Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[C:14]([O-])([O-])=O.[K+].[K+]>O1CCOCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:10]([C:9]1[CH:12]=[CH:13][C:6]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:7][CH:8]=1)=[CH2:14]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(-n2cncn2)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Product: C=Cc1ccc(-n2cncn2)cc1
Temperature: 70 °C
Yield: 62.9 %

Procedure:
To a stirred solution of 4-[1,2,4]triazol-1-yl-benzaldehyde (9.0 g, 52 mmol) in 1,4-dioxane (100 mL), were added K2CO3 (10.76 g, 78 mmol) and methyl triphenyl phosphonium bromide (22.2 g, 62.4 mmol) at room temperature. The resultant reaction mixture was heated to 70° C. for 18 h. After completion of the reaction (TLC), the reaction mixture was cooled to room temperature and filtered and the obtained filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 25-30% EtOAc in petroleum ether) to afforded the title compound as a white solid (5.6 g, 63%): ESIMS m/z 172.09 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]3[CH2:16][C@H:15]3[NH:17]C(=O)OC(C)(C)C)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]3[CH2:16][C@H:15]3[NH2:17])=[CH:10][CH:9]=2)=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(OCc2ccc(Br)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N[C@@H]1C[C@H]1c1ccc(OCc2ccc(Br)cc2)cc1
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a solution of tert-butyl(trans)-2-(4-(4-bromobenzyloxy)phenyl)cyclopropylcarbamate (11 g, 26.37 mmol) in dioxane (110 mL) at 0° C., HCl in Dioxane (110 mL) was added and stirred for 1 h. After completion, the solvent was evaporated and residue was triturated with Et2O (15 mL) to give crude salt. The crude salt was dissolved in water (150 mL), basified with Na2CO3 solution, extracted with EtOAc (3×100 mL). The combined extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4, filtered and evaporated to get (8.2 g, 98%) (trans)-2-(4-(4-bromobenzyloxy)phenyl)cyclopropanamine
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:19]=[C:18]([CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[C:17](=[O:27])[C:8]4[CH:9]=[C:10]([OH:16])[CH:11]=[C:12]([S:13][C:14]=2[CH:15]=1)[C:7]3=4.Br[CH2:29][CH2:30][CH2:31][OH:32]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:19]=[C:18]([CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[C:17](=[O:27])[C:8]4[CH:9]=[C:10]([O:16][CH2:29][CH2:30][CH2:31][OH:32])[CH:11]=[C:12]([S:13][C:14]=2[CH:15]=1)[C:7]3=4
Reactant: OCCCBr
Reactant: O=c1c(Cc2cccnc2)cn2c3c(cc(O)cc13)Sc1cc(Br)ccc1-2
Product: O=c1c(Cc2cccnc2)cn2c3c(cc(OCCCO)cc13)Sc1cc(Br)ccc1-2
Yield: 53 %

Procedure:
According to Example 34, the compound (120 mg) produced in Example 54 was reacted with 3-bromopropanol (0.04 mL) to obtain the title compound (72 mg; 53%).
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[CH:13]=[CH:12][C:11]2[N:10]3[CH:14]=[CH:15][CH:16]=[C:9]3[C:8](=O)[C:7]=2[CH:6]=1>N1C=CC=CC=1>[Cl:4][C:5]1[CH:13]=[CH:12][C:11]2[N:10]3[CH:14]=[CH:15][CH:16]=[C:9]3[C:8](=[N:2][OH:3])[C:7]=2[CH:6]=1
Reactant: O=C1c2cc(Cl)ccc2-n2cccc21
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: ON=C1c2cc(Cl)ccc2-n2cccc21
Yield: 84.6 %

Procedure:
Add 3.9 g (56.1 mmol) of hydroxylamine hydrochloride to a solution of 4.6 g (22.6 mmol) of 7-chloropyrrolo[1,2-a]indol-9-one in 80 ml of pyridine, then heat the reaction mixture at reflux for 3 hours. After cooling, the pyridine is removed under reduced pressure and the residue is taken up in water and extracted with 300 ml of diethyl ether. The ethereal phase is washed with 100 ml of 0.5N hydrochloric acid and then with water, dried over magnesium sulfate, rendered colourless with animal charcoal and then concentrated under reduced pressure to yield 4.18 g of the title product.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15](I)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CCN(CC)CC.[CH3:40][Si:41]([C:44]#[CH:45])([CH3:43])[CH3:42]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.[Cu]I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15]([C:45]#[C:44][Si:41]([CH3:43])([CH3:42])[CH3:40])[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCc1cccc(-c2nc(C#C[Si](C)(C)C)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 0.55 g (1.00 mmol) of [2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 2), 0.057 g (0.3 mmol) of copper(I) iodide, 0.117 g (0.1 mmol) of tetrakis-(triphenylphosphine)-palladium and 1.134 g (3.00 mmol) of tetrabutylammoniumiodide in 10 ml of DMF were added 2.027 ml=1.471 g (14.5 mmol) of Et3N. After stirring at RT for 30 min, 0.57 ml=0.394 g (4.0 mmol) of trimethylsilylacetylene were added and the reaction was heated up to 70° C. for 1 hour and subsequently cooled down to RT. The reaction mixture was then poured into crashed ice and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 9:1) to give 0.52 (100%) of the title compound as brown oil. MS: 519.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][NH:9][C:10]([NH:12][CH2:13][CH3:14])=[S:11])=O)=[CH:4][CH:3]=1.[OH-].[Na+]>O.C(O)(=O)C>[NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]2[N:12]([CH2:13][CH3:14])[C:10](=[S:11])[NH:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CCNC(=S)NNC(=O)c1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCn1c(-c2ccc(N)cc2)n[nH]c1=S
Temperature: 24 °C
Yield: 82.1 %

Procedure:
A mixture of 3.0 g (12.6 mmol) of 1-(4-aminobenzoyl)-4-ethylthiosemicarbazide and 4.8 mL of 2N sodium hydroxide in 38 mL of water was heated at reflux for 2 hours. The reaction mixture was cooled to 24° C. and diluted with glacial acetic acid to pH=3. The precipitate which formed was collected by filtration and washed with ethyl acetate:methanol (1:1 v/v) to provide 2.28 g (82%) of 5-(4-aminophenyl)-4-ethyl-2,4-dihydro-[1,2,4]triazol-3-thione, mp 240°-250° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[C:12](=[O:16])[NH:13][CH:14]=[N:15][C:6]=3[C:5]([CH2:21][CH2:22][CH:23]3[CH2:25][CH2:24]3)([C:17]([F:20])([F:19])[F:18])[C:4]=2[CH:3]=1.[CH3:26][N:27]1C(=O)CCC1>[C-]#N.[C-]#N.[Zn+2].[Zn]>[C:26]([C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[C:12](=[O:16])[NH:13][CH:14]=[N:15][C:6]=3[C:5]([CH2:21][CH2:22][CH:23]3[CH2:24][CH2:25]3)([C:17]([F:18])([F:20])[F:19])[C:4]=2[CH:3]=1)#[N:27]
Reactant: CN1CCCC1=O
Reactant: O=c1[nH]cnc2c1Nc1ccc(Cl)cc1C2(CCC1CC1)C(F)(F)F
Agent: [C-]#N
Agent: [Zn+2]
Agent: [Zn]
Product: N#Cc1ccc2c(c1)C(CCC1CC1)(C(F)(F)F)c1nc[nH]c(=O)c1N2
Temperature: 170 °C
Yield: 46 %

Procedure:
A mixture of 17 (110 mg, 0.297 mmol), Zn(CN)2 (71 mg, 0.594 mmol, 2 equiv), [(t-Bu)3P]2 Pd (0.78 g, 0.149 mmol, 0.5 equiv) and Zn powder (29 mg, 0.446 mmol, 1.5 eq) were suspended in anhydrous NMP and degassed. The reaction mixture was heated to 170° C. for 30 h. After cooling to 25° C., the reaction was quenched with 2 N NH4OH (20 mL) and extracted with EtOAc (2×25 mL). The combined organic phases were washed with brine, dried (MgSO4) and concentrated. Chromatography (SiO2, 50 to 60% EtOAc-hexane) afforded the desired product as an off-white solid (49 mg, 46%). mp >280° C. ESI HRMS m/z 361.1293 (M++H, C18H16F3N4O requires 361.1276).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:40]=[CH:39][C:12]([CH2:13][N:14]([CH2:35][CH2:36][CH2:37][CH3:38])[C:15](=[O:34])[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([O:31][CH2:32][CH3:33])[C:26]([O:28]CC)=[O:27])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>C(#N)C.O.[OH-].[K+]>[CH2:1]([O:8][C:9]1[CH:40]=[CH:39][C:12]([CH2:13][N:14]([CH2:35][CH2:36][CH2:37][CH3:38])[C:15](=[O:34])[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([O:31][CH2:32][CH3:33])[C:26]([OH:28])=[O:27])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCN(Cc1ccc(OCc2ccccc2)cc1)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Agent: [K+]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CCCCN(Cc1ccc(OCc2ccccc2)cc1)C(=O)COc1ccc(C[C@H](OCC)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
To a solution of ethyl(2S)-3-(4-{2-[[4-(benzyloxy)benzyl](butyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate (0.116 g, 0.21 mmol) in acetonitrile (10 mL) was added aqueous 0.10 M LiOH (5 mL) and the reaction mixture was stirred at room temperature overnight. The solvent volume was reduced in vacuo and the remaining aqueous phase was diluted with water and aqueous 1 M KOH and washed with diethyl ether (2×50 mL). The aqueous phase was acidified with 5% HCl and extracted with ethyl acetate (3×50 mL). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo to afford 0.070 g (63%) of a colourless oil.
Reaction SMILES: C(O)(=O)CCC(O)=O.[F:9][C:10]([F:37])([F:36])[C:11]1[N:12]=[C:13]([CH:23]2[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]2)[N:14]([CH2:16][CH2:17][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:15]=1.Cl>CO>[F:37][C:10]([F:9])([F:36])[C:11]1[N:12]=[C:13]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[N:14]([CH2:16][CH2:17][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C(F)(F)F)cn2CCN2CCCC2)CC1
Agent: Cl
Agent: O=C(O)CCC(=O)O
Solvent: CO
Product: FC(F)(F)c1cn(CCN2CCCC2)c(C2CCNCC2)n1
Temperature: 50 °C
Yield: 95.8 %

Procedure:
Add tert-butyl 4-(4-(trifluoromethyl)-1-(2-pyrrolidin-1-ylethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate succinate (120 g, 224.48 mmol) in methanol (720 mL) to 37% aqueous hydrogen chloride (76.08 mL, 4 eq) at room temperature. Stir the solution at 50° C. Concentrate the reaction mixture. Add 500 mL water and wash with methyl tert-butyl ether (200 mL). Basify the aqueous solution with 6M aqueous sodium hydroxide at 0° C. Extract with ethyl acetate (4×200 mL). Dry the organics over anhydrous sodium sulfate and concentrate in vacuo to give the title compound (68 g, 96%). MS (ES) m/z=317 [M]+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:9]1([CH3:14])[O:13][CH2:12][CH2:11][O:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:15]1([C:21]2[C:22]([O:24][C:25](=O)[CH:26]=2)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[O:23]=[C:22]1[C:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:26][C:25](=[O:24])[N:1]1[CH2:2][CH:3]([C:9]1([CH3:14])[O:10][CH2:11][CH2:12][O:13]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(CN)C1(C)OCCO1
Reactant: O=C1C=C(c2ccccc2)C(=O)O1
Product: CCOC(=O)C(CN1C(=O)C=C(c2ccccc2)C1=O)C1(C)OCCO1

Procedure:
Ethyl 3-(2,5-dioxo-3-phenyl-2,5-dihydro-pyrrol-1-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.41 g, 58%) in the same manner as described in the above example 5 (20) from ethyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.40 g, 1.96 mmol) and phenylmaleic anhydride (0.57 g, 2.16 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: [B:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([F:13])[CH:5]=1)([OH:3])[OH:2].[F:14][CH:15]([F:24])[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH2:17].CCN(C(C)C)C(C)C.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CN(C=O)C>[F:14][CH:15]([F:24])[CH:16]([NH:17][C:8]([C:7]1[CH:11]=[CH:12][C:4]([B:1]([OH:2])[OH:3])=[CH:5][C:6]=1[F:13])=[O:10])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1F
Reactant: NC(c1ccccc1)C(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(NC(c1ccccc1)C(F)F)c1ccc(B(O)O)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-borono-2-fluorobenzoic acid (200 mg, 1.087 mmol), 2,2-difluoro-1-phenylethanamine (232 mg, 1.196 mmol), and DIEA (0.570 mL, 3.26 mmol) in THF (3.866 mL) and DMF (0.483 mL) was added HOAt (296 mg, 2.175 mmol) and EDC (521 mg, 2.72 mmol). After 3 h stirring at room temperature, 10% citric acid solution was added (pH ˜3) and extracted with 2-methyl THF and EtOAc (1:1). The organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The crude 4-(2,2-difluoro-1-phenylethylcarbamoyl)-3-fluorophenylboronic acid was obtained (90%) and used for the next step without purification. LCMS (m/z): 375.3 (MH+), 0.48 min.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][CH:17]=[C:16]4[CH3:22])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:42][C@@H:43]2[O:45][CH2:44]2)(=O)=O)=CC=1>CN(C=O)C>[CH3:24][O:23][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:42][C@H:43]1[CH2:44][O:45]1)[N:9]=[CH:8][N:7]=[C:6]2[O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH3:22]
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1O
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H]1CO1
Temperature: 60 °C
Reaction time: 2 h
Yield: 53.1 %

Procedure:
A mixture of 7-hydroxy-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (1.35 g, 4.2 mmol), (prepared as described for the starting material in Example 271), potassium carbonate (1.74 g, 12.6 mmol) and (2R)-(−)-glycidyl tosylate (1.92 g, 8.4 mmol) in DMF (25 ml) was stirred at 60° C. for 2 hours and allowed to cool to ambient temperature. The reaction mixture was filtered and the solvent removed in vacuo. The residue was dissolved in dichloromethane and washed with saturated sodium hydrogen carbonate solution. The organic layer was then dried (MgSO4), filtered and solvent removed in vacuo to give a solid. This was triturated with ether and the solid filtered off and dried to give (2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline (842 mg, 53%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[C:23]([CH2:28][C:29]([NH2:31])=[O:30])=[N:24][CH:25]=[CH:26][N:27]=4)[C:17]([C:32]([F:35])([F:34])[F:33])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C=O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:38][N:1]1[CH2:2][CH2:3][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([CH2:20][CH2:21][C:22]4[C:23]([CH2:28][C:29]([NH2:31])=[O:30])=[N:24][CH:25]=[CH:26][N:27]=4)[C:17]([C:32]([F:33])([F:35])[F:34])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NC(=O)Cc1nccnc1CCc1nc(Nc2ccc(C3CCNCC3)cc2)ncc1C(F)(F)F
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4nccnc4CC(N)=O)n3)cc2)CC1
Reaction time: 3 h
Yield: 78.2 %

Procedure:
2-(3-(2-(2-((4-(Piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)pyrazin-2-yl)acetamide (26) (42 mg, 0.087 mmol) was dissolved in methanol (4 mL) and 37% formaldehyde (26 μL, 0.35 mmol) was added. After five minutes sodium tri(acetoxy)borohydride (92 mg, 0.44 mmol) was added and the mixture stirred for three hours. The solution was concentrated, and the residue suspended in 10% sodium hydroxide (1 mL). After five minutes brine (2 mL) was added, and the mixture extracted with ethyl acetate (5×3 mL). The combined ethyl acetate phases were washed with brine, dried (sodium sulphate) and evaporated to give the title compound (27) (34 mg, 77% yield) as an off-white solid; 1H NMR (400 MHz, dr DMSO) δ 10.07 (s, 1H), 8.64 (s, 1H), 8.42 (d, J=2.6 Hz, 1H), 8.38 (d, J=2.6 Hz, 1H), 7.61 (s, 1H), 7.55 (d, J=7.3 Hz, 2H), 7.15 (d, J=8.5 Hz, 2H), 7.08 (s, 1H), 4.09 (d, J=4.7 Hz, 1H), 3.77 (s, 2H), 3.17 (d, J=4.3 Hz, 2H), 3.05-2.92 (m, 2H), 2.33 (s, 3H), 2.20 (s, 2H), 1.82-1.61 (m, 4H). LCMS Method C: rt 4.53 min; m/z 500.1 [M+H]+; m/z 498.2 [M−H]−.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:28])[N:5]([C:9]([NH:11][CH:12]2[CH2:21][C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[C:18]([S:22](=[O:25])(=[O:24])[NH2:23])[CH:19]=3)[O:14][CH2:13]2)=[O:10])[CH2:6][C:7]=1[CH3:8])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:35][N:36]=[C:37]=[S:38]>CS(C)=O>[CH2:1]([C:3]1[C:4](=[O:28])[N:5]([C:9]([NH:11][CH:12]2[CH2:21][C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[C:18]([S:22]([NH:23][C:37]([NH:36][CH3:35])=[S:38])(=[O:24])=[O:25])[CH:19]=3)[O:14][CH2:13]2)=[O:10])[CH2:6][C:7]=1[CH3:8])[CH3:2]
Reactant: CN=C=S
Reactant: CCC1=C(C)CN(C(=O)NC2COc3cc(OC)c(S(N)(=O)=O)cc3C2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCC1=C(C)CN(C(=O)NC2COc3cc(OC)c(S(=O)(=O)NC(=S)NC)cc3C2)C1=O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
2.05 g (5 mmol) of 3-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)-6-sulfamoyl-7-methoxychroman, 2.07 g (15 mmol) of finely powdered potassium carbonate and 0.44 g (6 mmol) of methyl isothiocyanate were suspended or dissolved in 20 ml of DMSO. The reaction mixture was stirred at 80° C. for 1 hour. The mixture was poured onto ice-water and the product was precipitated by acidification with hydrochloric acid. After the crude product had been filtered off with suction and dried, it was purified by chromatography over silica gel (eluting agent methylene chloride/glacial acetic acid 19:1). The product had a melting point of 205° C.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[C:17]([Cl:18])[N:11]2[N:10]=[C:9]1[CH:19]=CN(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:25].[Na+]>C1COCC1>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[C:17]([Cl:18])[N:11]2[N:10]=[C:9]1[CH:19]=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=Cc1nn2c(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1nn2c(Cl)ccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 84.6 %

Procedure:
A mixture of 3-benzyl-7-chloro-2-(2-dimethylamino-vinyl)-3H-pyrrolo[2,1-f][1,2,4]-triazin-4-one (1.84 g, 5.59 mmole) and sodium periodate (6.0 g, 28 mmol) in THF (70 mL) and pH 7 buffer was stirred at rt under nitrogen for 45 min. The reaction mixture was filtered through Celite®, the filtrate was extracted with EtOAc (2×80 mL). The EtOAc solution was dried over MgSO4. Concentration and purification of the crude product by flash column chromatography (SiO2, EtOAc/hexane 1.5:8.5 to 4:1) gave the title compound as a white solid (1.36 g, 84%): 1H NMR (CDCl3) δ 9.48 (s, 1H), 7.20 (m, 5H), 7.10 (d, 1H, J=4.4 Hz), 6.60 (d, 1H, J=4.4 Hz), 5.68 (s, 2H); MS (ESI+) 288.08 (M++H).
Reaction SMILES: [C-:1]#[N:2].[K+].[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=3)=[N:14][N:13]3[C@H:23]([CH2:26]OS(C)(=O)=O)[CH2:24][CH2:25][C:12]=23)=[CH:7][CH:6]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.O.C(OCC)(=O)C>[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=3)=[N:14][N:13]3[C@H:23]([CH2:26][C:1]#[N:2])[CH2:24][CH2:25][C:12]=23)=[CH:7][CH:6]=1
Reactant: [C-]#N
Reactant: Cc1cccc(-c2nn3c(c2-c2ccc(F)cc2)CC[C@H]3COS(C)(=O)=O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(-c2nn3c(c2-c2ccc(F)cc2)CC[C@H]3CC#N)n1
Temperature: 70 °C

Procedure:
A mixture of potassium cyanide (44 mg, 0.67 mmol), tetrabutylammonium iodide (catalytic), and (S)-methanesulfonic acid 3-(4-fluoro-phenyl)-2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-6-ylmethyl ester (54 mg, 0.135 mmol) in N,N-dimethylformamide (0.35 mL) and water (0.13 mL) is heated at 70° C. for 4 h. The mixture is cooled, taken up in ethyl acetate (20 mL), washed with water and brine, dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue is chromatographed on SiO2 (2% methanol/chloroform) to yield the title compound, 25 mg (56%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[N:11]=[C:10]([O:16][C:17]2[CH:25]=[CH:24][C:23]3[NH:22][C:21]([CH3:26])=[CH:20][C:19]=3[C:18]=2[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[N:9]=1.[OH-].[Na+].CN(C)[CH:41]=[O:42]>>[CH3:15][O:14][C:12]1[CH:13]=[C:8]([O:7][CH3:6])[N:9]=[C:10]([O:16][C:17]2[CH:25]=[CH:24][C:23]3[NH:22][C:21]([CH3:26])=[C:20]([CH:41]=[O:42])[C:19]=3[C:18]=2[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[N:11]=1
Reactant: CN(C)C=O
Reactant: COc1cc(OC)nc(Oc2ccc3[nH]c(C)cc3c2C(=O)OCc2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(OC)nc(Oc2ccc3[nH]c(C)c(C=O)c3c2C(=O)OCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
0.46 ml of phosphorus oxychloride was dropwise added to 1.8 ml of N,N-dimethylformamide under cooling with ice, and the mixture was stirred for 30 minutes. Then, 2.3 g of benzyl 5-[(4,6-dimethoxypyrimidin-2-yl)oxy]-2-methylindol-4-carboxylate was dissolved in 10 ml of N,N-dimethylformamide, and the solution was dropwise added to the above mixture under cooling with ice. The mixture was stirred for 30 minutes, and then poured into ice water. An aqueous sodium hydroxide solution was added thereto for adjustment to pH9, followed by extraction with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure, was crystallized from isopropyl ether to obtain 2 g (yield: 81.5%) of the desired compound. mp: 148°-149° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:21]([CH2:22][OH:23])=[C:20]([Cl:24])[N:19]=[C:18]3[CH2:25][CH2:26][CH2:27][CH3:28])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2].C[O-].[Na+].[CH3:32][C:33]([CH3:40])([CH3:39])[C:34]([O:36][CH2:37]Cl)=[O:35]>CN(C)C=O>[CH3:32][C:33]([CH3:40])([CH3:39])[C:34]([O:36][CH2:37][O:2][C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:21]([CH2:22][OH:23])=[C:20]([Cl:24])[N:19]=[C:18]3[CH2:25][CH2:26][CH2:27][CH3:28])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)=[O:3])=[O:35]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2cccc(C(=O)O)c2)cc1
Reactant: CC(C)(C)C(=O)OCCl
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2cccc(C(=O)OCOC(=O)C(C)(C)C)c2)cc1
Reaction time: 96 h
Yield: 90 %

Procedure:
To a solution of 1.25 g of 1-[(3'-carboxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethylimidazole in 10 mL of dimethylformamide at 25° was added 0.17 g of sodium methoxide followed after 5 minutes by 0.45 g of chloromethyl trimethylacetate. The mixture was stirred at 25° for 4 days. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. This solution was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography on silica gel afforded 1.38 g of the product as a glassy solid. NMR (200 MHz, CDCl3) δ 7.87 (d, 1H); 7.54 (t, 1H); 7.43 (t, 1H); 7.29 (d, 1H); 7.11 (A2B2, 4H); 5.72 (s, 2H); 5.24 (s, 2H); 4.5 (s, 2H); 2.61 (t, 2H); 2.06 (br s, 1H); 1.68 (quint., 2H); 1.36 (sext., 2H); 1.17 (s, 9H); 0.88 (t, 3H).