Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH2:15][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[Cl:52])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: Clc1ccccc1CCBr
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(CCc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(2-bromoethyl)-2-chlorobenzene and isolated as light-yellow gum. MS(m/e): 421.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH:18]1([NH2:21])[CH2:20][CH2:19]1.O>CN1C(=O)CCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][CH:18]2[CH2:20][CH2:19]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: NC1CC1
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1)CC2
Solvent: CN1CCCC1=O
Solvent: O
Product: Clc1nc(NC2CC2)c2c(n1)C(c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
To a solution of 2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (170 mg, 0.641 mmol) in NMP (2 mL) was added cyclopropanamine (110 mg, 1.924 mmol) dropwise. The mixture was stirred at RT for 3 hours. 8 mL of water was added to precipitate out the product. The solid was filtered out and air-dried to give a crude 2-chloro-N-cyclopropyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (175 mg, 0.612 mmol, 96% yield), which was used for the next step without any purification. LC-MS (M+H)+=286.1
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]([CH2:16][O:17][CH3:18])[CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.[CH3:19][C:20]1[NH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([NH2:29])=[CH:24][CH:23]=2>>[CH3:18][O:17][CH2:16][N:12]1[CH:13]=[CH:14][N:15]=[C:11]1[C:9]1[S:10][C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[NH:29][C:25]2[CH:26]=[C:27]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20]([CH3:19])=[CH:28]3)[CH:8]=1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: COCn1ccnc1-c1cc2nccc(Cl)c2s1
Product: COCn1ccnc1-c1cc2nccc(Nc3ccc4[nH]c(C)cc4c3)c2s1

Procedure:
The title compound was prepared from 7-chloro-2-(1-methoxymethyl-1H-imidazol-2-yl)-thieno[3,2-b]pyridine and 2-methyl-5-aminoindole by the procedure analogous to example 148(c) above. 1H NMR (400 MHz, CD3OD) δ8.15 (d, 1H), 7.85 (s, 1H), 7.53 (s, 1H), 7.37 (m, 2H), 7.11 (s, 1H), 7.02 (d, 1H), 6.81 (d, 1H), 6.19 (s, 1H), 5.46 (s, 2H), 3.38 (s, 1H), 2.44 (s, 1H); RP18-HPLC RT: 4.38 minutes; API MS: 390 (M+1).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[C:28]([N:31]([CH2:39][CH2:40][N:41]([CH3:43])[CH3:42])[C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1)(=[O:30])[CH3:29]>>[C:28]([N:31]([C:32]1[CH:37]=[CH:36][C:35]([NH:38]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:34][CH:33]=1)[CH2:39][CH2:40][N:41]([CH3:43])[CH3:42])(=[O:30])[CH3:29]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Reactant: CC(=O)N(CCN(C)C)c1ccc(N)cc1
Product: COc1cc2c(cc1OC)/C(=C(/Nc1ccc(N(CCN(C)C)C(C)=O)cc1)c1ccccc1)C(=O)N2

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and N-acetyl-N-(2-dimethylamino-ethyl)-p-phenylenediamine
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([O:8][C:9](=[O:24])[NH:10][C:11]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=1)([CH3:16])[C:12](=O)[C:13]#[CH:14])([CH3:7])([CH3:6])[CH3:5]>CCO>[C:4]([O:8][C:9](=[O:24])[NH:10][C:11]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=1)([C:12]1[CH:13]=[CH:14][NH:3][N:2]=1)[CH3:16])([CH3:7])([CH3:6])[CH3:5]
Reactant: C#CC(=O)C(C)(NC(=O)OC(C)(C)C)c1cccc(Br)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(C)(c1cccc(Br)c1)c1cc[nH]n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
Hydrazine hydrate (2.48 mL, 51.10 mmol) was added to a solution of rac-[1-(3-bromo-phenyl)-1-methyl-2-oxo-but-3-ynyl]-carbamic acid tert-butyl ester (1.8 g, 5.11 mmol) in EtOH (30 mL) and the mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the residue was dissolved in DCM and washed with water. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; AcOEt in DCM 0/100 to 50/50). The desired fractions were collected and concentrated in vacuo to yield rac-[1-(3-bromo-phenyl)-1-(1H-pyrazol-3-yl)-ethyl]-carbamic acid tert-butyl ester (1.62 g, 87% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:10]=2)[CH:5]=[CH:6][N:7]=1.[NH2:22][CH2:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:22][CH2:23][C:24]1[CH:29]=[C:28]([C:2]2[C:3]3[N:4]([N:8]=[C:9]([NH:11][C:12]4[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=4)[N:10]=3)[CH:5]=[CH:6][N:7]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: NCc1cccc(B(O)O)c1
Reactant: COc1cc(Nc2nc3c(Cl)nccn3n2)cc(OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(Nc2nc3c(-c4cccc(CN)c4)nccn3n2)cc(OC)c1
Temperature: 120 °C

Procedure:
To a solution of (8-chloro-[1,2,4]triazolo[1,5-a]pyrazine-2-yl]-(3,5-dimethoxy-phenyl)-amine (0.2 g, 0.65 mmol, 1 eq) in a mixture of dimethoxy ethane (3 ml) and water (1 ml), 3-aminomethylphenyl boronic acid (0.28 g, 1.31 mmol, 2 eq), sodium carbonate (0.14 g, 1.31 mmol, 2 eq)) and dichlorobis(triphenyl-phospine)palladium (II) (0.023 g, 0.03 mmol, 5%) are taken in a microwave vial and heated at 120° C. for 2 hours. The reaction mixture is concentrated and the residue is taken in dichloromethane (10 ml×1), washed with brine solution (10 ml×1), the organic layer is dried over anhydrous MgSO4 and concentrated. The crude product obtained is purified by silica gel column using (230-400) mesh to get the titled product as yellow solid.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:6]=1[N+:19]([O-:21])=[O:20])(=O)C.[OH-].[Na+]>CO.O>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:6]=1[N+:19]([O-:21])=[O:20]
Reactant: CC(=O)Nc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]

Procedure:
The 1-acetamido-4-benzyloxy-2-nitrobenzene so produced is treated with sodium hydroxide in methanol, warmed briefly on a steam bath for about 15 minutes until the reaction is complete, diluted with water and extracted with dichloromethane to give 1-amino-4-benzyloxy-2-nitrobenzene.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH:22]=[N:23][N:24]([CH2:26][C:27]([OH:29])=O)[CH:25]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11].Cl.C[NH:32]C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH:22]=[N:23][N:24]([CH2:26][C:27]([NH2:32])=[O:29])[CH:25]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11]
Reactant: C[C@H](c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(CC(=O)O)c3)cc12
Reactant: CNC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(CC(N)=O)c3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (4-{3-[(S)-1-(2,6-dichloro-3-fluorophenyl)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-pyrazol-1-yl)-acetic acid (10.0 mg, 0.0231 mmol), dimethylamine hydrochloride (9.41 mg, 0.115 mmol), TBTU (14.8 mg, 0.0462 mmol), DIPEA (0.021 mL, 0.115 mmol) and DCM (3 mL) was stirred at rt for 30 min. The solution was concentrated in vacuo, redissolved in MeOH and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.89 (d, J=7.1 Hz, 3 H), 2.99 (s, 3 H), 3.14 (s, 3 H), 5.16 (s, 2 H), 5.29 (q, J=7.3 Hz, 1 H), 7.13-7.23 (m, 1 H), 7.38 (d, J=1.3 Hz, 1 H), 7.39-7.52 (m, 2 H), 7.63 (s, 1 H), 7.81 (s, 1 H), 8.34 (d, J=1.8 Hz, 1 H). MS (ES+): m/z 460.02 (100) [MH+]. HPLC: tR=3.26 min (ZQ3, polar—5 min).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])=[N:6][CH:7]=1.C([Li])CCC.CN(C)[CH:30]=[O:31]>O1CCCC1.CCCCCC>[CH:30]([C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])=[N:6][CH:7]=1)=[O:31]
Reactant: CN(C)C=O
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(I)cn1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)cn1
Reaction time: 0.25 h
Yield: 79 %

Procedure:
To a solution of 5-iodo-2-[2-(5-methyl-2-phenyl-4-oxazolyl) ethoxy]pyridine (2.5 g) in tetrahydrofuran (40 ml), a solution of n-butyl lithium in hexane (1.6M, 4.61 ml) was added dropwise at -65° C. in a nitrogen stream. After the mixture was stirred at the same temperature for 15 minutes, N,N-dimethylformamide (0.71 ml) was added dropwise. After the cooling bath was removed and the mixture was stirred for 30 more minutes, a saturated aqueous solution of ammonium chloride (6 ml) was added. The reaction mixture was poured into water and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and dried (MgSO4), the solvent was distilled off under reduced pressure, to yield 5-formyl-2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]pyridine (1.5 g, 79%), which was then recrystallized from ethyl acetate-hexane to yield a colorless crystal.
Reaction SMILES: [CH:1]1([C:4](=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:14][CH2:15][CH2:16][CH2:17]Br>CN(C=O)C>[CH3:9][O:8][C:6]([C:5]1([C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:10])[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:7]
Reactant: BrCCCCBr
Reactant: COC(=O)CC(=O)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1(C(=O)C2CC2)CCCC1
Reaction time: 0.17 h
Yield: 22.9 %

Procedure:
To a solution of methyl 3-cyclopropyl-3-oxopropanoate (2.0 g, 14 mmol) in DMF (70 mL) was added sodium hydride (60% in mineral oil, 1.41 g, 35 mmol). The reaction mixture was stirred for 10 min then 1,4-dibromobutane (1.85 mL, 15 mmol) was slowly added. The reaction mixture was stirred for 2.5 h then carefully quenched with water and extracted with diethyl ether (2×). The combined organics were washed with water (2×) and brine then dried over Na2SO4 and concentrated. The residue was purified by chromatography over 60 g SiO2 (0% to 10% EtOAc/hexanes) to afford 0.63 g (23%) of 1-cyclopropanecarbonyl-cyclopentane carboxylic acid methyl ester as a colorless oil.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([N:15]3[CH2:19][C@H:18]([CH2:20][N:21]4[CH:25]=[CH:24][N:23]=[N:22]4)[O:17][C:16]3=[O:26])=[CH:10][C:9]=2[F:27])=[CH:4][CH2:3]1.N1C=CC=CC=1.[CH3:34][C:35]1([CH3:43])[O:39][C@H:38]([C:40](Cl)=[O:41])[CH2:37][O:36]1>ClCCl>[CH3:34][C:35]1([CH3:43])[O:39][C@H:38]([C:40]([N:2]2[CH2:7][CH2:6][C:5]([C:8]3[C:9]([F:27])=[CH:10][C:11]([N:15]4[CH2:19][C@H:18]([CH2:20][N:21]5[CH:25]=[CH:24][N:23]=[N:22]5)[O:17][C:16]4=[O:26])=[CH:12][C:13]=3[F:14])=[CH:4][CH2:3]2)=[O:41])[CH2:37][O:36]1
Reactant: CC1(C)OC[C@@H](C(=O)Cl)O1
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1cc(F)c(C2=CCNCC2)c(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)OC[C@@H](C(=O)N2CC=C(c3c(F)cc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)CC2)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
A solution of (5R)-3-(4-(1,2,5,6-tetrahydropyridin-4-yl)-3,5-difluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one hydrochloride (650 mg, 1.64 mM) in dry dichloromethane (20 ml) at 0–4°, was treated with pyridine (648 mg, 8.2 mM) followed by dropwise addition of (4S)-2,2-dimethyl-1,3-dioxolane-4-carbonyl chloride (430 mg, 2.64 mM). The solution was allowed to warm to ambient temperature and stir for 1 hour. The reaction mixture was washed with water and brine, dried (sodium sulfate) and evaporated to a gum which crystallised readily on trituration with diethyl ether to give the title compound (788 mg).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[N:6]2[N:5]=1)=O.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1.CN1CCCC1=O>CO>[CH3:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:6]3[C:7]([CH:8]=[N:9][C:4]([NH:36][C:33]4[CH:32]=[CH:31][C:30]([N:27]5[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]5)=[CH:35][CH:34]=4)=[N:5]3)=[CH:10][CH:11]=2)=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CS(=O)c1ncc2ccc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Solvent: CN1CCCC1=O
Solvent: CO
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5ccc(S(C)(=O)=O)cc5)n4n3)cc2)CC1
Temperature: 150 °C

Procedure:
Into a 30 mL vial, 2-Methanesulfinyl-7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (80 mg, 0.0002 mol), 4-(4-Methyl-piperazin-1-yl)-phenylamine (0.100 g, 0.000525 mol) and N-Methylpyrrolidinone (0.25 mL, 0.0026 mol) were added. The reaction mixture was heated at 150° C. for 90 minutes. The reaction was cool to room temperature. Methanol (15 mL) was added. The solid was filtered and washed with hot MeOH (10 mL) to afford [7-(4-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine as a light brown solid. MP 234-238° C. LCMS (E/I+) 373.18 (M+H). NMR 1H (DSMO-d6)-9.31 (s, 1H), 9.00 (s, 1H), 8.48 (d, 2H, J=8.48 Hz), 8.02 (d, 2H, J=8.16 Hz), 7.57 (d, 2H, J=8.79 Hz), 7.33 (d, 1H, J=4.77 Hz), 6.95 (d, 1H, J=4.76 Hz), 6.95-7.04 (m, 3H), 3.28 (s, 3H), 3.09 (bs, 4H), 2.40-2.56 (m, 4H), 2.22 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[F:26][CH:27]([F:37])[CH2:28][N:29]([CH3:36])[C@H:30]1[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]1>>[F:37][CH:27]([F:26])[CH2:28][N:29]([CH3:36])[C@H:30]1[CH2:35][CH2:34][CH2:33][N:32]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:25])[C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:20])[CH2:31]1
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Reactant: CN(CC(F)F)[C@H]1CCCNC1
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCC[C@H](N(C)CC(F)F)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)—N-(2,2-difluoroethyl)-N-methylpiperidin-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41-1.93 (m, 3H) 1.98-2.06 (m, 1H) 2.33 (d, J=2.27 Hz, 3H) 2.52-3.90 (m, 9H) 4.26-4.73 (m, 1H) 5.99-6.62 (m, 1H) 7.63 (d, J=7.33 Hz, 1H) 7.74 (t, J=7.58 Hz, 1H) 8.08 (d, J=8.34 Hz, 1H) 8.13-8.51 (m, 2H) 8.54 (d, J=1.77 Hz, 1H). ESI-MS m/z [M+H]+ 499.3.
Reaction SMILES: [CH3:1][C:2]1[Se:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.[Se](=O)=[O:12].O>C(O)(=O)C>[CH:1]([C:2]1[Se:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1)=[O:12]
Reactant: COC(=O)c1ccc(C)[se]1
Reactant: O=[Se]=O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C=O)[se]1
Reaction time: 0.25 h
Yield: 74.9 %

Procedure:
To a solution of methyl 5-methylselenophene-2-carboxylate (5.0 g, 24.6 mmol) in acetic acid (30 mL) was added selenium dioxide (10.84 g, 98.4 mmol) at rt and the mixture was refluxed for 8 h. The cooled reaction mixture was poured into ice cooled water and stirred for 15 min. The solution was extracted with chloroform (3×100 mL) and the combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using hexane-EtOAc (9:1) as eluents to give the product as pale yellow color solid (4.0 g, 75%), mp 63-65° C.; 1H NMR (400 MHz, CDCl3): δ 9.84 (1H, s, —CHO), 8.11 (1H, d, J=4.0 Hz, H-3), 7.99 (1H, d, J=4.0 Hz, H-4), 3.92 (3H, s, —COOCH3).
Reaction SMILES: [C:1]([C:4]1[C:12]2[S:11][C:10](=[O:13])[NH:9][C:8]=2[C:7]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br-:22].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C1COCC1.O>[CH2:15]([O:14][C:7]1[C:8]2[NH:9][C:10](=[O:13])[S:11][C:12]=2[C:4]([C:1](=[O:3])[CH2:2][Br:22])=[CH:5][CH:6]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(=O)sc12
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)sc12
Temperature: 80 °C
Yield: 93.3 %

Procedure:
To a solution of 7-acetyl-4-(benzyloxy)-1,3-benzothiazol-2(3H)-one (68 mg) in dry THF (3 ml) under nitrogen, was added phenyltrimethylammonium tribromide (90 mg) and the mixture heated at 80° C. under nitrogen for 2 h. The mixture was diluted with water, extracted with ethyl acetate, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified on a 5 g silica SPE cartridge, eluting with stepped gradient of 10% to 100% ethyl acetate-cyclohexane mixtures, to give the title compound (49 mg).
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:26][NH:25][C:8]2=[N:9][C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:12]=[C:7]2[CH:6]1[O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2].O=[CH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[C:1]([O:4][CH:5]1[CH2:26][N:25]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:8]2=[N:9][C:10]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:12]=[C:7]2[CH:6]1[O:27][C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCCCC=O
Reactant: CC(=O)OC1CNc2nc(-c3ccccc3)c(-c3ccccc3)nc2C1OC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCOC(=O)CCCCCCN1CC(OC(C)=O)C(OC(C)=O)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of rac-2,3-diphenyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine-7,8-diyl diacetate (Intermediate I) (69 mg, 0.171 mmol) in DCE (3 ml) was added ethyl 7-oxoheptanoate (88 mg, 0.513 mmol) followed by sodium triacetoxyborohydride (109 mg, 0.513 mmol). The reaction was left to stir overnight at room temperature under an atmosphere of nitrogen. To the reaction mixture was added further ethyl 7-oxoheptanoate (88 mg, 0.513 mmol) followed by sodium triacetoxyborohydride (109 mg, 0.513 mmol). The reaction mixture was left to stir at RT under an atmosphere of nitrogen for 4 days. The mixture was diluted with water and extracted with EtOAc (3×20 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The resulting crude product was purified by chromatography on silica eluting with 0-70% EtOAc/iso-hexane to afford the title compound;
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.FC(F)(F)C(O)=O.CO[CH2:16][N:17]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)[CH2:18][Si](C)(C)C>ClCCl>[F:31][C:30]([F:32])([F:33])[C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][N:17]1[CH2:18][CH:2]2[C:1](=[O:6])[CH2:5][CH2:4][CH:3]2[CH2:16]1
Reactant: O=C1C=CCC1
Reactant: COCN(Cc1cccc(C(F)(F)F)c1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCC2CN(Cc3cccc(C(F)(F)F)c3)CC12

Procedure:
Cyclopent-2-enone (3.31 g, 40.4 mmol) and trifluoroacetic acid (0.031 mL, 0.404 mmol) were combined in dichloromethane (40 mL). 1-Methoxy-N-(3-(trifluoromethyl)benzyl)-N-((trimethylsilyl)methyl)methanamine (12.33 g, 40.4 mmol) from Step B was added as a solution in 10 mL of dichloromethane dropwise via addition funnel over 45 minutes at room temperature under nitrogen. The reaction was quenched with aqueous sodium bicarbonate and extracted with 2×100 mL of dichloromethane. The organic washes were combined and washed with brine. The solvent was removed in vacuo to give 2-(3-(trifluoromethyl)benzyl)hexahydrocyclopenta[c]pyrrol-4(5H)-one: 1H NMR (300 MHz, CDCl3) δ ppm 7.54-7.34 (m, 4H), 3.66 (d, J=13.4, 1H), 3.52 (d, J=13.4, 1H), 3.04 (dd, J=1.8, 8.9, 1H), 2.91 (ddd, J=2.8, 7.4, 11.7, 1H), 2.72-2.65 (m, 1H), 2.62 (d, J=8.9, 1H), 2.52-2.23 (m, 4H), 2.15 (ddd, J=8.1, 12.9, 17.1, 1H), 1.85-1.70 (m, 1H).
Reaction SMILES: C[O-].[Na+].C(O)(=O)C.[CH:8]([NH2:10])=[NH:9].[C:11]([CH2:15][C:16](OC)=[O:17])(=O)[CH2:12][CH3:13].Cl>CO>[CH2:12]([C:11]1[N:10]=[CH:8][NH:9][C:16](=[O:17])[CH:15]=1)[CH3:13]
Reactant: CCC(=O)CC(=O)OC
Reactant: N=CN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCc1cc(=O)[nH]cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of sodium methoxide (4.19 kg, 77.6 mol) and formamidine acetate (3.0 kg, 28.8 mol) in methanol (45 L) at 5°-10° C. was added slowly a solution of methyl propionylacetate (2.5 kg, 19.2 mol) in methanol (10 L) maintaining the temperature below 20° C. throughout the addition. The resulting mixture was stirred at room temperature overnight after which time the pH was adjusted to 7 by the addition of concentrated hydrochloric acid. The reaction mixture was concentrated under reduced pressure to ca. 10 L in volume, diluted with water (10 L) and was extracted with 2-butanone (2×30 L). The combined organic extracts were concentrated under reduced pressure to ca. 2 L in volume and diluted with ethyl acetate (4 L). The desired product crystallised from the solution (2,4 kg, 70%) and was recrystallised from isopropanol to yield a product of m.p. 132°-134° C. Found: C,58.45; H,6.37; N,22.41; C6H8N2O requires: C,58.05; H,6.50; N,22.57%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].Cl.Br[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1>>[N:20]1[CH:21]=[CH:22][C:17]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=2)=[CH:18][CH:19]=1
Reactant: Brc1ccncc1
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Agent: Cl
Product: COC(=O)CCc1ccc(C#Cc2ccncc2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (94 mg, 0.50 mmol) and 4-bromopyridine hydrochloride (108 mg, 0.55 mmol) according to the general procedure IC to give 72 mg (54%) of a white solid after purification by flash chromatography (SiO2, EtOAc:PE, 1:5). Rf=0.26 (EtOAc:PE, 1:1); 1H NMR (CDCl3) δ 8.52 (dd, J=4.5, 1.5 Hz, 2H), 7.45-7.39 (m, 2H), 7.29 (dd, J=4.5, 1.6 Hz, 2H), 7.14 (d, J=8.3 Hz, 2H), 3.60 (s, 3H), 2.90 (t, J=7.7 Hz, 2H), 2.57 (t, J=7.7 Hz, 2H); 13C NMR (CDCl3) δ 172.0, 148.8, 141.0, 131.0, 130.5, 127.5, 124.5, 119.0, 92.9, 85.5, 50.7, 34.3, 29.8; ESI-MS m/z 288.1 (M+Na+).