Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.C1(=O)NC(=O)CC1.[CH:16]1([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][C:29]([OH:31])=[O:30])=[C:24]([OH:32])[CH:23]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(Cl)Cl>[Cl:1][C:27]1[C:22]([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:23][C:24]([OH:32])=[C:25]([CH2:28][C:29]([OH:31])=[O:30])[CH:26]=1
Reactant: O=C(O)Cc1ccc(C2CCCCC2)cc1O
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C1CCC(=O)N1
Solvent: ClCCl
Product: O=C(O)Cc1cc(Cl)c(C2CCCCC2)cc1O

Procedure:
3.54 g of N-chlorosuccinimide and 5.25 g of succinimide are added to a solution of 6.2 g of 4-cyclohexyl-2-hydroxy-phenylacetic acid in 200 ml of dry methylene chloride and the mixture left to react for 5 days at room temperature. The clear reaction solution is washed twice with 1 N hydrochloric acid and once with water, dried and evaporated. The white crystalline residue can either be worked up directly or purified by recrystallization from methylene chloride/petroleum ether.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]1[N:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=1)[CH2:6][CH2:5]2.[NH2:19][C:20]1[C:21]([CH3:29])=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH2:25])=[O:24].C(N(C(C)C)C(C)C)C.CC(O)C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]1[N:13]=[CH:14][N:15]=[C:16]([NH:19][C:20]3[C:21]([CH3:29])=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23]([NH2:25])=[O:24])[N:17]=1)[CH2:6][CH2:5]2
Reactant: Cc1c(N)cccc1C(N)=O
Reactant: Clc1ncnc(N2CCc3cc(Br)ccc3C2)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Nc2ncnc(N3CCc4cc(Br)ccc4C3)n2)cccc1C(N)=O
Temperature: 95 °C
Yield: 25.1 %

Procedure:
To a vial charged with 6-bromo-2-(4-chloro-1,3,5-triazin-2-yl)-1,2,3,4-tetrahydroisoquinoline (163 mg, 499 μmol) and 3-amino-2-methylbenzamide (75 mg, 499 μmol) was added N-ethyl-N-isopropylpropan-2-amine (174 μl, 999 μmol) and propan-2-ol (1665 μl, 499 μmol). The vial was sealed and heated to 95° C. overnight. The product was purified by reverse phase liquid chromatography using TFA as a modifier. Fractions containing the product were combined and neutralized with saturated NaHCO3 (35 mL). The product was extracted with DCM (3×30 mL). The organics were separated, dried over Na2SO4, and filtered to afford 3-(4-(6-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-1,3,5-triazin-2-ylamino)-2-methylbenzamide (55 mg, 25%) as a white solid upon drying.
Reaction SMILES: C[CH:2](NC=O)[CH2:3][C:4]1[S:5][CH:6]=[CH:7][CH:8]=1.P(Cl)(Cl)(Cl)=O.O.[OH-].[Na+].[C:20](#[N:22])[CH3:21]>>[CH3:2][CH:3]1[N:22]=[CH:20][C:21]2[S:5][CH:6]=[CH:7][C:8]=2[CH2:4]1
Reactant: CC(Cc1cccs1)NC=O
Reactant: CC#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CC1Cc2ccsc2C=N1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of 6.6 g (33.1 mmol) N-(1-methyl-2-thiphen-2-yl-ethyl)-formamide in 200 ml acetonitrile is cooled in the ice bath and slowly combined with a solution of 6.1 ml (66.3 mmol) phosphorus oxychloride in 50 ml acetonitrile. The mixture is first of all stirred for a further three hours in the ice bath and then for 16 hours at RT. Then it is poured onto 200 ml of water, made alkaline with 9 g of solid sodium hydroxide and extracted three times with ethyl acetate. The combined organic phases are combined with activated charcoal and sodium sulphate, filtered and evaporated down i. vac.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Cl.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[N:8]1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: Fc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(cnn2Cc2cccc(F)c2)c1
Temperature: 70 °C
Yield: 33 %

Procedure:
A mixture of 5-nitro-1H-indazole (8.15 gm, 50 mmole), m-fluoro-benzyl chloride (7.95 gm, 1.1 equiv), K2CO3 (7.59 gm, 1.1 equiv), and KI (8.47 gm, 1.02 equiv) in dry DMF (75 mL) was heated at 70° C. overnight. After cooling to RT, water (75 mL) was slowly added to give a precipitate that consisted of about a one to one mixture of isomers [HPLC Ret Time: 1.92 (1-substitued isomer vs. 2.03 (2-substituted isomer) YMC C18 S5 4.6×50 mm, 3 min gradient, 4 mL/min]. This was collected by filtration and washed with water. The solid was crystallized twice from acetone/water to afford the desired 1-(3-fluoro-benzyl)-5-nitro-1H-indazole (4.47 gm, 33%). A suspension of this material (3.00 gm, 11.1) and 10% Pd/C (3.00 gm) in EtOH (21 mL) was kept under an H2 atmosphere (balloon) for 24 hr. The catalyst was removed by filtration and the solvent was evaporated to leave the product as a solid (2.4 gm, 90%). 1H NMR (CDCl3): δ 3.61 (br s, 2H), 5.52 (s, 2H), 6.81-7.85 (m, 7H), 7.85 (s, 1H); MS: 242 (M+H)+; HPLC Ret Time: 1.03 min (YMC Xterra ODS S7, 3.0×50 mm column, 2 min gradient, 5 mL/min).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH:11]=[CH:10][NH:9][C:5]=2[N:6]=[CH:7][N:8]=1.FC1C(C=O)=C(F)C=CC=1NS(CCC)(=O)=O.[F:29][C:30]1[C:35]([CH:36]=O)=[C:34]([F:38])[CH:33]=[CH:32][C:31]=1[NH:39][S:40]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=[O:42])=[O:41].C(OC1C2C=CNC=2N=CN=1)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[F:29][C:30]1[C:35]([CH2:36][C:11]2[C:4]3[C:3]([O:2][CH3:1])=[N:8][CH:7]=[N:6][C:5]=3[NH:9][CH:10]=2)=[C:34]([F:38])[CH:33]=[CH:32][C:31]=1[NH:39][S:40]([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)(=[O:42])=[O:41]
Reactant: COc1ncnc2[nH]ccc12
Reactant: O=Cc1c(F)ccc(NS(=O)(=O)c2ccccc2)c1F
Agent: CCCS(=O)(=O)Nc1ccc(F)c(C=O)c1F
Agent: CCOc1ncnc2[nH]ccc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1ncnc2[nH]cc(Cc3c(F)ccc(NS(=O)(=O)c4ccccc4)c3F)c12

Procedure:
were prepared similarly to the protocol of Scheme 7, steps 2 and 3, replacing 4-methyl-7H-pyrrolo[2,3-d]pyrimidine 42 with 4-methoxy-7H-pyrrolo[2,3-d]pyrimidine 3 and propane-1-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide 9 with N-(2,4-Difluoro-3-formyl-phenyl)-benzenesulfonamide in step 2 for P-0072 and replacing 4-methyl-7H-pyrrolo[2,3-d]pyrimidine 42 with 4-ethoxy-7H-pyrrolo[2,3-d]pyrimidine 47 in step 2 for P-0075. Alternatively, the intermediate in the reaction to form P-0072 was reduced using triethylsilane and trifluoroacetic acid to form N-[2,4-difluoro-3-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-phenyl]-benzenesulfonamide P-0073
Reaction SMILES: [Cl:1][C:2]12[C:14]([Cl:16])([Cl:15])[C:5]([Cl:17])([C:6]3[C:7]([OH:13])=[CH:8][CH:9]=[C:10]([OH:12])[C:11]=31)[C:4]([Cl:18])=[C:3]2[Cl:19].[C:20](O)(=[O:22])[CH3:21]>>[CH3:21][C:20]([C:8]1[C:7]([OH:13])=[C:6]2[C:11](=[C:10]([OH:12])[CH:9]=1)[C:2]1([Cl:1])[C:14]([Cl:15])([Cl:16])[C:5]2([Cl:17])[C:4]([Cl:18])=[C:3]1[Cl:19])=[O:22]
Reactant: CC(=O)O
Reactant: Oc1ccc(O)c2c1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Product: CC(=O)c1cc(O)c2c(c1O)C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Temperature: 40 °C

Procedure:
76 g. of 1,2,3,4,9,9-hexachloro-1,4-dihydro-1,4-methanonaphthalene-5,8-diol, prepared according to Example 2, were suspended in 100 ml. of acetic acid and then 20 ml. of boron trifluoride-diethyl ether complex were added. This mixture was heated at 100°-105° C for 5 hours. After being cooled to 40° C, the mixture was poured into ice water. After repeated recrystallization from benzene white crystals were obtained, m.p. 135°-140° C.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH2:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(O)(=O)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: CC(C)C(=O)CNC(=O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(NC(=O)c1ccc(Cl)cc1)C(=O)C(C)C
Yield: 92 %

Procedure:
6 g of N-(4-chlorobenzoyl)isobutyrylmethylamine are dissolved in 30 ml of dimethylformamide, and 1.4 g of 61% sodium hydride are added thereto at -50° C. to -40° C. under stirring. When, 6.0 g of ethyl bromoacetate are added to the mixture at the same temperature. After the temperature of the mixture is risen to about 0° C. gradually, said mixture is further stirred until it becomes a clear solution. After the reaction, the mixture is neutralized with acetic acid, and then water is added thereto. The aqueous solution is extracted with ethyl acetate. The extract is washed with water, dried and then condensed under reduced pressure to remove solvent. The residue is recrystallized from a mixture of isopropyl ether and n-hexane. 7.5 g of ethyl 3-(4-chlorobenzoylamino)-3-isobutyrylpropionate are obtained. Yield: 92.0%.
Reaction SMILES: C[N:2]1[CH2:23][CH2:22][N:5]2[C:6]3[CH:21]=[CH:20][CH:19]=[CH:18][C:7]=3[CH2:8][N:9]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[CH:11]=[C:10]3[CH:4]2[CH2:3]1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C1(C)C=CC=CC=1.C(OCC)C>[CH2:28]([O:27][C:25]([N:2]1[CH2:23][CH2:22][N:5]2[C:6]3[CH:21]=[CH:20][CH:19]=[CH:18][C:7]=3[CH2:8][N:9]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[CH:11]=[C:10]3[CH:4]2[CH2:3]1)=[O:26])[CH3:29]
Reactant: CCOC(=O)Cl
Reactant: CN1CCN2c3ccccc3Cn3c(cc4ccccc43)C2C1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)N1CCN2c3ccccc3Cn3c(cc4ccccc43)C2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 712 mg of 1,3,4,16b-tetrahydro-2-methyl-2H,10H-indolo[2,1-c]pyrazino[1,2-a][1,4]benzodiazepine in 5 ml toluene is added 1.2 g of ethyl chloroformate and the reaction mixture is heated at reflux temperature with stirring for 8 hours. On cooling to room temperature the reaction mixture is diluted with 50 ml of diethyl ether and the resulting precipitate collected by filtration and washed well with ether. The filtrate is evaporated to dryness under reduced pressure to yield 1,3,4,16b-tetrahydro-2-ethoxycarbonyl-2H,10H-indolo[2,1-c]pyrazino[1,2-a][1,4]benzodiazepine as an oil which is used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.B([O-])[O-].[C:13]([O:17][C:18]([NH:20][C@@H:21]([CH2:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=1)[C:22]([OH:24])=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)C.O>[NH2:1][C:2]1[N:3]=[C:4]([C:29]2[CH:28]=[CH:27][C:26]([CH2:25][C@H:21]([NH:20][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[C:22]([OH:24])=[O:23])=[CH:31][CH:30]=2)[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)O
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(Cl)nc(N)n2)cc1)C(=O)O
Temperature: 80 °C
Yield: 79.3 %

Procedure:
To a 500 ml 3-neck round-bottom flask equipped with a mechanical stirrer, a thermocontroller was charged 2-amino-4,6-dichloropyrimidine (12.57 g, 1.5 equiv), boronate compound 7 (20.00 g, 51.1 mmol), potassium carbonate (21.19 g, 3.0 equiv) and ethanol/water (200 ml, 5:1 by volume). The mixture was stirred and the catalyst bis(triphenylphosphine)palladium(II) dichloride (359 mg, 1 mol %) was added. The mixture was heated to 80° C. and stirred for 2 hours. The reaction was cooled to room temperature and diluted with water (100 ml). The mixture was then concentrated under reduced pressure to remove most of ethanol and 1 N NaOH (60 ml) was added. The mixture was extracted twice with ethyl acetate (2×200 ml) and the aqueous layer was acidified to pH˜3 using 1 N HCl. The mixture was extracted with ethyl acetate twice (200 ml and 100 ml, respectively) and the combined organic layers were concentrated and the residue was purified by column chromatography (gradient 1:20 to 1:10 methanol/dichloromethane) to afford compound 8 as a pale yellow solid (15.92 g, 79%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C(Cl)Cl.CC([O-])=O.[K+].Br[C:39]1[S:40][C:41]2[C:47]([C:48]3[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=3)=[C:46]([C@H:55]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])[C:56]([O:58][CH2:59][CH3:60])=[O:57])[C:45]([CH3:66])=[CH:44][C:42]=2[N:43]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:62]([O:61][C@@H:55]([C:46]1[C:45]([CH3:66])=[CH:44][C:42]2[N:43]=[C:39]([C:2]3[CH:7]=[CH:6][C:5]([F:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=3)[S:40][C:41]=2[C:47]=1[C:48]1[CH:49]=[CH:50][C:51]([Cl:54])=[CH:52][CH:53]=1)[C:56]([O:58][CH2:59][CH3:60])=[O:57])([CH3:63])([CH3:64])[CH3:65]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc(F)c([N+](=O)[O-])c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A microwave vial was charged with 4-bromo-1-fluoro-2-nitrobenzene (0.3 mL, 2.41 mmol), Bis(pinacolato)diboron (677 mg, 2.67 mmol), PdCl2(dppf).CH2Cl2 (203 mg, 0.25 mmol), then KOAc (864 mg, 8.80 mmol). The vial was flushed with argon, diluted with dioxane (6 mL), sealed, then heated to 100° C. for 1 hour. The reaction mixture was allowed to cool to room temperature and then a portion of this cooled solution (1.3 mL, 0.52 mmol) was added to a vial that was charged with (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (130 mg, 0.26 mmol) and Pd(PPh3)4 (44 mg, 0.04 mmol). The mixture was diluted with dioxane (5.0 mL) and to this was added 2M aqueous K2CO3 (0.50 mL, 1.00 mmol). The vial was sealed, heated to 100° C. for 1 hour, and then allowed to cool to room temperature. The mixture was diluted with EtOAc, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (0-25% EtOAc/Hex gradient) to afford the desired product. LCMS-ESI+: calc'd C28H27ClFN2O5S: 557.1 (M+H+); Found: 557.1 (M+H+).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([CH2:18][CH2:19][CH2:20]OS(C)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:28]([NH:30][CH2:31][CH2:32][OH:33])[CH3:29]>>[CH2:28]([N:30]([CH2:20][CH2:19][CH2:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:27])([F:1])[F:26])=[CH:8][CH:7]=3)=[N:10][S:11][C:12]=2[CH:17]=1)[CH2:31][CH2:32][OH:33])[CH3:29]
Reactant: CS(=O)(=O)OCCCc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Reactant: CCNCCO
Product: CCN(CCO)CCCc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 17.1; Methanesulfonic acid 3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-propyl ester and 2-ethylaminoethanol were converted to yield 2-(Ethyl-{3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-propyl}-amino)-ethanol as light brown oil, MS: 409 (MH+).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:31])[S:9][CH2:8][CH2:7][N:6]2[C:10]([C:13]3([C:16]4[CH:21]=[CH:20][C:19]([C:22]5[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][N:23]=5)=[CH:18][CH:17]=4)[CH2:15][CH2:14]3)=[N:11][N:12]=[C:5]2[CH2:4]1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:31][C:3]1([CH2:2][OH:1])[S:9][CH2:8][CH2:7][N:6]2[C:10]([C:13]3([C:16]4[CH:17]=[CH:18][C:19]([C:22]5[CH:30]=[CH:29][C:25]([C:26]([N:32]6[CH2:37][CH2:36][O:35][CH2:34][CH2:33]6)=[O:27])=[CH:24][N:23]=5)=[CH:20][CH:21]=4)[CH2:14][CH2:15]3)=[N:11][N:12]=[C:5]2[CH2:4]1
Reactant: C1COCCN1
Reactant: CC1(CO)Cc2nnc(C3(c4ccc(-c5ccc(C(=O)O)cn5)cc4)CC3)n2CCS1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5ccc(C(=O)N6CCOCC6)cn5)cc4)CC3)n2CCS1
Yield: 29.8 %

Procedure:
A solution of the compound (200 mg, 0.458 mmol) obtained in Example 66, morpholine (200 μL, 2.29 mmol), N,N-dimethylaminopyridine (6 mg, 46 μmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (264 mg, 1.37 mmol) in N,N-dimethylformamide (4.00 mL) was stirred at room temperature for 14 h. Saturated aqueous sodium hydrogencarbonate (100 mL) was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with water and dried with anhydrous sodium sulfate. Then the solvent was distilled off under reduced pressure. The residue was purified by preparative TLC (dichloromethane:methanol=9:1) to obtain the title compound (69 mg, 11%) as a white solid.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]3[CH2:24][NH:25][CH2:26][CH2:27][C:21]3=[N:20][C:19]=2[NH:28][CH:29]([CH3:31])[CH3:30])[CH2:14][CH2:13]1.C([O-])([O-])=O.[Cs+].[Cs+].FC(F)I>CC(N(C)C)=O>[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:23]=[C:22]3[CH2:24][N:25]([CH:2]=[O:1])[CH2:26][CH2:27][C:21]3=[N:20][C:19]=2[NH:28][CH:29]([CH3:31])[CH3:30])[CH2:16][CH2:17]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CNCC2
Agent: FC(F)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)N(C)C
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CN(C=O)CC2
Temperature: 50 °C

Procedure:
A mixture of 3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (36 mg, 0.058 mmol), Cs2CO3 (66.0 mg, 0.203 mmol), and difluoroiodomethane (0.051 mL, 0.579 mmol) in DMA (0.5 mL) was heated in a microwave on high absorbance for 15 min at 50° C. The resulting crude material was filtered, rinsed with DMSO (2×0.5 mL), and purified by HPLC Method B using a 30% to 70% ACN gradient to give the title compound as a TFA salt (11.2 mg, 35.5%) as a yellow solid. 1H NMR (500 MHz, methanol-d4) δ ppm 1.29 (d, J=6.4 Hz, 6H), 1.90-2.01 (m, 2H), 2.07-2.18 (m, 2H), 2.78-2.89 (m, 2H), 3.02-3.10 (m, 2H), 3.39-3.45 (m, 2H), 3.76-3.86 (m, 2H), 4.14 (quin, J=6.4 Hz, 1H), 4.46-4.49 (m, 3H), 6.85-6.91 (m, 1H), 6.95-7.01 (m, 1H), 7.14-7.21 (m, 1H), 8.16-8.27 (m, 1H); ESI-MS m/z [M+H]+ 432.4.
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]1[NH:7][C:6]2[CH:8]=[C:9]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:10]=[C:11]([O:12][CH3:13])[C:5]=2[N:4]=1.[Cl:23][C:24]1[N:29]=[C:28](Cl)[N:27]=[C:26]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:25]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:23][C:24]1[N:25]=[C:26]([N:31]2[CH2:32][CH2:33][O:34][CH2:35][CH2:36]2)[N:27]=[C:28]([N:7]2[C:6]3[CH:8]=[C:9]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH:10]=[C:11]([O:12][CH3:13])[C:5]=3[N:4]=[C:3]2[CH:2]([F:1])[F:22])[N:29]=1
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Reactant: COc1cc(NC(=O)OC(C)(C)C)cc2[nH]c(C(F)F)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(NC(=O)OC(C)(C)C)cc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
A mixture of tert-butyl 2-(difluoromethyl)-4-methoxy-1H-benzimidazol-6-yl-carbamate (0.47 g, 1.5 mmol), 2,4-dichloro-6-(4-morpholinyl)-1,3,5-triazine (0.35 g, 1.5 mmol), and powdered K2CO3 (0.83 g, 6 mmol) in DMF (10 mL) was stirred at room temperature for 30 min. The reaction mixture was then diluted with water. The resulting precipitate was collected, washed with water and then MeOH, and dried to give 0.45 g (59% yield) of tert-butyl 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazol-6-yl-carbamate: mp (CH2Cl2/MeOH)>300° C.; 1H NMR (CDCl3) δ 8.45 (d, J=0.6 Hz, 1H), 7.57 (t, JHF=53.6 Hz, 1H), 6.67 (br, exchangeable with D2O, 1H), 6.63 (d, J=0.9 Hz, 1H), 4.11 (m, 2H), 4.02 (s, 3H), 3.97 (m, 2H), 3.88 (m, 2H), 3.82 (m, 2H), 1.52 (s, 9H); Anal. Calcd. for C21H24ClF2N7O4: C, 49.3; H, 4.7; N, 19.15. Found: C, 49.4; H, 4.8; N, 19.2%.
Reaction SMILES: FC1C=CC(C2C(OC(C)C)=NC=C(C=2)C(O)=O)=CC=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:33](=[O:34])[N:32]([CH:35]([CH3:37])[CH3:36])[CH:31]=[C:30]([C:38]([OH:40])=O)[CH:29]=2)=[CH:24][CH:23]=1.[CH3:41][C:42]1[N:46]=[C:45]([C@H:47]([NH2:49])[CH3:48])[O:44][N:43]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl>CN(C=O)C>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[C:33](=[O:34])[N:32]([CH:35]([CH3:36])[CH3:37])[CH:31]=[C:30]([C:38]([NH:49][C@@H:47]([C:45]3[O:44][N:43]=[C:42]([CH3:41])[N:46]=3)[CH3:48])=[O:40])[CH:29]=2)=[CH:26][CH:27]=1
Reactant: Cc1noc([C@@H](C)N)n1
Reactant: CC(C)n1cc(C(=O)O)cc(-c2ccc(F)cc2)c1=O
Agent: CC(C)Oc1ncc(C(=O)O)cc1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc([C@@H](C)NC(=O)c2cc(-c3ccc(F)cc3)c(=O)n(C(C)C)c2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.4 %

Procedure:
To a solution of 5-(4-fluorophenyl)-6-isopropoxynicotinic acid and 5-(4-fluorophenyl)-1-isopropyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (50 mg, 0.09 mmol) in DMF (0.5 mL) were added hydrochloride salt of (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine (21.8 mg, 0.11 mmol), HATU (0.5 M in DMF; 0.27 mL, 0.14 mmol) and diisopropylethylamine (63 μL, 0.36 mmol). The mixture was stirred at ambient temperature. After 10 min, HCl (1.0 M) was added and the mixture was purified by reverse chromatography (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) to give the N-alkylated product, 5-(4-fluorophenyl)-1-isopropyl-N-[(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]-6-oxo-1,6-dihydropyridine-3-carboxamide (example 5.61) (20.9 mg), HRMS 385.1685. 1H NMR (400 MHz, CDCl3): δ 8.21 (d, J=2.5 Hz, 1H); 7.69-7.63 (m, 3H); 7.12 (t, J=8.5 Hz, 2H); 6.52 (d, J=7.7 Hz, 1H); 5.60-5.51 (m, 1H); 5.37-5.27 (m, 1H); 2.41 (s, 3H); 1.70 (d, J=7.1 Hz, 3H); 1.45 (dd, J=6.8, 2.2 Hz, 6H). The o-alkylated product was repurified by reverse chromatography (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.05% ammonium hydroxide) to give 5-(4-fluorophenyl)-6-isopropoxy-N-[(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]nicotinamide (example 3.24) (16.1 mg). HRMS 385.1679. 1H NMR (400 MHz, CDCl3): δ 8.59 (s, 1H); 8.01 (d, J=2.3 Hz, 1H); 7.55 (dd, J=8.3, 5.4 Hz, 2H); 7.16-7.08 (m, 2H); 6.63 (d, J=7.7 Hz, 1H); 5.63-5.55 (m, 1H); 5.51-5.43 (m, 1H); 2.40 (s, 3H); 1.71 (d, J=7.1 Hz, 3H); 1.35 (d, J=6.2 Hz, 6H).
Reaction SMILES: N#N.[N+:3]([C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:14](O)[CH:15]([N+:17]([O-:19])=[O:18])[CH3:16])([O-:5])=[O:4].C(OC(=O)C)(=O)C.C1OCCOCCOCCOCCOCCOC1.[F-].[K+]>O>[N+:3]([C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH3:16])([O-:5])=[O:4]
Reactant: COc1cccc(C(O)C(C)[N+](=O)[O-])c1[N+](=O)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: N#N
Agent: [F-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1cccc(C=C(C)[N+](=O)[O-])c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 64 h
Yield: 95.9 %

Procedure:
To a 5 L three-necked round-bottomed flask equipped with a mechanical stirrer and a N2 bubbler were added 1-(2-nitro-3-methoxyphenyl)-2-nitropropanol (170 g, 0.66 mol), acetic anhydride (450 mL), 18-Crown-6 (17 g) and KF (38.25 g). The reaction mixture was stirred at RT for 64 h, then cooled in an ice-water bath. Water (2250 mL) was added slowly. The resulting slurry was stirred at 0° C. for 2 h and then filtered. The cake was washed with DI water (3×250 mL) and suction dried for 20 h to give 1-(2-nitro-3-methoxyphenyl)-2-nitropropene (150.7 g, 96% yield). 1H NMR (CDCl3) δ2.30 (s, 3H), 3.95 (s, 3H), 6.94 (d, J=7.8 Hz, 1H), 7.13 (d, J=8.5 Hz, 1H), 7.53 (pseudo t, J=8.1 Hz, 1H), 7.89 (s, 1H).