Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]1[C:8]2[CH:9]=[CH:10][C:11]([NH2:13])=[CH:12][C:7]=2[CH2:6][NH:5][CH2:4][CH2:3]1.I.[S:15]1[CH:19]=[CH:18][C:17]([C:20](SC)=[NH:21])=[CH:16]1.[OH-].[NH4+]>C(O)C.O>[O:2]1[C:8]2[CH:9]=[CH:10][C:11]([NH:13][C:20]([C:17]3[CH:18]=[CH:19][S:15][CH:16]=3)=[NH:21])=[CH:12][C:7]=2[CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: CSC(=N)c1ccsc1
Reactant: Nc1ccc2c(c1)CNCCO2
Agent: Cl
Agent: I
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: N=C(Nc1ccc2c(c1)CNCCO2)c1ccsc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 22.1 %

Procedure:
2,3,4,5-Tetrahydro-1,4-benzoxazepin-7-ylamine hydrochloride (1.84 g, 8.4 mmol) was dissolved in 95% ethanol (40 ml) and 3-thiophenecarboximidothioic acid, methyl ester, hydroiodide (2.85 g, 10 mmol) was added. The mixture was stirred at room temperature for 2 days and then heated at 60° C. overnight and cooled. The solid (1.02 g) was collected. The filtrate was evaporated and the residue treated with ethyl acetate. The resulting crystals were collected and combined with the solid obtained previously. They were dissolved in water (20 ml), basified with conc. ammonium hydroxide, and extracted with methylene chloride (3×30 ml). The organic extracts were washed with water, dried over magnesium sulfate, and concentrated to give a solid (0.508 g), m.p. 150-152° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]Cl)=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1C=CC=CC=1>[CH2:8]([C:7]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:1])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1CCl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: Cc1ccccc1Cc1ccccc1
Reaction time: 4 h
Yield: 89.8 %

Procedure:
A solution of 70 parts of o-xylyl chloride and 200 parts of benzene is added in the course of 2 hours, whilst stirring thoroughly, to a mixture of 250 parts of 70 per cent strength by weight sulfuric acid and 72 parts of phosphorus pentoxide at from 75° to 77° C. After a further 4 hours at from 75° to 77° C, the organic phase is separated off and 80.9 parts (89.8% of theory) of o-benzyltoluene boiling at 98° C at 0.2 mm Hg are isolated by fractional distillation.
Reaction SMILES: [BH4-].[Na+].C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.[O:13]=[C:14]([C@@H:20]([O:28][SiH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:21]=[CH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:15][C:16]([O:18][CH3:19])=[O:17].Cl.[Cl-].[Na+]>C1COCC1.C(OCC)(=O)C>[OH:13][C@@H:14]([C@@H:20]([O:28][SiH2:29][C:30]([CH3:31])([CH3:33])[CH3:32])[CH:21]=[CH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: CCCCCC=C[C@H](O[SiH2]C(C)(C)C)C(=O)CC(=O)OC
Agent: Cl
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: [BH4-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCC=C[C@H](O[SiH2]C(C)(C)C)[C@H](O)CC(=O)OC
Temperature: -20 °C
Reaction time: 43 h
Yield: 89 %

Procedure:
NaBH4 (2.03 g, 53.72 mmol) was added in portions to a solution of L-tartaric acid (8.06 g, 53.72 mmol) in dry THF (125 ml), and the suspension thus obtained was heated at reflux temperature for 2.75 h and then cooled to −20° C. A solution of methyl (4S)-3-oxo-4-tert-butylsilyloxyundec-5-enoate (5.38 g, 11.55 mmol) in dry THF (75 ml) was then added dropwise, the temperature remaining at −20° C. After 43 h, hydrochloric acid (1M, 125 ml) was added to the reaction mixture, on account of which the temperature increased to room temperature. The mixture was stirred for a further 15 minutes. Ethyl acetate (500 ml), followed by solid sodium chloride, was then introduced until the saturation point was reached. The aqueous phase was separated off and extracted with a further 200 ml of ethyl acetate. The organic phases were combined, washed twice with 150 ml in each case of saturated sodium bicarbonate solution and then with 100 ml of a saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (90:10 to 80:20), petroleum ether:ethyl acetate), by means of which methyl (3R, 4S)-3-hydroxy-4-tert-butylsilyloxyundec-5-enoate was obtained as a colorless oil in a yield of 89% (4.77 g, 10.20 mmol).
Reaction SMILES: [C:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:7]=2)(O)=[O:2].C(Cl)(=O)C(Cl)=O.C[N:28](C=O)C.C([O-])(=O)C.[NH4+]>C(Cl)Cl>[C:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:7]=2)(=[O:2])[NH2:28]
Reactant: O=C(O)c1cc2ccc(OCc3ccccc3)cc2[nH]1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [NH4+]
Solvent: ClCCl
Product: NC(=O)c1cc2ccc(OCc3ccccc3)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A solution of 2-carboxy-6-benzyloxy-1H-indole (0.125 g; 0.468 mmol), oxalyl chloride (0.5 mmol) and DMF (0.2 ml) in CH2Cl2 was stirred at room temperature for 2 hours. After evaporation to dryness, the residue was redissolved in acetone; ammonium acetate (0.074 g; 0.95 mmol) was added to the solution and the mixture was stirred at room temperature for 1 hour. After evaporation, the residue was purified by flash chromatography eluting with CH2Cl2/acetone 80/20 to give 2-carbamoyl-6-benzyloxy-1H-indole.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1(O)[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]1.[OH-].[Na+]>FC(F)(F)C(O)=O>[F:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH:13]=1
Reactant: CCCN1CCC(O)(c2cccc(C(F)(F)F)c2F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CCCN1CC=C(c2cccc(C(F)(F)F)c2F)CC1
Yield: 75 %

Procedure:
A solution of 4-[2-fluoro-3-(trifluoromethyl)phenyl]-1-propylpiperidin-4-ol (8.0 g, 26 mmol) in trifluoroacetic acid (80 ml) was heated at reflux for 20 h. The mixture was poured on to ice and was basified with 10 M sodium hydroxide. The mixture was extracted with ethylacetate (3×100 ml) and the combined organic phases was dried (MgSO4), filtered and evaporated to dryness. The residue was purified by flash column chromatography (ethylacetate/methanol, 1:1) to give the title compound (5.6 g). MS m/z (rel. intensity, 70 eV) 287 (M+, 22), 259 (16), 258 (bp), 177 (10), 147 (10).
Reaction SMILES: [CH3:1][C:2]1([CH3:43])[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16]([CH2:18][CH2:19][CH2:20][C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])=[O:17])[C:5](=[O:28])[N:4]([C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[C:31]([C:38](F)(F)F)[CH:30]=2)[C:3]1=[O:42].NC1C=[CH:49][C:48]([N:51]2C(=O)C(C)(C)N(CCCCCCCCCSCCCC(F)(F)C(F)(F)F)[C:52]2=[O:79])=[CH:47][C:46]=1C>>[CH3:1][C:2]1([CH3:43])[C:3](=[O:42])[N:4]([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:52]([NH:51][CH:48]([CH3:49])[CH2:47][CH3:46])=[O:79])=[C:31]([CH3:38])[CH:30]=2)[C:5](=[O:28])[N:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16]([CH2:18][CH2:19][CH2:20][C:21]([F:27])([F:26])[C:22]([F:23])([F:25])[F:24])=[O:17]
Reactant: Cc1cc(N2C(=O)N(CCCCCCCCCSCCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)ccc1N
Reactant: CC1(C)C(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C(=O)N1CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F
Product: CCC(C)NC(=O)Nc1ccc(N2C(=O)N(CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)cc1C
Yield: 63 %

Procedure:
The experimental protocol used is the same as that described for the synthesis of the compound of Example 2, the compound of Example 25 replacing the compound of Example 1. A colourless oil is obtained with a yield of 63%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=3)=[CH:9][S:8][C:7]=2[CH:24]=1.[Br:25]N1C(=O)CCC1=O>C1COCC1>[Br:25][C:9]1[S:8][C:7]2[CH:24]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)/C=C/c1ccc(Oc2csc3cc(OC)ccc23)cc1
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1ccc(Oc2c(Br)sc3cc(OC)ccc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To a solution (E)-methyl 3-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (2.1 g, 6.17 mmol) in THF 201 mL) at room temperature was added N-bromosuccinimide (1.208 g, 6.79 mmol). The resulting solution was stirred vigorously at room temperature for 2 h after which time the reaction was quenched by addition of sat. aq. Sodium Thiosulfate solution and extracted with EtOAc (3×). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (SiO2, 0-40% EtOAc/Heptane) to afford (E)-methyl 3-(4-((2-bromo-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (2.4 g, 5.72 mmol, 93% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.65 (d, J=16.0 Hz, 1H), 7.46 (d, J=8.7 Hz, 2H), 7.32 (d, J=8.9 Hz, 1H), 7.20 (d, J=2.2 Hz, 1H), 6.95 (d, J=8.7 Hz, 2H), 6.91 (dd, J=8.8, 2.2 Hz, 1H), 6.31 (s, 1H), 3.86 (s, 3H), 3.79 (s, 3H), LC/MS (m/z, MH+): 420.9.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:45])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([N:26]4[C:34]5[C:29](=[CH:30][C:31]([Cl:36])=[C:32]([Cl:35])[CH:33]=5)[CH:28]=[N:27]4)[N:24]=3)[N:19](COCC[Si](C)(C)C)[CH:18]=2)=[O:16])[CH:11]2[CH2:13][CH2:12]2)[CH2:5][CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O.C(N)CN>C(Cl)Cl>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:45])[C@H:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([N:26]4[C:34]5[C:29](=[CH:30][C:31]([Cl:36])=[C:32]([Cl:35])[CH:33]=5)[CH:28]=[N:27]4)[N:24]=3)[NH:19][CH:18]=2)=[O:16])[CH:11]2[CH2:12][CH2:13]2)[CH2:5][CH2:4]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(-n3ncc4cc(Cl)c(Cl)cc43)cnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: NCCN
Product: N#CC1CCN(C(=O)[C@H](NC(=O)c2c[nH]c3ncc(-n4ncc5cc(Cl)c(Cl)cc54)nc23)C2CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.6 %

Procedure:
To a solution of 2-(5,6-dichloro-indazol-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (220 mg, 0.33 mmol) in CH2Cl2 (4 mL) was added TFA (2.0 mL, 26.0 mmol). The yellow reaction mixture was stirred at room temperature for 3 h then concentrated. The residue was redissolved in CH2Cl2 (4 mL) and ethylenediamine (0.4 mL, 5.92 mmol) was added. The reaction mixture was stirred at room temperature for 0.5 h then quenched with water and extracted with CH2Cl2 (3×). The combined organics were concentrated and the residue was purified by silica gel chromatography with 0% to 5% MeOH/CH2Cl2 (0.5% NH4OH) then triturated with Et2O to afford 95 mg (54%) of 2-(5,6-dichloro-indazol-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide as a light yellow solid. MS: (M+Na)+=559; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.91 (br. s., 1H), 8.91 (s, 1H), 8.79 (s, 1H), 8.44 (s, 1H), 8.41 (d, J=7.9 Hz, 1H), 8.29 (d, J=7.9 Hz, 1H), 8.18 (s, 1H), 4.77 (t, J=7.6 Hz, 1H), 3.59-3.86 (m, 2H), 3.32-3.46 (m, 1H), 2.95-3.05 (m, 2H), 1.45-1.92 (m, 4H), 1.24 (br. s., 1H), 0.32-0.48 (m, 4H).
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([NH:16][C:17]2([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])[CH2:10][CH2:9]1)=O)(C)C.Cl.C(OCC)(=O)C>C(OCC)(=O)C.Cl>[N:11]1([C:14]([NH:16][C:17]2([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)NC2(C(=O)OCc3ccccc3)CCCCC2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(NC1(C(=O)OCc2ccccc2)CCCCC1)N1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.9 %

Procedure:
2.5 g (5.6 mmol) of phenylmethyl 1-[N-[4-(2-methyl-2-propyloxycarbonyl) piperazine-1-carbonyl]amino]cyclohexanecarboxylate synthesized in Reference Example 8 was dissolved in ethyl acetate and 14 ml (56 mmol) of 4N hydrogenchloride-ethyl acetate solution (56 mmol) was added to the above prepared mixture under 0° C. and stirred for 3 hours at the room temperature. After completion of concentration of the reaction solution, the reaction solution was dissolved in 1N hydrochloric acid and washed with ethyl acetate. The water layer was separated out and was made into pH 9 with the addition of sodium carbonate and extracted three times with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, whereby 1.7 g of phenylmethyl 1-[N-(piperazine-1-carbonyl)amino]cyclohexanecarboxylate was obtained.
Reaction SMILES: C(OC(=O)NC1CC2C(=CC=C(NC(C3C(C4C=CC(C(F)(F)F)=CC=4)=CC=CC=3)=O)C=2)C1)(C)(C)C.C1(S([NH:46][CH:47]2[CH2:55][C:54]3[C:49](=[CH:50][CH:51]=[C:52]([NH:56][C:57]([C:59]4C(C5C=CC(C(F)(F)F)=CC=5)=CC=CC=4)=[O:58])[CH:53]=3)[CH2:48]2)(=O)=O)C=CC=CC=1.NC1C=C2C(=CC=1)CC(NC(=O)C)C2.[Br:89][C:90]1[CH:98]=[CH:97][CH:96]=[CH:95][C:91]=1[C:92](Cl)=[O:93]>>[C:57]([NH:56][CH:52]1[CH2:53][C:54]2[C:50](=[CH:49][CH:48]=[C:47]([NH:46][C:92](=[O:93])[C:91]3[CH:95]=[CH:96][CH:97]=[CH:98][C:90]=3[Br:89])[CH:55]=2)[CH2:51]1)(=[O:58])[CH3:59]
Reactant: O=C(Nc1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)C2)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)c1ccccc1Br
Agent: CC(=O)NC1Cc2ccc(N)cc2C1
Agent: CC(C)(C)OC(=O)NC1Cc2ccc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)cc2C1
Product: CC(=O)NC1Cc2ccc(NC(=O)c3ccccc3Br)cc2C1

Procedure:
The title compound is prepared as described for {5-[(4′-trifluoromethylbiphenyl-2-carbonyl)-amino]-indan-2-yl}-carbamic acid tert-butyl ester (the title E compound of Example 1) using N-(5-amino-indan-2-yl)-acetamide (the title A compound; 1.05 g, 5.50 mmol) and 2-bromo-benzoyl chloride (the title B compound; 1.21 g, 5.50 mmol) to give the product, mp 216-217° C. MS (ES+), m/z 373 (M+H), 375 (M+H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10]([CH3:16])([CH3:15])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[BH4-].[Na+].[Cl-].[NH4+]>CO>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[C:10]([CH3:16])([CH3:15])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C)(C)C1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(O)C(C)(C)C1
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a stirring solution of 1-Boc-3,3-dimethylpiperidin-4-one (0.48 g, 2.1 mmol) in methanol (20 mL) at 0° C., was added sodium borohydride (0.096 g, 2.5 mmol). After 1 h, satd aq ammonium chloride (1 mL) was added and the solution was concentrated in vacuo. The residue was flushed through a pad of silica gel, eluting with ethyl acetate and the filtrate was concentrated in vacuo to give 0.46 g (96%) of a clear colorless oil.
Reaction SMILES: S(Cl)(Cl)=O.[NH:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1.[C:14](O)(=[O:18])[CH2:15][CH:16]=[CH2:17]>ClCCl>[N:5]1([C:14](=[O:18])[CH2:15][CH:16]=[CH2:17])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1
Reactant: C=CCC(=O)O
Reactant: c1ccc2[nH]nnc2c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: C=CCC(=O)n1nnc2ccccc21
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
Sulfurous dichloride (6.91 g, 58.1 mmol) was added to a stirred solution of 1H-benzo[d][1,2,3]triazole (27.7 g, 232 mmol) in anhydrous dichloromethane (100 mL) at room temperature under argon atmosphere. The mixture was stirred for 30 min and but-3-enoic acid (5.0 g, 58.1 mmol) was added in one portion and stirring was continued for 2 h. The resulting suspension was filtered off and washed with 2.0 M NaOH (3×50 mL), dried over MgSO4, and purified by column chromatography to give the title compound as white solid (5.12 g). LCMS m/z=188.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 4.24 (d, J=6.57 Hz, 2H), 5.28-5.42 (m, 2H), 6.04-6.19 (m, 1H), 7.61 (t, J=7.71 Hz, 1H), 7.78 (t, J=7.71 Hz, 1H), 8.24 (dd, J=10.61, 8.34 Hz, 2H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][CH:7]1[C@H:15]2[N:11]([CH2:12][CH2:13][CH2:14]2)[C:10](=[O:16])[CH2:9][C:8]1=O>C(O)C>[CH3:6][CH:7]1[C@H:15]2[N:11]([CH2:12][CH2:13][CH2:14]2)[C:10](=[O:16])[CH:9]=[C:8]1[N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: CC1C(=O)CC(=O)N2CCC[C@@H]12
Solvent: CCO
Product: CC1C(N2CCCC2)=CC(=O)N2CCC[C@@H]12
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 106.1 %

Procedure:
2.62 ml (31.4 mmol) of pyrrolidine were added to a solution of 2.62 g (15.7 mmol) of (8aS)-8-methyl-1,2,3,5,6,7,8,8a-octahydroindolizine-5,7-dione [obtained as described in Preparative Example 9(iii)′ above] in 30 ml of ethanol and the resulting mixture was stirred for 30 minutes at 80° C. After the reaction was completed, the solvent and excess pyrrolidine were removed from the reaction mixture by evaporation under reduced pressure to afford 3.67 g (yield: quantitative) of the title compound as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([O:18][C:19]3[S:20][CH:21]=[CH:22][N:23]=3)[CH:17]=2)[C:11]([O:13]C)=[O:12])=[N:6][CH:7]=1.[OH-].[Li+].Cl>O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([O:18][C:19]3[S:20][CH:21]=[CH:22][N:23]=3)[CH:17]=2)[C:11]([OH:13])=[O:12])=[N:6][CH:7]=1
Reactant: COC(=O)c1cc(Oc2nccs2)cc(-c2ccc(C)cn2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(Oc3nccs3)cc(C(=O)O)c2)nc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-(5-methylpyridin-2-yl)-5-(thiazol-2-yloxy)benzoate (240 mg, 0.74 mmol) in tetrahydrofuran (6 mL) was added 2.5 M of aqueous lithium hydroxide solution (1.6 mL, 4.1 mmol). The reaction mixture was stirred at 60° C. overnight. The aqueous solution was acidified with 15% HCl (aq.) to pH=5-6, and extracted with EtOAc. The combined organic layers were concentrated in vacuo to get the title compound as a white solid. 1H NMR (CDCl3, 400 MHz): 8.77 (s, 1H), 8.70 (s, 1H), 8.08 (s, 1H), 8.04 (s, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.64 (dd, J=8.0, 2.0 Hz, 1H), 7.25 (d, J=4.8 Hz, 1H), 6.85 (d, J=4.0 Hz, 1H), 2.41 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:25])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N:11]1([C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:23])([F:22])[F:24])=[O:25])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.8 %

Procedure:
A solution of 4-(2-trifluoromethylbenzoyl)piperazine-1-carboxylic acid tert-butyl ester (0.948 g, 2.65 mmol) in 50 mL of a 1:4 mixture of trifluoroacetic acid and dichloromethane was stirred at room temperature for 20 h. After concentration in vacuo, the residue was dissolved in dichloromethane (100 mL) and washed with 1 N NaOH (10 mL), water (15 mL), and brine (15 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to yield the title compound as a light brown oil (0.657 g, 2.54 mmol). 1H NMR (300 MHz, CDCl3) δ 7.69, 7.54, 7.30, 3.78, 3.15, 2.94, 2.76. MS (ES+) m/z 259.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=1.[CH3:16][C:17]([CH3:19])=[O:18].CO.[OH-].[K+]>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11](/[CH:14]=[CH:16]/[C:17](=[O:18])[CH3:19])=[CH:12][CH:13]=1
Reactant: O=Cc1ccc(-c2ccccc2F)cc1
Reactant: CC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)/C=C/c1ccc(-c2ccccc2F)cc1

Procedure:
200.2 Gm (1.0 mol) of 2'-fluoro-4-biphenyl-carboxaldehyde, 3500 gm (60.3 mols) of acetone and 200 ml of methanol were charged into a 6-liter three-neck-flask equipped with a stirrer, a dropping funnel and an internal thermometer. While thoroughly stirring the contents of the flask, a solution of 2.805 gm (0.05 mol) of potassium hydroxide in 16 ml of water was added dropwise thereto while maintaining a reaction temperature of 20° to 25°C, and the resulting mixture was stirred for three hours more. Thereafter, the precipitated solid side product was filtered off, the filtrate was made neutral by dropwise addition of glacial acetic acid, and the neutral solution was evaporated in vacuo. The residue was recrystallized three times from diisopropyl ether and then once from a mixture of ethyl acetate and diisopropyl ether (volumetric ratio 1:1) in the presence of activated charcoal, yielding 101.2 gm (42% of theory) of the fallow crystalline compound of the formula ##SPC20##
Reaction SMILES: [Br-].[CH3:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[Zn+].[CH2:9]([CH:11]([C:14]1[N:19]2[N:20]=[C:21]([CH3:24])[C:22](I)=[C:18]2[N:17]=[C:16]([CH3:25])[CH:15]=1)[CH2:12][CH3:13])[CH3:10]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1COCC1>[CH3:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:22]1[C:21]([CH3:24])=[N:20][N:19]2[C:14]([CH:11]([CH2:9][CH3:10])[CH2:12][CH3:13])=[CH:15][C:16]([CH3:25])=[N:17][C:18]=12
Reactant: Cc1ccsc1[Zn+]
Reactant: CCC(CC)c1cc(C)nc2c(I)c(C)nn12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nc2c(-c3sccc3C)c(C)nn12
Temperature: 100 °C

Procedure:
Charge an oven dried flask with 3-methyl-2-thienylzinc bromide (11.0 mL, 5.5 mmol), anhydrous THF (6.0 mL) and 7-(1-ethyl-propyl)-3-iodo-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (0.536 g, 1.56 mmol). Degas for 10-15 min with positive argon pressure and add dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane (0.12 g, 0.15 mmol). Reflux overnight in an oil bath (100° C.) under an inert atmosphere. Cool the reaction to room temperature, quench with saturated ammonium chloride, and dilute with ethyl acetate (75 mL). Separate and extract the aqueous portion with ethyl acetate (50 mL). Combine the organic phases, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the resulting residue using flash chromatography, eluting with 100% pentane/0% (25% ethyl acetate/pentane) to 0% pentane/100% (25% ethyl acetate/pentane) in a step gradient of 10% increments to give a white foam. Triturate with hexane and filter. (0.432 g, 8%). 1H NMR (400 MHz, CDCl3): 7.26 (d, J=4.8, MHz, 1H), 6.96 (d, J=5.3 Hz, 1H), 6.42 (s, 1H), 3.64-3.60 (m, 1H), 2.53 (s, 3H), 2.43 (s, 3H), 2.14 (s, 3H), 1.87-1.79 (m, 4H), 0.88 (t, J=7.0 Hz, 6H).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[NH:8][CH:9]=[C:10]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1)=[O:6]>CO>[CH2:12]([C:10]1[CH:11]=[C:7]([C:5]([OH:6])=[O:4])[NH:8][CH:9]=1)[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1cc(CCc2ccccc2)c[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(CCc2ccccc2)c[nH]1

Procedure:
Freshly prepared aq. NaOH (10 M in H2O, 1.65 mmol) was added to a stirring, room temperature solution of 27 (0.0755 g, 0.329 mmol) in MeOH (0.82 mL, 0.4 M) under N2. Another 0.7 mL of MeOH was added due to precipitation of the starting material, and the reaction was heated to reflux until the reaction was judged complete by HPLC (2 h): The reaction was concentrated and then dissolved in 0.55 mL H2O. 10% aq. HCl was added dropwise until the pH=2. The white solid that precipitated from the reaction was filtered off and washed with cold H2O. The solid was dried under vacuum overnight to obtain pure 28. 1H (CDCl3, 400 MHz): δ 10.87 (1H, broad s), 7.25-7.18 (2H, m), 7.17-7.69 (3H, m), 6.70 (1H, s), 6.67 (1H, s), 2.83 (2H, t, J=7.6 Hz), 2.74 (2H, t, J=7.6 Hz) ppm. 13C (CDCl3, 100 MHz): δ 164.53, 143.39, 129.50, 129.21, 126.76, 126.38, 123.49, 122.85, 116.48, 38.68, 29.94 ppm. DEPT (CDCl3, 100 MHz): CH2 carbons: 38.68, 29.94; CH carbons: 129.50, 129.21, 126.76, 122.85, 116.48 ppm. HPLC: 8.579 min.