Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([N:11]([C:13]([CH2:15][NH2:16])=[O:14])[CH3:12])[CH:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[C:22]1([CH2:28][CH2:29][CH2:30]Br)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>C1COCC1.CCOC(C)=O>[OH:10][C@@H:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C@@H:2]([N:11]([CH3:12])[C:13](=[O:14])[C@H:15]([NH2:16])[CH2:30][CH2:29][CH2:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:1]
Reactant: CC(C(O)c1ccccc1)N(C)C(=O)CN
Reactant: BrCCCc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H]([C@@H](O)c1ccccc1)N(C)C(=O)[C@H](N)CCCc1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of pseudoephedrine glycinamide (1.5 g, 6.75 mmol), prepared and used by the method of Myers et al. (J. Am. Chem. Soc. 1997, 119, 656), and LiCI (1.71 g, 40.5 mmol) in THF (30 mL) was cooled to −78° C. and n-BuLi was added (13.16 mmol, 5.25 mL of a 2.5 M solution). After stirring for 20 min at −78° C., the reaction was warmed to 0° C. and stirred an additional 20 minutes. 3-Phenyl-1-bromopropane (1.3 mL, 7.42 mmol) was added and the reaction was stirred for 2 h at 0° C. Aqueous 1 N HCl (50 mL) and EtOAc (50 mL) were added, the organic phase was separated and extracted with 1 N HCl (50 mL). The aqueous extracts were combined, cooled in an ice bath and slowly basified to pH 14 with 6 N NaOH. The product was extracted with CH2Cl2 (4×50 mL) and the combined extracts were dried over MgSO4 and concentrated to give a yellow oil. Purification by flash chromatography (SiO2 gel, 92:4:4, CH2Cl2:MeOH:triethylamine) delivered 400 mg (78%) of the Product of Example 199, Step A: +APcI MS (M+1)+ 341; 1H NMR=400 MHz (CDCl3) δ: 7.38 (m, 10H), 5.26 (m, 1H), 4.15 (m, 1H), 3.86 (m, 1H), 2.36 (s, 3H).
Reaction SMILES: FC1C=C(Cl)C(OC2CCCC2)=CC=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].COC1C=C(CC[NH2:38])C=CC=1OC.C(N(CC)CC)C>C1C=CC=CC=1>[C:16]([NH2:38])(=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH2:15])=[O:20]
Reactant: COc1ccc(CCN)cc1OC
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: NC(=O)C1=C(C(N)=O)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 250.8 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), 2-(3,4-dimethoxyphenyl)ethylamine (0.600 g, 3.31 mmol), triethylamine (0.310 g, 3.06 mmol) and benzene (20. ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-{2-3,4-dimethoxyphenyl)ethyl)-3,4,5,6-tetrahydrophthalamide as white crystals (1.16 g, 77.5% yield).
Reaction SMILES: I[C:2]1[CH:9]=[N:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(N(CC)CC)C.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[CH:25])=[CH:20][CH:19]=1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][C:2]2[CH:9]=[N:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])=[CH:20][CH:19]=1
Reactant: N#Cc1ccncc1I
Reactant: C#Cc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1ccncc1C#Cc1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 3-iodo-isonicotinonitrile (911 mg, 3.96 mmol) in DMF (10 ml) are added bis(triphenylphosphine)-palladium(II)-chloride (139 mg, 0.20 mmol), copper(I) iodide (22.6 mg, 0.12 mmol), triethylamine (1.10 ml, 7.9 mmol) and 1-bromo-4-ethynyl-benzene (716 mg, 3.96 mmol). The mixture is flushed with nitrogen, heated to 80° C. and stirred in a closed reaction vial at this temperature for 18 hours. The reaction mixture is allowed to cool to room temperature and partitioned between dichloromethane and 1 N HCl. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to give 3-(4-bromo-phenylethynyl)-isonicotinonitrile as beige solid; HPLC/MS 2.13 min (A), [M+H] 283/285.
Reaction SMILES: C1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)C=CC=CC=1.[CH3:17][C@H:18]1[NH:23][C@@H:22]([CH3:24])[CH2:21][N:20]([C:25]([C:27]2[C:28]([CH3:34])=[C:29]([CH:32]=O)[NH:30][CH:31]=2)=[O:26])[CH2:19]1>C(O)C.N1CCCCC1>[CH3:17][C@H:18]1[NH:23][C@@H:22]([CH3:24])[CH2:21][N:20]([C:25]([C:27]2[C:28]([CH3:34])=[C:29]([CH:32]=[C:13]3[CH:12]=[CH:8][CH:7]=[C:15]([N:11]4[C:12]5[C:8](=[CH:7][CH:15]=[CH:14][CH:13]=5)[CH2:9][C:10]4=[O:16])[CH2:14]3)[NH:30][CH:31]=2)=[O:26])[CH2:19]1
Reactant: O=C1Cc2c(cccc2-c2ccccc2)N1
Reactant: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=C1C=CC=C(N2C(=O)Cc3ccccc32)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.9 %

Procedure:
To a solution of 4-phenyl-1,3-dihydro-indol-2-one (52.3 mg, 0.25 mmol) and 4-[(cis)3,5-dimethyl-piperazine-carbonyl]-3-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-[4-((cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene]-phenyl-1,3-dihydro-indol-2-one as a yellow solid (21.5 mg, 20%).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([S:22]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[CH2:10][CH2:11]2)(=[O:23])=[O:24])=[CH:26][CH:27]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(CCc2ccc(OC)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CCN2CCC(C(=O)O)(S(=O)(=O)c3ccc(OC)cc3)CC2)cc1

Procedure:
4(4methoxy-benzenesulfonyl)-1-[2-(4methoxyphenyl)-ethyl]-piperidine-4carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-1-[2-(4-methoxyphenyl)-ethyl]-piperidine-4-carboxylic acid ethyl ester (5.0 g, 10.8 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17](O)=[O:18])[CH:15]=3)[N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.Cl.[CH2:40]([NH:47][C:48]1([CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[F:62])[CH2:53][CH2:52][CH2:51][CH:50]([NH2:54])[CH2:49]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH2:40]([NH:47][C:48]1([CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[F:62])[CH2:53][CH2:52][CH2:51][CH:50]([NH:54][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]([C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:9]=[C:8]3[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[O:18])[CH2:49]1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: NC1CCCC(Cc2ccccc2F)(NCc2ccccc2)C1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)O)cc23)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NC4CCCC(Cc5ccccc5F)(NCc5ccccc5)C4)cc23)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction mixture of 3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (0.15 mmol, 75 mg), HCl salt of N1-benzyl-1-(2-fluorobenzyl)cyclohexane-1,3-diamine (0.15 mmol, 52 mg), HATU (0.15 mmol, 57 mg) and DIEA (0.1 mL) in DMA (0.5 mL) was stirred at room temperature for overnight. The product, N-(3-(benzylamino)-3-(2-fluorobenzyl)cyclohexyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide, was purified by column chromatography on silica gel.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:40])[C@@H:6]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:7][C:8]1[CH:31]=[CH:30][C:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][C@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19]([OH:21])=O)=[O:14])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].[C:41]([S:60][CH2:61][C@@H:62]([C:64]([NH2:66])=[O:65])[NH2:63])([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[NH2:66][C:64](=[O:65])[C@@H:62]([NH:63][C:19](=[O:21])[C@@H:18]([NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:17][CH2:16][NH:15][C:13]([O:12][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C@@H:6]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:40])[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34])=[CH:31][CH:30]=1)=[O:14])[CH2:61][S:60][C:41]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: NC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(N)=O)cc1)NC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
2.50 g (4.42 mmol) of the compound from example 2A was dissolved in 100 ml dichloromethane. 1.602 g (4.42 mmol) S-Trityl-L-cysteinamide, 0.77 ml (4.42 mmol) N,N-diisopropylethylamine and 1.68 g (4.42 mmol) HATU were added. The reaction mixture was split into 5 portions. The portions were heated for 30 min in a sealed tube at 60° C. in a microwave synthesizer. From the combined reaction mixture the solvent was removed by rotary evaporation (approx. 40° C., approx. 200 mbar, approx. 30 min.). The raw product was dissolved in dichloromethane and chromatographed over approx. 600 ml silica gel. Solvents used were dichloromethane/ethyl acetate 2/1, dichloromethane/ethyl acetate 1/1, dichloromethane/methanol 20/1 and dichloromethane/methanol 10/1. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 4.12 g (3.30 mmol, 75% of theory, 73% purity) of the desired product.
Reaction SMILES: [Li]CCCC.Br[C:7]1[N:8]=[C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)[S:10][CH:11]=1.C(O[B:24]1[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]1)(C)C>CCOCC>[CH3:19][C:15]1[N:14]=[C:13]([O:12][C:9]2[S:10][CH:11]=[C:7]([B:24]3[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]3)[N:8]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cccc(Oc2nc(Br)cs2)n1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1cccc(Oc2nc(B3OC(C)(C)C(C)(C)O3)cs2)n1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 29.2 %

Procedure:
According to Scheme 5, Step 3: At −78° C., under a nitrogen atmosphere, BuLi (3.69 mmol, 1.48 mL) was added dropwise to a solution of 2-(4-bromothiazol-2-yloxy)-6-methylpyridine (1.68 mmol, 455 mg) in Et2O (17 mL). After 5 minutes of stirring at −78° C., 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.69 mmol, 0.75 mL) was added and the resulting mixture was stirred at room temperature for 20 minutes. The reaction was quenched with a NH4Cl saturated aqueous solution and was extracted with EtOAc. The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The crude mixture was purified by flash chromatography over silica gel using cyclohexane/EtOAc (70:30 to 30:70) as eluent to yield 2-(6-methylpyridin-2-yloxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (0.49 mmol, 157 mg, 29%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[CH:12][C:13]([C:19]([O:21]C)=[O:20])=[CH:14][CH:15]=3)[N:10]=2)[CH2:4][CH2:3]1.CO.[OH-].[Na+].Cl>C1COCC1>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[CH:12][C:13]([C:19]([OH:21])=[O:20])=[CH:14][CH:15]=3)[N:10]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 2-[(trans-4-hydroxycyclohexyl)amino]quinazoline-7-carboxylate (3090 mg, 10.3 mmol) in THF (100 mL) was added MeOH (20 mL) followed by 2 M NaOH (20 mL, 40 mmol) and the mix stirred at R.T. for 3 hours. The solvents were stripped and the mix acidified with a stoichiometric amount of 1M HCl giving a yellow precipitate that was filtered off and washed with water and air dried to yield the title compound as a bright yellow solid, 2.7 g, 92%. 1H NMR (400 MHz, DMSO-D6) δ ppm 13.30 (1H, s) 9.17 (1H, s) 7.96 (1H, s) 7.85 (1H, d, J=8.34 Hz) 7.64 (1H, d, J=8.34 Hz) 7.48 (1H, s) 4.57 (1H, s) 3.79 (1H, s) 1.79-2.04 (4H, m) 1.17-1.43 (4H, m); MS (API−) for C15H17N3O3 m/z 286.1 (M−H)+.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:16]3[CH:17]=[C:18]([C:21](O)=[O:22])[S:19][CH:20]=3)=[CH:9][N:10]([CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:6]=2[CH:5]=[CH:4][NH:3]1.CC[N:26]=C=NCCCN(C)C.Cl>CC(N(C)C)=O.O>[O:1]=[C:2]1[C:7]2[C:8]([C:16]3[CH:17]=[C:18]([C:21]([NH2:26])=[O:22])[S:19][CH:20]=3)=[CH:9][N:10]([CH:11]([CH2:12][CH3:13])[CH2:14][CH3:15])[C:6]=2[CH:5]=[CH:4][NH:3]1
Reactant: CCC(CC)n1cc(-c2csc(C(=O)O)c2)c2c(=O)[nH]ccc21
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCC(CC)n1cc(-c2csc(C(N)=O)c2)c2c(=O)[nH]ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
To a solution of 4-(4-oxo-1-(pentan-3-yl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)thiophene-2-carboxylic acid (23.0 mg) in DMA (2 mL) were added EDCI hydrochloride (16.0 mg) and HOBt ammonium salt (13.1 mg) at room temperature, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate to ethyl acetate/methanol) to give the title compound (20.6 mg).
Reaction SMILES: CC(C1C=CC=C(C(C)C)C=1[CH2:13][C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:15])C.[CH:33]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38](C(C)C)[C:37]=1CC(O)=O)(C)C.C(O)(=O)CCC1C=CC=CC=1>>[O:15]=[C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:28])(=[O:29])[NH2:27])[C:19]([CH:22]([CH3:23])[CH3:24])=[CH:20][CH:21]=1)[CH2:13][CH2:33][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)O
Agent: O=C(O)CCc1ccccc1
Product: CC(C)c1ccc(C(=O)CCc2ccccc2)c(C(C)C)c1OS(N)(=O)=O

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with hydrocinnamic acid, mp 121°-124° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8](O)=[O:9])=[N:4][N:5]([CH3:7])[CH:6]=1.C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[BH4-].[Na+]>C1COCC1>[F:1][C:2]1[C:3]([CH2:8][OH:9])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: Cn1cc(F)c(C(=O)O)n1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1cc(F)c(CO)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
To a 50 mL round-bottomed flask containing 4-fluoro-1-methyl-1H-pyrazole-3-carboxylic acid (344 mg, 1.7 mmol) in THF (17 mL), was added triethylamine (0.23 mL, 1.7 mmol) and the reaction mixture was cooled to 0° Celsius. Isobutylchloroformate (216 μL, 1.7 mmol) was added and the reaction mixture was stirred at 0° Celsius for 30 minutes. The solids were removed by filtration, the filtrate was collected, transferred to a 25 mL round bottomed flask and sodium borohydride (95 mg, 2.5 mmol) and the reaction mixture was stirred at RT for 10 min. The reaction mixture was concentrated to dryness and purified by FCC without additional work up to provide the title compound (120 mg, 55% yield) as a yellow oil. The compound showed very low UV activity and did not ionize by MS.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[P:13](OCC)([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:14]>>[CH3:10][O:9][C:7]([C:6]1[CH:11]=[CH:12][C:3]([CH2:2][P:13](=[O:14])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])=[CH:4][CH:5]=1)=[O:8]
Reactant: CCOP(=O)(OCC)OCC
Reactant: COC(=O)c1ccc(CBr)cc1
Product: CCOP(=O)(Cc1ccc(C(=O)OC)cc1)OCC
Temperature: 150 °C
Reaction time: 24 h
Yield: 68.9 %

Procedure:
A mixture of methyl 4-(bromomethyl)benzoate (25 g, 109 mmol) and triethyl phosphate (24.3 ml, 142 mmol) was stirred at 150° C. for 24 h. The resulting mixture was purified by distillation (165-172° C., 1 mmHg) to obtain diethyl 4-(methoxycarbonyl)benzylphosphonate (21.5 g, 69%). To a mixture of diethyl 4-(methoxycarbonyl)benzylphosphonate (20.5 g, 71.5 mmol), 15-crown-5 (1.4 ml, 7.1 mmol) and THF (120 ml) was added sodium hydride (60% in oil, 2.9 g, 71.5 mmol) at 0° C. The mixture was stirred at 0° C. for 0.5 h. A solution of tert-butyl 4-oxo-1-piperidinecarboxylate (11.9 g, 59.6 mmol) in THF (45 ml) was added dropwise to the resulting mixture over period of 10 min at 0° C. The mixture was stirred at room temperature for 20 h. The resulting mixture was poured into ice-water (200 ml) and the whole was extracted with ethyl acetate (100 ml×2). The extracts were washed with 5% aqueous sodium bicarbonate(100 ml), saturated sodium chloride solution (100 ml) successively. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel 200 g, ethyl acetate/hexane=1/10) followed by recrystallization from hexane to give tert-butyl 4-(4-methoxycarbonylbenzylidene)piperidine-1-carboxylate (6.9 g, 35%) as a colorless crystalline powder. A mixture of tert-butyl 4-(4-methoxycarbonylbenzylidene)piperidine-1-carboxylate (6 g, 18 mmol) in methanol (150 ml) was hydrogenated over 10% palladium carbon (50% wet, 1 g) for 5 h at room temperature. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel 90 g, ethyl acetate/hexane=1/10) to obtain the title compound (6.1 g, 100%) as pale yellow oil.
Reaction SMILES: [Na+].[O:2]=[C:3]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:4]([O-:6])=[O:5].[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C.C(Cl)(Cl)Cl>[CH3:9][CH:8]([CH3:10])[CH2:7][C:3](=[O:2])[C:4]([O:6][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5]
Reactant: ClCc1ccccc1
Reactant: CC(C)CC(=O)C(=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)CC(=O)C(=O)OCc1ccccc1
Reaction time: 5 h
Yield: 93.7 %

Procedure:
A mixture of 2-Oxo-4-methyl pentanoic acid sodium salt (10 g, 65.7 mmol) and benzyl chloride (8 g, 63 mmol) in 300 ml DMF was stirred at 40°-50° C. for 5 h. It was filtered, and the filtrate was evaporated under reduced pressure to provide an oil. The oil was dissolved in chloroform, washed with water, dried, filtered, and evaporated to provide the desired product (13 g, 94%). 1H NMR (CDCl3, TMS) δ0.95 (d,6H), 2.15 (m,1H), 2.7 (d,2H), 5.28 (s,2H), 7.4 (m,5H). Mass spectrum: (M+H)+ =221.
Reaction SMILES: [CH:1]([CH:4]1[C:9](=O)[NH:8][CH2:7][CH2:6][N:5]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])([CH3:3])[CH3:2].Br[C:19]1[CH:25]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=[CH:22][C:20]=1[NH2:21].CN[C@@H]1CCCC[C@@H]1NC>CN1C(=O)CCC1.O.[Cu]I>[CH:1]([CH:4]1[N:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:7][N:8]2[C:19]3[CH:25]=[C:24]([S:26]([CH3:29])(=[O:27])=[O:28])[CH:23]=[CH:22][C:20]=3[N:21]=[C:9]12)([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(N)c(Br)c1
Reactant: CC(C)C1C(=O)NCCN1C(=O)OC(C)(C)C
Agent: [Cu]I
Agent: CN[C@H]1CCCC[C@H]1NC
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)C1c2nc3ccc(S(C)(=O)=O)cc3n2CCN1C(=O)OC(C)(C)C
Temperature: 150 °C
Reaction time: 1 h
Yield: 33.7 %

Procedure:
To a solution of tert-butyl 2-isopropyl-3-oxopiperazine-1-carboxylate (200 mg, 0.83 mmol) in NMP (3 mL) were added 2-bromo-4-(methylsulfonyl)aniline (207 mg, 0.83 mmol), (1R,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (12.0 mg, 0.08 mmol), K3PO4.3H2O (660 mg, 2.48 mmol) and CuI (16 mg, 0.08 mmol). The mixture was stirred at 150° C. for 1 h in a microwave oven. The mixture was diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by preparative TLC with CH2Cl2/MeOH 35/1 to afford tert-butyl 1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2(1H)-carboxylate (110 mg, 34% yield) as a white solid. LC-MS m/z 394.1 [M+H]+. 1H NMR (CDCl3 400 MHz): δ 7.94 (s, 1H), 7.83-7.76 (m, 2H), 5.35-5.17 (m, 1H), 4.73-4.42 (m, 1H), 4.22-4.12 (m, 1H), 4.11-3.99 (m, 1H), 3.53-3.37 (m, 1H), 3.03 (s, 3H), 2.38-2.27 (m, 1H), 1.42 (s, 9H), 1.19 (d, J=6.8 Hz, 3H), 0.97 (d, J=6.8 Hz, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:11][C:4]1[CH:3]=[C:2]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(-n2cncn2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 24 h

Procedure:
4-Fluoro-2-methyl-nitrobenzene (2 g, 0.013 mol), 1,2,4-triazole (0.9 g, 0.013 mol), potassium carbonate (1.78 g, 0.013 mol) were dissolved in DMSO (50 ml) and stirred at 90° C. for 24 h under dry conditions. The yellow suspension was poured into water (150 ml), extracted (EtOAc), dried (Na2SO4) and evaporated under reduced pressure to afford an orange solid which was purified by flash column chromatography on silica eluting with n-pentane/ethyl acetate (50-100%) to afford a white solid (2.83 g 69%).
Reaction SMILES: C[O-].[Na+].[C:4]1([N:10]=[N:11][CH:12]([C:15]#[N:16])[C:13]#[N:14])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:17][C:18]1[CH:36]=[CH:35][CH:34]=[CH:33][C:19]=1[CH2:20][N:21]1[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[C:23]([C:30]([NH2:32])=[NH:31])=[N:22]1>>[F:17][C:18]1[CH:36]=[CH:35][CH:34]=[CH:33][C:19]=1[CH2:20][N:21]1[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[C:23]([C:30]2[N:32]=[C:13]([NH2:14])[C:12](/[N:11]=[N:10]/[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[C:15]([NH2:16])[N:31]=2)=[N:22]1
Reactant: N#CC(C#N)N=Nc1ccccc1
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2ncccc12
Agent: C[O-]
Agent: [Na+]
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(N)c1/N=N/c1ccccc1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
3.87 g of sodium methanolate and then 12.2 g (71.7 mmol) of phenylazomalononitrile (L. F. Cavalieri, J. F. Tanker, A. Bendich, J. Am. Chem. Soc., 1949, 71, 533) are added to a stirred solution of 21.92 g (71.7 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamidine in N,N-dimethylformamide from Example 6A. The mixture is stirred at 110° C. overnight and allowed to cool. The solid which precipitates is filtered off with suction and washed with ethanol. Drying results in 23 g (73% of theory) of the target compound.