Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:30]1[CH2:29][CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=3)[CH2:32][CH2:31]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Reactant: Clc1ccc(N2CCNCC2)cc1
Product: COc1nc2cc(F)ccc2nc1NC(=O)N1CCN(c2ccc(Cl)cc2)CC1
Yield: 86 %

Procedure:
Ethyl N-(6-fluoro-3-methoxyquinoxalin-2-yl)carbamate and 1-(4-chlorophenyl)piperazine were reacted by the same way with the example 85 to obtain the titled compound (yield, 86%). 1H NMR (300 MHz, CDCl3): δ 3.24-3.27 (m, 4H), 3.74-3.77 (m, 4H), 4.15 (s, 3H), 6.84-6.89 (m, 2H), 7.14-7.43 (m, 5H), 7.77-7.82 (m, 1H).
Reaction SMILES: [NH2:1][CH:2]([CH:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)[C:3]([OH:5])=[O:4].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>>[C:13]([NH:1][CH:2]([CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)[C:3]([OH:5])=[O:4])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(C(=O)O)C1CCC(O)CC1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: O=C1CCC(C(NC(=O)c2ccccc2)C(=O)O)CC1

Procedure:
Bicyclic diamines of general formula (32), wherein P2 is a nitrogen protecting group, can be prepared as described in (Org. Mass Spectrum. (1984) 19(9), 459-460). Amino(4-hydroxyphenyl)acetic acid, purchased commercially, can be treated with Raney nickel and heat to provide amino(4-hydroxycyclohexyl)acetic acid. Amino(4-hydroxycyclohexyl)acetic acid can be treated with benzoyl chloride and then oxidized with Jones' reagent to provide (benzoylamino)(4-oxocyclohexyl)acetic acid. (Benzoylamino)(4-oxocyclohexyl)acetic acid can be subjected to a Beckmann rearrangement using hydroxylamine and a sulfonyl chloride such as phenyl sulfonyl chloride to provide (benzoylamino)(7-oxo-4-azepanyl)acetic acid. (Benzoylamino)(7-oxo-4-azepanyl)acetic acid can be treated with concentrated HCl and heat to provide 2-amino-3-(2-aminoethyl)hexanedioic acid. 2-Amino-3-(2-aminoethyl)hexanedioic acid can be distilled at 180-200° C./0.1 torr to provide octahydro[1,7]naphthyridine-2,8-dione. Octahydro[1,7]naphthyridine-2,8-dione can be treated with lithium aluminum hydride and monoprotected with a nitrogen protecting reagent such as acetyl chloride/acetic anhydride, di-tert-butyl dicarbonate, benzyloxycarbonyl chloride, or benzyl bromide to provide bicyclic diamines of general formula (32).
Reaction SMILES: [C:1]1([NH:11][C:12](=[S:15])[NH:13][NH2:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH:16][C:17]1[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:18]=1[CH:19]=O.S(NN)(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[OH:16][C:17]1[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:18]=1[CH:19]=[N:14][NH:13][C:12]([NH:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[S:15]
Reactant: NNC(=S)Nc1cccc2ccccc12
Reactant: O=Cc1ccc(O)cc1O
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: CN(C)C=O
Product: Oc1ccc(C=NNC(=S)Nc2cccc3ccccc23)c(O)c1
Reaction time: 40 h
Yield: 17.3 %

Procedure:
A solution of 4-(naphth-1-yl)-3-thiosemicarbazide (26 mg, 0.12 mmol) and 2,4-dihydroxybenzaldehyde (20 mg, 0.144 mmol) in dimethylformamide (1 mL) was shaken with 4 Å molecular sieves for 60 h. PS-TsNHNH2 resin (29 mg, 0.085 mmol) was added and shaking continued for 40 h, then the resin was filtered off. The solvent was removed under vacuum and the residue dissolved in ethanol. The solvent was again removed and the process repeated to give the title compound (7 mg, 18%) as a solid. MS (ES−) m/e 336 [M−H]−.
Reaction SMILES: C(NCC)C.C[Al](C)C.[CH2:10]([C:12]1[N:21]=[C:20]([CH2:22][CH3:23])[CH:19]=[C:18]2[C:13]=1[CH:14]=[C:15]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:16](=[O:24])[NH:17]2)[CH3:11].Cl.C[OH:32]>ClCCl>[CH2:10]([C:12]1[N:21]=[C:20]([CH2:22][CH3:23])[CH:19]=[C:18]2[C:13]=1[C:14]([OH:32])=[C:15]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:16](=[O:24])[NH:17]2)[CH3:11]
Reactant: CO
Reactant: CCOC(=O)c1cc2c(CC)nc(CC)cc2[nH]c1=O
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCNCC
Product: CCOC(=O)c1c(O)c2c(CC)nc(CC)cc2[nH]c1=O
Reaction time: 0.5 h

Procedure:
Diethylamine (0.63 ml) was added dropwise to a stirred solution of trimethylaluminium (2M solution in toluene; 3 ml) in dichloromethane (5 ml) under an atmosphere of argon. The mixture was stirred for 30 minutes then a solution of ethyl 5,7-diethyl-2-oxo-1,2-dihydro-1,6-naphthyridine-3-carboxylate (548 mg) in dichloromethane (5 ml) was added dropwise. The resulting mixture was heated at reflux for 4 hours then cooled in ice. A mixture of 2M hydrochloric acid (1 ml) and methanol (1 ml) was added dropwise. The mixture was filtered and the filtrate was concentrated by evaporation to give a brown oil which was purified by flash chromatography, eluting with methanol/ethyl acetate (1:24 v/v), to give 5,7-diethyl-2-oxo-1,2-dihydro-1,6-naphthyridine-3-N,N-diethylcarboxamide (B) (391 mg) as a solid, m.p. 56°-59° C.; NMR (CDCl3): 1.17(t, 3H), 1.25-1.4(complex m, 9H), 2.85(q, 2H), 3.07(q, 2 H), 3.32(q, 2H), 3.63(q, 2H), 6.95(s, 1H), 8.08(s, 1H), 12.28(s, 1H); mass spectrum (CI, ammonia): 302 (M+H)+ ; microanalysis, found C, 66.4; H, 7.6; N, 13.6%; C17H23N3O2.0.25H2O requires: C, 66.7; H, 7.7; N, 13.7%.
Reaction SMILES: [NH2:1][C@H:2]([C:7](O)=O)[CH2:3][C:4](O)=[O:5].[NH2:10][C@@H:11]([C:16](O)=O)[CH2:12]C(O)=O.C(N[C@H](C)C(OC)=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OC(=O)CNCC1C=CC=CC=1)C>>[CH3:12][C@@H:11]1[CH2:16][N:1]2[C@@H:2]([CH2:3][CH2:4][O:5][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=32)[CH2:7][NH:10]1
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: N[C@H](CC(=O)O)C(=O)O
Reactant: COC(=O)[C@@H](C)NCc1ccccc1
Agent: CCOC(=O)CNCc1ccccc1
Product: C[C@@H]1CN2c3ccccc3OCC[C@H]2CN1

Procedure:
The title compound was prepared according to the procedure outlined in Example 255 substituting L-aspartic acid for D-aspartic acid and (R)-methyl 2-(benzylamino)propanoate for N-benzylglycine ethyl ester. Purification via flash chromatography (0-30% methanol/dichloromethane) afforded the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 6.84-7.01 (m, 3H), 6.73-6.85 (m, 1H), 4.35-4.51 (m, 1H), 3.99-4.14 (m, 1H), 2.80-3.28 (m, 6H), 1.95-2.14 (m, 1H), 1.66-1.85 (m, 1H), 1.20 (d, J=6.44 Hz, 3H); MS (DCI) m/z 219 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([F:12])=[CH:10][C:9]([C:13]3[O:14][C:15]4[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:8][C:7]=2[F:23])[CH2:3][CH2:2]1.O[CH2:25][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([F:12])=[CH:10][C:9]([C:13]3[O:14][C:15]4[CH:21]=[C:20]([O:22][CH2:27][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH3:25])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:8][C:7]=2[F:23])[CH2:2][CH2:3]1
Reactant: Oc1ccc2nc(-c3cc(F)c(OCC4CC4)c(F)c3)oc2c1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C[C@@H](COc1ccc2nc(-c3cc(F)c(OCC4CC4)c(F)c3)oc2c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.6 %

Procedure:
To a solution of 2-(4-(cyclopropylmethoxy)-3,5-difluorophenyl)-1,3-benzoxazol-6-ol (1.92 g), tert-butyl ((2S)-1-hydroxypropan-2-yl)carbamate (1.59 g) and triphenylphosphine (2.38 g) in THF (15 mL) was added dropwise diisopropyl azodicarboxylate toluene solution (1.9 M, 4.78 mL), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (2.60 g). 1H NMR (300 MHz, CDCl3) δ 0.29-0.37 (2H, m), 0.56-0.67 (2H, m), 1.17-1.36 (4H, m), 1.46 (9H, s), 3.94-4.19 (5H, m), 4.67-4.82 (1H, m), 6.97 (1H, dd, J=8.7, 2.3 Hz), 7.10 (1H, d, J=2.3 Hz), 7.62 (1H, d, J=8.7 Hz), 7.68-7.81 (2H, m).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:2]1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:23][N:22]=[CH:21][C:20]=2[C:24](O)=[O:25])=[CH:15][CH:14]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN1CCCC1=O.O>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[O:23][N:22]=[CH:21][C:20]=2[C:24]([N:1]2[CH2:5][CH2:4][CH:3]([C:6]3[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=3)[CH2:2]2)=[O:25])=[CH:17][CH:18]=1
Reactant: O=C(O)c1cnoc1-c1ccc(Cl)cc1
Reactant: c1cncc(C2CCNC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(c1cnoc1-c1ccc(Cl)cc1)N1CCC(c2cccnc2)C1
Reaction time: 96 h

Procedure:
To a 150 mL round-bottomed flask equipped with magnetic stirring was added 3-(pyrrolidin-3-yl)pyridine (1.0 g, 6.7 mmol, source: ASDI Inc.) in 25 mL of N-methylpyrrolidinone (NMP). To this solution was added 5-(4-chlorophenyl)isoxazole-4-carboxylic acid (1.6 g, 7.1 mmol, source: CiVentiChem), 1-hydroxybenzotriazole (1.0 g, 7.4 mmol), and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.6 g, 8.1 mmol), and the mixture was stirred at ambient temp. After ca. 4 days, water was added (ca. 150 mL) and the aqueous layer was extracted with EtOAc (3×75 mL). The organic extracts were combined, washed with water, sat'd NaHCO3, and brine. The organic layers were combined and dried over MgSO4, filtered and concentrated in vacuo. The crude material was absorbed onto silica gel and purified on a 120 g Isco Redi-sep® silica gel column using CH2Cl2 with 3% (2M NH3 in CH3OH) as the eluant to give the desired product. Mass Spec. m/z+ion=354.1, m/z negative ion=352.1.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[C:19]1([S:25]([C:28]2[S:32][C:31]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[N:30][CH:29]=2)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([S:25]([C:28]2[S:32][C:31]([N:33]3[CH2:38][CH2:37][N:36]([C:7]([C:6]4[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:5]=4[O:4][CH:1]([CH3:2])[CH3:3])=[O:9])[CH2:35][CH2:34]3)=[N:30][CH:29]=2)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: O=S(=O)(c1ccccc1)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(S(=O)(=O)c3ccccc3)s2)CC1
Yield: 47 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-(5-benzenesulfonyl-thiazol-2-yl)-piperazine hydrochloride. The crude material was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as a white crystalline solid (yield 47%). MS (m/e): 550.2 (M+H+, 100%), 567.2 (M+NH4+, 100%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[N+:33]([C:35]([CH3:38])([CH3:37])[CH3:36])#[C-:34]>CO>[C:35]([NH:33][C:34]1[N:7]2[CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:4]=[CH:5][C:6]2=[N:9][C:16]=1[C:15]1[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[CH:14]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: O=Cc1cccc(F)c1
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: [C-]#[N+]C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(C)(C)Nc1c(-c2cccc(F)c2)nc2ccc(C(F)(F)F)cn12
Reaction time: 0.33 h
Yield: 9.7 %

Procedure:
5-(trifluoromethyl)pyridin-2-amine (200 mg, 1.23 mmol, Eq: 1.00), 3-fluorobenzaldehyde (161 mg, 137 μl, 1.3 mmol, Eq: 1.05) and p-toluenesulfonic acid monohydrate (70.4 mg, 370 μmol, Eq: 0.3) were dissolved in MeOH (2.00 mL) and the intensive yellow solution was stirred for 20 min. To this yellow solution was added dropwise 2-isocyano-2-methylpropane (103 mg, 140 μl, 1.23 mmol, Eq: 1.00) and the corresponding light yellow solution was stirred for 90 min. The solvent was removed, the remaining solid was treated with MeOH, the precipitate was filtered off, washed with MeOH (2 mL) and dried under vacuum to give the product as a white solid (42 mg, 9.7%). MS: 352.2 [M+H]+; 1H-NMR (CDCl3): δ 8.53 (s, 1H), 7.67-7.53 (m, 3H), 7.35 (m, 1H), 7.24 (dd, 1H), 6.98 (ddd, 1H), 3.06 (s, 1H), 1.01 (s, 9H).
Reaction SMILES: Cl.[OH:2][C@@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[N+:8]([C:11]1[CH:21]=[CH:20][C:14]([CH2:15][O:16][C:17](Cl)=[O:18])=[CH:13][CH:12]=1)([O-:10])=[O:9].C(N(CC)CC)C>C(Cl)Cl>[OH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:17]([O:16][CH2:15][C:14]2[CH:13]=[CH:12][C:11]([N+:8]([O-:10])=[O:9])=[CH:21][CH:20]=2)=[O:18])[CH2:4]1
Reactant: O[C@@H]1CCNC1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.2 %

Procedure:
To a suspension of (3R)-3-hydroxypyrrolidine hydrochloride (7.00 g, 56.6 mmol) in methylene chloride (210 ml) were added chloroformic acid p-nitrobenzyl ester (13.4 g, 62.3 mmol) and triethylamine (17.4 ml, 125 mmol) in an ice bath. The mixture was stirred at room temperature for 5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:1)→ethyl acetate as the eluant to afford (3R)-3-hydroxy-1-(p-nitrobenzyloxycarbonyl)-pyrrolidine (13.6 g, yield 90%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([C:3]1([C:16]([OH:18])=O)[CH2:15][CH:6]2[CH2:7][N:8]([C:10](=[O:14])[N:11]([CH3:13])[CH3:12])[CH2:9][CH:5]2[CH2:4]1)[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[N-:32]=[N+:33]=[N-:34].[Na+]>CC(C)=O.O>[CH2:1]([C:3]1([C:16]([N:32]=[N+:33]=[N-:34])=[O:18])[CH2:15][CH:6]2[CH2:7][N:8]([C:10](=[O:14])[N:11]([CH3:13])[CH3:12])[CH2:9][CH:5]2[CH2:4]1)[CH3:2]
Reactant: CCC1(C(=O)O)CC2CN(C(=O)N(C)C)CC2C1
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: CCC1(C(=O)N=[N+]=[N-])CC2CN(C(=O)N(C)C)CC2C1
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 81.4 %

Procedure:
5-Ethyl-2-dimethylcarbamoyl-hexahydro-cyclopenta[c]pyrrole-5-carboxylic acid 19c (0.56 g, 2.2 mmol) was dissolved in 60 mL of acetone upon cooling by an ice-water bath. When cooled to −5° C., triethylamine (0.245 mg, 2.43 mmol) and a solution of 2 mL of ethyl chloroformate (263 mg, 2.43 mmol) in acetone were added dropwise. After the reaction mixture was stirred for 15 minutes, a solution of sodium azide (0.286 g, 4.4 mmol) in 2 mL of water was added. The reaction mixture was stirred at −5° C.˜0° C. for another 30 minutes. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was diluted with 10 mL of water, extracted with ethyl acetate (10 mL×5). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound 5-ethyl-2-dimethylcarbamoyl-hexahydro-cyclopenta[c]pyrrole-5-carbonyl azide 19d (0.5 g) as a light yellow oil which was directly used in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19]([OH:21])=O)=[CH:5]2.[CH3:22][C:23]1[C:28]([NH2:29])=[CH:27][CH:26]=[C:25]([N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:24]=1>>[CH3:22][C:23]1[C:28]([NH:29][C:19]([C:6]2[N:7]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)=[O:21])=[CH:27][CH:26]=[C:25]([N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:24]=1
Reactant: Cc1nc(N2CCCC2)ccc1N
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Product: Cc1nc(N2CCCC2)ccc1NC(=O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Yield: 48.3 %

Procedure:
The process is carried out according to the method described in example 5.3, using 0.4 g (1.39 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (example 1.1) and 0.32 g (1.81 mmol) of 2-methyl-6-(pyrrolidin-1-yl)-3-aminopyridine (compound no. Vd), described in step 9.2. 0.3 g of the expected product is thus isolated.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1.[CH3:19][O:20][C:21](=[O:42])[CH2:22][CH:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][C:32](C3C=CC(Br)=CN=3)=[CH:31][CH:30]=2)[CH2:25][CH2:24]1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH3:19][O:20][C:21](=[O:42])[CH2:22][CH:23]1[CH2:24][CH2:25][CH:26]([C:29]2[CH:30]=[CH:31][C:32]([C:2]3[CH:7]=[N:6][C:5]([NH:8][C:9]4[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=4)=[CH:4][N:3]=3)=[CH:33][CH:34]=2)[CH2:27][CH2:28]1
Reactant: FC(F)(F)c1ccc(Nc2cnc(Br)cn2)cn1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ccc(Br)cn3)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)CC1CCC(c2ccc(-c3cnc(Nc4ccc(C(F)(F)F)nc4)cn3)cc2)CC1
Temperature: 130 °C

Procedure:
A solution of (5-Bromo-pyrazin-2-yl)-(6-trifluoromethyl-pyridin-3-yl)-amine (0.072 g) and {4-[4-(5-bromo-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (0.087 g) in 2 Ml DME was charged with 2 M sodium carbonate (1 Ml) and Pd(PPh3)4 (0.027 g, 0.1 equiv). The biphasic mixture was sparged with nitrogen for 3 min, then stirred at 130° C. under microwave heating for 30 min. The reaction was partitioned between EtOAc and water, and the organic extracts were dried over magnesium sulphate and concentrated in vacuo. Purification by silica gel chromatography (33% EtOAc in hexanes) afforded the title compound: (M+H)+ 471.2.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].[C:6]1(=O)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[BH4-].[Na+]>C(O)C>[CH:6]1([NH:1][CH2:2][CH:3]([OH:5])[CH3:4])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CC(O)CN
Reactant: O=C1CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)CNC1CCCCC1
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-amino-2-propanol (15 g, 0.199 mol) in ethanol (300 ml) was added cyclohexanone (31.4 mL, 0.299 mol). The reaction mixture was stirred at 0-10° C. for 10 minutes. Sodium borohydride (10.8 g, 0.285 mol) was added at 0° C., then stirred at rt for 15 minutes. The resultant reaction mixture was quenched with water, filtered through the Celite® reagent, and solvent was evaporated. The residue was dissolved in 2N HCl, washed with ethyl acetate; the pH of the aqueous layer was adjusted to 8 using saturated sodium bicarbonate solution. The compound was extracted with ethyl acetate. The organic layer was dried over sodium sulphate, concentrated to dryness, and the crude material was subjected to column chromatography to obtain 1-(cyclohexylamino)propan-2-ol. Yield: 22 g (70.1%); 1H NMR (400 MHz, DMSO-d6) δ 8.25 (bs, 1 H), 5.25 (bs, 1 H), 3.95-3.91 (m, 1 H), 2.89-2.88 (dd, J=6, 9 Hz, 2 H), 2.71-2.66 (m, 1 H), 2.00-1.99 (m, 2 H), 1.75-1.72 (m, 2 H), 1.60-1.57 (m, 1 H), 1.36-0.93 (m, 8 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:23]2[CH:22]=[CH:21][C:20]([CH3:25])([CH3:24])[C:19]=2[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:20]([CH3:25])([CH3:24])[CH:21]=[CH:22][C:23]=4[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCC2=C1C=CC2(C)C
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1C2=C(CCN1C(=O)c1cc3ncc(Br)cn3n1)C(C)(C)C=C2

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1,5,5-trimethyl-2,3,4,5-tetrahydro-1H-[2]pyrindine to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[C@H:6]([O:7][N+]([O-])=O)[CH2:5][C:4](=[O:11])[C:3]=1[CH2:12][CH:13]=[CH2:14].C(=O)([O-])[O-].[Ca+2].O>C(Cl)(Cl)Cl>[OH:7][C@H:6]1[CH2:5][C:4](=[O:11])[C:3]([CH2:12][CH:13]=[CH2:14])=[C:2]1[CH3:1]
Reactant: C=CCC1=C(C)[C@H](O[N+](=O)[O-])CC1=O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=CCC1=C(C)[C@@H](O)CC1=O
Reaction time: 3 h
Yield: 78.9 %

Procedure:
A mixture of 1.97 g of (R)-3-methyl-4-nitroxy-2-(2-propenyl)-2-cyclopenten-1-one prepared in Example 10, 0.20 g of calcium carbonate and 30 ml of water was stirred at 85°-90° C. for 3 hours. Thereafter, with the same operations as in Example 3, 1.20 g of (S)-4-hydroxy-3-methyl-2-(2-propenyl)-2-cyclopenten-1-one (chemical purity: 93.6%, [α]D24 : +11.2° (C=1.23, in chloroform), (R)-isomer/(S)-isomer=14.8/85.2) was obtained.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[C:15]([NH2:20])[CH:16]=[CH:17][CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[Cl:23][C:24]1[C:25]([C:38](O)=[O:39])=[N:26][C:27]([CH2:30][NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:28][CH:29]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[C:25]([C:38]([NH:20][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:14]=2[N:13]=[CH:12][N:11]=[C:10]3[NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=2)=[O:39])=[N:26][C:27]([CH2:30][NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:34])[CH3:35])=[CH:28][CH:29]=1
Reactant: Nc1cccc2c(Nc3cccc(C(F)(F)F)c3)ncnc12
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Nc4cccc(C(F)(F)F)c4)ncnc23)n1
Yield: 43.8 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(3-(trifluoromethyl)phenyl)quinazoline-4,8-diamine (Intermediate-7, 50 mg, 0.164 mmol), 3-chloro-6-(pivalamidomethyl)picolinic acid (Intermediate-3, 85 mg, 0.314 mmol), oxalyl chloride (59 mg, 0.47 mmol), DMF (1 drop) and DIPEA (63 mg, 0.49 mmol) in CH2Cl2 (2 mL) to afford 40 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 11.62 (s, 1H), 10.14 (s, 1H), 8.94 (d, J=7.8 Hz, 1H), 8.77 (s, 1H), 8.32-8.27 (m, 4H), 8.11 (d, J=8.7 Hz, 1H), 7.75-7.64 (m, 2H), 7.51-7.46 (m, 2H), 4.49 (d, J=5.7 Hz, 2H), 1.17 (s, 9H); MS [M+H]+: 557.16.