Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH2:3][CH2:2]1.Br[CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=1[O:31][CH3:32].C([O-])([O-])=O.[K+].[K+].C(#N)C>O>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([CH:4]2[CH2:3][CH2:2][N:1]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=3[O:31][CH3:32])[CH2:6][CH2:5]2)=[N:8]1
Reactant: COc1cc(C(C)=O)ccc1OCCCCBr
Reactant: c1ccc2c(C3CCNCC3)n[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OCCCCN1CCC(c2n[nH]c3ccccc23)CC1
Yield: 78.6 %

Procedure:
A mixture of 3-(4-piperidinyl)-1H-indazole (3.2 g, 16 mmol), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (5.0 g, 16 mmol), K2CO3 (2.2 g) and acetonitrile (100 ml) was stirred and refluxed for 6 hours. The reaction was poured into water and the resulting yellow solid that formed was collected to afford 5.3 g of product. The compound was recrystallized from acetonitrile and then from ethyl acetate to yield 3.0 g (45%) of a slightly yellow solid of 1-[4-[4-[4-(1H-indazol-3-yl)-1-piperidinyll-butoxy]-3-methoxyphenyl]ethanone, m.p.=133°-135° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:10][CH:9]2[C:11](O)=[O:12])=[CH:4][CH:3]=1.[NH2:17]C(N)=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:10][CH:9]2[C:11](=[O:12])[NH:17][C:14]3=[O:16])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C2(C(=O)O)CC2C(=O)O)cc1
Reactant: NC(N)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(C23CC2C(=O)NC3=O)cc1

Procedure:
A mixture of purified 1-(4-methylphenyl)-1,2-cyclopropanedicarboxylic acid (58 kg), toluene (465 kg) and urea (23.8 kg) was heated to reflux and the mixture held at reflux until the reaction was complete. On completion of the reaction period, the solution was cooled to 80–90° C. and washed with water (69 L). The lower aqueous layer was discarded. In this way (±)-1-(4-methylphenyl)-3-azabicyclo[3.1.0]hexan-2,4-dione was obtained as a solution in toluene.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12]1([CH:18]=[CH:19][CH2:20]O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.P(=O)(O)(O)O>>[C:12]1([CH:18]=[CH:19][CH2:20][O:5][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:2]=2[OH:1])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc(C(=O)O)c(O)c1
Reactant: OCC=Cc1ccccc1
Agent: O=P(O)(O)O
Product: Cc1ccc(C(=O)OCC=Cc2ccccc2)c(O)c1
Yield: 89.1 %

Procedure:
Using the method of example 1, 15.24 g of 2-hydroxy-4-methylbenzoic acid (0.1 moles), 40.251 g of 3-phenyl-2-propen-1-ol (0.3 moles) and 4.9 g of anhydrous phosphoric acid (0.05 moles) give 23.9 g (89% yield) of (3-phenyl-2-propenyl)-2-hydroxy-4-methylbenzoate, m.p. 196°14 196.5° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][C@H:18]([C:31]([O:33]CC2C=CC=CC=2)=[O:32])[CH2:19][CH2:20][C:21]([O:23]CC2C=CC=CC=2)=[O:22])=[O:16])=[CH:10][CH:9]=1)[CH2:5][CH2:6][Cl:7]>CN(C=O)C.[Pd]>[Cl:1][CH2:2][CH2:3][N:4]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]([NH:17][C@H:18]([C:31]([OH:33])=[O:32])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:16])=[CH:12][CH:13]=1)[CH2:5][CH2:6][Cl:7]
Reactant: O=C(Nc1ccc(N(CCCl)CCCl)cc1)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=C(O)CC[C@H](NC(=O)Nc1ccc(N(CCCl)CCCl)cc1)C(=O)O

Procedure:
A solution of dibenzyl N-(4-[N,N-bis-(2-chloroethyl)amino]-phenylcarbamoyl)-L-glutamate (1.138 g) in DMF (15 ml) was hydrogenated over 10% Pd/C for 16 h. After filtration and evaporation in vacuo, the residue was dissolved in CHCl3 (20 ml). After 18 h the crystalline precipitate was filtered off and dried in vacuo to obtain N-(4-[N,N-bis-(2-chloroethyl)amino]phenylcarbamoyl)-L-glutamic acid. Yield, 730 mg (93%). After recrystallization from acetone/CHCl3 microscopic rods formed m.p. 116-118°. NMR (CD3COCD3): δ 8.0(s)1H; 7.2(d)2H; 6.6(d)2H; 6.2(d)2H NH; 4.4(m)1H; 3.6(m)8H; 2.5-1.9(m)4H.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH2:23][CH2:24][NH:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH:12]=[CH:13][C:14]=2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CN(C)[CH:36]=[O:37]>>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH2:23][CH2:24][N:25]([CH2:11][CH2:10][CH2:9][CH2:14][CH2:13][CH2:12][O:37][CH2:36][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:26](=[O:31])[C:27]([F:29])([F:30])[F:28])[CH:12]=[CH:13][C:14]=2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(NCCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(F)(F)F
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: O=C(N(CCCCCCOCCc1ccccc1)CCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(F)(F)F
Temperature: 70 °C

Procedure:
A solution of N-[2-[3,4-Bis(phenylmethoxy) phenyl]ethyl]-2,2,2-trifluoroacetamide (11g) in dry dimethylformamide (30 ml) was added dropwise to a stirred suspension of sodium hydride (0.615 g) in dry dimethylformamide (20 ml) in (a) nitrogen atmosphere. The mixture was heated at 70° C. for 1 hour and then cooled to room temperature.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:34])=[C:7]2[C:12](=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[N:14]=1)[N:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10](=[O:27])[C:9]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:8]2)=[O:4].[NH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[OH:34][C:6]1[C:5]([C:3]([NH:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:4])=[N:14][C:13]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[C:12]2[C:7]=1[CH:8]=[C:9]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:10](=[O:27])[N:11]2[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)c1nc(-c2ccncc2)c2c(cc(-c3ccccc3)c(=O)n2-c2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2ccncc2)c2c(cc(-c3ccccc3)c(=O)n2-c2ccccc2)c1O
Temperature: 25 °C
Yield: 13.3 %

Procedure:
A mixture of 5-hydroxy-2-oxo-1,3-diphenyl-8-pyridin-4-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (40 mg, 0.089 mmol), β-alanine (635 mg, 7.13 mmol) and NaOMe solution (10.7 mL, 5.35 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (10-100% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 6 mg of the title compound as a white solid. MS: (+) m/z 507.49 (M+1).
Reaction SMILES: [N:1]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][CH2:29][C@H:2]1[C:3]([N:5]([CH3:28])[C@H:6]([C:14]([NH:16][C@H:17]([C:25](O)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[NH2:39][CH2:40][C:41]([NH:43][C@H:44]([C:49]([NH:51][C@H:52]([C:57]([NH2:59])=[O:58])[CH2:53][CH2:54][S:55][CH3:56])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42].C1(N=C=NC2CCCCC2)CCCCC1.ON1C(=O)CCC1=O>>[N:1]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][CH2:29][C@H:2]1[C:3]([N:5]([CH3:28])[C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:39][CH2:40][C:41]([NH:43][C@H:44]([C:49]([NH:51][C@H:52]([C:57]([NH2:59])=[O:58])[CH2:53][CH2:54][S:55][CH3:56])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42])=[O:26])[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:15])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: CN(C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CN)C(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Yield: 50 %

Procedure:
Condensation of BocPro-MePhe-PheOH (670 mg.) and HGly-Leu-MetNH2 (Example 7, 418 mg.) using dicyclohexylcarbodiimide and N-hydroxysuccinimide gave BocPro-MePhe-Phe-Gly-Leu-MetNH2 in 50% yield. De-t-butoxycarbonylation of BocPro-MePhe-Phe-Gly-Leu-MetNH2 (480 mg.) using hydrogen chloride in ethyl acetate gave HPro-MePhe-Phe-Bly-Leu-MetNH2, which was isolated as the amorphous white solid hydrochloride salt monohydrate in 85% yield.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C@H:19]([O:23][CH2:24][CH3:25])[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[CH:26](O)=[O:27].C(OC(=O)C)(=O)C>O1CCCC1>[CH2:24]([O:23][C@@H:19]([CH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([NH:2][CH:26]=[O:27])=[CH:8][CH:7]=2)=[CH:13][CH:14]=1)[C:20]([OH:22])=[O:21])[CH3:25]
Reactant: O=CO
Reactant: CCO[C@@H](Cc1ccc(OCCc2ccc(N)cc2)cc1)C(=O)O
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CCO[C@@H](Cc1ccc(OCCc2ccc(NC=O)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
3-{4-[2-(4-Aminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid hydro chloride (described in Example 56a) (0.115 g, 0.314 mmole) in tetrahydrofuran (3 ml) was mixed with a mixture of formic acid (0.5 ml) and acetic anhydride (0.3 ml). The resulting mixture was stirred at room temperature overnight. Tetrahydrofuran was evaporated. Ethyl acetate and water were added into the residue. The phases were separated. The organic phase was washed with brine, dried with magnesium sulfate and the solvent was evaporated. Chromatography of the residue on silica gel (Isolute, SI) using dichloromethane, then methanol/dichloromethane (1%), followed by methanol/dichloromethane (2%) as eluants gave 0.07 g (yield 62%) of (S)-2-ethoxy-3-(4-{[4-(formylamino)phenethyl]oxy}phenyl)propanoic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][N:13]([C:16]2[N:17]=[C:18]([C:26]3[C:27](=[O:42])[NH:28][C:29](=[O:41])[C:30]=3[C:31]3[C:39]4[C:34](=[C:35]([CH3:40])[CH:36]=[CH:37][CH:38]=4)[NH:33][CH:32]=3)[C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:12][C:9]21[CH2:11][CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:43]=[O:44]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][N:13]([C:16]2[N:17]=[C:18]([C:26]3[C:27](=[O:42])[N:28]([CH2:43][OH:44])[C:29](=[O:41])[C:30]=3[C:31]3[C:39]4[C:34](=[C:35]([CH3:40])[CH:36]=[CH:37][CH:38]=4)[NH:33][CH:32]=3)[C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:12][C:9]21[CH2:11][CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cccc2c(C3=C(c4nc(N5CCN(C(=O)OC(C)(C)C)C6(CC6)C5)cc5ccccc45)C(=O)NC3=O)c[nH]c12
Reactant: C=O
Solvent: CO
Product: Cc1cccc2c(C3=C(c4nc(N5CCN(C(=O)OC(C)(C)C)C6(CC6)C5)cc5ccccc45)C(=O)N(CO)C3=O)c[nH]c12
Temperature: 85 °C
Reaction time: 4 h

Procedure:
To a solution of 7-{1-[4-(7-methyl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-isoquinolin-3-yl}-4,7-diaza-spiro[2.5]octane-4-carboxylic acid tert-butyl ester (3.00 g, 5.32 mmol) in MeOH (25 mL) was added an aqueous 37% solution of formaldehyde (9.5 g, 8.72 mL, 117 mmol) under argon at r.t. The reaction mixture was heated to 85° C. and stirred for 4 h. The reaction mixture was cooled to r.t. under continuous stirring and filtered. The solids were washed with ice-water and dried at high vacuum (<1 mm Hg) to afford the title compound as dark red crystals. 1H-NMR (400 MHz, DMSO-d6): 11.96 (s, 1H), 8.05 (s, 1H), 7.69-7.64 (m, 2H), 7.47 (t, 1H), 7.12-7.06 (m, 2H), 6.76 (d, 1H), 6.42 (t, 1H), 6.01 (d, 1H), 5.00 (d, 2H), 3.49-3.10 (m, 6H), 2.39 (s, 3H), 1.41 (s, 9H), 0.89-0.57 (m, 4H). LCMS: [M]+=593.7, Rt(1)=2.34 min.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[F:17][C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1[CH:20]=[CH:21][C:22](O)=O>>[F:17][C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1/[CH:20]=[CH:21]/[C:22]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: O=C(O)C=Cc1ccccc1F
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccccc3F)nc2n(CCC)c1=O
Yield: 68 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 3.00 g (13.3 mmol) of 5,6-diamino-1,3-dipropyluracil and 2.43 g (14.6 mmol) of 2-fluorocinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 3.23 g (yield 68% of Compound 43 as white needles.
Reaction SMILES: [S:1]1[C:5]2[C:6]([C:10]3[O:19][C:13]4=[C:14]([NH2:18])[N:15]=[CH:16][CH:17]=[C:12]4[CH:11]=3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[I:20]C1C=NC(N)=C2OC(C3C=CC=C4C=3C=CN=C4)=CC=12>>[S:1]1[C:5]2[C:6]([C:10]3[O:19][C:13]4=[C:14]([NH2:18])[N:15]=[CH:16][C:17]([I:20])=[C:12]4[CH:11]=3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: Nc1ncc(I)c2cc(-c3cccc4cnccc34)oc12
Reactant: Nc1nccc2cc(-c3cccc4ccsc34)oc12
Product: Nc1ncc(I)c2cc(-c3cccc4ccsc34)oc12
Yield: 51 %

Procedure:
The title compound was prepared in 51% yield from 2-(1-benzothiophen-7-yl)furo[2,3-c]pyridin-7-amine by a procedure analogous to Intermediate 10, Step B. 1H NMR (300 MHz, DMSO-d6) δ 8.20 (d, J=7.5 Hz, 1H), 8.01 (d, J=7.6 Hz, 1H), 7.95 (d, J=1.5 Hz, 2H), 7.64-7.58 (m, 2H). 7.18 (s, 1H). 6.67 (br s, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=2)[N:6]=1.[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([CH3:25])[C:19]=1[S:26](Cl)(=[O:28])=[O:27]>>[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([CH3:25])[C:19]=1[S:26]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:11][CH:12]=2)[N:6]=1)(=[O:28])=[O:27]
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Reactant: CC(=O)Nc1ccc(-c2csc(N)n2)cc1
Product: CC(=O)Nc1ccc(-c2csc(NS(=O)(=O)c3c(C)cc(Cl)cc3Cl)n2)cc1

Procedure:
The title compound was prepared N-[4-(2-amino-1,3-thiazol-4-yl)phenyl]acetamide and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white-yellow solid (8.1 mg) with purity >80%. MS (pos) m/z 456.2, 458.1.
Reaction SMILES: [SH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[Br:7][C:8]([F:15])([F:14])[CH:9]([F:13])[CH2:10][CH2:11]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:7][C:8]([F:15])([F:14])[CH:9]([F:13])[CH2:10][CH2:11][S:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1
Reactant: Sc1nccs1
Reactant: FC(CCBr)C(F)(F)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: FC(CCSc1nccs1)C(F)(F)Br
Reaction time: 1.5 h
Yield: 96.5 %

Procedure:
2-Mercaptothiazole (11.7 g) in acetone (30 cm3) containing 1,4-dibromo-1,1,2-trifluorobutane (27.0 g) was treated portionwise with anhydrous potassium carbonate (13.8 g) under an atmosphere of nitrogen. The reaction was stirred for 1.5 hours, filtered and the insolubles washed with further acetone (4×25 cm3). The filtrate was evaporated under reduced pressure and the residue fractionated by chromatography (silica, eluant 10% ethyl acetate in hexane) to give 2-(4-bromo-3,4,4-trifluorobutylthio)thiazole (29.5 g). 1H NMR: δ 22-2.5(2H,m); 3.2-3.6(2H,m); 4.7-5.0(1H,m); 7.23(1H,d); 7.68(1H,d).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:29])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:20](O)[C:21]4[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=4)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:28]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl>[Br:1][C:2]1[C:3]([F:29])=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([CH2:20][C:21]4[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=4)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:28]=1
Reactant: COC(=O)c1nc2n(c1C(O)c1ccnn1C)C1CC(C1)c1cc(F)c(Br)cc1-2
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1nc2n(c1Cc1ccnn1C)C1CC(C1)c1cc(F)c(Br)cc1-2
Temperature: 25 °C

Procedure:
To a solution of methyl 10-bromo-9-fluoro-3-(hydroxy(1-methyl-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate (140 mg, 0.3035 mmol) in dichloromethane (0.91 mL) was added triethylamine (4.0 equiv., 0.171 mL, 1.214 mmol) followed by methanesulfonyl chloride (1.2 equiv., 0.029 mL, 0.3642 mmol). The reaction was stirred at room temperature until LC/MS analysis indicated complete consumption of starting material.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH3:12][C@H:13]1[CH2:18][NH:17][CH2:16][CH2:15][N:14]1[C:19](=[O:27])[C@:20]([OH:26])([CH3:25])[C:21]([F:24])([F:23])[F:22].C(N(CC)CC)C>C(Cl)Cl>[CH3:12][C@H:13]1[CH2:18][N:17]([C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:16][CH2:15][N:14]1[C:19](=[O:27])[C@:20]([OH:26])([CH3:25])[C:21]([F:24])([F:22])[F:23]
Reactant: C[C@H]1CNCCN1C(=O)[C@@](C)(O)C(F)(F)F
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H]1CN(C(=O)c2ccc(C#N)cc2)CCN1C(=O)[C@@](C)(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
4-Cyanobenzoyl chloride (0.30 g) was added to a stirred solution of the (R)-[2-(S)-methyl-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropionyl)piperazine] (Example 27; 0.40 g) and triethylamine (0.30 ml) in DCM (10 ml). The reaction mixture was allowed to stir at room temperature for 17 hours (overnight), and then partitioned between DCM (20 ml) and 2 M HCl (20 ml). The organic phase was separated, dried and concentrated to give a gum. The residue was purified by chromatography on an 8 g silica Biotage cartridge eluting 1:1 EtOAc/isohexane to give the title compound (0.445 g) as a white solid. NMR (DMSO-d6, 100° C.): 1.17 (d, 3H), 1.58 (s, 3H), 3.05-3.14 (m, 1H), 3.23-3.29 (m, 2H); 3.73 (brs, 1H), 3.88 (brs, 1H), 4.47 (d, 1H), 4.79 (brs, 1H), 6.79 (s, 1H), 7.58 (d, 2H), 7.88 (d, 2H); m/z 368.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:18]([C:21]([CH3:23])=[CH2:22])([O-:20])=[O:19]>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:22][CH:21]([N+:18]([O-:20])=[O:19])[CH3:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: C=C(C)[N+](=O)[O-]
Solvent: c1ccccc1
Product: CC(Cc1c[nH]c2ccc(OCc3ccccc3)cc12)[N+](=O)[O-]

Procedure:
To a stirred 0.5 M benzene solution of 5-benzyloxy-1H-indole (6 mL) was added 2-nitro-propene (5.2 mL of the 10% benzene solution). The reaction was heated at reflux under a nitrogen atmosphere overnight. The volatiles were removed and residue was purified by silica gel chromatography (20% EtOAc/hexanes) to afford 5-benzyloxy-3-(2-nitro-propyl)-1H-indole (550 mg).
Reaction SMILES: [Na].C([O:4][C:5](=[O:8])[CH2:6][SH:7])C.Cl/[C:10](=[C:12]1\[C@H:13]2[C@@H:15]([CH2:16][C:17]\1=O)[C:14]2([CH3:20])[CH3:19])/[CH3:11].[Li+].[OH-]>C(O)C>[CH3:19][C:14]1([CH3:20])[C@@H:15]2[CH2:16][C:17]3[C:12]([C@H:13]12)=[C:10]([CH3:11])[S:7][C:6]=3[C:5]([OH:4])=[O:8]
Reactant: C/C(Cl)=C1\C(=O)C[C@@H]2[C@H]1C2(C)C
Reactant: CCOC(=O)CS
Agent: [Li+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Product: Cc1sc(C(=O)O)c2c1[C@H]1[C@@H](C2)C1(C)C
Temperature: 30 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
Alternatively, (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid is also obtained by the following procedure: To a solution of sodium (2.80 g, 122 mmol) in ethanol (400 mL) a solution of mercaptoacetic acid ethyl ester (14.64 g, 122 mmol) in ethanol (40 mL) is added. The solution is stirred for 5 min before (1S,5R)-2-(1-chloro-(E)-ethylidene)-6,6-dimethyl-bicyclo[3.1.0]hexan-3-one (15.0 g, 81.2 mmol) in ethanol (40 mL) is added dropwise. The solution becomes slightly warm (approx. 30° C.) and turns orange to brown. A fine precipitate forms. Stirring is continued at rt for 1 h. Then, a solution of sodium (2.24 g, 97.5 mmol) in ethanol (75 mL) is added rapidly and the mixture is heated to 75° C. for 1 h. A 2N aq. solution of LiOH (75 mL) is added and stirring is continued at 75° C. for 2h, then at rt for 16 h. About ⅔ of the solvent is removed in vacuo, the remaining mixture is diluted with water (250 mL) and extracted with DCM (200 mL). The organic extract is washed twice with 1 N aq. (100 mL). The combined aqueous layers are acidified by adding 2N aq. HCl and extracted three times with diethyl ether (3×300 mL). The organic extracts are dried over MgSO4 and evaporated. The remaining residue is suspended in acetonitrile, filtered, washed with additional acetonitrile and dried under high vacuum to give the title compound (12.02 g) as a pale yellow to beige crystalline powder.
Reaction SMILES: [Na].CO.[CH2:4]([NH:6][S:7]([C:10]([F:34])([F:33])[C:11]([F:32])([F:31])[C:12]([F:30])([F:29])[C:13]([F:28])([F:27])[C:14]([F:26])([F:25])[C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])(=[O:9])=[O:8])[CH3:5].[N:35]1[C:42](Cl)=[N:41][C:39](Cl)=[N:38][C:36]=1[Cl:37]>CC(C)=O>[Cl:37][C:36]1[N:35]=[C:42]([N:6]([CH2:4][CH3:5])[S:7]([C:10]([F:34])([F:33])[C:11]([F:31])([F:32])[C:12]([F:29])([F:30])[C:13]([F:27])([F:28])[C:14]([F:25])([F:26])[C:15]([F:23])([F:24])[C:16]([F:21])([F:22])[C:17]([F:20])([F:19])[F:18])(=[O:9])=[O:8])[N:41]=[C:39]([N:6]([CH2:4][CH3:5])[S:7]([C:10]([F:33])([F:34])[C:11]([F:31])([F:32])[C:12]([F:29])([F:30])[C:13]([F:27])([F:28])[C:14]([F:25])([F:26])[C:15]([F:23])([F:24])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])(=[O:9])=[O:8])[N:38]=1
Reactant: CCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na]
Solvent: CO
Solvent: CC(C)=O
Product: CCN(c1nc(Cl)nc(N(CC)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)n1)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
Metallic sodium (4.08 g, 177 mmols) was reacted with methanol (150 mls). N-Ethyl perfluorooctyl sulphonamide (93.28 g, 177 mmols) was added, and the resulting solution was stirred for 30 minutes. The methanol was removed at the pump (a vacuum pump was required to remove the final traces of solvent). The resulting sticky solid was dissolved in acetone (300 mls) and cooled to −65° C. under argon. Recrystalised cyanuric chloride (16.33 g, 88.5 mmols) dissolved in acetone (100 mls) was added to the reaction mixture dropwise such that the temperature did not rise above −50° C. (˜1 hour). After the addition, the reaction mixture was allowed to slowly warm to room temperature (1 hour) and then stirred for a further 3 hours. The precipated solid was removed by filtration and dried under vacuum. Purification by soxhlet extraction with acetone afforded 61 g (56.9%) of a fine white powder.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:26]=1>ClCCl>[OH:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][C:3]2([CH2:2][NH:1][S:31]([C:27]3[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=3)(=[O:33])=[O:32])[CH2:4][CH2:5][CH2:6][CH2:7]2)=[CH:10][CH:11]=1
Reactant: NCC1(Cc2ccc(CCO)cc2)CCCC1
Reactant: O=S(=O)(Cl)c1cccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NCC1(Cc2ccc(CCO)cc2)CCCC1)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
To a mixture of 300 mg (1.086 mmol) of 2-(4-{[1-(aminomethyl)-cyclo-pentyl]methyl}phenyl)ethanol (EP 472 449), 30 ml of dichloromethane and 537.6 μl (3.857 mmol) of triethylamine is added dropwise, at −20° C., a solution of 310.1 mg (1.222 mmol) of 3-pyridinesulfonyl chloride in 10 ml of dichloromethane. The mixture is allowed to warm to room temperature slowly (over 3 hours) and is stirred for a further 2 hours. The reaction medium is then washed with water and dried over Na2SO4. After concentrating the organic phase under vacuum, the oil obtained is purified by flash chromatography on silica gel with a dichloromethane/methanol mixture (99/1). 266 mg of an amorphous white solid are obtained.