Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=2[CH:5]=[CH:4]1.C(#N)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>O.CO>[CH3:19][S:20]([N:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=2[CH:5]=[CH:4]1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: O
Product: COC(=O)c1cccc2c1ccn2S(C)(=O)=O
Temperature: 25 °C
Yield: 118.1 %

Procedure:
Sodium hydride (1.1 g of a 80% dispersion in mineral oil), methyl 1H-indole 4-carboxylate (5.46 g) and anhydrous acetonitrile were mixed under an inert atmosphere at 0° C. and stirred at room temperature for an hour. Methanesulphonyl chloride (1.8 g) was added at 0° C. and the mixture stirred at room temperature for 18 hours. Methanol and then water were then added and the mixture extracted with dichloromethane. The organic phase was washed with 2N hydrochloric acid, water, 1M sodium carbonate and water, dried over anhydrous magnesium sulphate and evaporated in vacuo. The residue was purified by column chromatography eluting with ethyl acetate/hexane obtaining methyl 1-(methylsulphonyl)indole-4-carboxylate (4.7 g) as a white solid, m.p. 102°-104° C.
Reaction SMILES: CC([O-])(C)C.[K+].C1COCC1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH2:21][C:22]([NH2:24])=[O:23])=[CH:13]1.C[O:26][C:27](=O)[C:28]([C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:38]=1[N:37]([CH2:39][CH3:40])[CH:36]=[CH:35]2)=O.Cl>CN(C=O)C.CCOC(C)=O>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]2[C:22](=[O:23])[NH:24][C:27](=[O:26])[C:28]=2[C:30]2[CH:31]=[CH:32][CH:33]=[C:34]3[C:38]=2[N:37]([CH2:39][CH3:40])[CH:36]=[CH:35]3)=[CH:13]1
Reactant: CCn1ccc2cccc(C(=O)C(=O)OC)c21
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCn1ccc2cccc(C3=C(c4c[nH]c5ccccc45)C(=O)NC3=O)c21
Temperature: 50 °C
Reaction time: 12 h
Yield: 38.6 %

Procedure:
A 1.0 M solution of KOtBu in THF (6 mL, 6 mmol) was added to a solution of 2-(1H-indol-3-yl)-acetamide (478 mg, 2.75 mmol) and (1-ethyl-1H-indol-7-yl)-oxo-acetic acid methyl ester (635 mg, 2.75 mmol) in DMF (20 mL). The deep red-orange solution was stirred 12 h at 50° C., allowed to cool, and 1N HCl added. The orange mixture was poured into EtOAc, and the EtOAc layer was separated and washed with 1N HCl, water, saturated NaHCO3 and brine, dried (MgSO4), filtered, and concentrated onto SiO2. Flash chromatography (1:1 EtOAc:hexanes) followed by precipitation from hot methanol afforded the title compound (377 mg, 37%) as a orange-red solid. Heating under vacuum at 70° C. afforded material which was used without further purification. 1H NMR (400 MHz, DMSO-d6) 11.83 (br s, 1H), 11.13 (s, 1H), 7.94 (d, J=3 Hz, 1H), 7.61 (dd, J=8, 1.5 Hz, 1H), 7.3 (m, 2H), 6.93–7.0 (m, 3H), 6.48 (m, 3H), 6.48 (m, 2H), 6.3 (d, J=7 Hz, 1H), 4.0 (m, 2H), 1.06 (t, J=5 Hz, 3H). MS (electrospray, m/z) 354 (M−−1).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=[O:18])[C:8]3[C:13]4[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=4[S:11][C:9]=3[S:10][C:4]=2[CH:3]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1C=CC=CC=1>[F:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=[O:18])[C:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[S:10][C:4]=2[CH:3]=1
Reactant: O=C1Nc2ccc(F)cc2Sc2sc3c(c21)CCCC3
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: O=C1Nc2ccc(F)cc2Sc2sc3ccccc3c21

Procedure:
In the same manner as in Example 77 and using 8-fluoro-1,2,3,4-tetrahydro-[1]benzothieno[2,3-b][1,5]benzothiazepin-12(11H)-one, dichlorodicyano-p-benzoquinone and benzene, 8-fluoro-[1]benzothieno[2,3-b][1,5]benzothiazepin-12(11H)-one is obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]O.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12]([CH3:20])[CH:11]=1.[I-].[K+]>C(N(CC)CC)C>[CH3:20][C:12]1[CH:11]=[C:10]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:13]2[CH2:14][CH2:19][CH2:10][CH2:11][CH2:12]2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: Cc1cc(Cl)c2ccccc2n1
Reactant: NCCCCCCO
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Product: Cc1cc(NCCCCCCN2CCCCC2)c2ccccc2n1

Procedure:
Synthesis and purification were performed according to the procedure stated in example 152 using reagents 6-aminohexanol (15 mmol), 4-chloro-2-methylquinoline (15 mmol), 5 ml of triethylamine, and catalytic amounts of potassium iodide in the first step. The final product was purified by column chromatography (eluent: ethyl acetate/triethylamine (95/5)). The solvent was removed under reduced pressure. The residue was crystallized with oxalic acid from diethyl ether/ethanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[CH2:12][C:11](=O)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.CN.[C:25]([BH3-])#[N:26].[Na+]>C1COCC1.CO.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[CH2:12][CH:11]([NH:26][CH3:25])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc2c(c1)C(c1ccc(Cl)c(Cl)c1)CC(=O)C2
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CO
Product: CNC1Cc2ccc(OC)cc2C(c2ccc(Cl)c(Cl)c2)C1

Procedure:
To a solution of the tetralone 30a in THF in methanol was added methylamine hydrochloride. After dissolution (10 min), sodium cyanoborohydride was added in a single portion. The resultant mixture was stirred at 50° C. for three hours. After cooling, the mixture was diluted with sodium bicarbonate solution and extracted with MTBE. The organic layer was evaporated to give the crude amine 32a (160 mg) as a mixture of four configurational isomers.
Reaction SMILES: II.[CH3:3][O:4][C:5]([CH:7]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:8]([O:10][CH3:11])=[O:9])=[O:6]>CO>[OH:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:7]([C:5]([O:4][CH3:3])=[O:6])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C(CCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC
Agent: II
Solvent: CO
Product: COC(=O)C(CCCCCCO)C(=O)OC
Temperature: 50 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
Iodine (1.0 g, 7.9 mmol) was dissolved in MeOH (100 mL). Compound 15 (4.5 g, 9.5 mmol) was added, and the mixture was stirred at 50° C. for one hour. The reaction mixture was evaporated to dryness. The residue was dissolved in CH2Cl2 and washed with 10% Na2SO3 (40 mL). The organic phase was dried with Na2SO4 and evaporated to dryness. Purification on silica gel (petroleum ether, by 40-60° C./ethyl acetate 10:1→5:3) yielded 1.96 g (89%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.[NH2:32][C:33]1[CH:37]=[CH:36][N:35]([CH2:38][C:39]([CH3:42])([OH:41])[CH3:40])[N:34]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:41][C:39]([CH3:42])([CH3:40])[CH2:38][N:35]1[CH:36]=[CH:37][C:33]([NH:32][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:30])=[N:34]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)O)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.1 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (62 mg, 0.3 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 114.06 mg, 0.3 mmol) and iPr2NEt (0.1 mL, 0.6 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, dried over Na2SO4 and filtered. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (23.1 mg, 20.8%) as an off-white powder. HRMS (ES+) m/z Calcd for C30H33Cl2F2N5O2S+H [(M+H)+]: 604.2052. found: 604.2052.
Reaction SMILES: [BrH:1].Br.C1(C[N:10]2[CH2:15][C@H:14]3[CH2:16][C@@H:11]2[CH2:12][NH:13]3)C=CC=CC=1.C1(C)C=CC(S(N2C[C@H]3C[C@@H]2CN3CC2C=CC=CC=2)(=O)=O)=CC=1.Br>CC(O)=O>[BrH:1].[BrH:1].[C@@H:11]12[CH2:16][C@@H:14]([NH:13][CH2:12]1)[CH2:15][NH:10]2
Reactant: c1ccc(CN2C[C@H]3C[C@@H]2CN3)cc1
Agent: Br
Agent: Cc1ccc(S(=O)(=O)N2C[C@H]3C[C@@H]2CN3Cc2ccccc2)cc1
Solvent: CC(=O)O
Product: C1N[C@H]2CN[C@@H]1C2
Temperature: 70 °C
Yield: 92 %

Procedure:
(1R,4R)-5-phenylmethyl-2,5-diazabicyclo[2.2.1] heptane dihydrobromide. A mixture of (1R,4R)-2-(4-toluenesulfonyl)-5-phenylmethyl-2,5-diazabicyclo[2.2.1]heptane (38.95 g, 0.11 mole) in AcOH (500 mL) containing HBr (30% wt) was heated at 70° C. for 18 h. The mixture was allowed to cool and the precipitate that formed was filtered and washed with acetone. The filtrate was concentrated to one-third of the original volume and the resulting solid was combined with the first precipitate to give the title compound (36.55 g, 92%, m.p. 272°-275° C.).
Reaction SMILES: [S:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:12][CH2:13][C:14]([OH:16])=O)[CH2:4][CH2:3][CH2:2]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>CN(C)C=O>[CH3:39][O:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[N:47]1[CH2:52][CH2:51][N:50]([C:14](=[O:16])[CH2:13][CH2:12][O:11][C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[S:1][CH2:2][CH2:3][CH2:4]3)[CH2:49][CH2:48]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=C(O)CCOc1cccc2c1SCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(C(=O)CCOc2cccc3c2SCCC3)CC1
Reaction time: 24 h

Procedure:
Under argon, 110 mg (4.61×10-4 mol) of 3-[(thiochroman-8-yl)oxy]propionic acid (Indian Journal of Chemistry (1977) 15 pp. 715-719) are dissolved in 1.5 cm3 of dimethylformamide. The flask is cooled in an ice-bath. 100 mg (5.07×10-4 mol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 71 mg (4.61×10-4 mol) of 1-hydroxybenzotriazole and 100 mg (5.07×10-4 mol) of 1-(2-methoxyphenyl)piperazine are added. The mixture is allowed to come gradually to room temperature. After 24 hours, the solvent is evaporated off. The residue is taken up in H2O and extracted with CH2Cl2. The product is dried over MgSO4.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=1)=[O:13].[Cl:21][CH2:22][C:23](Cl)=[O:24]>>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([NH:1][C:23](=[O:24])[CH2:22][Cl:21])=[C:3]([C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=3)=[O:13])[NH:4]2)=[CH:9][CH:8]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1
Product: Cc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2NC(=O)CCl)c1

Procedure:
The title compound was prepared, according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(4-methylpyridine-2-carbonyl)indole (Example 70) and chloroacetyl chloride. m.p.: 224-225° C.
Reaction SMILES: N[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[C:12]([Cl:14])[C:11]([C:15](=[O:23])[C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[C:10]([Cl:24])[CH:9]=2)[N:5]=[N:4][C:3]=1[C:25]([NH2:27])=[O:26].Cl.C(=N)(OCC)C.C(O)C>C(OCC)C>[ClH:14].[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]([C:11]2[C:12]([Cl:14])=[CH:13][C:8]([CH2:7][N:6]3[CH:2]=[C:3]([C:25]([NH2:27])=[O:26])[N:4]=[N:5]3)=[CH:9][C:10]=2[Cl:24])=[O:23])=[CH:21][CH:20]=1
Reactant: NC(=O)c1nnn(Cc2cc(Cl)c(C(=O)c3ccc(Cl)cc3)c(Cl)c2)c1N
Agent: CCOC(C)=N
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: NC(=O)c1cn(Cc2cc(Cl)c(C(=O)c3ccc(Cl)cc3)c(Cl)c2)nn1

Procedure:
A mixture of 5-amino-1-[4-(4-chlorobenzoyl)-3,5-dichlorobenzyl]-1,2,3-triazole-4-carboxamide (4.3 g), ethyl acetimidate hydrochloride (1.2 g) and absolute ethanol (50 ml) is heated at reflux under nitrogen for 20 hours. The reaction mixture is cooled and diluted with ethyl ether (50 ml). The solid is filtered and dried to give 5-((amino)ethylidine) amino)-1[4-(4-chlorobenzoyl)-3,5-dichlorobenzyl]-1,2,3-triazole-4-carboxamide hydrochloride.
Reaction SMILES: [CH2:1]([Zn]CC)C.[C:6]([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[CH2:15])=[CH:12][CH:11]=1)(=[O:8])[CH3:7].ICI>C1(C)C=CC=CC=1>[CH:14]1([C:13]2[CH:16]=[CH:17][C:10]([O:9][C:6](=[O:8])[CH3:7])=[CH:11][CH:12]=2)[CH2:1][CH2:15]1
Reactant: C=Cc1ccc(OC(C)=O)cc1
Reactant: CC[Zn]CC
Solvent: Cc1ccccc1
Solvent: ICI
Product: CC(=O)Oc1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.1 %

Procedure:
To a solution of diethylzinc (200 mL, 0.220 mol, 1.1 M in toluene) in toluene (270 mL) was added 4-acetoxystyrene (16.8 mL, 0.110 mol) and subsequently diiodomethane (23.0 mL, 0.286 mol). After the reaction mixture was stirred at rt for 5 hours, it was heated at reflux for 12 hours. The reaction was quenched with aqueous 2N HCl. The organic layer was separated and washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound as a brown oil (16.1 g, 83%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O.[Br-].[CH3:24][C:25]1[CH:50]=[C:49]([CH3:51])[CH:48]=[C:47]([CH3:52])[C:26]=1[CH2:27][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH3:52][C:47]1[CH:48]=[C:49]([CH3:51])[CH:50]=[C:25]([CH3:24])[C:26]=1/[CH:27]=[CH:18]/[C:17]1[CH:16]=[C:15]([CH2:14][CH2:13][CH2:12][N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])[CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cc(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1
Reactant: O=Cc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Agent: [Br-]
Product: Cc1cc(C)c(/C=C/c2cccc(CCCN3C(=O)c4ccccc4C3=O)c2)c(C)c1

Procedure:
Phthalimide 29 was coupled with 2,4,6-trimethylbenzyltriphenylphosphonium bromide to give (E)-2-(3-(3-(2,4,6-trimethylstyryl)phenyl)propyl)isoindoline-1,3-dione. Yield (0.2485 g, 46%), trans-/cis-isomer ratio 4:1. Trans-isomer: 1H NMR (400 MHz, CDCl3) δ 7.84-7.87 (m, 2H), 7.72-7.74 (m, 2H), 7.26-7.36 (m, 3H), 7.16 (s, 1H), 7.12 (d, J=16.4 Hz, 1H), 6.94 (s, 2H), 6.57 (d, J=16.8 Hz, 1H), 3.82 (t, J=7.2 Hz, 2H), 2.76 (t, J=7.2 Hz, 2H), 2.39 (s, 6H), 2.33 (s, 3H), 2.10-2.17 (m, 2H).
Reaction SMILES: [CH2:1]1[C:4](=[O:5])[N:3]2[C@@H:6]([C:12]([O:14]CC3C=CC=CC=3)=[O:13])/[C:7](/[O:11][C@H:2]12)=[CH:8]/[CH2:9][OH:10].C(=O)([O-])O.[Na+]>C(O)C.[Pd]>[CH2:1]1[C:4](=[O:5])[N:3]2[C@@H:6]([C:12]([OH:14])=[O:13])/[C:7](/[O:11][C@H:2]12)=[CH:8]/[CH2:9][OH:10]
Reactant: O=C(OCc1ccccc1)[C@H]1/C(=C/CO)O[C@@H]2CC(=O)N21
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C(O)[C@H]1/C(=C/CO)O[C@@H]2CC(=O)N21
Yield: 69.8 %

Procedure:
Substantially pure benzyl clavulanate (281 mg) in ethanol (25 ml.) containing sodium hydrogen carbonate (82 mg.) was hydrogenated over 10% Pd/C (90 mg.) for 25 minutes at room temperature and atmospheric pressure. The catalyst was filtered off, washed with water and ethanol, and the combined filtrates evaporated under reduced pressure at room temperature. The residual semi-solid was triturated with acetone, filtered and washed with ether to yield sodium clavulanate (135 mg.)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[C:4]([OH:11])[CH:3]=1.C(N1C=CN=C1)([N:14]1C=CN=C1)=O.C(N(CC)CC)C>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]([CH3:9])=[N:14][O:11][C:4]=2[CH:3]=1
Reactant: CC(=O)c1ccc(F)cc1O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1noc2cc(F)ccc12

Procedure:
A mixture of 4′-fluoro-2′-hydroxyacetophenone, oxime (47.0 g, 0.278 mol) in tetrahydrofuran is heated to just under reflux, treated with a solution of 1,1′-carbonyldiimidazole (55.0 g, 0.340 mol) and triethylamine (39.0 g, 0.390 mol) in tetrahydrofuran, refluxed for one hour, cooled, concentrated in vacuo, and poured into an ice-water mixture. The resultant aqueous mixture is extracted with ether. The organic extracts are combined, washed sequentially with saturated ammonium chloride solution and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain an oil. Column chromatography of the oil using silica gel and a methylene chloride/hexanes solution (1:1) gives the title product as a yellow oil which is identified by 1H NMR spectral analysis.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].I[C:12]1[CH:13]=[CH:14][C:15]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])=[C:16]([CH2:18][OH:19])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN[C@H]1CCCC[C@@H]1NC>C1(C)C=CC=CC=1.CCOC(C)=O.O.[Cu]I>[NH2:10][C:8]1[N:7]([C:12]2[CH:13]=[CH:14][C:15]([O:20][Si:21]([CH:25]([CH3:27])[CH3:26])([CH:28]([CH3:30])[CH3:29])[CH:22]([CH3:23])[CH3:24])=[C:16]([CH2:18][OH:19])[CH:17]=2)[N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=1
Reactant: CC(C)(C)c1cc(N)[nH]n1
Reactant: CC(C)[Si](Oc1ccc(I)cc1CO)(C(C)C)C(C)C
Agent: [Cu]I
Agent: CN[C@H]1CCCC[C@@H]1NC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2N)cc1CO)(C(C)C)C(C)C
Temperature: 150 °C
Yield: 14.6 %

Procedure:
3-(Tert-butyl)-1H-pyrazol-5-amine (0.32 g, 2.30 mmol) was treated with a solution of Intermediate 61b (1.04 g, 2.60 mmol) in toluene (4 mL) then potassium carbonate (0.68 g, 4.90 mmol), (1S,2S)—N,N′-bis-methyl-1,2-cyclohexane-diamine (0.07 g, 0.47 mmol) and copper (I) iodide (0.022 g, 0.11 mmol) were added. The mixture was degassed then heated at 150° C. for 1 h using microwave irradiation. Another portion of copper (I) iodide (0.022 g, 0.11 mmol) was added and the reaction mixture heated at 150° C. for a further 1 h using microwave irradiation. The mixture was diluted with EtOAc and water and the phases separated. The aqueous layer was then extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The organic layer was evaporated in vacuo. The residue was purified by FCC, using 0-15% EtOAc in DCM, to give the title compound (0.14 g, 15%). LCMS (Method 3): Rt 3.87 min, m/z 418 [MH+].
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C([Mg]Br)C.[CH3:15][C:16]1([CH3:24])[C:18]([CH3:20])([CH3:19])[CH:17]1[C:21](Cl)=[O:22]>ClCCl.[Cl-].[Zn+2].[Cl-]>[CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:21]([CH:17]3[C:18]([CH3:20])([CH3:19])[C:16]3([CH3:24])[CH3:15])=[O:22])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2cc[nH]c2c1
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: Cc1ccc2c(C(=O)C3C(C)(C)C3(C)C)c[nH]c2c1
Yield: 65.8 %

Procedure:
A mixture of 6-methylindole (1.0 g, 7.6 mmol), ethylmagnesium bromide (1.0 M solution in THF, 9.1 mL, 9.1 mmol), zinc chloride (1.0 M solution in Et2O, 9.1 mL, 9.1 mmol) and the product of Example 1A (11 mmol) in 25 mL of dichloromethane was processed as described in Example 1B to provide the title compound (1.3 g, 5.0 mmol, 65% yield). MS (DCI/NH3) m/z 256 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:10](=O)[CH2:9][CH:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:7][C:6]=2[NH:5][CH:4]=1)[CH3:2].[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl.O>C(O)C>[ClH:24].[CH2:1]([C:3]1[C:11]2[C:10](=[N:23][NH:22][C:19]([NH2:21])=[NH:20])[CH2:9][CH:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:7][C:6]=2[NH:5][CH:4]=1)[CH3:2]
Reactant: N=C(N)NN
Reactant: CCc1c[nH]c2c1C(=O)CC(c1ccccc1)C2
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCc1c[nH]c2c1C(=NNC(=N)N)CC(c1ccccc1)C2
Yield: 31.7 %

Procedure:
A mixture of 3-ethyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.5 g), aminoguanidine hydrochloride (0.25 g), concentrated hydrochloric acid (0.1 ml), water (0.1 ml) and ethanol (30 ml) was refluxed for 7 hours, and to the mixture was added 1N hydrochloric acid (0.1 ml). Under reduced pressure, the solvent was evaporated. The resulting crystals were washed with water and recrystallized from ethanol to give 3-ethyl-4-guanidinoimino-6-phenyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 3) (0.22 g) as colorless crystals.
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4]([C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([NH:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)[N:16]=[C:15]([O:33][CH3:34])[N:14]=2)[CH:10]=[CH:9][C:8]=1[F:35])([CH3:6])[CH3:5].[OH-].[Na+]>O.CO.C1COCC1>[F:35][C:8]1[CH:9]=[CH:10][C:11]([C:13]2[CH:18]=[C:17]([NH:19][CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][C:29]([F:32])([F:30])[F:31])=[CH:26][CH:27]=3)[N:16]=[C:15]([O:33][CH3:34])[N:14]=2)=[CH:12][C:7]=1[C:4]([CH3:6])([CH3:5])[C:3]([OH:36])=[O:2]
Reactant: COC(=O)C(C)(C)c1cc(-c2cc(NCCc3ccc(OC(F)(F)F)cc3)nc(OC)n2)ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1nc(NCCc2ccc(OC(F)(F)F)cc2)cc(-c2ccc(F)c(C(C)(C)C(=O)O)c2)n1

Procedure:
A mixture of 2-(2-fluoro-5-{2-methoxy-6-[2-(4-trifluoromethoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid methyl ester (should this be the right starting material? 1.9 g) and sodium hydroxide (2.46 g) in water (19 mL), MeOH (19 mL) and THF (19 mL) is stirred at 40° C. for 40 hours. The solution is evaporated in vacuo and acidified to pH=6 with concentrated HCl (1.6 mL). The solid is filtered, air dried and chromatographed on silica gel eluting with 50% EtOAc in heptane to afford 2-(2-fluoro-5-{2-methoxy-6-[2-(4-trifluoromethoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid (1.12 g, Example 70). MS: 494 (M+H); 1H NMR (300 MHz, CD3OD), □7.8, (d, 1H, J=0.3 Hz); 7.7 (m, 1H); 7.4 (d, 2H, J=0.4 Hz); 7.2-7.3 (m, 4H); 6.6 (s, 1H); 4.2 (s, 3H); 3.9 (m, 2H); 3.05 (t, 2H); 1.65 (s, 6H). IC50=193 nM
Reaction SMILES: [C:1]([C:4]1[NH:5][CH:6]=[NH+:7][C:8]=1[O-:9])(=[O:3])[NH2:2].[CH3:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[S:16])=[CH:13][CH:12]=1>>[CH3:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([O:9][C:8]2[N:7]=[CH:6][NH:5][C:4]=2[C:1](=[O:3])[NH2:2])=[S:16])=[CH:13][CH:12]=1
Reactant: NC(=O)c1[nH]c[nH+]c1[O-]
Reactant: Cc1ccc(C(=S)Cl)cc1
Product: Cc1ccc(C(=S)Oc2nc[nH]c2C(N)=O)cc1
Yield: 96.2 %

Procedure:
1.258 g of 5-carbamoyl-1H-imidazol-4-yl p-methylthiobenzoate was synthesized from 0.636 g of 4-carbamoylimidazolium-5 olate and 1.4 g of p-methylthiobenzoyl chloride.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([CH3:18])=[N:17][C:12]3=[N:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+]>Br.C(O)(=O)C>[CH3:18][C:16]1[CH:15]=[CH:14][N:13]2[C:9]([C:5]3[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=3)=[CH:10][N:11]=[C:12]2[N:17]=1
Reactant: COc1cccc(-c2cnc3nc(C)ccn23)c1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1ccn2c(-c3cccc(O)c3)cnc2n1
Temperature: 130 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
A mixture of 3-(3-methoxyphenyl)-7-methylimidazo[1,2-a]pyrimidine (5.02 g, 21 mmol) in hydrogen bromide (25 ml of a 30 wt. % solution in acetic acid) was heated at 130° C. for 8 h. A further portion of hydrogen bromide solution was added (25 ml) and heating continued for 16 h. The reaction was cooled to ambient temperature and diluted with ice-cold water (200 ml). The aqueous phase was made neutral with 4N sodium hydroxide then extracted with dichloromethane (2×250 ml). The organics were combined, washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The residue was triturated with ether to afford 3-(7-methylimidazo[1,2-a]pyrimidin-3-yl)-phenol as a light-grey solid (4.4 g, 93%): m/z (ES+) 226 (M++H).