Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([OH:23])=O)=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:47][CH:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:51]2[CH2:52][CH2:53][CH:48]([CH3:47])[CH2:49][CH2:50]2)=[O:23])=[CH:15]3)=[O:11])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Reactant: CC1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3[nH]2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4-methyl piperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: C([O:5][C:6](=[O:21])[C@H:7]([CH:18]([CH3:20])[CH3:19])[NH:8][C:9](=[O:17])[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][C:9]([NH:8][C@H:7]([C:6]([OH:21])=[O:5])[CH:18]([CH3:20])[CH3:19])=[O:17])[CH:12]=1
Reactant: CC(C)[C@H](NC(=O)Cc1cccnc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)Cc1cccnc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3.4 g of N-(3-pyridylacetyl)-(L)-valine-tert-butyl ester are dissolved in 20 ml of trifluoroacetic acid/methylene chloride (1:1) and the solution is stirred at RT for 16 h. The reaction solution is fully concentrated by evaporation and the residue is digested with DIPE. The title compound is obtained in the form of a white amorphous solid. 1H-NMR (200 MHz, CD3OD): 8.9-8.6 (m, broad, 1H), 8.5 (m, 1H), 7.95 (m, 1H), 4.33 (m, 1H), 3.93 (s, 2H), 2.2 (m, 1H), 0.98 (2d, 6H).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:6](=[O:7])[N:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]#[N:19])=[CH:10][CH:9]=2)[C:4](=[O:20])[NH:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39]Br)(=[O:34])[CH3:33]>>[C:18]([C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([N:5]2[C:6](=[O:7])[C:2]([CH3:21])([CH3:1])[N:3]([CH2:39][CH2:38][CH2:37][CH2:36][O:35][C:32](=[O:34])[CH3:33])[C:4]2=[O:20])=[CH:9][CH:10]=1)#[N:19]
Reactant: CC1(C)NC(=O)N(c2ccc(C#N)c3ccccc23)C1=O
Reactant: CC(=O)OCCCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CC(=O)OCCCCN1C(=O)N(c2ccc(C#N)c3ccccc23)C(=O)C1(C)C

Procedure:
This compound was prepared from the compound of Example 17 by KHMDS deprotonation and N-alkylation with 4-acetoxybutyl bromide in a manner similar to that previously described in Example 9, to afford the desired hydantoin as a solid. LC/MS (ES) m/z 394 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=C1CNCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CCNC(=O)C2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.6 %

Procedure:
The mixture of piperazin-2-one (1.11 g, 11.1 mmol, Aldrich), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (2.43 g, 12.21 mmol, Aldrich) and sodium triacetoxyborohydride (2.59 g, 12.21 mmol, Aldrich) in dichloromethane (50 mL) was stirred at ambient temperature for 2 h. After the aqueous work up, the crude residue was purified by flash column chromatography (silica gel, Isco system, eluting with ethyl acetate and hexane) to give 4-(3-oxo-piperazin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.78 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH:21](O)[CH3:22])([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O>O1CCCC1.CN(C1C=CC=CN=1)C>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH:21]([CH3:22])[O:14]2)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)c1ccccc1C1(O)CCN(Cc2ccccc2)CC1
Agent: CN(C)c1ccccn1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1OC2(CCN(Cc3ccccc3)CC2)c2ccccc21
Temperature: 25 °C
Yield: 104.7 %

Procedure:
To a solution of (RS)-1-benzyl-4-[2-(1-hydroxy-ethyl)-phenyl]-piperidin-4-ol (3 g, 9.6 mmol) in tetrahydrofuran (30 ml) was added triethylamine (2.95 ml, 21.2 mmol), dimethylaminopyridine (120 mg, 0.96 mmol) and methanesulfonylchloride (0.84 ml, 10.6 mmol). The reaction mixture was refluxed for 3 hours, cooled to room temperature, quenched with water (15 ml) and ethylacetate (15 ml). The organic phase was dried over Na2SO4 and concentrated in vacuo to yield 2.95 g (quant.) of (RS)-1′-benzyl-3-methyl-3H-spiro[2-benzofuran-1,4′-piperidine] as an orange oil. MS m/e: 294 (M+H+).
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[N:7][N:6]=[C:5]1[C:9]1[S:10][C:11]2[CH2:12][CH2:13][O:14][C:15]3[CH:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][C:16]=3[C:17]=2[N:18]=1)([CH3:3])[CH3:2].[CH3:25][O:26][CH2:27][CH2:28][NH2:29]>>[CH:1]([N:4]1[CH:8]=[N:7][N:6]=[C:5]1[C:9]1[S:10][C:11]2[CH2:12][CH2:13][O:14][C:15]3[CH:22]=[C:21]([CH2:23][NH:29][CH2:28][CH2:27][O:26][CH3:25])[CH:20]=[CH:19][C:16]=3[C:17]=2[N:18]=1)([CH3:3])[CH3:2]
Reactant: CC(C)n1cnnc1-c1nc2c(s1)CCOc1cc(C=O)ccc1-2
Reactant: COCCN
Product: COCCNCc1ccc2c(c1)OCCc1sc(-c3nncn3C(C)C)nc1-2
Yield: 56 %

Procedure:
Following the procedure for 119, 2-(4-isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carbaldehyde and 2-methoxyethylamine were reacted. After purification by flash chromatography the resulting oil was dissolved in ether and treated with 1M HCl in ether to give a solid that was filtered off and dried to give 120 as a yellow solid (129 mg, 56%). LCMS: RT=6.11 min, [M+H]+=400. 1H NMR δ (ppm) (DMSO-d6): 9.17 (2 H, s), 8.93-8.90 (1 H, m), 8.29 (1 H, d, J=8.13 Hz), 7.28 (1 H, dd, J=8.22, 1.81 Hz), 7.24 (1 H, d, J=1.76 Hz), 5.47-5.38 (1 H, m), 4.33 (2 H, t, J=4.98 Hz), 4.10 (2 H, t, J=5.38 Hz), 3.56 (2 H, t, J=5.15 Hz), 3.43-3.30 (2 H, m), 3.25 (3 H, s), 3.02 (2 H, t, J=5.63 Hz), 1.56-1.49 (6 H, m)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15](O)=[O:16])=[CH:9][CH:8]=1.O[N:22]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]([NH2:22])=[O:16])=[CH:9][CH:8]=1
Reactant: O=C(O)C#Cc1ccc(OCc2cccc(F)c2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)C#Cc1ccc(OCc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
50 mg (0.19 mmol) of [4-(3-fluoro-benzyloxy)-phenyl]-propynoic acid is dissolved in 3 ml of THF and treated with 27 mg (0.2 mmol) of 1-hydroxybenzotriazole and 37 mg (0.19 mmol) of N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride. The resulting mixture is stirred at RT for 30 minutes, cooled to 0° C. and treated with 1 ml of concentrated ammonia. The suspension is stirred overnight at RT, diluted with water and extracted three times with dichloromethane. Flash-chromatography (silica gel, dichloromethane/methanol) yields 29 mg (59%) of a colorless solid. MS: m/e=270.2 (M++H).
Reaction SMILES: ClC1C=CC=C([C:8](OO)=[O:9])C=1.[Si:12]([O:19][CH2:20][C:21]1[C:30]2[C:25](=[C:26]([CH3:31])[CH:27]=[CH:28][CH:29]=2)[C:24]([O:32][CH2:33][O:34][CH3:35])=[C:23](C=O)[CH:22]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>ClCCl>[Si:12]([O:19][CH2:20][C:21]1[C:30]2[C:25](=[C:26]([CH3:31])[CH:27]=[CH:28][CH:29]=2)[C:24]([O:32][CH2:33][O:34][CH3:35])=[C:23]([O:9][CH3:8])[CH:22]=1)([C:15]([CH3:17])([CH3:18])[CH3:16])([CH3:14])[CH3:13]
Reactant: COCOc1c(C=O)cc(CO[Si](C)(C)C(C)(C)C)c2cccc(C)c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COCOc1c(OC)cc(CO[Si](C)(C)C(C)(C)C)c2cccc(C)c12
Yield: 72.6 %

Procedure:
10.8 g of 80 to 85% m-chloroperbenzoic acid was added to a dichloromethane (130 ml) solution of 10 g of 1-(t-butyldimethylsilyl)oxymethyl-4-methoxymethoxy-5-methyl-3-naphthalenecarbaldehyde and heated for 1 hour under reflux. The reaction solution was washed with a sodium thiosulfate aqueous solution, after which it was further washed with water, a saturated sodium hydrogencarbonate aqueous solution and a saturated saline solution in this order and dried with anhydrous magnesium sulfate, followed by removal of the solvent by distillation. 9.3 g of the resultant brown oily substance and 2.1 g of sodium hydride were suspended in 21 ml of methanol and 21 ml of water and refluxed for 15 minutes. After cooling, the suspension was rendered acidic by means of dilute hydrochloric acid, followed by extraction with ethyl acetate. After washing with a saturated saline solution, the extract was dried with anhydrous magnesium sulfate, from which the solvent was distilled off. 5 ml of methyl iodide was added to an N,N-dimethylformamide (100 ml) solution of 8.5 g of the resultant brown oily substance and 22.1 g of potassium carbonate, followed by reaction at 60° to 70° C. for 1 hour. The insoluble matters were removed by filtration and the resultant filtrate was diluted with ether. After washing with water, the diluted filtrate was washed with a saturated saline solution and dried with magnesium sulfate. After removal of the solvent by distillation, the residue was purified by silica gel column chromatography (5% ethyl acetate/hexane) to obtain 7.3 g of the captioned compound as a brown oily substance.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([CH2:8]O)[CH:5]=[CH:6][CH:7]=1.CN(C)C1C=CC=CC=1.S(Cl)([Cl:29])=O.Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][Cl:29])[C:3]=1[S:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(Cl)c1SCc1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: ClCc1cccc(Cl)c1SCc1ccccc1
Temperature: 15 °C
Reaction time: 1 h

Procedure:
To a mixture of 54 g of the compound of Example 2 in 200 mL of chloroform (ethanol-free) and of N,N-dimethylaniline, a solution of 30 g of thionyl chloride in 50 mL of chloroform (ethanol-free) was added while maintaining the reaction temperature at 15° C. with an ice-water bath. The mixture was stirred at 25° C. for 1 hour, then refluxed for 3 hours. The mixture was acidified with 1 N aqueous hydrochloric acid and the organic layer was collected. The organic layer was washed once with 1 N aqueous hydrochloric acid, dried over magnesium sulfate, and filtered. The filtrate was passed through a silica gel column, eluted with methylene chloride, and after evaporation of the eluant, 54 g subject compound was obtained as a yellow oil.
Reaction SMILES: O[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:4]=1.C(N(S(F)(F)[F:30])CC)C>ClCCl>[F:30][CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:4]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: NS(=O)(=O)c1ccc(-n2nc(CO)cc2-c2ccccc2)cc1
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-n2nc(CF)cc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of the alcohol from Step 3 (212 mg, 0.64 mmol) in dichloromethane (4 mL) was added diethylaminosulfur trifluoride (0.13 mL, 1.0 mmol). The reaction mixture was stirred at room temperature for 3 hours and partitioned between water and dichloromethane. The organic solution was washed with brine and concentrated. The residue was chromatographed on silica (72 mg, 34%): mp 162°-163° C.; Anal. calc'd for C16H14N3O2SF: C, 58.00; H, 4.26; N, 12.68. Found: C, 57.95; H, 4.03; N, 12.58.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]2[S:22][CH:23]([CH2:26][C:27]([O:29]CC)=[O:28])[CH2:24][N:25]=2)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]2[S:22][CH:23]([CH2:26][C:27]([OH:29])=[O:28])[CH2:24][N:25]=2)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)ccc3[nH]2)S1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(Oc2ccc3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 58.6 %

Procedure:
To a solution of ethyl [2-(5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetate (4 g) in ethanol (50 mL) and tetrahydrofuran (50 mL) was added 1N aqueous sodium hydroxide solution (17.4 mL), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated, and water was added to the residue, and the mixture was washed with ethyl acetate. To the aqueous layer was added 1N hydrochloric acid for neutralization, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure, and crystallized from ethyl acetate and diethyl ether to give the title compound (2.2 g, yield 59%) as yellow powder.
Reaction SMILES: [Si](OC1C=C(C=CC=1)C([C:21]1[CH:33]=[CH:32][C:24]([C:25]([N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=1)N1C[C@H](C)N[C@H](C)C1)(C(C)(C)C)(C)C.C(O)=O.C=O>Cl>[CH2:30]([N:27]([CH2:28][CH3:29])[C:25](=[O:26])[C:24]1[CH:32]=[CH:33][CH:21]=[CH:22][CH:23]=1)[CH3:31]
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc(O[Si](C)(C)C(C)(C)C)c2)N2C[C@@H](C)N[C@@H](C)C2)cc1
Agent: C=O
Agent: Cl
Solvent: O=CO
Product: CCN(CC)C(=O)c1ccccc1
Temperature: 80 °C

Procedure:
A mixture of (±)-4-(3-((tert-butyldimethylsilyl)oxy)-α-(cis-3,5-dimethyl -1-piperazinyl)benzyl)-N,N-diethylbenzamide (18.5 g, 36.5 mmol) (from Example 11), 88% formic acid (5.1 g, 110 mmol) and 37.6% formaldehyde (2.8 g, 95 mmol) was heated at 80° C. overnight. The reaction mixture was cooled to room temperature and 20 mL of 7.2M hydrochloric acid was added slowly. The mixture was washed three times with 40 mL of dichloromethane. The pH of the aqueous layer was adjusted to 8 with a saturated solution of sodium bicarbonate and then extracted with 3×40 mL of dichloromethane. The organic extracts were dried over magnesium sulfate and evaporated to dryness to give 12.6 g (84%) of (±)-4-(3-hydroxy)-α-(cis 3,4,5-trimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide as a tan foam. NMR (300 MHz, CDCl3): δ1.0-1.3 (br m, 2d, J=6 Hz and J=6 Hz, 12H); 2.3 (br dd, 2H), 2.6 (s 3H); 2.7-3.0 (br m, 4H); 3.2-3.6 (br m, 4H); 4.2 (s, 1H), 6.7 (d, J=7 Hz, 1H); 6.8 (d, J=8 Hz, 1H); 6.9 (s, 1H); 7.1 (t, J=8 Hz, 1H); 7.25 and 7.40 (AB q, J=8 Hz, 4H). A portion of the product was dissolved in dichloromethane:ethanol and converted to the dihydrochloride salt with an excess of ethereal hydrogen chloride. The solvent was removed and the residue was redissolved in a minimum amount of dichloromethane. Diethyl ether was added to give an oily precipitate which solidified with stirring. Filtration gave the hydrated dihydrochloride salt. Calc. for C25H35N3O2 2 HCl 1.5 H2O C, 58.93; H, 7.91; N, 8.25; Cl, 13.92. Found: C, 58.84; H, 7.89; N, 8.09; Cl, 13.69.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].[F:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][C:33]=1[CH3:39]>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:36][C:35]3[CH:37]=[CH:38][C:32]([F:31])=[C:33]([CH3:39])[CH:34]=3)=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: Cc1cc(N)ccc1F
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Product: CCOC(=O)c1cnn2c(Nc3ccc(F)c(C)c3)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 99.6 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine (0.10 g, 0.23 mmol) obtained in Example 81, step 2 and 4-fluoro-3-methylaniline (0.044 g, 0.35 mmol), the title compound (0.119 g, 99%) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:10]2[C:11]([CH3:22])([CH3:21])[N:12](C(OC(C)(C)C)=O)[CH2:13][C:9]=2[C:8]([NH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:7]1)=[O:5])[CH3:2].Cl>C(Cl)Cl.O1CCOCC1>[CH2:27]([O:26][C:24]([NH:23][C:8]1[C:9]2[CH2:13][NH:12][C:11]([CH3:22])([CH3:21])[C:10]=2[N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=1)=[O:25])[CH3:28]
Reactant: CCOC(=O)Nc1nn(C(=O)OCC)c2c1CN(C(=O)OC(C)(C)C)C2(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)Nc1nn(C(=O)OCC)c2c1CNC2(C)C
Reaction time: 1 h

Procedure:
To a solution of 3-Ethoxycarbonylamino-6,6-dimethyl-4,6-dihydro-pyrrolo[3,4-c]pyrazole-1,5-dicarboxylic acid 5-tert-butyl ester 1-ethyl ester (5.69 g, 14.4 mmol) in CH2Cl2 (10 mL) was added 4M HCl in 1,4-dioxane (20 mL). The solution was stirred for 1 h, at which time the volatiles were removed in vacuo to yield the desired product F1(i) as a white solid (4.8 g, 91%). Mass Spectrum: Calcd for C13H21N4O4(M+H): 297. Found: 297.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([O:10]CC)=[O:9])=[C:5]([CH3:7])[N:6]=1.[Cl:13][C:14]1[S:18][C:17]([S:19](Cl)(=[O:21])=[O:20])=[CH:16][C:15]=1[C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[F:30]>>[Cl:13][C:14]1[S:18][C:17]([S:19]([NH:1][C:2]2[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([CH3:7])[N:6]=2)(=[O:21])=[O:20])=[CH:16][C:15]=1[C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[F:30]
Reactant: CCOC(=O)c1sc(N)nc1C
Reactant: O=S(=O)(Cl)c1cc(-c2cc(F)ccc2F)c(Cl)s1
Product: Cc1nc(NS(=O)(=O)c2cc(-c3cc(F)ccc3F)c(Cl)s2)sc1C(=O)O
Yield: 17 %

Procedure:
The product was prepared from ethyl 2-amino-4-methylthiazole-5-carboxylate (9.3 mg, 0.050 mmol) and 5-chloro-4-(2,5-difluorophenyl)thiophene-2-sulfonyl chloride (Intermediate 20) (17 mg, 0.050 mmol) according to the General Procedure 10, described in Example 128. The title compound was obtained in 17% yield (3.9 mg). 1H NMR (500 MHz, MeOH-d4) δ ppm 2.50 (s, 3 H) 7.18-7.23 (dddd, J=9.16, 7.57, 3.91, 3.05 Hz, 1 H) 7.26 (td, J=9.16, 4.60 Hz, 1H) 7.26 (ddd, J=8.70, 5.70, 3.05 Hz, 1 H) 7.57 (d, J=1.71 Hz, 1 H). MS (ESI+) m/z 451 [M+H]+.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([O:34][CH2:35][CH:36]([CH3:38])[CH3:37])[N:20]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO>[CH:1]1([CH:4]([C:11]2[CH:16]=[C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([O:34][CH2:35][CH:36]([CH3:38])[CH3:37])[N:20]=3)[N:14]=[CH:13][N:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cc(NCc2ccc(-c3cc(OC)ccc3F)c(OCC(C)C)n2)ncn1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(F)c(-c2ccc(CNc3cc(C(CC(=O)O)C4CC4)ncn3)nc2OCC(C)C)c1
Temperature: 50 °C
Reaction time: 15 h
Yield: 82.9 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(6-(((5-(2-fluoro-5-methoxyphenyl)-6-isobutoxypyridin-2-yl)methyl)amino)pyrimidin-4-yl)propanoate (65 mg) in methanol (5.0 mL) was added 1N aqueous sodium hydroxide solution (0.37 mL), and the mixture was stirred at 50° C. for 15 hr. 1N Hydrochloric acid was added, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from hexane/diethyl ether to give the title compound (51 mg) as a white solid.
Reaction SMILES: [C:1]([N:5](C)[S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH3:26])[CH:21]=3)[C:16]=2[O:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:30][CH:29]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>>[CH3:26][O:25][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[C:16]([O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:30][CH:29]=1)=[C:15]([C:12]1[CH:11]=[CH:10][C:9]([S:6]([NH:5][CH3:1])(=[O:8])=[O:7])=[CH:14][CH:13]=1)[CH:24]=[CH:23]2
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(=O)(=O)N(C)C(C)(C)C)cc3)ccc2c1
Solvent: O=C(O)C(F)(F)F
Product: CNS(=O)(=O)c1ccc(-c2ccc3cc(OC)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Temperature: 25 °C
Yield: 88.6 %

Procedure:
In a round bottom flask place the product of Example 68 (80 mg, 0.13 mmol) and trifluoroacetic acid (5 mL). Heat this solution at reflux for 15-20 minutes then cool to ambient temperature. Quench the reaction mixture by pouring it over saturated aqueous sodium bicarbonate then extract into ethyl acetate. Wash the combined extracts with saturated aqueous sodium bicarbonate, water and brine; then dry (sodium sulfate) and evaporate in vacuo. Purify the resulting material on a Chromatotron (silica gel; 4%-8% MeOH gradient in CH2Cl2) to obtain 63 mg of the title compound (89%). MS (IS+) m/e 547 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([O:19]C)[CH:13]=[C:12]([O:21]C)[C:11]=2[C@@H:23]1[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]1[CH2:29][N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1.Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([OH:19])[CH:13]=[C:12]([OH:21])[C:11]=2[C@@H:23]1[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]1[CH2:29][N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1
Reactant: COc1cc(OC)c2c(=O)cc(-c3ccccc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1Cn1ccnc1
Agent: Cl
Solvent: c1ccncc1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4ccccc4Cl)oc23)[C@@H]1Cn1ccnc1

Procedure:
A mixture of compound of example 112 (0.3 g, 0.625 mmol) and pyridine hydrochloride (3.0 g, 26.0 mmol) was heated as described in example 17 to get the title compound.
Reaction SMILES: [OH:1][C:2]([CH3:27])([CH:9]=[CH:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:3][C:4]([O:6]CC)=[O:5].[Br:28]Br.C(=O)([O-])O.[Na+]>CO>[OH:1][C:2]1([CH3:27])[CH:9]([Br:28])[CH:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:6][C:4](=[O:5])[CH2:3]1
Reactant: CCOC(=O)CC(C)(O)C=CCCc1ccccc1OCc1ccccc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC1(O)CC(=O)OC(CCc2ccccc2OCc2ccccc2)C1Br

Procedure:
The carboxylic acid (2.15 g) prepared by hydrolyzing ethyl 3-hydroxy-3-methyl-7-(o-benzyloxyphenyl)-4-heptenoate was treated with 1.6 g of bromine in an aqueous methanol solution of sodium hydrogen carbonate and the reaction mixture was worked up according to the method described in Example 1 (b). The product was recrystallized from ether to give 2.3 g of the desired compound melting at 122°-125° C.