Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].CC(C)([O-])C.[Li+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C=O)C>[O:1]=[C:2]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:5][C:4](=[O:7])[N:3]1[CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: BrCc1ccccc1
Reactant: O=C(CN1C(=O)CNC1=O)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)CN(Cc2ccccc2)C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
To a solution of phenylmethyl 2-(2,5-dioxoimidazolidinyl)acetate (4.0 g, 16.1 mmol) in DMF (50 ml) at 0° C. were added lithium tert-butoxide (1.6 g, 19.3 mmol) and benzyl bromide (2.1 ml, 17.7 mmol). After stirring the mixture at room temperature overnight, the reaction mixture was poured into water (100 ml) and the mixture was extracted with ethyl acetate. The organic phase was washed with water, 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine. The organic solution was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, n-hexane:ethyl acetate=3:1) to give phenylmethyl 2-(2,5-dioxo-3-benzylimidazolidinyl)acetate (3.42 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[Cl:16][C:17]1[CH:36]=[C:35]([OH:37])[CH:34]=[C:33]([Cl:38])[C:18]=1[CH2:19][C@@H:20]1[CH2:24][CH2:23][N:22]([N:25]2[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]2)[C:21]1=[O:32]>CS(C)=O.C(OCC)(=O)C>[Cl:16][C:17]1[CH:36]=[C:35]([CH:34]=[C:33]([Cl:38])[C:18]=1[CH2:19][C@@H:20]1[CH2:24][CH2:23][N:22]([N:25]2[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]2)[C:21]1=[O:32])[O:37][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1
Reactant: O=C1[C@H](Cc2c(Cl)cc(O)cc2Cl)CCN1N1CCC(O)CC1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Oc2cc(Cl)c(C[C@@H]3CCN(N4CCC(O)CC4)C3=O)c(Cl)c2)cc1
Yield: 49.7 %

Procedure:
Add potassium carbonate (0.385 g, 2.8 mmol) and 4-fluorobenzonitrile (0.253 g, 2.1 mmol) to a solution of (R)-3-(2,6-dichloro-4-hydroxy-benzyl)-1-(4-hydroxy-piperidin-1-yl)-pyrrolidin-2-one (0.5 g, 1.4 mmol) in DMSO. Stir the reaction at 80° C. for 3 hours. Cool the reaction, dilute with ethyl acetate, and wash three times with water and one time with brine. After drying the organic layer over sodium sulfate, filter and concentrate under vacuum. Purify the residue by silica gel chromatography with 50% ethyl acetate/hexane to 100% ethyl acetate gradient to afford 0.32 g (50%) of the title compound. MS (m/z): 460 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:18][CH2:19][C:20](Cl)=[O:21].[OH-].[NH4+:24]>>[Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:18][CH2:19][C:20]([NH2:24])=[O:21]
Reactant: [NH4+]
Reactant: O=C(Cl)COc1ccc2c(-c3ccccc3F)noc2c1Cl
Agent: [OH-]
Product: NC(=O)COc1ccc2c(-c3ccccc3F)noc2c1Cl
Reaction time: 2 h

Procedure:
To 3.5 g of {[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetyl chloride is added 50 ml of conc ammonium hydroxide at 0° C. After stirring for 2 hr the precipitate is filtered and washed with ice-cold acetonitrile. Recrystallization of the filter cake from acetonitrile gives {[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetamide, mp 172° C.
Reaction SMILES: CO[C:3]([CH:5]1[C:11](=[O:12])[C:10]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:9]=2[N:8]([CH3:18])[C:7](=[O:19])[CH2:6]1)=[O:4].[NH2:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1>C1(C)C=CC=CC=1>[Cl:17][C:15]1[CH:14]=[CH:13][C:10]2[C:11](=[O:12])[CH:5]([C:3](=[O:4])[NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)[CH2:6][C:7](=[O:19])[N:8]([CH3:18])[C:9]=2[CH:16]=1
Reactant: Nc1nccs1
Reactant: COC(=O)C1CC(=O)N(C)c2cc(Cl)ccc2C1=O
Solvent: Cc1ccccc1
Product: CN1C(=O)CC(C(=O)Nc2nccs2)C(=O)c2ccc(Cl)cc21

Procedure:
The mixture of 23.0 g of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1-benzazepine-2,5-dione-4-carboxylic acid methyl ester, 8.9 g of 2-aminothiazole and 360 ml of toluene is distilled for 20 hours so that after collecting 100 ml of toluene each, this amount is returned to the reaction mixture. It is finally concentrated to a volume of 150 ml, the resulting suspension cooled with ice, filtered and the residue recrystallized from chloroform-acetonitrile, to yield the 8-chloro-1-methyl-4-(2-thiazolylcarbamoyl)-2,3,4,5-tetrahydro-1-benzazepine-2,5-dione of the formula ##SPC3##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=[C:11]3[CH:10]=[CH:9]2)=[CH:5][CH:4]=1.F[C:23]1[C:28]([NH2:29])=[CH:27][CH:26]=[C:25]([F:30])[N:24]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.N1C=CC=CC=1>[F:30][C:25]1[N:24]=[C:23]2[O:19][C:17]([C:15]3[CH:16]=[C:11]4[CH:10]=[CH:9][N:8]([CH2:7][C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:21][CH:20]=5)[C:12]4=[N:13][CH:14]=3)=[N:29][C:28]2=[CH:27][CH:26]=1
Reactant: COc1ccc(Cn2ccc3cc(C(=O)O)cnc32)cc1
Reactant: Nc1ccc(F)nc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ccc3cc(-c4nc5ccc(F)nc5o4)cnc32)cc1
Temperature: 150 °C

Procedure:
To a stirred solution of 1-(4-methoxy-benzyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (47 mg, 0.17 mmol) in CH2Cl2 (2 mL) was added 1-chloro-N,N-2-trimethylpropenylamine (45 μL, 0.34 mmol). Following formation of the resulting acid chloride, the reaction mixture was concentrated affording a residue that was dissolved in pyridine (2 mL) before 2,6-difluoro-pyridin-3-ylamine (20 mg, 0.15 mmol) was added in one portion. After an additional 30 minutes the reaction mixture was concentrated to dryness affording a residue, to which was added DMF (2 mL) and K2CO3 (64 mg, 0.46 mmol). The resulting mixture was heated by microwave to 150° C. for 10 min, after which the resulting mixture was filtered and concentrated, affording 5-fluoro-2-[1-(4-methoxy-benzyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-oxazolo[5,4-b]pyridine as a crude residue which was subsequently used without further purification. ES MS (M+H+)=375.
Reaction SMILES: ClC1C=CC([N:8]([C:18](=O)[C:19]2[CH:24]=[CH:23]C(Cl)=CC=2Cl)C2SC(C)=C(C(O)=O)N=2)=CC=1.[Cl:28][C:29]1[CH:56]=[C:55]([Cl:57])[CH:54]=[CH:53][C:30]=1[C:31]([N:33]([C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[C:45]([O:51][CH3:52])[CH:44]=1)[C:34]1[S:35][C:36]([CH3:42])=[C:37]([C:39](O)=[O:40])[N:38]=1)=[O:32]>CCN(CC)CC>[Cl:28][C:29]1[CH:56]=[C:55]([Cl:57])[CH:54]=[CH:53][C:30]=1[C:31]([N:33]([C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[C:45]([O:51][CH3:52])[CH:44]=1)[C:34]1[S:35][C:36]([CH3:42])=[C:37]([C:39]([N:8]2[CH2:18][CH2:19][CH2:24][CH2:23]2)=[O:40])[N:38]=1)=[O:32]
Reactant: Cc1sc(N(C(=O)c2ccc(Cl)cc2Cl)c2ccc(Cl)cc2)nc1C(=O)O
Reactant: COc1ccc(N(C(=O)c2ccc(Cl)cc2Cl)c2nc(C(=O)O)c(C)s2)cc1OC
Solvent: CCN(CC)CC
Product: COc1ccc(N(C(=O)c2ccc(Cl)cc2Cl)c2nc(C(=O)N3CCCC3)c(C)s2)cc1OC

Procedure:
According to the procedure described fort he synthesis of Example 96 further derivatives have been synthesised from 2-[(4-Chloro-phenyl)-(2,4-dichloro-benzoyl)-amino]-5-methyl-thiazole-4-carboxylic acid or 2-[(2,4-Dichloro-benzoyl)-(3,4-dimethoxy-phenyl)-amino]-5-methyl-thiazole-4-carboxylic acid and various commercially available amines and comprise Examples 97-Example 124 below. In cases of Example 102 and 118 additionally 2 eq. NEt3 were added to the reaction mixture as amine hydrochlorides were used as starting materials.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[CH2:23][NH2:24].CCOC(C)=O>CS(C)=O>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[CH2:23][NH:24][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[N:3]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: Cc1ccc2nc(Cl)cnc2c1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2cnc3cc(C)ccc3n2)c(OC)c1
Yield: 95.8 %

Procedure:
2-Chloro-6-methylquinoxaline (0.51 g, 2.86 mmol), prepared according to J. Chem. Soc. 1948, 1310-1313, and (2,4-dimethoxyphenyl)methanamine (1.29 mL, 8.57 mmol) were microwaved in DMSO (2.5 mL) for 30 min at 150° C. This was diluted into 150 mL EtOAc and extracted three times with 100 mL brine. The crude product was purified by flash chromatography on a 90 g silica gel cartridge with 20 to 60% EtOAc in hexane, 50 min, at 40 mL/min to afford N-(2,4-dimethoxybenzyl)-6-methylquinoxalin-2-amine (848 mg, 2.74 mmol, 96% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C@@H:7]2[CH2:11][CH2:10][C@H:9]([C@H:12]([OH:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]2C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.[N:29]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=1)=[C:30]=[O:31].C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:19][C@H:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C@@H:9]1[NH:8][C@H:7]([CH2:6][C:5]2[CH:27]=[CH:28][C:2]([NH:1][C:30]([NH:29][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)=[O:31])=[CH:3][CH:4]=2)[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(N)cc2)CC[C@@H]1[C@H](O)c1ccccc1
Reactant: COc1cccc(N=C=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(NC(=O)Nc2ccc(C[C@@H]3CC[C@H]([C@H](O)c4ccccc4)N3)cc2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 30 mg (0.078 mmol) of tert-butyl (2S,5R)-2-(4-aminobenzyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidine-1-carboxylate (i-13a) in CH2Cl2 (0.5 mL) was added 14 mg (0.094 mmol) of 1-isocyanato-3-methoxybenzene. The reaction mixture was stirred at ambient temperature for 2.5 h. It was then added TFA (0.4 mL) and was stirred at ambient temperature for another 3 h. After removal of the volatiles, it was purified by reverse-phase HPLC (TMC Pro-Pac C18; 10-80% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). The pure fractions were lyophilized overnight to give the title compound as a white solid. LC/MS 432.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br.Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>CC#N>[CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1[C@@H]1CCC[C@H](c2ncccc2C)N1
Reactant: BrCc1ccccn1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cccnc1[C@H]1CCC[C@@H](c2ncccc2C)N1Cc1ccccn1
Reaction time: 15.5 h
Yield: 57 %

Procedure:
A solution of (2′R,6′S)-3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (166 mg, 0.621 mmol), 2-(bromomethyl)pyridine hyrdobromide (189 mg, 0.745 mmol), DIPEA (265 μL, 1.52 mmol) and KI (10 mg, 0.060 mmol) in CH3CN (6 mL) was warmed to 50° C. and stirred for 15.5 h according to General Procedure A. Purification by flash chromatography on silica gel using CH2Cl2/MeOH/NH4OH (94:5:1) afforded COMPOUND 73 (127 mg, 57%) as an orange solid. 1H NMR (CDCl3) δ 1.75-1.85 (m, 3H), 1.93-2.02 (m, 1H), 2.09-2.21 (m, 2H), 2.42 (s, 6H), 3.80 (bs, 2H), 6.81-6.85 (m, 2H), 6.96 (dd, 2H, J=7.7, 3.9 Hz), 7.23-7.30 (m, 3H), 8.18 (d, 1H, J=4.8 Hz), 8.40 (d, 2H, J=4.4 Hz); ES-MS m/z 359 (M+H).
Reaction SMILES: [C:1]([N:4]1[C:8]2[N:9]=[CH:10][CH:11]=[C:12]([C:13]#[N:14])[C:7]=2[CH:6]=[CH:5]1)(=[O:3])[CH3:2].CCN(CC)CC>[Pd].CCO>[NH2:14][CH2:13][C:12]1[CH:11]=[CH:10][N:9]=[C:8]2[N:4]([C:1](=[O:3])[CH3:2])[CH:5]=[CH:6][C:7]=12
Reactant: CC(=O)n1ccc2c(C#N)ccnc21
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)n1ccc2c(CN)ccnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-acetyl-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile (0.872 g, step D), 10% Pd/C (0.882 g), 20 mL of Et3N, and 80 mL of EtOH was stirred at RT under balloon pressure of H2 for overnight. Solid was removed by filtration through a pad of Celite® and the filtrate was concentrated to yield a cream color residue, which was purified by chromatography through silica gel (70 g, 2 to 5% MeOH/CHCl3 with 1% NH4OH) to afford 1-(4-aminomethyl-pyrrolo[2,3-b]pyridin-1-yl)-ethanone as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH:15]([C:17]1[C:18]([NH:23][C:24](=O)[O:25]CC)=[N:19][CH:20]=[CH:21][CH:22]=1)=O.[BH4-].[Na+].C1(C)C=CC=CC=1>CO.C(O)(=O)C>[O:25]=[C:24]1[NH:23][C:18]2[N:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:15][N:1]1[CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CCOC(=O)Nc1ncccc1C=O
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(N2Cc3cccnc3NC2=O)CC1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 44 %

Procedure:
4-Amino-1-N-Boc-piperidine (290 mg, 1.4 mmol) was added to a solution of ethyl 3-formylpyridin-2-ylcarbamate (240 mg, 1.2 mmol) in methanol (10 mL). Mixture was warmed to 60° C. and held for 1.5 hours. Mixture was cooled to room temperature. Sodium borohydride (62 mg, 1.6 mmol) was added to the mixture. Reaction stirred at room temperature for 30 minutes. Toluene (20 mL) was added to the mixture followed by acetic acid (1.0 mL). Mixture was warmed to 110° C. Methanol was driven from the reaction mixture and collected in a Dean-Stark trap. Mixture was held at 110° C. for 5 hours. Mixture was cooled to room temperature and held for 16 hours. Reaction was quenched with aqueous sodium bicarbonate. Mixture was extracted with ethyl acetate (2×30 mL). Combined organics were washed successively with water (30 mL) and brine (20 mL). Organic layer was dried (magnesium sulfate), filtered and concentrated in vacuo. Silica gel chromatography afforded the title compound as white solid in 44% yield. MS m/e (M−H)−=311.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]2([C:33]3[CH:34]=[CH:35][CH:36]=[C:37]([F:38])[C:32]=3[O:31][CH2:30]2)[CH2:26][CH2:25]1)=[O:23].[CH2:39]([S:41]([NH2:44])(=[O:43])=[O:42])[CH3:40]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:44][S:41]([CH2:39][CH3:40])(=[O:43])=[O:42])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:25][CH2:26][C:27]2([C:33]3[CH:34]=[CH:35][CH:36]=[C:37]([F:38])[C:32]=3[O:31][CH2:30]2)[CH2:28][CH2:29]1)=[O:23]
Reactant: Cc1ccc(C)c(Nc2c(C(=O)N3CCC4(CC3)COc3c(F)cccc34)cnc3c(C(=O)O)cnn23)c1
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)N3CCC4(CC3)COc3c(F)cccc34)cnc12
Yield: 66.2 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2,5-dimethylphenylamino)-6-(7-fluoro-2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.063 g, 0.122 mmol) obtained in step 2 and ethanesulfonamide (0.066 g, 0.610 mmol), the title compound (0.049 g, 66%) was obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.CCN(CC)CC.[Cl:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[CH:22][N:21]=1>C(O)C>[Cl:19][C:20]1[N:25]=[C:24]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]2)[CH:23]=[CH:22][N:21]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(c2ccnc(Cl)n2)CC1
Temperature: 80 °C
Reaction time: 0.13 h
Yield: 87.2 %

Procedure:
To a solution of ethyl piperidine-4-carboxylate (13.0 g, 82.69 mmol,) in ethanol (130 ml) were added Et3N (17.29 ml, 124 mmol) and 2,4-dichloropyrimidine (13.55 g, 90.96 mmol). After stirring for 8 minutes at 80° C., the solvent was removed under reduced pressure and the crude product was purified by normal phase chromatography, eluting with Heptane with 50% ethyl acetate to give compound ethyl 1-(2-chloropyrimidin-4-yl)piperidine-4-carboxylate (19.45 g) as a colourless oil.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[Br:19][C:20]1[CH:21]=[C:22]([C:26]([O:29][CH3:30])=[CH:27][N:28]=1)[C:23]([OH:25])=O.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][NH2:39])=[CH:34][CH:33]=1.CCN(CC)CC>C(Cl)Cl.O>[Br:19][C:20]1[CH:21]=[C:22]([C:26]([O:29][CH3:30])=[CH:27][N:28]=1)[C:23]([NH:39][CH2:38][C:35]1[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=1)=[O:25]
Reactant: COc1cnc(Br)cc1C(=O)O
Reactant: NCc1ccc(F)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cnc(Br)cc1C(=O)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
T3P (2.4 g, 7.4 mmol) was added to a solution of 2-bromo-5-methoxyisonicotinic acid (1.0 g, 3.7 mmol), (4-fluorophenyl)methanamine (466 mg, 3.7 mmol) and Et3N (1.1 g, 11.1 mmol) in DCM (10 mL) at 0° C. The mixture was stirred at RT for 1 h. Water (50 mL) was added and the mixture was extracted with DCM. The organic layer was washed with brine and dried over Na2SO4. After being concentrated, the residue was purified by column chromatography (PE:EtOAc=2:1) to give the product of compound 2-bromo-N-(4-fluorobenzyl)-5-methoxyisonicotinamide (1.1 g, yield: 92%). 1H-NMR (CDCl3, 400 MHz) δ 8.18 (d, J=2.8 Hz, 2H), 7.96 (s, 1H), 7.31 (dd, J=5.2, 8.4 Hz, 2H), 7.04 (t, J=8.8 Hz, 2H), 4.61 (d, J=6.0 Hz, 2H), 4.03 (s, 3H). MS (M+H)+: 339/341.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10](=[S:12])[NH:9][C:8]=2[CH:13]=1)([O-:3])=[O:2].C(N(CC)CC)C.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1>C(Cl)(Cl)Cl.C(OCC)(=O)C>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][S:12][C:10]2[O:11][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][C:8]=3[N:9]=2)=[CH:24][CH:25]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: O=[N+]([O-])c1ccc2oc(=S)[nH]c2c1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc2oc(SCc3ccc(Cl)cc3)nc2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
To a suspension of 5-nitrobenzo[d]oxazole-2(3H)-thione (196.2 mg, 1.0 mmol) in chloroform (10 mL) was added triethylamine (278 μL, 2 mmol) followed by 1-(bromomethyl)-4-chlorobenzene (226 mg, 1.1 mmol). The reaction was stirred at 60° C. for 2 h. After cooling, the reaction was diluted with ethyl acetate, washed with dilute aqueous hydrochloric solution and brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 1:10 v/v to afford 250 mg (78%) of the title compound (LCMS RT=7.64 min)
Reaction SMILES: [CH2:1]([NH:9][C:10]([NH2:12])=[S:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:13][CH:14]([CH3:23])[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O>C(O)C>[BrH:13].[CH2:1]([NH:9][C:10]1[S:11][C:14]([CH3:23])=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:12]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: NC(=S)NCCc1ccccc1
Solvent: CCO
Product: Br
Product: Cc1sc(NCCc2ccccc2)nc1-c1ccccc1
Yield: 69.3 %

Procedure:
N-phenethylthiourea (2.0 grams, 0.011 moles) and α-bromopropiophenone (2.34 grams, 0.011 moles, Aldrich Chem. Co.) in 10 ml absolute ethanol were heated to reflux temperature for 90 minutes under nitrogen. The ethanol was then removed under vacuum, excess ethyl acetate added and the solids filtered and dried over phosphorous pentoxide. Recrystallization from absolute ethanol yielded 2.86 grams (70%) of 2-phenethylamino-4-phenyl-5-methylthiazole hydrobromide, m.p. 172°-175° C.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[F:14])#N.[C:15]1([CH:22]=[CH:21][CH:20]=[C:18]([OH:19])[CH:17]=1)[OH:16].Cl.C([O-])([O-])=[O:25].[Na+].[Na+]>B(F)(F)F.CCOCC.O>[OH:16][C:15]1[CH:17]=[C:18]([OH:19])[CH:20]=[CH:21][C:22]=1[C:1](=[O:25])[CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[F:14]
Reactant: Oc1cccc(O)c1
Reactant: COC(=O)c1ccc(CC#N)c(F)c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: FB(F)F
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COC(=O)c1ccc(CC(=O)c2ccc(O)cc2O)c(F)c1
Temperature: 75 °C
Reaction time: 16 h
Yield: 48 %

Procedure:
To a solution of methyl 4-(cyanomethyl)-3-fluorobenzoate (8 g, 41 mmol) and resorcinol (6.8 g, 62 mmol) in BF3-Et2O (100 ml) was bubbled with HCl at 0° C. for 15 min. The mixture was stirred at 75° C. for 16 hours. Then H2O (100 ml) was added and the solution was heated at 95° C. for 16 hours. The mixture was cooled to room temperature and neutralized by Na2CO3 and extracted with EtOAc (100 ml×3). The organic layers were combined, dried with anhydrous Na2SO4, filtered and evaporated to give the crude product. Purification by column chromatography (PE/EtOAc=10/1 to 3/1) gave Intermediate I as a white solid (6 g, 48%).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)=O.[CH:21]1([C:24](=[O:29])[CH2:25][C:26](=O)[CH3:27])[CH2:23][CH2:22]1>C(O)(=O)C.S(=O)(=O)(O)O>[CH:21]1([C:24]([C:25]2[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)=[C:3]3[C:4]4[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=4[S:6][C:2]3=[N:1][C:26]=2[CH3:27])=[O:29])[CH2:23][CH2:22]1
Reactant: Nc1sc2c(c1C(=O)c1ccc(Cl)c(Cl)c1)CCCC2
Reactant: CC(=O)CC(=O)C1CC1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sc3c(c2c(-c2ccc(Cl)c(Cl)c2)c1C(=O)C1CC1)CCCC3
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 24 %

Procedure:
To a stirred solution of 60 mg (0.18 mmol) (2-amino-4,5,6,7-tetrahydro-benzo[b]thiophen-3-yl)-(3,4-dichloro-phenyl)-methanone in 2 ml acetic acid was added 31 mg (0.24 mmol) of 1-cyclopropyl-butane-1,3-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 18 mg (23%) cyclopropyl-[(4-(3,4-dichloro-phenyl)-2-methyl-5,6,7,8-tetrahydro-benzo[4,5]thieno [2,3-b]pyridin-3-yl)]-methanone as a light brown solid. ES-MS m/e (%): 416 (M+H+, 100).
Reaction SMILES: [BH4-].[Na+].[OH:3][CH:4]([CH2:14][CH2:15][C:16]1[C:17]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][N:19]2[C:28]=1[CH:29]([CH3:31])[CH3:30])[CH2:5][C:6](=[O:13])[CH2:7][C:8]([O:10]CC)=[O:9].[OH-].[Na+].C(O)(=O)C>CO.O>[OH:13][CH:6]([CH2:5][CH:4]([OH:3])[CH2:14][CH2:15][C:16]1[C:17]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][N:19]2[C:28]=1[CH:29]([CH3:30])[CH3:31])[CH2:7][C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)CC(=O)CC(O)CCc1c(-c2ccccc2)c2c3ccccc3ccn2c1C(C)C
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CC(C)c1c(CCC(O)CC(O)CC(=O)O)c(-c2ccccc2)c2c3ccccc3ccn12
Reaction time: 0.5 h
Yield: 101.7 %

Procedure:
Sodium borohydride (38 mg) was added to a stirred solution of ethyl 5-hydroxy-7-(3-isopropyl-1-phenylpyrrolo[2,1-a]isoquinolin-2-yl)-3-oxoheptanoate (760 mg; prepared as described in Reference Example 3) in methanol (20 ml) at 0° C. under an argon atmosphere. The mixture was stirred at 30 minutes and then a solution of sodium hydroxide (320 mg) in water (8 ml) was added and the mixture was stirred for 1 hour. The mixture was then diluted with water (20 ml) and acidified with glacial acetic acid. The resulting milky solution was extracted with diethyl ether (3×50 ml) and the combined extracts were dried over magnesium sulphate and evaporated, to give 3,5-dihydroxy-7-(3-isopropyl-1-phenylpyrrolo[2,1-a]-isoquinolin-2-yl)heptanoic acid (730 mg), in the form of a yellow gum.