Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][C:8]1[NH:12][N:11]=[C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[N:14]=2)[N:9]=1.Br[CH2:30][C:31]1[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=1>C1COCC1>[CH3:7][C:8]1[N:12]([CH2:30][C:31]2[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=2)[N:11]=[C:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]([F:28])([F:26])[F:27])=[CH:22][CH:23]=3)[N:14]=2)[N:9]=1
Reactant: Oc1cccc(CBr)c1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(O)c1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A mixture of K2CO3 (2.63 g, 19.0 mmol), 5-(5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (Intermediate B, 3.70 g, 11.9 mmol) and 3-(bromomethyl)phenol (1.78 g, 9.52 mmol) was dissolved in THF (48 mL) and stirred at 50° C. for 16 h. The reaction mixture was filtered, the solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography (0% to 80% EtOAc in Hexanes) to afford the title compound. MS (ES+) C19H14F3N5O3 requires: 417. found 418 [M+H]+; 1H-NMR (600 MHz, CD3OD) δ ppm 8.22 (d, J=8.8 Hz, 2H), 7.61 (d, J=8.0 Hz, 2H), 7.19 (d, J=7.8 Hz 1H), 6.72 (m, 2H), 6.67 (s, 1H), 5.49 (s, 2H), 2.56 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[C:4]([N:26]2[CH2:35][CH2:34][C:29]3([CH2:33][NH:32][CH2:31][CH2:30]3)[CH2:28][CH2:27]2)=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([CH2:24][OH:25])=[C:19]([CH:22]=[O:23])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2].C=O.[CH3:38]C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([C:3]1[C:4]([N:26]2[CH2:27][CH2:28][C:29]3([CH2:33][N:32]([CH3:38])[CH2:31][CH2:30]3)[CH2:34][CH2:35]2)=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][C:18]([CH2:24][OH:25])=[C:19]([CH:22]=[O:23])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cnc(NC(=O)N2CCCc3cc(CO)c(C=O)nc32)cc1N1CCC2(CCNC2)CC1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Solvent: ClCCl
Product: CN1CCC2(CCN(c3cc(NC(=O)N4CCCc5cc(CO)c(C=O)nc54)ncc3C#N)CC2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of N-(5-cyano-4-(2,8-diazaspiro[4.5]decan-8-yl)pyridin-2-yl)-7-formyl-6-(hydroxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 44, 22 mg, 0.046 mmol) in DCM (0.5 ml) was added formaldehyde (37% in H2O, 0.035 ml, 0.463 mmol) and AcOH (2.65 μl, 0.046 mmol). The reaction mixture was stirred at room temperature for 15 min, then sodium triacetoxyborohydride (14.7 mg, 0.069 mmol) was added and the reaction mixture was stirred for 30 min. The reaction mixture was poured into sat. aq. NaHCO3 and extracted with DCM (2×). The organic phase was then dried over Na2SO4, filtered and evaporated. The crude material was purified by normal phase chromatography (4 g silica gel cartridge, DCM/(DCM/MeOH 9/1+1% Et3N) 100:0 to 0:100) to give the title compound as a colorless powder.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)=[CH2:2].[Cl-].[NH4+:10].[OH-].[Na+]>CO.O>[N:10]1[CH:7]=[CH:8][C:3]([NH:4][CH2:5][CH3:6])=[CH:1][CH:2]=1
Reactant: [NH4+]
Reactant: C=Cc1ccccn1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCNc1ccncc1

Procedure:
A slurry of vinyl pyridine (161.4 mL, 1.5 mol) and ammonium chloride (240.7 g, 4.5 mol) in 1:1 MeOH/H2O (1.2 L) was heated to reflux for 18 h. The resulting homogenous solution was basified to pH13 with 3N NaOH and extracted repeatedly with CH2Cl2. The organic extracts were combined and concentrated to give a green oil, which was fractionally distilled to give 2-1 as an amber liquid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[NH:17][C:18]4[C:24]([NH:25][C:26](=O)[C:27]5[CH:32]=[C:31]([F:33])[C:30]([F:34])=[C:29]([F:35])[CH:28]=5)=[CH:23][C:22]([C:37]([F:40])([F:39])[F:38])=[CH:21][C:19]=4[N:20]=3)[C@H:12]([CH3:41])[CH2:11]2)=[N:4][CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1.B.C1COCC1>C1COCC1.CO.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[N:4][C:3]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16]2[NH:17][C:18]3[C:24]([NH:25][CH2:26][C:27]4[CH:28]=[C:29]([F:35])[C:30]([F:34])=[C:31]([F:33])[CH:32]=4)=[CH:23][C:22]([C:37]([F:39])([F:38])[F:40])=[CH:21][C:19]=3[N:20]=2)[C@H:12]([CH3:41])[CH2:11]1
Reactant: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(NC(=O)c3cc(F)c(F)c(F)c3)c2[nH]1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(NCc3cc(F)c(F)c(F)c3)c2[nH]1
Temperature: 0 °C

Procedure:
To a solution of N-{2-[(2R)-4-(3-chloro-5-hydroxymethyl-pyridin-2-yl)-2-methyl-piperazin-1-yl]-6-trifluoromethyl-3H-benzoimidazol-4-yl}-3,4,5-trifluoro-benzamide (120 mg, 0.2 mmol, Example 170c) in THF (1 mL) was added BH3.THF (0.6 mL, 0.6 mmol, Aldrich) dropwise with stirring at 0° C. The mixture was heated at reflux for 5 h, cooled to room temperature and diluted with 1:1 mixture of MeOH and 1N NaOH (2 mL). The mixture was stirred at room temperature for 30 min and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography, eluting with 5% MeOH/CH2Cl2 to give the title compound as a white solid. MS (ESI, pos. ion) m/e: 586 (M+1).
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[C:25]([F:28])([F:27])[F:26])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:30][OH:31].O.O.O.C([O-])(=O)C.[Na+]>CCO.O>[C:1]1(/[C:7](/[C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[C:25]([F:28])([F:27])[F:26])=[N:30]\[OH:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O/N=C(\c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Reaction time: 8 h
Yield: 75.2 %

Procedure:
Phenyl[4-phenyl-8-(trifluoromethyl)quinolin-3-yl]methanone (Example 1, 0.128 g, 0.339 mmol) was taken into EtOH/H2O (7 mL, 7:3 mixture) along with hydroxylamine hydrochloride (0.028 g, 0.407 mmol) and sodium acetate trihydrate (0.061 g, 0.447 mmol) and this mixture was refluxed for 1.5 hours. TLC and LC-MS showed no reaction. Therefore, excess quantities of hydroxylamine hydrochloride and sodium acetate trihydrate were added and refluxing was continued overnight. The reaction was concentrated and the resulting material was taken up into CH2Cl2/H2O. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organics were dried over sodium sulfate and concentrated. The product was purified via column chromatography using 15% ethyl acetate in hexane as the eluent to afford 0.100 g of desired product as a white solid. MS (ESI) m/z 393 ([M+H]+);
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:14]=[C:15]([OH:30])[C:16]3[C:21]4[CH2:22][CH:23]([CH3:26])[CH2:24][CH2:25][C:20]=4[C:19]([CH3:28])([CH3:27])[O:18][C:17]=3[CH:29]=2)([CH3:12])[CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.[ClH:31].[N:32]1([CH2:38][CH2:39][CH2:40][C:41](O)=[O:42])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:31].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:12])([C:13]2[CH:14]=[C:15]([O:30][C:41](=[O:42])[CH2:40][CH2:39][CH2:38][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[C:16]3[C:21]4[CH2:22][CH:23]([CH3:26])[CH2:24][CH2:25][C:20]=4[C:19]([CH3:28])([CH3:27])[O:18][C:17]=3[CH:29]=2)[CH2:9][CH2:10][CH3:11])=[CH:6][CH:7]=1
Reactant: CCCC(C)(c1ccc(F)cc1)c1cc(O)c2c(c1)OC(C)(C)C1=C2CC(C)CC1
Reactant: O=C(O)CCCN1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCCC(C)(c1ccc(F)cc1)c1cc(OC(=O)CCCN2CCCCC2)c2c(c1)OC(C)(C)C1=C2CC(C)CC1

Procedure:
2.5 g. (6.76 mmole) of 3-(4-fluorophenyl-1-methylbutyl)-1-hydroxy-6,6,9-trimethyl-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran is combined with 1.41 g. (6.76 mmole) of γ-piperidinobutyric acid hydrochloride and 1.48 g. (7.16 mmole) of dicyclohexylcarbodiimide in 125 ml. of methylene chloride and stirred at room temperature for 16 hours. The by-product of dicyclohexylurea is removed by filtration and the filtrate is evaporated to a residue. The residue is dissolved in ether and the small amount of solid which appears is removed by filtration. The ether is removed on a rotary evaporator and the gummy residue which remains is triturated several times with small quantities of hexane. The material is thoroughly dried to yield the product as a powder.
Reaction SMILES: [NH2:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]#[N:8].[CH2:9]([N:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17](=O)[CH3:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.P(Cl)(Cl)(Cl)=O>C(#N)C>[C:20]1([N:16]([C:17](=[N:1][C:2]2[NH:6][CH:5]=[N:4][C:3]=2[C:7]#[N:8])[CH3:18])[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: N#Cc1nc[nH]c1N
Reactant: CC(=O)N(Cc1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=Nc1[nH]cnc1C#N)N(Cc1ccccc1)c1ccccc1

Procedure:
5-Aminoimidazole-4-carbonitrile is condensed with N-benzyl-N-phenyl-acetamide in the presence of phosphoryl chloride in acetonitrile at room temperature to yield 5-[1-(N-phenyl-N-benzylamino)ethylideneamino]-imidazole-4-carbonitrile. Such is cyclized with sodium hydride in dioxane to yield 7-amino-N-phenyl-N-benzyl-3H-imidazo[4,5-b]pyridine-5-amine. Hydrogenolysis in ethanol with palladium on charcoal yields 7-amino-N-phenyl-3H-imidazo[4,5-b]pyridine-5-amine.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=1[NH2:12].C(N(C(C)C)CC)(C)C>C(O)CCC>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:12][C:11]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:10]=2[CH3:9])[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1ccc([N+](=O)[O-])cc1Nc1cc(Cl)ncn1

Procedure:
4,6-Dichloropyrimidine (5.37 g, 36.0 mmol) and 2-methyl-5-nitroaniline (5.48 g, 36.0 mmol) are heated in n-butanol (58 mL) with diisopropylethylamine (4.66 g, 36 mmol) for 3 days at 110° C. The mixture is evaporated and the product is purified by standard methods.
Reaction SMILES: I[C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[CH:16]([OH:22])[CH2:15]2.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>[Cu]I.C1(C)C=CC=CC=1>[N+:11]([C:4]1[CH:3]=[C:2]([O:22][CH:16]2[CH:17]3[CH2:20][CH2:21][N:14]([CH2:19][CH2:18]3)[CH2:15]2)[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=1)([O-:13])=[O:12]
Reactant: OC1CN2CCC1CC2
Reactant: O=[N+]([O-])c1cc(I)c2occc2c1
Agent: [Cu]I
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(OC2CN3CCC2CC3)c2occc2c1
Temperature: 140 °C
Yield: 100 %

Procedure:
7-Iodo-5-nitro-1-benzofuran (1.00 g, 3.46 mmol), quinuclidin-3-ol (1.10 g, 8.65 mmol), 1,10-phenanthroline (0.25 g, 1.38 mmol), CuI (0.13 g, 0.69 mmol) and toluene (20 mL) were mixed together and heated at 140° C. overnight. The solvent was removed in vacuo and the crude product was purified by flash chromatography (eluent: hexane and chloroform:MeOH:triethylamine; 9:0.9:0.1) to give 3-[(5-nitro-1-benzofuran-7-yl)oxy]quinuclidine (3.46 mmol).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:10]3[C:14]4=[N:15][C:16]([CH:19]=[CH2:20])=[CH:17][CH:18]=[C:13]4[N:12]=[CH:11]3)[CH:8]=2)[CH2:3][CH2:2]1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C>ClCCl>[CH3:21][S:22]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:10]3[C:14]4=[N:15][C:16]([CH:19]=[CH2:20])=[CH:17][CH:18]=[C:13]4[N:12]=[CH:11]3)[CH:8]=2)[CH2:3][CH2:2]1)(=[O:24])=[O:23]
Reactant: C=Cc1ccc2ncn(-c3ccc4c(c3)NCC4)c2n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=Cc1ccc2ncn(-c3ccc4c(c3)N(S(C)(=O)=O)CC4)c2n1

Procedure:
A solution of 3-(2,3-dihydro-1H-indol-6-yl)-5-vinyl-3H-imidazo[4,5-b]pyridine (Intermediate 16.1) (1.10 g, 4.19 mmol), methanesulfonyl chloride (0.65 ml, 8.39 mmol), and triethylamine (3.49 ml, 25.16 mmol) in dichloromethane (50 ml) is stirred for 15 min at ambient temperature. The mixture is successively extracted with saturated aqueous ammonium chloride and saturated aqueous sodium bicarbonate. The organic layer is dried over sodium sulfate and concentrated in vacuo to render 1.40 g (98%) of the respective sulfonamide. HPLC (over 10 min 10-85% MeCN/100 mM aq. NaOAc): 99% purity, tR 7.03 min (tR(SM) 7.06 min). MS (ESI) m/z (C17H16N4O2S) 341.0 (M+1, 100) Finnegan LCQ.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:37])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:34][CH3:35])[CH2:25][NH:26][S:27]([CH2:30][CH2:31][CH2:32]Cl)(=[O:29])=[O:28])[C:5]1=[O:36])[CH:2]=[CH2:3].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH2:1]([C@@:4]1([CH3:37])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:34][CH3:35])[CH2:25][N:26]2[CH2:32][CH2:31][CH2:30][S:27]2(=[O:29])=[O:28])[C:5]1=[O:36])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CNS(=O)(=O)CCCCl)C1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN2CCCS2(=O)=O)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)-3-chloropropane-1-sulfonamide prepared above in Step A (36.1 mg, 0.062 mmol) in DMF (1.2 mL) was added DBU (46.4 μL, 0.308 mmol) at rt. After being stirred at rt overnight, the reaction was quenched (10% citric acid), extracted (3×EtOAc), and washed (saturated aq. NaHCO3 and sat. aq. NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to provide the title compound as a pale brown film.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21](O)=[O:22])=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:6][N:7]=1.N1(C(N2C=CN=C2)=O)C=CN=C1.C(N(C(C)C)C(C)C)C.[N:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[NH2:51]>CN(C1C=CN=CC=1)C.CS(C)=O.O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:12][CH2:13]2)=[N:4][C:3]=1[C:21](=[O:22])[NH:51][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][N:45]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc(N)c(C(=O)O)n2)CC1
Reactant: Nc1ccccn1
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cnc(N)c(C(=O)Nc3ccccn3)n2)CC1
Temperature: 110 °C
Reaction time: 20 h
Yield: 54.9 %

Procedure:
To a mixture of 3-amino-6-(4-tert-butoxycarbonylpiperazin-1-yl)pyrazine-2-carboxylic acid (8.08 g, 24.99 mmol), di(imidazol-1-yl)methanone (4.863 g, 29.99 mmol), DMAP (152.7 mg, 1.250 mmol) and N-ethyl-N-isopropyl-propan-2-amine (8.074 g, 10.88 mL, 62.47 mmol) in DMSO (80.80 mL) was added pyridin-2-amine (4.704 g, 49.98 mmol) and the resulting solution stirred at 110° C. for 20 hours. Water (500 mL) was added and the mixture extracted into EtOAc (3×300 mL), dried and concentrated to give a residue which was triturated with EtOAc and filtered to give the required product as a yellow solid (5.48 g, 55% Yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[C:17]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[N:18]3[C:23]=2[C:22]([NH2:24])=[N:21][CH:20]=[N:19]3)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:32][C:33]([N:35]([CH3:37])[CH3:36])=[O:34]>>[NH2:24][C:22]1[C:23]2=[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:10]=3)[CH:16]=[C:17]([CH:25]3[CH2:30][CH2:29][N:28]([CH2:32][C:33]([N:35]([CH3:37])[CH3:36])=[O:34])[CH2:27][CH2:26]3)[N:18]2[N:19]=[CH:20][N:21]=1
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3cccc(OCc4ccccc4)c3)c12
Reactant: CN(C)C(=O)CCl
Product: CN(C)C(=O)CN1CCC(c2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnn23)CC1
Yield: 23.6 %

Procedure:
In a manner similar to the procedure described for the preparation of Example 355 and using 5-(3-benzyloxyphenyl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine and 2-chloro-N,N-dimethylacetamide as starting material, 20 mg (23.6%) of the desired product was isolated. 1H NMR (400 MHz, DMSO-d5) δ 7.90 (s, 1H), 7.44-7.32 (m, 6H), 7.10 (s, 1H), 7.02-6.98 (m, 2H), 6.59 (s, 1H), 5.16 (s, 2H), 3.16 (s, 2H), 3.15-3.04 (m, 1H), 3.03 (s, 3H), 2.97-2.90 (m, 2H), 2.80 (s, 3H), 2.22-2.14 (m, 2H), 1.98-1.92 (m, 2H), 1.74-1.64 (m, 2H); LC-MS m/z [M+H]+485.2, RT 2.29 min.
Reaction SMILES: CC1(C)O[C:6](=[O:8])[C:5](=[CH:9][NH:10][C:11]2[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=2)C(=O)O1.C1(OC2C=CC=CC=2)C=CC=CC=1>CC(C)=O>[CH3:16][N:13]1[CH:14]=[C:15]2[C:11]([NH:10][CH:9]=[CH:5][C:6]2=[O:8])=[N:12]1
Reactant: Cn1ccc(NC=C2C(=O)OC(C)(C)OC2=O)n1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CC(C)=O
Product: Cn1cc2c(=O)cc[nH]c2n1
Yield: 40.4 %

Procedure:
A mixture of the product of Example 8a (1.50 g, 5.97 mmol) and diphenyl ether (25 mL) was heated under reflux for 1 h, with removal of the resultant acetone by distillation. The solvent was then decanted, and the remaining solid residue was dissolved in dichloromethane (5 mL) and purified by chromatography on silica gel, eluting with a 0-10% MeOH/CH2Cl2 gradient, to provide the title compound (0.360 g, 40% yield).
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:13][C:14]([C:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][CH:17]=2)=O)=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)(=[O:3])[CH3:2].[OH-].[Na+]>O1CCOCC1>[O:18]1[CH:17]=[C:16]([C:14]2[CH2:2][C:1](=[O:3])[C:4]3[C:5](=[CH:6][C:7]4[O:11][CH2:10][O:9][C:8]=4[CH:12]=3)[N:13]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]1=2
Reactant: CC(=O)c1cc2c(cc1NC(=O)c1coc3ccccc13)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C1CC(c2coc3ccccc23)=Nc2cc3c(cc21)OCO3

Procedure:
The synthetic procedure of target compounds 158 is illustrated in Scheme 12. The starting 2-amino-4,5-methylenedioxy acetophenone (148) was first reacted with benzo[b]furan-3-carbonyl chloride (154) to give N-(6-Acetyl-1,3-benzodioxol-5-yl)-1-benzofuran-3-carboxamide (155). Then, the intermediates (155) was subjected to cyclization in dioxane, in the presence of NaOH, to afford 2-(3-Benzo[b]furyl)-6,7-methylenedioxyquinolin-4-one (156). Compound 156 was first reacted with tetrabenzylpyrophosphate in THF, in the presence of NaH, to yield dibenzyl 2-(3-benzo[b]furyl)-6,7-methylenedioxyquinolin-4-yl phosphate (157). Compound 157 was then subjected to catalytic hydrogenation in MeOH to give its diphosphoric acid (158).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]3[C:19]4[N:20]=[CH:21][CH:22]=[N:23][C:24]=4[C:25](C4C(Cl)=C(OC)C=C(OC)C=4Cl)=[CH:26][CH:27]=3)=[O:17])=[N:13][CH:14]=2)[CH2:4][CH2:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N1CCN(C2C=C(NC(C3C4N=CC=NC=4C([C:89]4[C:98]5[C:93](=[CH:94][CH:95]=[CH:96][CH:97]=5)[CH:92]=[N:91][CH:90]=4)=CC=3)=O)C=CC=2)CC1)C>C(Cl)Cl.CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]3[C:19]4[N:20]=[CH:21][CH:22]=[N:23][C:24]=4[C:25]([C:89]4[C:98]5[C:93](=[CH:94][CH:95]=[CH:96][CH:97]=5)[CH:92]=[N:91][CH:90]=4)=[CH:26][CH:27]=3)=[O:17])=[N:13][CH:14]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1Cl
Reactant: CCN1CCN(c2cccc(NC(=O)c3ccc(-c4cncc5ccccc45)c4nccnc34)c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(Cc2ccc(NC(=O)c3ccc(-c4cncc5ccccc45)c4nccnc34)nc2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but stirring the reaction mixture for 17 h at rt, using 2 equiv of 5-(4-methyl-piperazin-1-ylmethyl)pyridin-2-ylamine hydrochloride (Example 31), TBTU (2 equiv) and 8-isoquinolin-4-ylquinoxaline-5-carboxylic acid (Example 52). Title compound: ESI-MS: 490.0 [M+H]+; tR=2.21 min (System 1); TLC: Rf=0.17 (DCM/MeOH, 9:1).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:22])[NH:18][C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.Cl.Cl[CH2:35][CH2:36][N:37]([CH3:39])[CH3:38]>>[F:32][C:2]([F:31])([F:1])[C:3]1[CH:26]=[C:25]([C:27]([F:29])([F:28])[F:30])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:22])[N:18]([CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])[C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CN(C)CCCl
Agent: Cl
Product: CN(C)CCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-[(1-{[2,4-Bis(trifluoromethyl)phenyl]methyl}-1H-indazol-5-yl)methylidene]-3-[2-(dimethylamino)ethyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[2,4-bis-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 6) and 2-chloro-N,N-dimethylethylamine hydrochloride following General Procedure H.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](C)=[CH:9][NH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].[Br:15]Br>C(O)(=O)C.O>[Br:15][C:8]1[C:7]2[N:2]([CH3:1])[C:3](=[O:14])[N:4]([CH3:13])[C:5](=[O:12])[C:6]=2[NH:10][CH:9]=1
Reactant: BrBr
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(=O)c2[nH]cc(Br)c2n(C)c1=O
Reaction time: 3 h
Yield: 57.4 %

Procedure:
To a solution of Intermediate 1 (500 mg, 2.800 mmol) in acetic acid (5 mL) was added a solution of bromine (430 mg, 2.700 mmol) in acetic acid (5 mL) dropwise with stirring, after which water (1.2 mL) was added. The reaction mixture was stirred for another 20 min and diluted with two volumes of cold water. After 3 h, the precipitate was filtered off and washed with diethyl ether to afford 400 mg of the product as a white solid; 1H NMR (δ ppm, 300 MHz, DMSO-d6) 3.23 (s, 3H), 3.65 (s, 3H), 7.42 (s, 1H), 12.59 (br s, 1H); APCI-MS (m/z) 258.19 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:10]1[C:11]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH2:22])=[O:21])[C:12]=2[N:13]=[N:14][N:15]=1>>[CH2:1]([NH:8][C:10]1[C:11]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH2:22])=[O:21])[C:12]=2[N:13]=[N:14][N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1cccc2c(O)nnnc12
Reactant: NCc1ccccc1
Product: NC(=O)c1cccc2c(NCc3ccccc3)nnnc12

Procedure:
Compound 6 was prepared following general synthetic scheme 7 wherein benzylamine was reacted with 4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give the title compound. LC-MS [280 (M+1)], 1H NMR (400 MHz, DMSO-d): δ 9.42 (s, 1H), 9.31 (t, 1H), 8.53 (t, 1H), 8.04 (s, 1H), 7.98 (t, 1H), 7.41 (d, 2H), 7.34 (t, 2H), 7.28-7.24 (m, 1H), 4.92 (d, 2H).