Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[C:31]([O:33][CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH:30]=[C:29]([F:40])[C:28]=1[C:41]1[N:46]=[C:45]([C:47](O)=[O:48])[CH:44]=[CH:43][C:42]=1[F:50]>>[NH2:9][C@H:8]1[C@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:47](=[O:48])[C:45]2[CH:44]=[CH:43][C:42]([F:50])=[C:41]([C:28]3[C:29]([F:40])=[CH:30][C:31]([O:33][CH:34]4[CH2:35][CH2:36][O:37][CH2:38][CH2:39]4)=[CH:32][C:27]=3[F:26])[N:46]=2)[CH2:6][CH2:7]1
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cc(OC3CCOCC3)cc2F)n1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: Cn1ncc(NC(=O)c2ccc(F)c(-c3c(F)cc(OC4CCOCC4)cc3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(2,6-difluoro-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-5-fluoropicolinic acid (see US2012/225062) gave 197. 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.25 (dd, J=8.7, 4.0 Hz, 1H), 8.11 (t, J=8.9 Hz, 1H), 7.91 (s, 1H), 6.99 (d, J=10.2 Hz, 2H), 4.82 (dd, J=10.4, 3.7 Hz, 1H), 4.77-4.66 (m, 1H), 4.21 (ddd, J=49.1, 7.8, 2.9 Hz, 1H), 4.10-3.90 (m, 2H), 3.90-3.80 (m, 2H), 3.75 (s, 3H), 3.51 (ddd, J=12.0, 9.4, 2.8 Hz, 2H), 3.14-3.01 (m, 1H), 2.10-1.97 (m, 3H), 1.85-1.55 (m, 5H). LCMS (ES+) m/z 564 (M+1).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][NH:3][CH:2]1[C:6]([OH:8])=[O:7].[N:9]([O-])=[O:10].[Na+]>C(O)(=O)C.O>[N:9]([N:3]1[CH2:4][CH2:5][S:1][CH:2]1[C:6]([OH:8])=[O:7])=[O:10]
Reactant: O=N[O-]
Reactant: O=C(O)C1NCCS1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=NN1CCSC1C(=O)O
Reaction time: 5 h

Procedure:
To a suspension of thiazolidine-2-carboxylic acid (39.9 g, 0.30 mol) in 1,000 ml of acetic acid was added a solution of 31.0 g (0.45 mol) of sodium nitrite in 500 ml of water over 13 minutes at room temperature and stirred for 5 hours. The reaction solution was concentrated under reduced pressure. Acetone (500 ml) was added to the residue and the precipitate was filtered through a pad of Celite. The pad was washed with acetone (500 ml). The filtrate was concentrated under reduced pressure to dryness and crude 3-nitrosothiazolidin-2-carboxylic acid was obtained as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:3]([I:12])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[C:13]([C:16]1[CH:17]=[C:18]([CH:21]=O)[NH:19][CH:20]=1)(=[O:15])[CH3:14].C1COCC1>N1CCCCC1.CC(O)C>[C:13]([C:16]1[CH:17]=[C:18](/[CH:21]=[C:5]2\[C:6](=[O:11])[NH:7][C:8]3[C:4]\2=[C:3]([I:12])[C:2]([F:1])=[CH:10][CH:9]=3)[NH:19][CH:20]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)c1c[nH]c(C=O)c1
Reactant: O=C1Cc2c(ccc(F)c2I)N1
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(I)c32)c1
Temperature: 25 °C

Procedure:
1,3-Dihydro-5-fluoro-4-iodo-2H-indol-2-one (0.77 g, 2.8 mmol) (see Example 2A, supra) and 4-acetyl-2-formylpyrrole (0.42 g, 3.06 mmol) (Example 90A above) were suspended in 1% piperidine in 2-propanol (12 mL) and THF (5 mL) and heated at 85° C. for 2 h. Yellow precipitate was formed. After cooling to room temperature, product was collected by filtration and washed with aqueous 2-propanol and dried in vacuum oven to yield (Z)-3-[(4-Acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one. (Yield 0.89 g, 80.8%).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH2:23]([C:27]1[C:36](=O)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([C:45]3[C:46]([C:51]([O:53][CH3:54])=[O:52])=[CH:47][CH:48]=[CH:49][CH:50]=3)=[CH:41][CH:40]=2)[CH:28]=1)[CH2:24][CH2:25][CH3:26].O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:23]([C:27]1[C:36](=[S:10])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([C:45]3[C:46]([C:51]([O:53][CH3:54])=[O:52])=[CH:47][CH:48]=[CH:49][CH:50]=3)=[CH:41][CH:40]=2)[CH:28]=1)[CH2:24][CH2:25][CH3:26]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCCCc1cn(Cc2ccc(-c3ccccc3C(=O)OC)cc2)c2ccccc2c1=O
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCc1cn(Cc2ccc(-c3ccccc3C(=O)OC)cc2)c2ccccc2c1=S
Yield: 26169.9 %

Procedure:
2.10 mg of Lawesson reagent were added to a solution of 400 mg of the product of Example 3 in 20 ml of toluene and the mixture was refluxed for 90 minutes. The mixture was poured into 100 ml of water and extraction was carried out with ethyl acetate. Th extracts were washed with water, dried, filtered and evaporated to dryness to obtain 0.6 g of the expected product which was chromatographed on silica (eluant: methylene chloride-acetone (98-2)) to collect 0.42 g of the desired product melting at 158° C.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.[CH3:12][O:13][C:14]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:15]=1[C:16]([Cl:18])=[O:17].C(=O)([O-])[O-].[Na+].[Na+].O>C(Cl)(Cl)Cl>[ClH:18].[N:6]12[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7]1)[CH:4]([NH:3][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:14]=1[O:13][CH3:12])[CH2:5]2
Reactant: NC1CN2CCC1CC2
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)NC2CN3CCC2CC3)c(OC)c1
Yield: 23.7 %

Procedure:
A mixture of 3-aminoquinuclidine dihydrochloride, 6.95 g, (0.0349), 2,4-dimethoxybenzoyl chloride, 700 g, (0.0349 mole), anhydrous sodium carbonate, 36.99 g, (0.349 mole), 175 ml water, and 175 ml chloroform was stirred rapidly to achieve good mixing of the 2 layers for 20 hrs. The chloroform layer was then separated, washed with water, dried over anhydrous magnesium sulfate, and concentrated to an impure oil. The oil was triturated twice with 20 ml portions of petroleum ether to remove some impurities. The oil was then dissolved in ether and filtered to remove a small amount of insoluble material. The filtrate was treated with ethereal hydrogen chloride and the resulting salt collected to yield 2.70 g (23.7% yield) white solid. The salt was recrystallized from ethanol-isopropyl ether. Further recrystallization from methanol-ethyl ether yielded a white solid, m.p. 211°-212° C. The NMR analysis was satisfactory.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12]([NH:14][CH2:15][CH2:16][OH:17])=[O:13])[C:5]([CH3:22])=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.[CH3:34][NH:35]C(=O)CN.CN1CCOCC1>>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12]([NH:14][CH2:15][C:16]([NH:35][CH3:34])=[O:17])=[O:13])[C:5]([CH3:22])=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]
Reactant: Cc1ccc(C(=O)NCCO)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Cl)c1=O
Reactant: CNC(=O)CN
Agent: Cl
Solvent: CN1CCOCC1
Product: CNC(=O)CNC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3F)c(Cl)c2=O)c1
Yield: 33 %

Procedure:
The title compound was prepared by a procedure similar to the one described for (±)3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-N-(2-hydroxyethyl)-4-methylbenzamide using glycine methyl amide HCl (1.77 g, 14.25 mmol) as the amine and with an addition of a second equivalent of N-methylmorpholine. After reverse phase HPLC purification, the organic extracts were concentrated under reduced pressure and dried in vacuo to afford the desired product (1.55 g, 33%) as white solid. 1H-NMR (CD3OD, 400 MHz) δ 7.97 (dd, 1H, J=1.6 Hz), 7.73 (d, 1H, J=1.6 Hz), 7.62 (m, 1H), 7.57 (d, 1H, J=8 Hz), 7.01 (m, 2H), 5.59 (q, 2H, J=12.4 Hz), 3.98 (s, 2H), 2.74 (s, 3H), 2.18 (s, 3H), 2.14 (s, 3H); ES-HRMS m/z 491.1262 (M+H C23H22ClF2N4O4 requires 491.1292). Both (+) and (−) atropomers will be resolved and characterized.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH2:9])=[NH:8])[CH2:2][CH3:3].Cl[C:15]1[C:20]([C:21](OCC)=[O:22])=[CH:19][N:18]=[C:17]([S:26][CH3:27])[N:16]=1>CC(O)C>[CH3:27][S:26][C:17]1[N:18]=[C:19]2[N:8]=[C:7]([C:6]3[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=3[O:4][CH2:1][CH2:2][CH3:3])[NH:9][C:21](=[O:22])[C:20]2=[CH:15][N:16]=1
Reactant: CCCOc1ccccc1C(=N)N
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: CC(C)O
Product: CCCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Temperature: 2 °C
Reaction time: 2 h

Procedure:
2-Propoxybenzamidine (from sodium, 0.3 g, in ethanol, 50 ml, and 2-propoxybenzamidine hydrochloride, 2.77 g) was dissolved in 2-propanol (20 ml) and the resulting cooled (2° C.) solution was added to a cooled (2° C.) solution of ethyl 4-chloro-2-methylthio-5-pyrimidine carboxylate (2 g) in 2-propanol (30 ml). The reaction mixture was stirred at 2° C. for 2 hours and was then left overnight at ambient temperature to yield a white crude product, 1.18 g, m.p. 179-181° C. Recrystallization from ethanol yielded the title compound, 0.92 g, m.p. 186-187° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]3[CH:13]=[CH:14][C:15]([F:28])=[C:16]([NH:18][C:19]([C:21]4[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=4)=[O:20])[CH:17]=3)=[N:7][N:6]2[CH:29]=1.[Cl-].[CH3:31][O:32][NH3+:33].C(N(CC)CC)C.CN(C)[CH:43]=[O:44]>>[F:28][C:15]1[CH:14]=[CH:13][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]3[N:6]([CH:29]=[C:3]([NH:2][C:43]([NH:33][O:32][CH3:31])=[O:44])[N:4]=3)[N:7]=2)=[CH:17][C:16]=1[NH:18][C:19]([C:21]1[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=1)=[O:20]
Reactant: CO[NH3+]
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2F)n(C)n1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: CONC(=O)Nc1cn2nc(Oc3ccc(F)c(NC(=O)c4cc(C)nn4C)c3)ccc2n1
Yield: 54 %

Procedure:
Using N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-fluorophenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide hydrochloride (200 mg, 0.48 mmol), 1,1′-carbonylimidazole (233 mg, 1.44 mmol), O-methylhydroxyammonium chloride (120 mg, 1.44 mmol), triethylamine (0.27 mL, 1.92 mmol) and N,N-dimethylformamide (6.0 mL), and by a reaction in the same manner as in Example 200, the title compound (117 mg, 54%) was obtained as pale-yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:4][N:3]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][C:2]1[C:6]([C:7]([N:16]2[CH2:20][CH2:19][CH2:18][CH:17]2[CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:9])=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:4][N:3]=1
Reactant: c1cncc(CC2CCCN2)c1
Reactant: Cc1noc(-c2ccccc2)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(-c2ccccc2)c1C(=O)N1CCCC1Cc1cccnc1
Temperature: 25 °C

Procedure:
3-Methyl-5-phenyl-4-isoxazolecarboxylic acid (40 mg, 0.197 mmol), 3-(pyrrolidin-2-ylmethyl)pyridine (50.5 mg, 0.215 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (86.2 mg, 0.268 mmol) and diisopropylethylamine (25.4 mg, 0.197 mmol) were mixed in dimethylformamide (1.0 mL) and stirred at room temperature. Solvent was evaporated in vacuo, and the residue was taken up in methanol (1 mL), filtered and purified by preparative chromatography. The combined fractions were partitioned between NaHCO3 (sat) and ethylacetate. The organic layer was washed with water and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C21H21N3O2: 347.1634, found 347.1642.
Reaction SMILES: [K].S(=O)(=O)(O)O.C(=O)([O-])[O-:8].[Na+].[Na+].[NH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[Cl:24]>O>[Cl:24][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:14]=1[N:13]=[O:8])[C:18]([O:20][CH3:21])=[O:19]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(N)c(Cl)c1
Agent: O=S(=O)(O)O
Agent: [K]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc(N=O)c(Cl)c1
Temperature: 0 °C

Procedure:
8.00 g (29.6 mmol) potassium peroxodisulphate are added to 6.0 ml of conc. sulphuric acid with stirring, stirred for 30 minutes at ambient temperature under a nitrogen atmosphere, the mixture is stirred into 50 g ice and neutralised with 14 g sodium carbonate. The solution obtained is combined with a suspension of 2.78 g (15.0 mmol) methyl 4-amino-3-chloro-benzoate in 300 ml of water and stirred for 16 hours at ambient temperature. The reaction mixture is suction filtered, the filter cake is washed with water, dried in the air and purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate 9:1).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=1[C:23]([F:26])([F:25])[F:24].[F:27][C:28]1[CH:29]=[CH:30][C:31]([O:38][CH3:39])=[C:32]([C:34](=[N:36]O)[NH2:35])[CH:33]=1.CCN(C(C)C)C(C)C>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([O:38][CH3:39])=[C:32]([C:34]2[N:35]=[C:18]([C:17]3[CH:21]=[CH:22][C:14]([N:9]4[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]4[CH3:7])=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:16]=3)[O:20][N:36]=2)[CH:33]=1
Reactant: COc1ccc(F)cc1C(N)=NO
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(F)cc1-c1noc(-c2ccc(N3CCCCC3C)c(C(F)(F)F)c2)n1

Procedure:
Oxalyl chloride (106 μL; 1.25 mmol; 3 eq.), Intermediate 24 (120 mg; 0.42 mmol; 1 eq.), Intermediate 23 (77 mg; 0.42 mmol, 1 eq.) and DIEA (2164; 1.25 mmol; 3 eq.) were reacted according to general procedure 2. Purification by preparative HPLC (increasing amount of 0.1% TFA in CH3CN, in 0.1% TFA in water) afforded the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])P(=O)(OCC)OCC.[H-].[Na+].[CH:20]([C:22]1[N:27]2[CH:28]=[C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:30]=[C:26]2[CH:25]=[CH:24][CH:23]=1)=O>C1C=CC=CC=1.C(Cl)(Cl)Cl.O>[CH2:15]([O:14][P:10]([O:11][CH2:12][CH3:13])(/[CH:1]=[CH:20]/[C:22]1[N:27]2[CH:28]=[C:29]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:30]=[C:26]2[CH:25]=[CH:24][CH:23]=1)=[O:17])[CH3:16]
Reactant: CCOC(=O)c1cn2c(C=O)cccc2n1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)c1cn2c(/C=C/P(=O)(OCC)OCC)cccc2n1
Reaction time: 2 h

Procedure:
Tetraethyl methylenediphosphonate (Lancaster) in benzene was added to a benzene solution of sodium hydride (NaH). The product from Example 54, also dissolved in benzene, was then added dropwise to the reaction mixture. After stirring the resulting mixture for 2 h under an Ar atmosphere, the reaction was diluted with CHCl3 /H2O (2/1). The CHCl3 layer was separated and the aqueous layer extracted with CHCl3. Chromatography of the residue after removal of all solvent from the combined extracts gave the title product.
Reaction SMILES: Cl[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[CH:7]=O.[SH:9][CH2:10][C:11]([O:13][CH3:14])=[O:12].C(N(CC)CC)C>N1C=CC=CC=1>[S:9]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][C:3]2[CH2:4][CH2:5][CH2:6][C:2]1=2
Reactant: COC(=O)CS
Reactant: O=CC1=C(Cl)CCC1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2c(s1)CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
To a 100-mL round-bottom flask containing a solution of 2-chlorocyclopent-1-ene-1-carbaldehyde (1.2 g, 9.19 mmol, 1.00 equiv) and methyl 2-sulfanylacetate (1.17 g, 11.02 mmol, 1.20 equiv) in pyridine (10 mL) was added triethylamine (2 mL) dropwise at 0° C. The resulting solution was stirred for 1 h at room temperature. The reaction was then quenched by the addition of 2 mL of 48% aqueous KOH solution and diluted with 100 mL of water. The resulting solution was extracted with 3×100 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 1.3 g (78%) of methyl 4H,5H,6H-cyclopenta[b]thiophene-2-carboxylate as a yellow solid. MS (ES): m/z 183 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][N:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].CCO.O.N>[Fe].CC(O)=O>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[N:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Agent: [Fe]
Agent: N
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)N1CCN(c2ccc(N)cn2)CC1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of iron powder (1.4 g, 25.3 mmol, 4 equiv), 1-isopropyl-4-(5-nitro-pyridin-2-yl)piperazine (1.58 g, 6.32 mmol), EtOH (20 mL), H2O (5 mL), and AcOH (2.5 mL) is stirred for 2 h at 90° C., allowed to cool to RT, basified by addition of aqueous ammonia, filtered through a pad of celite and partially concentrated to remove EtOH. The aqueous residue is saturated with sodium chloride and extracted with EtOAc and DCM. The combined organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (DCM/MeOH/NH3aq, 91:8:1) to afford the title compound as a purple solid: ESI-MS: 221.1 [MH]+; TLC: Rf=0.20 (DCM/MeOH/NH3aq, 91:8:1).
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13](C=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24]([CH:29]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:26][CH2:27][CH3:28])=[O:25].[CH2:49]1COCC1>>[CH2:27]([O:26][C:24](=[O:25])[CH:29]=[CH:49][C:13]1[S:12][C:11]([NH:10][C:8]([N:7]([CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)[CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:9])=[N:15][CH:14]=1)[CH3:28]
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: C1CCOC1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)C=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Yield: 69 %

Procedure:
A solution of 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (Example 252) (90 mg, 0.27 mmol) and (carbethoxymethylene)triphenylphosphorane (102 mg, 0.30 mmol) in THF (5 mL) was stirred at 40° C. for 12 h. The reaction mixture was concentrated and the residue was purified by flash chromatography (silica, CH2Cl2-EtOAc, 4:1) to obtain 3-[2-(3,3-dicyclohexylureido)-thiazol-5-yl]-acrylic acid ethyl ester (75 mg) in 69% yield.
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CS(C)=O>[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCCCNc1ccccn1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: NCCCCN(Cc1ccccc1)c1ccccn1
Yield: 36.3 %

Procedure:
Sodium hydride (1.6 g) was disolved in DMSO (35 ml) at 70°-75° C. under nitrogen. The solution was cooled and 2-(4-aminobutylamino)pyridine (10 g) in DMSO (10 ml) added at room temperature. Benzyl bromide (10.35 g) in DMSO (10 ml) was added dropwise maintaining the temperature at 25°-30° C. After a further 2 hr water (200 ml) was added and the mixture extracted with chloroform. The chloroform extract was washed with 2N hydrochloric acid and the aqueous layer basified to pH 4. After extracting with chloroform the pH was raised to 14 and again extracted with chloroform. After stripping the latter extract the residue was taken up in ether and the solution washed with water. The ether layer was dried (K2CO3) and stripped to give 2-[N-(4-aminobutyl)-N-benzylamino]pyridine (5.61 g) as an oil which was used without further purification. (ii) 2-[N-(4-aminobutyl)-N-benzylamino]pyridine (1 g) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)pyrimid-4-one (0.82 g) were heated together under reflux in pyridine (5 ml) for 22 hr. After cooling the mixture was stripped, the residue triturated with ether and crystallised from ethanol/ether to give 2-[4-(N-benzyl-N-pyrid-2-ylamino)butylamino]-5-(6-methylpyrid-3-ylmethyl)pyrimid-4-one 0.4H2O, 1.15 g (80%) mp softens 98°-100° C. melts 120°-22° C. (from ethanol/water).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:43](=[O:49])[O:44][C:45](Cl)(Cl)Cl)Cl.[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([S:58][CH2:59][CH2:60]CO)=[C:54]([CH3:63])[CH:53]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:44][CH2:45][CH2:60][CH2:59][S:58][C:55]2[CH:56]=[CH:57][C:52]([Cl:51])=[CH:53][C:54]=2[CH3:63])=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(Cl)ccc1SCCCO
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCCCSc4ccc(Cl)cc4C)cc3C)c2cc1OC
Temperature: 25 °C
Yield: 51.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (90 mg) was added to toluene/triethylamine=10/1 (9 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (120 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-[4-chloro-2-methylphenyl]sulfanyl-1-propanol (80 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (81 mg, yield 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[NH2:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([OH:26])=[C:21]([CH3:27])[CH:20]=1>>[ClH:1].[CH3:25][C:24]1[CH:23]=[C:22]([OH:26])[C:21]([CH3:27])=[CH:20][C:19]=1[NH:18][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cnccn2)n1
Reactant: Cc1cc(O)c(C)cc1N
Product: Cc1cc(Nc2cc(C(F)(F)F)nc(-c3cnccn3)n2)c(C)cc1O
Product: Cl

Procedure:
The title compound was prepared from a mixture of 4-chloro-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.191 mmol) and 4-amino-2,5-dimethylphenol (39 mg, 0.287 mmol) similar to Example 117 and isolated as an orange solid (35 mg, 47%). 1H NMR (CDCl3): 9.75 (d, J=1.2 Hz, 1H), 8.79–8.78 (m, 1H), 8.73 (d, J=2.4 Hz, 1H), 7.20 (s, 1H), 7.01 (s, 1H), 6.78 (s, 1H), 6.52 (s, 1H), 5.43 (s, 1H), 2.25 (s, 3H), 2.16 (s, 3H).