Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:22][O:23][CH2:24][C@@H:25]1[CH2:29][CH2:28][CH2:27][NH:26]1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:26]4[CH2:27][CH2:28][CH2:29][C@@H:25]4[CH2:24][O:23][CH3:22])=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: COC[C@@H]1CCCN1
Solvent: CN(C)C=O
Solvent: CCO
Product: COC[C@H]1CCCN1C[C@@H](O)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and (S)-(+)-2-(methoxymethyl)pyrrolidine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=401.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:35])[CH3:34])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27](Cl)=[O:28])[C@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:7]=1.[C:38]([CH2:40][CH2:41][N:42]([CH3:52])[C:43](=[O:51])[CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)#[N:39]>>[Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:34])[CH3:35])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27]([N:48]3[CH2:49][CH2:50][N:45]([CH2:44][C:43]([N:42]([CH2:41][CH2:40][C:38]#[N:39])[CH3:52])=[O:51])[CH2:46][CH2:47]3)=[O:28])[C@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:7]=1
Reactant: CN(CCC#N)C(=O)CN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)CCC#N)CC1

Procedure:
2-{4-[(4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N-(2-cyano-ethyl)-N-methyl-acetamide was prepared from (4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12k) and N-(2-cyano-ethyl)-N-methyl-2-piperazin-1-yl-acetamide (example 16d) in an analogous manner as described in example 25. LR-MS: 748.3 [(M+H)+]
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:16])[NH:7][C:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4].[CH:17]12[CH2:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][CH:18]2[CH2:24][C:25](Cl)=[O:26]>>[CH:17]12[CH2:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][CH:18]2[CH2:24][C:25]([NH:1][CH:2]([C:5]1[C:6](=[O:16])[NH:7][C:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4])=[O:26]
Reactant: O=C(Cl)CC1CC2CCC1C2
Reactant: CCC(N)c1nnc(C2CCCC2)[nH]c1=O
Product: CCC(NC(=O)CC1CC2CCC1C2)c1nnc(C2CCCC2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 150 mg (0.67 mmol) 6-(1-aminopropyl)-3-cyclopentyl-1,2,4-triazin-5(4H)-one, 130 mg (0.74 mmol) bicyclo[2.2.1]hept-2-ylacetyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[H-].[Na+].[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][OH:18].CN(C=O)C>C1(C)C=CC=CC=1.O>[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][O:18][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: OCc1cccc(Cl)c1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(OCc2cccc(Cl)c2)nc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 142.1 %

Procedure:
6-chloronicotinic acid (1.0 g, 6.3 mmol)) was added portion-wise over 30 min to a stirred suspension of sodium hydride (60%, 0.76 g, 19 mmol) in toluene (10 mL. The mixture was stirred for 30 min then cooled to 0° C. A solution of 3-chloro-benzyl alcohol (0.69 g, 6.4 mmol) in toluene (5 mL) was added drop-wise over 10 min. The mixture was warmed to room temperature, DMF (20 mL) was added and the mixture was heated to 95° C. and stirred for 18 h. The mixture was cooled to room temperature then poured into water (30 mL). The aqueous mixture was acidified to pH 2 and extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with water and brine, then dried over sodium sulfate and concentrated in vacuo to give a yellow solid (2.36 g). The residue was re-crystallised [2-propanol-water, (2:1)] to give the product as a white solid (0.85 g, 51%), m.p. 158° C. (dec.). 1H-NMR (400 MHz, CDCl3): 8.93 (1H, d, J=2.5 Hz), 8.24 (1H, dd, J=2.5, 8.5 Hz), 7.46 (1H, s), 7.35–7.29 (3H, m), 6.87 (1H, dd, J=1, 8.5 Hz) and 5.45 (2H, s).
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CCNCC1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-piperidone monohydrate hydrochloride (2.5 g, 14.56 mmol) and anhydrous potassium carbonate (7 g, 50.64 mmol) in dry DMF (25 mL) was stirred for 30 min at room temperature. Benzyl bromide (2 mL, 16.82 mmol) was added dropwise into the reaction mixture and heated at 65° C. for 14 h. The reaction mixture was cooled to room temperature, filtered and quenched with ice water (25 mL). The resulting mixture was extracted in ethyl acetate (2×20 mL) and the combined organic layers were washed with water (2×15 mL) followed by brine (20 mL). The organic phase obtained was dried over anhydrous sodium sulphate and evaporated. The crude product obtained was purified by crystallisation using 2% methanol in chloroform to afford the title compound.
Reaction SMILES: [C:1]([C:9]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:10]=1[C:11]([N:13]([CH2:22][C:23]#[N:24])[CH2:14][CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+]>CO>[C:23]([C:22]1[N:13]([CH2:14][CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[C:11](=[O:12])[C:10]2[C:9]([C:1]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:28][C:27]([O:29][CH3:30])=[CH:26][CH:25]=2)#[N:24]
Reactant: CCOC(CN(CC#N)C(=O)c1ccc(OC)cc1C(=O)c1ccccc1)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(Cn1c(C#N)c(-c2ccccc2)c2cc(OC)ccc2c1=O)OCC
Yield: 77.4 %

Procedure:
A solution of 5 (1.05 g, 2.65 mmol), sodium methoxide (4.62M in methanol, 1.43 mL, 6.63 mmol) and methanol (50 mL) was heated at reflux for 2 h. The solvent was removed in vacuo and sat. sodium bicarbonate was added. The resulting mixture was extracted with methylene chloride (3×). The combined organic extracts were dried with magnesium sulfate (anh.) and filtered. The filtrate was concentrated in vacuo to give an oil which was triturated with hexane/ethyl acetate to give 6 as a white solid (805 mg, 77%)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[C:6]2[N:7]([C:16](=[O:19])[NH:17][N:18]=2)[C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[C:10]([F:15])[CH:9]=2.Cl[C:21]1[N:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C(N(C(C)C)CC)(C)C>CS(C)=O.CCOC(C)=O>[F:15][C:10]1[CH:9]=[C:8]2[C:13]([N:14]=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:6]3[N:7]2[C:16](=[O:19])[NH:17][N:18]=3)=[CH:12][CH:11]=1
Reactant: NCCNc1nc2ccc(F)cc2n2c(=O)[nH]nc12
Reactant: Clc1ncccn1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=c1[nH]nc2c(NCCNc3ncccn3)nc3ccc(F)cc3n12
Reaction time: 18 h

Procedure:
A mixture of 50 mg of 4-(2-amino-ethylamino)-8-fluoro-2H-[1,2,4]triazolo[4,3-a]quinoxalin-1-one 13.5 mg of 2-chloropyrimidine, and 76 mg of diisopropylethylamine in DMSO (0.5 mL) was heated for 18 hrs. An additional 13.5 mg of 2-chloropyrimidine was added and heating was continued for another 18 hrs. The reaction was diluted with EtOAc, washed with water, and dried over sodium sulfate prior to concentration. The residue was separated by silica gel chromatography, and the isolated residue was recrystallized from MeOH to give the title compound. MS (M−H)−=339.0.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:18]=[CH:17][CH:16]=[N:15]3)=[CH:10][C:9]=2[O:19][CH3:20])=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH:30]=2)O1>>[CH3:20][O:19][C:9]1[CH:10]=[C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[N:15]2)[CH:12]=[CH:13][C:8]=1[C:5]1[N:4]=[N:3][C:2]([C:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH:30]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1cc(-n2cccn2)ccc1-c1ccc(Cl)nn1
Product: COc1cc(-n2cccn2)ccc1-c1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)nn1
Yield: 100 %

Procedure:
tert-Butyl 4-(6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (151 mg, 0.35 mmol, 100% yield) was prepared from Intermediate 2-1 and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate using General Method 1-4 for Suzuki coupling. LCMS Rt=1.58 min, M+1=434.8 (condition B).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[C:11]1[S:12][C:13]2[CH:14]=[N:15][CH:16]=[C:17]([F:20])[C:18]=2[N:19]=1>CC(O)=O.[Fe]>[F:1][C:2]1[C:3]([C:11]2[S:12][C:13]3[CH:14]=[N:15][CH:16]=[C:17]([F:20])[C:18]=3[N:19]=2)=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(F)c1-c1nc2c(F)cncc2s1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1cccc(F)c1-c1nc2c(F)cncc2s1
Temperature: 100 °C
Yield: 57.2 %

Procedure:
Iron powder (8.29 g, 148 mmol) was added to a solution of 2-(2-fluoro-6-nitrophenyl)-7-fluorothiazolo[5,4-c]pyridine (4.33 g, 14.8 mmol) in AcOH (144 mL). The reaction mixture was heated at 100° C. for 30 minutes and then allowed to cool to room temperature. The volatiles were removed under reduced pressure and the resultant residue was dissolved in DCM/MeOH and filtered through Celite® washing the filter pad thoroughly with further DCM/MeOH. The filtrate was concentrated under reduced pressure and the resultant residue was purified by column chromatography on silica gel eluting with 0-2% MeOH in DCM, then triturated with DCM and then dried to afford the title compound as a yellow solid (2.23 g, 57% yield). LCMS (Method D): RT=3.62 min, m/z: 264 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[N:22]=[CH:21][C:20]3[N:19]([CH3:23])[C:18](=[O:24])[CH2:17][N:16]([CH:25]([CH3:27])[CH3:26])[C:15]=3[N:14]=2)[CH:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:7]=1.[Cl:28][CH2:29][CH2:30][N:31]=[C:32]=[O:33].C(OC(C)C)(C)C>O1CCOCC1>[Cl:28][CH2:29][CH2:30][NH:31][C:32]([NH:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[C:4]([NH:12][C:13]2[N:22]=[CH:21][C:20]3[N:19]([CH3:23])[C:18](=[O:24])[CH2:17][N:16]([CH:25]([CH3:27])[CH3:26])[C:15]=3[N:14]=2)[CH:3]=1)=[O:33]
Reactant: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(N)cc(S(C)(=O)=O)c3)nc21
Reactant: O=C=NCCCl
Solvent: C1COCCO1
Solvent: CC(C)OC(C)C
Product: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(NC(=O)NCCCl)cc(S(C)(=O)=O)c3)nc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(3-Amino-5-(methylsulfonyl)-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (300 mg; 0.768 mmol) was diluted under nitrogen atmosphere in 3 ml of dry 1,4-dioxane, then a solution of 2-chloroethyl-isocyanate (0.09 ml; 0.999 mmol) in 2 ml of dry 1,4-dioxane was added drop-wise. The reaction mixture was stirred at room temperature for 3 h, then warmed to 60° C. and maintained at that temperature for 3 h. The reaction mixture was then concentrated in vacuo. The crude obtained was treated with isopropyl ether. The solid obtained was filtered. 261 mg (0.001 mol; 68.5 yield) of the desired compound were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[O:8][CH:9]([CH2:12][OH:13])[CH2:10][O:11][C:6]=2[CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:15]=[CH:14][C:7]2[O:8][CH:9]([CH2:12][OH:13])[CH2:10][O:11][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)OCC(CO)O2
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)OCC(CO)O2
Reaction time: 24 h
Yield: 75.9 %

Procedure:
(6-Nitro-2,3-dihydro-benzo[1,4]dioxin-2-yl)-methanol (1.0 g, 4.7 mmol) was dissolved in methanol (30 mL) and palladium on activated carbon was added (0.10 g, 5% wt). The mixture was shaken on a Parr Shaker under H2(g) atmosphere (60 PSI) for 24 hours. The mixture was filtered through Celite® and evaporated to give 646 mg of material as a white solid (77%), which was used as such for the next step. m/z=182 (M+1). LC: 0.82 minutes.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[C:28]([Cl:29])=[C:27]([CH3:30])[S:26][C:17]=2[N:18]=[C:19]([C:21]2[O:25][N:24]=[CH:23][CH:22]=2)[N:20]=1>>[O:25]1[C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[C:28]([Cl:29])=[C:27]([CH3:30])[S:26][C:17]=3[N:18]=2)=[CH:22][CH:23]=[N:24]1
Reactant: Cc1sc2nc(-c3ccno3)nc(Cl)c2c1Cl
Reactant: NCCc1ccc2c(c1)OCCO2
Product: Cc1sc2nc(-c3ccno3)nc(NCCc3ccc4c(c3)OCCO4)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(isoxazol-5-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-ethylenedioxyphenethylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[O:9]=[C:10](Cl)OC(Cl)(Cl)Cl.C(N(CC)CC)C>C1COCC1>[C:3]1(=[O:5])[O:4][C:10](=[O:9])[N:1]2[CH2:8][CH2:7][CH2:6][C@@H:2]12
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1OC(=O)N2CCC[C@@H]12
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 165.3 %

Procedure:
L-Proline (11.5 g, 0.10 mol) was added to a 500 ml three neck flask fitted with a 125 ml addition funnel, thermometer and a nitrogen inlet tube. To the flask was added dry tetrahydrofuran (115 ml) and the mixture cooled to 15° C. using an ice/water bath. The addition funnel was charged with diphosgene (7.2 ml, 0.06 mol) and dry THF(50 ml). The diphosgene solution was added dropwise to the proline mixture over 45 minutes while maintaining a reaction mixture temperature in the range of 15° to 20° C. Once the addition was complete the mixture was warmed to 35° C. for 1 hour. At the end of this time a clear and colorless solution was obtained. The reaction mixture was then cooled to room temperature and concentrated under vacuum to a volume of approximately 50 ml. The residue was redissolved in 115 ml of THF and cooled to 0°-5° C. using an ice bath. Triethylamine (12 ml, 0.086 mol) was added dropwise to the cooled solution over 30 minutes. The solution was stirred a further 30 minutes after which time the solids were filtered and washed with THF(100 ml). The organics were concentrated under reduced pressure to give the desired compound (4) (14 g, 99%) as a light beige solid. The material was stored under nitrogen at -78° C. in order to avoid decomposition, and used without further purification in subsequent reactions.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[C:14]2=[N:15][C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[C:18]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:17]=3[N:13]2[CH2:12][CH2:11]1)[CH:5]=O.[CH3:28][NH:29][CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(O)C.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][N:29]([CH3:30])[CH3:28])[CH:7]=[CH:8][C:9]=1[N:10]1[C:14]2=[N:15][C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[C:18]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:17]=3[N:13]2[CH2:12][CH2:11]1
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3c1ccc(C=O)cc1Cl
Reactant: CNC
Agent: [Ti+4]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)[O-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3c1ccc(CN(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-chloro-4-[8-chloro-5-(1-ethylpropyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl]benzaldehyde (68.3 mg, 0.170 mmol) in tetrahydrofuran (0.5 mL) and ethanol (0.5 mL) were added dimethylamine (2.0 M solution in tetrahydrofuran, 850 μL, 1.70 mmol) and titanium tetraisopropoxide (100.0 μL, 0.340 mmol). The reaction mixture was stirred at room temperature for 16 hr. To the mixture was added sodium triacetoxyborohydride (72.1 mg, 0.340 mmol) and the reaction mixture was stirred at room temperature for 5 hr. The reaction mixture was warmed to 40° C. and stirred for 3 hr. To the mixture were added sodium triacetoxyborohydride (360.0 mg, 1.70 mmol) and dimethylamine (2.0 M solution in tetrahydrofuran, 425 μL, 0.85 mmol). The reaction mixture was stirred at 40° C. for 0.5 hr. The reaction mixture was quenched with water and extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-100% ethyl acetate/n-hexane gradient mixture to give the title compound as an amorphous (32.5 mg, 0.0753 mmol, 44%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:16])=[NH:15])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.O=[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]1[C:31](=O)[CH:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:33].[O-]CC.[Na+]>C(O)C>[CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]3[N:16]=[C:31]([CH:32]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH3:33])[C:19]4[CH2:20][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:22][CH2:23][C:18]=4[N:15]=3)=[CH:11][CH:12]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CC(C(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O)c1ccccc1
Reactant: Cc1nccn1-c1ccc(NC(=N)N)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(C(C)c4ccccc4)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Yield: 36.9 %

Procedure:
1-(4-(2-Methyl-1H-imidazol-1-yl)phenyl)guanidine (700 mg, 3.25 mmol, example 9e), tert-butyl 4-oxo-3-(2-phenylpropanoyl)piperidine-1-carboxylate (1293 mg, 3.90 mmol) and sodium ethoxide (221 mg, 3.25 mmol) in ethanol (6 mL) were heated to 110° C. in a microwave reactor for 4 h. The solvent was evaporated and the crude was dissolved in ethyl acetate and washed with water. The organic phase was dried under MgSO4 and the solvent was evaporated under reduced pressure. Purification by flash chromatography using dichloromethane and methanol (0-10%) as eluent gave tert-butyl 2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-4-(1-phenylethyl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (612 mg, 36.9%). MS (ES+) m/z 511 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]=1[CH2:7][OH:8].C(N(CC)CC)C.[C:22](Cl)(=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>O1CCCC1>[C:22]([O:8][CH2:7][C:6]1[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][O:3][C:2]=1[CH3:1])(=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: Cc1occ(-c2ccccc2)c1CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)OCc1c(-c2ccccc2)coc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-methyl-4-phenyl-3-furanmethanol (Compound 59, 48 mg, 0.26 mmol) and triethylamine (39 mg. 0.38 mmol) in tetrahydrofuran (3 ml) at 0 degrees under argon was added lauroyl chloride (73 mg. 0.33 mmol). This solution was warmed gradually to room temperature and stirred for 4 1/2 hours. The organics were extracted into ethyl ether and washed with a 5% aqueous sodium bicarbonate solution, H2O and brine. Evaporation of the dried (magnesium sulfate) extracts gave an oil which was purified by flash chromatography on silica using 3% ether/hexanes to give the title compound.
Reaction SMILES: N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[C:15]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)#[N:16].CC(C)([O-])C.[Na+].CCCCCCCCCCCC.I[C:43]1[CH:44]=[C:45]([CH3:50])[CH:46]=[C:47]([CH3:49])[CH:48]=1>[Cu]I.O1CCOCC1>[CH3:50][C:45]1[CH:44]=[C:43]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([C:15]#[N:16])=[CH:18][CH:19]=2)[CH:48]=[C:47]([CH3:49])[CH:46]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1cc(C)cc(I)c1
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCCCCCCCCCCC
Product: Cc1cc(C)cc(Nc2ccc(C#N)cc2)c1
Temperature: 110 °C
Reaction time: 23 h
Yield: 68.8 %

Procedure:
An oven-dried resealable Schlenk tube was charged with CuI (10 mg, 0.0525 mmol, 5.0 mol %), 1,10-phenanthroline (20 mg, 0.111 mmol), 4-cyanoaniline (146 mg, 1.24 mg), sodium tert-butoxide (145 mg, 1.51 mmol), evacuated and backfilled with argon. Dodecane (235 μL), 5-iodo-m-xylene (150 μL, 1.04 mmol) and dioxane (1.0 mL) were added under argon. The Schlenk tube was sealed and the reaction mixture was stirred magnetically at 110° C. for 23 h. The resulting brown suspension was cooled to room temperature and filtered through a 0.5×1 cm pad of silica gel eluting with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×15 cm; hexane-ethyl acetate 5:1; 10 mL fractions). Fractions 7-16 provided 159 mg (69% yield) of the product as white crystals. 1H NMR (400 MHz, CDCl3): δ 7.51-7.47 (m, 2H), 6.91-6.95 (m, 2H), 6.83-6.80 (m, 2H), 6.80-6.78 (m, 1H), 6.02 (br s, 1H), 2.33 (q, J=0.5 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.C([O:9][C:10](=O)[CH:11]([C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[C:18]=1[F:25])[C:12](OCC)=[O:13])C.C(N(CCCC)CCCC)CCC>[OH-].[Na+]>[OH:9][C:10]1[C:11]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[C:18]=2[F:25])=[C:12]([OH:13])[N:3]2[N:4]=[CH:5][N:6]=[C:2]2[N:1]=1
Reactant: Nc1nc[nH]n1
Reactant: CCOC(=O)C(C(=O)OCC)c1cc(F)cc(F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCN(CCCC)CCCC
Product: Oc1nc2ncnn2c(O)c1-c1cc(F)cc(F)c1F
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
A mixture of 3-amino-1,2,4-triazole (14 g), diethyl(2,3,5-trifluorophenyl)-malonate (0.17 mol, obtained from Ex. 1) and tributylamine (50 ml) was heated at 180° C. for six hours. The reaction mixture was cooled to about 70° C. After addition of aqueous sodium hydroxide (21 g/200 ml H2O) the reaction mixture was stirred for 30 minutes. After separation of the organic phase the aqueous phase was extracted with diethyl ether. The aqueous phase was acidified with concentrated hydrochloric acid. The precipitate was collected by filtration and dried to yield 43 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][N:4]=1.Cl[C:15]1[N:20]=[N:19][C:18]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]3[C:35]4[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=4)[CH2:29][CH2:28]3)[CH2:23][CH2:22]2)=[CH:17][CH:16]=1>>[F:36][C:33]1[CH:34]=[C:35]2[C:30]([CH2:29][CH2:28][N:27]2[CH:24]2[CH2:25][CH2:26][N:21]([C:18]3[N:19]=[N:20][C:15]([C:6]4[CH:5]=[N:4][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:8][CH:7]=4)=[CH:16][CH:17]=3)[CH2:22][CH2:23]2)=[CH:31][CH:32]=1
Reactant: Fc1ccc2c(c1)N(C1CCN(c3ccc(Cl)nn3)CC1)CC2
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Product: Fc1ccc2c(c1)N(C1CCN(c3ccc(-c4ccc(C(F)(F)F)nc4)nn3)CC1)CC2

Procedure:
The title compound was prepared following the procedure as described in Example 1, Method A, STEP 4, reacting 2-trifluoromethylpyridine-5-boronic acid and 1-(1-(6-chloropyridazin-3-yl)piperidin-4-yl)-6-fluoroindoline.