Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9]O)[CH2:4]1)[CH3:2].[BrH:11]>>[Br:11][CH2:9][CH:5]1[CH2:6][CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[CH2:4]1
Reactant: CCN1CCCC(CO)C1
Reactant: Br
Product: CCN1CCCC(CBr)C1

Procedure:
A mixture of 5.0 g. (0.0349 mol.) of N-ethyl-3-hydroxymethylpiperidine and 52 ml. of 48% hydrogen bromide was refluxed for six hours then cooled and evaporated to dryness. The residue was made basic by addition of 5% aqueous sodium carbonate and extracted with methylene chloride. The methylene chloride solution was dried (MgSO4) and evaporated to dryness to give 3-bromomethyl-N-ethylpiperidine.
Reaction SMILES: [CH3:1][N:2]([CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=2)=[CH:23][CH:22]=1)=[O:19].C(NC(C)C)(C)C>>[F:36][C:34]([F:35])([F:37])[C:31]1[CH:32]=[CH:33][C:28]([O:27][C:24]2[CH:25]=[CH:26][C:21]([O:20][C:18]([N:14]3[CH2:15][CH2:16][CH:11]([N:2]([CH3:1])[CH2:3][CH2:4][C:5]4[CH:6]=[CH:7][N:8]=[CH:9][CH:10]=4)[CH2:12][CH2:13]3)=[O:19])=[CH:22][CH:23]=2)=[N:29][CH:30]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CN(CCc1ccncc1)C1CCNCC1
Solvent: CC(C)NC(C)C
Product: CN(CCc1ccncc1)C1CCN(C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)CC1

Procedure:
The title product was prepared from methyl-piperidine-4-yl-(2-pyridin-4-yl-ethyl)-amine and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, 3 equivalent of diisopropylamine was added, preparative HPLC (method C) (15%, colourless oil). HPLC-MS m/z=501.4 (M+1), Rt: 2.04 min.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:23])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:24](O)=[O:25])[CH:4]=[N:3]1.[NH:27]1[CH2:30][CH2:29][CH2:28]1.CCCP(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[N:18]1([C:16]2[N:17]=[C:11]3[CH:10]=[C:9]([NH:8][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[CH:4][C:5]=4[C:24]([N:27]4[CH2:30][CH2:29][CH2:28]4)=[O:25])=[O:23])[CH:14]=[CH:13][N:12]3[N:15]=2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(N3CCCC3)nc2c1
Reactant: C1CNC1
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(N3CCCC3)nc2c1
Reaction time: 18 h
Yield: 81.7 %

Procedure:
A mixture of 1-methyl-5-(2-(pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (150 mg, 422 μmol), azetidine (85.4 μl, 1.27 mmol), propylphosphonic anhydride (50% in ethyl acetate, 622 μl, 1.06 mmol) and N,N-diisopropylethylamine (287 μl, 1.69 mmol) in tetrahydrofuran (6 ml) was stirred for 18 hours at 70°. The solvent was evaporated, the residue was triturated with sodium hydrogencarbonate solution. The precipitated solid was filtered off, washed with water and dried affording 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid (2-pyrrolidin-1-yl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-amide (136 mg, 81.7%) as a light brown solid. mp: >250° C., MS: m/z=395.4 (M+H+).
Reaction SMILES: [F:1][C@@H:2]([CH3:24])[CH2:3][N:4]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[OH:23])[CH2:19][CH2:18][CH2:17]2)[S:5]([C:8]1[S:9][CH:10]=[C:11]([CH3:13])[N:12]=1)(=[O:7])=[O:6].C(P(CCCC)CCCC)CCC.O[CH2:39][C:40]1[CH:41]=[CH:42][C:43]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[N:44][CH:45]=1.N(/C(N1CCCCC1)=O)=N\C(N1CCCCC1)=O>C1COCC1>[F:1][C@@H:2]([CH3:24])[CH2:3][N:4]([S:5]([C:8]1[S:9][CH:10]=[C:11]([CH3:13])[N:12]=1)(=[O:7])=[O:6])[C:14]1[CH:15]=[C:16]2[C:20]([CH2:19][CH2:18][CH2:17]2)=[CH:21][C:22]=1[O:23][CH2:39][C:40]1[CH:41]=[CH:42][C:43]([C:46]([O:48][CH2:49][CH3:50])=[O:47])=[N:44][CH:45]=1
Reactant: CCOC(=O)c1ccc(CO)cn1
Reactant: Cc1csc(S(=O)(=O)N(C[C@H](C)F)c2cc3c(cc2O)CCC3)n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(/N=N/C(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(COc2cc3c(cc2N(C[C@H](C)F)S(=O)(=O)c2nc(C)cs2)CCC3)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
133 mg of N-[(2S)-2-fluoropropyl]-N-(6-hydroxy-2,3-dihydro-1H-inden-5-yl)-4-methyl-1,3-thiazole-2-sulfonamide, 94.4 mg of tributylphosphine, and 71.5 mg of ethyl 5-(hydroxymethyl)pyridine-2-carboxylate were dissolved in 1.33 mL of THF, and 118 mg of 1,1′-[(E)-diazene-1,2-diyldicarbonyl]dipiperidine was added thereto, followed by stirring overnight at room temperature. After the insoluble materials were removed by filtration, the solvent was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20) to obtain 116 mg of ethyl 5-{[(6-{[(2S)-2-fluoropropyl][(4-methyl-1,3-thiazol-2-yl)sulfonyl]amino}-2,3-dihydro-1H-inden-5-yl)oxy]methyl}pyridine-2-carboxylate.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]([CH3:27])=[C:21]2[C:28]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[S:31](=[O:39])(=[O:38])[NH:30][N:29]=1.Br[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]>CC#N.O.C(Cl)Cl>[C:45]([O:44][C:42](=[O:43])[CH2:41][N:23]1[C:24]2[C:20](=[CH:19][C:18]([F:17])=[CH:26][CH:25]=2)[C:21]([C:28]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[S:31](=[O:38])(=[O:39])[N:30]([CH2:2][CH2:3][O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:29]=2)=[C:22]1[CH3:27])([CH3:48])([CH3:47])[CH3:46]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1[nH]c2ccc(F)cc2c1C1=NNS(=O)(=O)c2ccccc21
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: Cc1c(C2=NN(CCOc3ccccc3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
β-Bromophenetole (14 mg, 67 μmol) and K2CO3 (10 mg, 72 μmol) were added to a solution of 4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine 1,1-dioxide (20 mg, 61 μmol) in CH3CN (1 mL), and stirred overnight at 80° C. An additional amount of K2CO3 (10 mg, 72 μmol) and tert-butyl bromoacetate (14 μL, 92 μmol) was added, and the reaction mixture stirred an additional 2 h at 80° C. The reaction mixture was diluted with H2O and CH2Cl2, and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the sub-title compound, which was carried onto the next step without further purification or characterization.
Reaction SMILES: Cl[C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:16][CH:17]1[NH:21][C:20](=O)[CH2:19][CH2:18]1>>[CH2:16]([CH:17]1[N:21]([C:20]2[CH2:19][CH2:18][CH:17]([CH2:16][CH2:4][CH2:5][CH3:6])[N:21]=2)[C:20]([N:7]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[O:14][C:15]3[C:6]2=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:19][CH2:18]1)[CH2:3][CH2:2][CH3:15]
Reactant: Clc1cccc2c1Oc1ccccc1N2
Reactant: CC1CCC(=O)N1
Product: CCCCC1CCC(N2C(N3c4ccccc4Oc4ccccc43)=CCC2CCCC)=N1

Procedure:
Reaction of 4-chlorophenoxazine with 5-methyl-2-pyrrolidinone according to the procedure of Example 4 provides
Reaction SMILES: [N:1]1[NH:2][C:3](=[O:8])[NH:4][C:5](=[O:7])[CH:6]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>>[C:9]([N:2]1[C:3](=[O:8])[NH:4][C:5](=[O:7])[CH:6]=[N:1]1)(=[O:11])[CH3:10]
Reactant: O=c1cn[nH]c(=O)[nH]1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)n1ncc(=O)[nH]c1=O

Procedure:
2H-[1,2,4]Triazin-3,5-dione (100 g, 884 mmol) is placed in 600 ml of acetic anhydride at reflux for 1.5 h. The reaction mixture is subsequently concentrated to dryness and the solid obtained is triturated in toluene. After filtering and rinsing with toluene, 130.5 g of beige crystals are isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:22]([OH:24])=[O:23])[S:12][C:13]=2[C:14]2[CH:19]=[C:18](F)[CH:17]=[C:16](Cl)[CH:15]=2)[CH:5]=[CH:6][C:7]=1F.BrC1SC(C(OCC)=O)=[N:28][C:27]=1C1C=CC=C(Cl)C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:22]([OH:24])=[O:23])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:27]#[N:28])[CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc(-c2cccc(Cl)c2)c(Br)s1
Reactant: O=C(O)c1nc(-c2ccc(F)c(Cl)c2)c(-c2cc(F)cc(Cl)c2)s1
Product: N#Cc1cccc(-c2sc(C(=O)O)nc2-c2cccc(Cl)c2)c1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 8A starting with the compound from Example 5A. 556 mg of the title compound having a purity of 41% (46% of theory) are obtained.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[C:17]3[CH:16]=[C:15]4[CH2:18][CH2:19][CH2:20][C:21](=[O:22])[C:14]4=[CH:13][C:12]=3[O:11][CH2:10][C:9]=2[CH:23]=1)=[O:4].[C:24]([O:28][C:29]([N:31]1[CH2:35][C@@H:34]([CH2:36][O:37][CH3:38])[CH2:33][C@H:32]1[C:39]([OH:41])=[O:40])=[O:30])([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)Cl>[CH3:38][O:37][CH2:36][C@@H:34]1[CH2:35][N:31]([C:29]([O:28][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:30])[CH:32]([C:39]([O:41][CH2:2][C:3](=[O:4])[C:5]2[CH:6]=[CH:7][C:8]3[C:17]4[CH:16]=[C:15]5[CH2:18][CH2:19][CH2:20][C:21](=[O:22])[C:14]5=[CH:13][C:12]=4[O:11][CH2:10][C:9]=3[CH:23]=2)=[O:40])[CH2:33]1
Reactant: COC[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(CBr)c1ccc2c(c1)COc1cc3c(cc1-2)CCCC3=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: COC[C@H]1CC(C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCCC4=O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
3-(2-Bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (7.47 g, 20.1 mmol) and (2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)pyrrolidine-2-carboxylic acid (5.22 g, 20.1 mmol) were suspended in 2-Me-THF (75 mL) and treated with Cs2CO3 (3.27 g, 10.1 mmol). After stirring 4 h at RT, the reaction mixture was diluted with diluted with DCM. The organic layer was washed with H2O. The aqueous layer was then back extracted 2× with DCM. The combined organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (10% to 50% EtOAc/DCM) to afford (4S)-1-tert-butyl 2-(2-oxo-2-(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)ethyl) 4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (7.73 g, 70%).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].Cl[S:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[C:29]([OH:36])[CH:28]=1)(=[O:26])=[O:25]>>[CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][S:24]([C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[C:29]([OH:36])[CH:28]=2)(=[O:26])=[O:25])=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1CCc1ccc(O)cc1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Product: CCCCc1oc2ccccc2c1CCc1ccc(OS(=O)(=O)c2ccc(C(=O)O)c(O)c2)cc1
Yield: 84.9 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using 4-[2-(2-butyl-benzofuran-3-yl)-ethyl]-phenol (0.410 g, 1.36 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.644 g, 2.72 mmol). Purification on 2% H3PO4/MeOH treated silica gel, eluting with EtOAc/hexane gave 0.571 g (85%) of the title compound as a light brown solid, mp 93-95° C. 1H NMR consistent. mass spectrum (−ESI) m/z 493 (M−H).
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:18]=[C:17](C(C)(C)C2C=CC=CC=2)[CH:16]=[C:12]([C:13]([OH:15])=[O:14])[C:11]=1[OH:28])(C)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(C2C=C(C(C)(C)C3C=CC=CC=3)C=[C:37]([C:38]([OH:40])=[O:39])[C:36]=2O)CCCCC1.C1(C2C=C(C(C)(C)C3C=CC(C(C)(C)C4C=CC=CC=4)=CC=3)C=C(C(O)=[O:64])C=2O)C=CC=CC=1.C1(C2C=C(C(C)(C)C3C=CC=CC=3)C=C(C(O)=O)C=2O)C=CC=CC=1>>[OH:64][C:1]1[C:37]([C:38]([OH:40])=[O:39])=[CH:36][C:8]2[C:3]([C:2]=1[C:10]1[CH:18]=[CH:17][CH:16]=[C:12]([C:13]([OH:15])=[O:14])[C:11]=1[OH:28])=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: CC(C)(c1ccccc1)c1ccc(C(C)(C)c2cc(C(=O)O)c(O)c(-c3ccccc3)c2)cc1
Reactant: CC(C)(c1ccccc1)c1cc(C(=O)O)c(O)c(C(C)(C)c2ccccc2)c1
Reactant: CC(C)(c1ccccc1)c1cc(C(=O)O)c(O)c(C2CCCCC2)c1
Agent: CC(C)(c1ccccc1)c1cc(C(=O)O)c(O)c(-c2ccccc2)c1
Product: O=C(O)c1cccc(-c2c(O)c(C(=O)O)cc3ccccc23)c1O

Procedure:
Of the above compounds, 3,5-di(α,α-dimethylbenzyl)salicylic acid, 3-[4'(α,α-dimethylbenzyl)-phenyl-5-(α,α-dimethylbenzyl)salicylic acid, 3-cyclohexyl-5-(α,α-dimethylbenzyl)salicylic acid, 3-phenyl-5-[4'-(α,α-dimethylbenzyl)-α,α-dimethylbenzyl]salicylic acid, and 3-phenyl-5-(α,α-dimethylbenzyl)salicylic acid are said to be most preferred.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH3:19])[C:11]3[N:12]([C:14]([C:17]#[CH:18])=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[N:26]=[CH:25][C:24](I)=[CH:23][N:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH3:19])[C:11]3[N:12]([C:14]([C:17]#[C:18][C:24]4[CH:23]=[N:22][C:21]([NH2:20])=[N:26][CH:25]=4)=[CH:15][N:16]=3)[CH:13]=2)=[CH:6][CH:7]=1
Reactant: C#Cc1cnc2c(C)cc(-c3ccc(Cl)cc3)cn12
Reactant: Nc1ncc(I)cn1
Product: Cc1cc(-c2ccc(Cl)cc2)cn2c(C#Cc3cnc(N)nc3)cnc12

Procedure:
The title compound was prepared from 6-(4-chloro-phenyl)-3-ethynyl-8-methyl-imidazo[1,2-a]pyridine (example C.21) (267 mg, 1 mmol) and commercially available 2-amino-5-iodopyrimidine (221 mg, 1 mmol) according to general procedure II. Obtained as an off-white solid (60 mg, 17%). MS (ISP) 360.1 [(M+H)+], 362 [(M+2+H)+]; mp 263° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]([C@H:11]1[N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14][N:13]2[C:24]3[CH:30]=[C:29]([S:31]([CH3:34])(=[O:33])=[O:32])[C:28]([C:35]([O:37][CH3:38])=[O:36])=[CH:27][C:25]=3[N:26]=[C:12]12)([CH3:10])[CH3:9]>C(Cl)Cl>[CH:8]([C@H:11]1[NH:16][CH2:15][CH2:14][N:13]2[C:24]3[CH:30]=[C:29]([S:31]([CH3:34])(=[O:33])=[O:32])[C:28]([C:35]([O:37][CH3:38])=[O:36])=[CH:27][C:25]=3[N:26]=[C:12]12)([CH3:10])[CH3:9]
Reactant: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(C(=O)OC(C)(C)C)[C@@H]3C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN[C@@H]3C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
TFA (4 mL) was added dropwise to a solution of containing (R)-2-tert-butyl 8-methyl 1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2,8(1H)-dicarboxylate (2.0 g, 4.4 mmol) in DCM (20 mL) at rt over 2 min. The mixture was stirred at rt for 3 h. TLC showed the starting material was consumed completely. The solvent was removed in vacuo at 30° C., and then DCM (10 mL) was added. The mixture was neutralized with sat. aq. NaHCO3 to pH=7. The mixture was extracted with DCM (3×20 mL) and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum to afford (R)-methyl 1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (1.5 g, 96.4% yield) as a white solid. LC-MS m/z 351.9 [M+H]+, 374.0 [M+Na]+. 1H NMR (CDCl3 300 MHz): δ 8.15 (s, 1H), 8.07 (s, 1H), 4.26-4.05 (m, 3H), 3.97 (s, 3H), 3.63-3.50 (m, 1H), 3.44 (s, 3H), 3.32-3.16 (m, 1H), 2.85-2.66 (m, 1H), 1.16 (d, J=6.9 Hz, 3H), 0.88 (d, J=6.6 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([CH2:28]OS(C)(=O)=O)[CH:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1.[N-:36]=[N+:37]=[N-:38].[Na+]>CS(C)=O.C(Cl)Cl.O>[F:35][C:2]([F:34])([F:1])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([CH2:28][N:36]=[N+:37]=[N-:38])[CH:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)OCc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ccn1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NCc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ccn1
Temperature: 80 °C

Procedure:
A mixture of methanesulfonic acid 4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]pyridine-2-ylmethyl ester (505 mg, 1.03 mmol) and sodium azide (201 mg, 3.12 mmol) in DMSO (5 mL) is heated at 80° C. for 2 h. The mixture is then diluted with DCM (100 mL) and water. The organic layer is washed further with brine and then dried over anhydrous Na2SO4. Following concentration the residue is separated via FCC (20-90% EtOAc/heptane) to give the title compound. MS (ESI) m/z 453.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][C@@H:24]2[CH2:26][C@H:21]1[CH2:22][NH:23]2)=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18]([N:20]1[CH2:25][C@@H:24]2[CH2:26][C@H:21]1[CH2:22][N:23]2[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([Cl:1])[N:11]=1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: Clc1nc(Cl)c2ccccc2n1
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1nc(Cl)nc2ccccc12
Temperature: 60 °C

Procedure:
To a solution of 2,4-dichloro-quinazoline (0.25 g, 1.26 mmol) in isoprapanol (6 mL) were added t-butyl-(1S,4S)-(−)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.25 g, 1.26 mmol) and the solution was heated at 60° C. for 4 h. The reaction was concentrated in vacuo and the residue was chromatographed over silica with 25:10:65, 35:10:55, and 50:10:40 EtOAc-CH2Cl2-Hexane; 1%, 3%, and 5% MeOH/CH2Cl2 to give the title compound. MS (ES+): 361.1 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]2[N:5]=[CH:6][N:7]([C:17]=2[N:18]=[CH:19][N:20]=1)[C@@H:8]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[C@H:9]1[OH:10].ClC1C=CC=C(C(OO)=[O:29])C=1.O>C(O)(=O)C>[CH3:1][NH:2][C:3]1[N+:20]([O-:29])=[CH:19][N:18]=[C:17]2[C:4]=1[N:5]=[CH:6][N:7]2[C@@H:8]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[C@H:9]1[OH:10]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CNc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: O
Solvent: CC(=O)O
Product: CNc1c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2nc[n+]1[O-]
Yield: 45 %

Procedure:
A solution of N6 -methyladenosine (2 g, 6.7 mmol) and m-chloroperbenzoic acid (2.3 g, 13.4 mmol) in acetic acid (20 ml) was stirred at room temperature for two days. Water (20 ml) was added to the reaction mixture, and a resulting thick precipitate was removed by filtration and discarded. The filtrate was co-evaporated repeatedly with water under high vacuum, and the foamy residue was chromatographed on a silica gel column (CHCl3 : MeOH 2:1). The product was obtained as a white solid (mp 145° C., crystallization from EtOH) in 45% yield (0.9 g). 1H NMR (DMSO)d: 8.62 (s, H-2), 8.55 (s, H-8), 5.88 (d, J=5.4 Hz, 1H, H-1), 4.51 (`t`, J=5.1 Hz, 1H, H-2'), 4.15 (`t`, J=4.5 Hz, 1H, H-3'), 3.94 (ABq, 1H, H-4'), 3.61 (ABdq, J=12, 4 Hz, 2H, H-5'), 3.46 (s, 3H, Me) ppm. MS (CI) m/e: 298 (MH+).
Reaction SMILES: [CH2:1]([CH:3]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:4][O:5][C:6](=[O:12])/[CH:7]=[CH:8]\[C:9]([O-:11])=[O:10])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:18]>>[Cl-:18].[CH2:1]([CH:3]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:4][O:5][C:6](=[O:12])/[CH:7]=[CH:8]\[C:9]([OH:11])=[O:10])[CH3:2]
Reactant: CCCCC(CC)COC(=O)/C=C\C(=O)[O-]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: CCCCC(CC)COC(=O)/C=C\C(=O)O
Product: [Cl-]
Temperature: 60 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A 4.1 g (20 mmol) quantity of mono(2-ethylhexyl)maleate manufactured by Aldrich Co. was slowly added dropwise to 4.1 g (20 mmol) of phosphorus pentachloride while maintaining a temperature not greater than 30° C. When the dropwise addition had been completed, stirring was conducted for 1 hr at room temperature. Subsequently, the mixture was heated to 60° C., the pressure was reduced with an aspirator, and the phosphorus oxychloride was distilled off, yielding 4.5 g (yield of 92 percent) of maleic acid mono(2-ethylhexyl)ester monochloride in the form of a tea-colored oily product.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([F:18])[CH:24]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4cccc(F)c4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, white solid (73 mg, 89%), MS (ISP) m/z=329.5 [(M+H)+], mp 239° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 3-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19][CH3:20])[CH2:14][CH2:13]2)[C:3]=1[C:4]#[N:5].[C:22]([O:28][CH2:29][CH3:30])(=[O:27])[CH2:23][C:24]([CH3:26])=O>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19][CH3:20])[CH2:14][CH2:13]2)[N:1]=[C:24]([CH3:26])[C:23]=1[C:22]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCC(=O)N1CCC(COc2cccc(N)c2C#N)CC1
Product: CCOC(=O)c1c(C)nc2cccc(OCC3CCN(C(=O)CC)CC3)c2c1N

Procedure:
Prepared as in Example Ba from 2-amino-6-((1-propionylpiperidin-4-yl)methoxy)benzonitrile (Example 21b) and ethyl acetoacetate as an off-white solid (41%). MS 400 (MH+).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[C@@H:10]([NH:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:9][CH:8]=[CH:7][CH2:6]1)=[O:4].[OH-].[Na+]>CO.O>[CH2:15]([O:14][C:12]([NH:11][C@@H:10]1[C@H:5]([C:3]([OH:4])=[O:2])[CH2:6][CH:7]=[CH:8][CH2:9]1)=[O:13])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)[C@@H]1CC=CC[C@@H]1NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(N[C@H]1CC=CC[C@H]1C(=O)O)OCc1ccccc1
Reaction time: 3 h
Yield: 83.6 %

Procedure:
Preparation A1, Step 2: A sample of (1R,6S)-6-benzyloxycarbonylamino-cyclohex-3-enecarboxylic acid methyl ester (91.4 g) was dissolved in MeOH (500 mL) prior to the dropwise addition of NaOH (25.3 g) in water (95 mL). After 3 h, the solution was partially concentrated and an Et2O/water mixture was added. The aqueous layer was separated and was acidified (pH ˜2) with concentrated HCl. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and brine before they were dried, filtered, and concentrated to give (1R,6S)-6-benzyloxycarbonylamino-cyclohex-3-enecarboxylic acid (72.7 g). MS found: (M+H)+=276.2.
Reaction SMILES: [N:1]([C:4]1[C:12]([CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:11]([O:23][CH3:24])[C:10]([CH3:25])=[C:9]2[C:5]=1[C:6](=[O:26])[O:7][CH2:8]2)=[C:2]=[O:3].[CH3:27][OH:28]>>[CH3:27][O:28][C:2]([NH:1][C:4]1[C:12]([CH2:13]/[CH:14]=[C:15](\[CH3:22])/[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:11]([O:23][CH3:24])[C:10]([CH3:25])=[C:9]2[C:5]=1[C:6](=[O:26])[O:7][CH2:8]2)=[O:3]
Reactant: CO
Reactant: COC(=O)CC/C(C)=C/Cc1c(N=C=O)c2c(c(C)c1OC)COC2=O
Product: COC(=O)CC/C(C)=C/Cc1c(NC(=O)OC)c2c(c(C)c1OC)COC2=O

Procedure:
A solution of methyl (E)-6-(1,3-dihydro-4-isocyanato-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate (1.0 g) in 10 ml methanol was heated to reflux for 4 hours and then evaporated to dryness. The residue was recrystallized from acetone/hexane to give 0.41 g of methyl (E)-6-(1,3-dihydro-4-methoxycarbonylamino-6-methoxy-7-methyl-3- oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate. The ester (0.35g) and 0.05 g of LiOH-H2O in 9 ml 2:1 MeoH-H2O was heated at reflux for 4hours. The mixture was acidified, extracted with ethyl acetate, and the organic layer was dried over MgSO4. The organic layer was concentrated and the residue was further purified by silica gel chromatography (eluant 60:40:2 hexaneethyl acetate:acetic acid) to give 0.21 g of (E)-6-(1,3-dihydro-4- methoxycarbonylamino-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl. 4-hexenoic acid, mp 155°-158° C.