2:3].[H-].[Na+].[CH3:20]I>O1CCCC1>[CH3:20][N:17]1[CH2:16][CH2:15][N:14]=[C:13]1[N:4]([CH2:1][CH:2]=[CH2:3])[C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12]
Reactant: C=CCN(C1=NCCN1)c1c(Cl)cccc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCN(C1=NCCN1C)c1c(Cl)cccc1Cl
Reaction time: 8 h

Procedure:
A mixture consisting of 2.7 gm (0.01 mol) of 2-[N-allyl-N-(2,6-dichloro-phenyl)-amino]-2-imidazoline, 0.44 gm of a 55% sodium hydride dispersion and 25 ml of absolute tetrahydrofuran was refluxed for 5.5 hours while stirring, and the reaction mixture was allowed to stand overnight at room temperature. Thereafter, 1 ml of methyl iodide (about 160% of the stoichiometrically required amount) was added, and the mixture was refluxed for two hours. The reaction mixture was then evaporated to dryness in vacuo, the residue was dissolved in dilute (about 1 N) hydrochloric acid, and the resulting solution was extracted several times with ether (the ethereal extracts were discarded). The aqueous acidic phase was fractionally extracted with ether at stepwisely increasing pH-values (addition of 2 N sodium hydroxide). The thin-layer chromatographically uniform fractions were combined, dried over magnesium sulfate, and the ether was evaporated in vacuo, leaving 0.65 gm (23.0% of theory) of an initially oily residue which crystallized after a short period of time. The crystalline product had a melting point of 59°-61° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:20]([CH3:21])[N:19]=[C:18]([C:22]([OH:24])=O)[C:17]=1[CH3:25].[CH3:26][O:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:20]([CH3:21])[N:19]=[C:18]([C:22]([N:33]2[CH2:34][CH2:35][N:30]([CH2:29][CH2:28][O:27][CH3:26])[CH2:31][CH2:32]2)=[O:24])[C:17]=1[CH3:25]
Reactant: Cc1c(C(=O)O)nn(C)c1-c1ccccc1-c1cc2ccccc2o1
Reactant: COCCN1CCNCC1
Product: COCCN1CCN(C(=O)c2nn(C)c(-c3ccccc3-c3cc4ccccc4o3)c2C)CC1

Procedure:
In analogy to the procedure described in Example 18], 5-(3-benzofuran-2-yl-phenyl)-1,4-dimethyl-1H-pyrazole-3-carboxylic acid (Example 16C]) and 1-(2-methoxy-ethyl)-piperazine gave the title compound in quant. yield as light brown foam. MS: 459.3 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][OH:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][O:12][S:20]([CH3:19])(=[O:22])=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1cccc(CCO)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(3-nitro-phenyl)-ethanol (1 eq) in dichloromethane at 0° C. was added pyridine (4 eq) and methanesulfonyl chloride (2 eq). After stirring at 0° C. for one hour, then room temperature overnight, the mixture was diluted with dichloromethane and washed once with water, once with 1 N HCl, dried with anhydrous sodium sulfate, filtered and concentrated. The product was clean enough to be taken on to the next step without purification. MH+=246.0.
Reaction SMILES: COC(=O)[CH2:4][C@H:5]([N:9]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:11][C:12](OC)=O)[C:6]([OH:8])=O.C[O-].[Na+].CO.[C:29](N)(C)(C)[CH3:30]>C1COCC1>[CH:6]([CH:5]1[N:9]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:10][CH2:11][C:12]2([CH2:30][CH2:29]2)[CH2:4]1)=[O:8]
Reactant: COC(=O)CCN(C(=O)OC(C)(C)C)[C@@H](CC(=O)OC)C(=O)O
Reactant: CC(C)(C)N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC2)CC1C=O
Temperature: 85 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
To a solution of (S)-2-[tert-Butoxycarbonyl-(2-methoxycarbonyl-ethyl)-amino]-succinic acid 4-methyl ester (intermediate 12, 420 g, 1.35 mol) in THF (2 L) under nitrogen cooled to 0° C. was added NaOMe/MeOH (1.5 L, 2.7M) in half an hour. The resulting yellow solution was stirred at 85° C. for 3 hours (after 1 hour a suspension was obtained). THF (1.5 L) was distilled off under the reduced pressure and water (2 L) was added. The resulting mixture was stirred at 110° C. for 20 hours. The mixture was washed with ethyl acetate (2×1 L). The aqueous solution was cooled to 0° C. and the value of pH was adjusted to 2.5 with concentrated HCl. The product was extracted with ethyl acetate (3×1 L) and the organic extracts were combined, washed with saturated NaCl (1 L), dried (Na2SO4) and filtered. The filtrate was cooled to 0° C. and tert-butylamine (145 ml, 1.35 mol) was added with stirring. The yellow solid was collected by filtration and dried, then boiled in isopropyl alcohol (1.5 L). The suspension was cooled to 5° C. and collected by filtration to give 180 g of intermediate 3 (light white solid, yield:45%).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([C:17]2[CH:30]=[CH:29][C:28]3[C:27](=[O:31])[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([CH3:35])[C:25]=4[N+:32]([O-])=O)[C:20](=[O:36])[C:19]=3[C:18]=2[NH2:37])=[O:16])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C1(C)C=CC=CC=1.[H][H]>[Pd].C(O)C>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]([C:17]2[CH:30]=[CH:29][C:28]3[C:27](=[O:31])[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([CH3:35])[C:25]=4[NH2:32])[C:20](=[O:36])[C:19]=3[C:18]=2[NH2:37])=[O:16])=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: [H][H]
Reactant: CCCCCCCc1ccc(OC(=O)c2ccc3c(c2N)C(=O)c2ccc(C)c([N+](=O)[O-])c2C3=O)cc1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCCCCc1ccc(OC(=O)c2ccc3c(c2N)C(=O)c2ccc(C)c(N)c2C3=O)cc1

Procedure:
A suspension of 0.426 g of 1-amino-6-methyl-5-nitro-2-anthraquinonecarboxylic acid p-heptylphenyl ester, 50 ml of toluene, 50 ml of ethanol and 0.10 g of palladium/barium carbonate catalyst poisoned with 2 wt.% lead was hydrogenated at room temperature until the hydrogen uptake came to a standstill. The mixture was filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica gel with methylene chloride as the eluent. Recrystallization from methylene chloride/hexane, yielded 0.334 of 1,5-diamino-6-methyl-2-anthraquinonecarboxylic acid p-heptylphenyl ester as violet crystals; m.p. (C-N) 163.7°-165.7° C., cl.p. (N-I) 190.9°-191.4° C., nematic; E277 =15280, E524 =14700.