Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:24]3[CH:25]=[CH:26][C:27]4[C:31]([CH:32]=3)=[N:30][N:29]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:28]=4)[CH:9]=[C:10]([C:11]3[CH2:12][CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][CH:16]=3)[N:6]2[N:5]=[CH:4][N:3]=1.Cl>CO.O1CCOCC1>[CH2:33]([N:29]1[CH:28]=[C:27]2[C:31]([CH:32]=[C:24]([C:8]3[CH:9]=[C:10]([C:11]4[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=4)[N:6]4[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)[CH:25]=[CH:26]2)=[N:30]1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1ncnn2c(C3=CCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 41 h
Yield: 112 %

Procedure:
To a solution of tert-butyl 4-[4-amino-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3,6-dihydropyridine-1(2H)-carboxylate (564 mg, 1.08 mmol) in MeOH (4 mL) was added 4M HCl in dioxane (2 mL). The mixture was stirred at rt for 41 h. The mixture was concentrated and the residue was dissolved in 3:1 CHCl3/isopropanol (25 mL). The mixture was washed with saturated, aqueous NaHCO3 (25 mL), brine, dried (Na2SO4) and concentrated to dryness to afford 510 mg (96%) of the desired product, which contained trace impurities. 1H NMR (400 MHz, DMSO-d6) δ 8.54-8.58 (s, 1 H), 7.92 (s, 1 H), 7.80 (d, 1 H), 7.61 (s, 1 H), 7.27-7.37 (m, 5 H), 7.14 (dd, 1 H), 7.01-7.06 (m, 1 H), 6.75 (s, 1 H), 5.65 (s, 2 H), 3.40-3.48 (m, 2 H), 2.92 (t, 1 H), 2.42-2.49 (m, 2 H); ES-MS m/z 422.06 [M+H]+, HPLC RT (min) 1.03 min.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[CH:13]1[CH:17]=[C:16]([CH2:18][NH2:19])[O:15][CH:14]=1.O>N1C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:19][CH2:18][C:16]2[O:15][CH:14]=[CH:13][CH:17]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCc1ccco1
Solvent: c1ccncc1
Solvent: O
Product: N#Cc1ccc(S(=O)(=O)NCc2ccco2)cc1
Reaction time: 2 h
Yield: 88.6 %

Procedure:
4-Cyanobenzenesulfonyl chloride (1.77 g, 8.78 mmol) was dissolved in 8 mL of anhydrous pyridine and 2-furfurylamine (1.04 g, 9.66 mmol, 0.98 mL) was added. After 2 h, the reaction solutions were added to 100 mL cold water and stirred for 10 min. Filtration and washing with water provided the title compound as a yellow solid (2.04 g, 7.78 mmol, 89%). 1H NMR (300 MHz, CDCl3) δ 7.90 (d, J=8.4 Hz, 2H), 7.75 (d, J=8.4 Hz, 2H), 7.18 (s, 1H), 6.19 (m, 1H), 6.10 (m, 1H), 4.95 (m, 1H), 4.28 (d, J=6.0 Hz, 2H) ppm.
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6]CC)=O.[H-].[Na+].[Cl:15][C:16]1[CH:35]=[C:34]([F:36])[C:33]([NH:37][C:38](OCC)=[O:39])=[CH:32][C:17]=1[O:18][C:19]1[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=1[O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>CN(C)C=O>[Cl:15][C:16]1[CH:35]=[C:34]([F:36])[C:33]([N:37]2[C:4](=[O:6])[CH:3]=[C:2]([C:9]([F:10])([F:11])[F:12])[NH:1][C:38]2=[O:39])=[CH:32][C:17]=1[O:18][C:19]1[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=1[O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: CCOC(=O)COc1ccccc1Oc1cc(NC(=O)OCC)c(F)cc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Temperature: 0 °C

Procedure:
To ethyl 3-amino-4,4,4-trifluorocrotonate are added N,N-dimethylformamide and sodium hydride and the mixture is stirred at 0° C. Thereafter, to the reaction solution is added a mixture of ethyl [2-(2-chloro-4-fluoro-5-ethoxycarbonylaminophenoxy)phenoxy]acetate [Intermediate compound A8-23] and N,N-dimethylformamide, and the mixture is stirred at 80° C. Then reaction solution is cooled to room temperature, then, poured into a mixture of hydrochloric acid and ice water, and the deposited crystal is collected by filtration to obtain ethyl [2-{2-chloro-5-[2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-4-fluorophenoxy}phenoxy]acetate.s
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1>>[C:2]1([NH:1][C:20]2[C:15]([C:12]3[CH:11]=[CH:10][CH:9]=[CH:14][CH:13]=3)=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: Brc1ccc(-c2ccccc2)cc1
Product: c1ccc(Nc2ccccc2-c2ccccc2)cc1

Procedure:
An improved process for producing diarylamines is to react an arylbromide and an aniline compound in the presence of a suitable catalyst. For example, aniline can be rapidly reacted with 4-bromobiphenyl to form N-phenyl-biphenylamine using palladium acetate ligated with 2,4,6-trioxa-1,3,5,7-tetramethyl-8-phosphaadamantane, which is manufactured as Cytop-216 (Cytec Industries), and sodium t-pentoxide base. This reaction proceeds rapidly, in about 4 to 6 hours, to produce the desired diarylamine.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[F:26][C:27]([F:40])([F:39])[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35](Cl)(=[O:37])=[O:36]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:35]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[O:28][C:27]([F:26])([F:39])[F:40])(=[O:37])=[O:36])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccccc4OC(F)(F)F)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 2-(trifluoromethoxy)benzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([OH:15])=O)[N:10]=[C:9]([C:16]3[N:17]=[CH:18][NH:19][CH:20]=3)[CH:8]=2)=[CH:4][CH:3]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([OH:29])[CH2:24]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:23]3[CH2:28][CH2:27][CH2:26][C@@H:25]([OH:29])[CH2:24]3)=[O:15])[N:10]=[C:9]([C:16]3[N:17]=[CH:18][NH:19][CH:20]=3)[CH:8]=2)=[CH:21][CH:22]=1
Reactant: O=C(O)Cn1nc(-c2c[nH]cn2)cc1Cc1ccc(F)cc1
Reactant: O[C@@H]1CCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(Cn1nc(-c2c[nH]cn2)cc1Cc1ccc(F)cc1)N1CCC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.6 %

Procedure:
A mixture of [5-(4-fluorobenzyl)-3-(1H-imidazol-4-yl)-1H-pyrazol-1-yl]acetic acid (0.5 g, 1.67 mmol), (R)-piperidin-3-ol (0.30 g, 2.50 mmol), EDCI (0.58 g, 3.0 mmol), HOBt (0.40 g, 3.0 mmol) and NMM (1.0 mL, 10.0 mmol) in DMF (15 mL) was stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue was diluted with water (5 mL). The mixture was extracted with CH2Cl2 (3×5 mL) and the organics combined, washed with 1 N aq. NaOH (3×10 mL), water (3×5 mL) and brine (25 mL), dried over MgSO4 and evaporated. The residue was purified via column chromatography (silica gel, EtOAc/Petroleum ether 1:4) to yield crude material (201.0 mg), which was further purified via prep. HPLC to yield the title compound (100 mg, 15%) as a white solid. 1H NMR (400 MHz, MeOD): δ ppm 8.837 (s, 1H), 7.699 (s, 1 H), 7.303 (m, 2 H), 7.078 (m, 2 H), 6.337 (s, 1 H), 3.992-3.039 (m, 7 H), 1.994-1.400 (m, 4 H).
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][CH:8]([NH:13][C:14](=[O:35])[CH:15]([CH2:19][C:20]([N:22]1[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:17][CH3:18])[C:9](=[O:12])[CH2:10][F:11])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:33]1[C:34]2[N:22]([C:20](=[O:21])[CH2:19][CH:15]([CH2:16][CH2:17][CH3:18])[C:14]([NH:13][CH:8]([C:9](=[O:12])[CH2:10][F:11])[CH2:7][C:6]([OH:36])=[O:5])=[O:35])[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]=2[CH:30]=[CH:31][CH:32]=1
Reactant: CCCC(CC(=O)n1c2ccccc2c2ccccc21)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CF
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC(CC(=O)n1c2ccccc2c2ccccc21)C(=O)NC(CC(=O)O)C(=O)CF
Reaction time: 2 h
Yield: 5.6 %

Procedure:
A solution of [3S/R, (2R)]-3-[2-(2-carbazol-9-yl-2-oxo-ethyl)-pentanoylamino]-5-fluoro-4-oxo-pentanoic acid tert-butyl ester (1.43 g, 2.88 mmol) in anhydrous DCM (20 ml) was treated with a solution of TFA (10 ml) in anhydrous DCM (10 ml) with stirring. The mixture was stirred at 0° C. for 2 h then at room temperature for 2 h. The mixture was concentrated under reduced pressure and then the residue was dissolved in dry DCM. This process was repeated several times in order to remove excess trifluoroacetic acid. The off-white solid was recrystallized from Et2O/40/60 hexanes to give the title compound as a white powder (71 mg): IR (solid) 1746, 1689, 1641, 1541, 1436, 1374, 1284, 1207, 1160 cm-1; 1H NMR (400 MHz, d6-DMSO) δ 0.80-1.00 (3H, m), 1.20-1.76 (4H, m), 2.30-2.90 (2H, m), 2.95-3.24 (1H, m), 3.26-3.59 (2H, m), 4.25-4.79 (1.5H, m), 5.02-5.43 (1.5H, m), 7.36-7.58 (4H, m), 8.10-8.30 (4H, m), 8.54-8.91 (1H, m); 13C NMR (100 MHz, DMSO) δ 14.31, 20.03, 20.13, 21.92, 22.51, 34.36, 34.77, 41.20, 41.62, 44.06, 51.77, 52.84, 83.45, 85.22, 116.70, 120.54, 123.91, 124.01, 127.85, 126.01, 138.20, 172.15, 172.36, 172.96, 173.00, 175.32, 175.48, 202.60, 203.10; 19F (376 MHz, DMSO) δ −226.68, −226.73, −231.21, −232.95, −233.38, −233.52.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:4]=2[N:3]=1.[C:12]1([NH:18][CH2:19][CH2:20][NH2:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>>[Cl:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:21][CH2:20][CH2:19][NH:18][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:3][C:4]=2[CH:10]=1
Reactant: Clc1ccc2[nH]c(Cl)nc2c1
Reactant: NCCNc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc2nc(NCCNc3ccccc3)[nH]c2c1
Temperature: 110 °C
Yield: 62.6 %

Procedure:
A neat mixture of 2,5-dichloro-1H-benzoimidazole (150 mg, 0602 mmol), N-phenyl ethylenediamine (110 mg, 0.808 mmol, 1 eq) and N,N-diisopropylethyl amine (210 mL, 1.21 mmol, 1.5 eq.) in sealed tube was heated overnight at 110° C. The mixture was directly loaded onto a silica gel column and eluted with 5% methanol in dichloromethane to provide 144 mg of N1-(6-chloro-1H-benzo[d]imidazol-2-yl)-N2-phenylethane-1,2-diamine.
Reaction SMILES: [NH4+:1].[OH-].C[O:4][C:5](=O)[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1>CO>[F:16][C:15]([F:18])([F:17])[O:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]([NH2:1])=[O:4])=[CH:9][CH:10]=1
Reactant: [NH4+]
Reactant: COC(=O)COc1ccc(OC(F)(F)F)cc1
Agent: [OH-]
Solvent: CO
Product: NC(=O)COc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
A 25% ammonia aqueous solution (20 ml) was added to (4-trifluoromethoxyphenoxy)acetic acid methyl ester in methanol (40 ml) and the mixture was stirred at room temperature overnight. After distilling the solvent off, the residue was washed with water and dried to afford the title compound as a white solid (12.1 g, yield 91%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[C:6]([C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=2)[N:4]2[CH:14]=[CH:15][CH:16]=[C:3]12.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[F:50][C:51]1[CH:56]=[CH:55][C:54]([NH2:57])=[C:53]([NH2:58])[CH:52]=1>O1CCCC1>[NH2:58][C:53]1[CH:52]=[C:51]([F:50])[CH:56]=[CH:55][C:54]=1[NH:57][C:11]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]1[CH:14]=[CH:15][CH:16]=[C:3]1[C:2]2=[O:1])=[O:13]
Reactant: Nc1ccc(F)cc1N
Reactant: O=C(O)c1cccc2c1-n1cccc1C2=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(F)ccc1NC(=O)c1cccc2c1-n1cccc1C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.6 %

Procedure:
In a 250 ml round-bottomed flask under argon, a mixture of 620 mg of 9-oxo-9H-pyrrolo[1,2-a]indole-5-carboxylic acid obtained according to the preceding stage, 1.50 g of o-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) and 0.44 ml of diisopropylethylamine in 55 ml of tetrahydrofuran is stirred at ambient temperature for 1 hour. 367 mg of 4-fluoro-o-phenylenediamine are then added and the stirring is maintained for 3 days. The reaction medium is evaporated to dryness under vacuum and the residue is taken up with 15 ml of a mixture of dichloromethane and methanol (90/10 v/v). The organic phase is washed with 10 ml of a saturated solution of sodium bicarbonate, then with 3 times 5 ml of distilled water, and dried over magnesium sulphate. After evaporation to dryness under vacuum, the residue is loaded as a dry spot onto a column of silica gel (40-63 μm) and chromatographed, elution being carried out with a mixture of dichloromethane and methanol (95/5 v/v). 379 mg of 9-oxo-9H-pyrrolo[1,2-a]indole-5-carboxylic acid (2-amino-4-fluorophenyl)amide are obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1.[C:11]([NH:13][C:14](=[N:17]CCSCC1N=CNC=1)SC)#[N:12]>C(O)C>[C:11]([NH:13][C:14]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)=[NH:17])#[N:12]
Reactant: NCCSCc1c[nH]cn1
Reactant: CSC(=NCCSCc1c[nH]cn1)NC#N
Solvent: CCO
Product: N#CNC(=N)NCCSCc1c[nH]cn1

Procedure:
4-((2-Aminoethyl)thiomethyl)imidazole is reacted with dimethyl-N-cyanoimidodithiocarbonate according to the procedure of Example 3(c)(i) and the resultant N-cyano-N'-[2-(4-imidazolylmethylthio)ethyl]-S-methylisothiourea treated with ammonical ethanol according to the procedure of Example 5 to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH2:19][C:20]([OH:22])=[O:21])[CH:8]=[C:9](OS(C(F)(F)F)(=O)=O)[CH:10]=1.[CH2:36]([Zn]CC)[CH3:37]>C1(C)C=CC=CC=1>[CH2:36]([C:9]1[CH:8]=[C:7]([CH2:19][C:20]([OH:22])=[O:21])[CH:6]=[C:5]([O:4][C:3]2[CH:23]=[CH:24][C:25]([S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:29])=[O:28])=[CH:26][C:2]=2[F:1])[CH:10]=1)[CH3:37]
Reactant: CC[Zn]CC
Reactant: O=C(O)Cc1cc(Oc2ccc(S(=O)(=O)c3ccccc3)cc2F)cc(OS(=O)(=O)C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: CCc1cc(CC(=O)O)cc(Oc2ccc(S(=O)(=O)c3ccccc3)cc2F)c1

Procedure:
The title compound was prepared as described in example 76 step (iii) but instead using the product of example 76 step (ii) and 2.0M diethylzinc in toluene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1.[C:14]1([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[BH4-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:27][CH:24]2[CH2:25][CH2:26][N:21]([CH2:20][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:22][CH2:23]2)=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: COc1ccc(C=O)c([N+](=O)[O-])c1
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNC2CCN(Cc3ccccc3)CC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3.0 g (16.561 mmol) of 4-methoxy-2-nitrobenzaldehyde, 3.2 g (16.817 mmol) of 1-phenylmethyl-4-piperidinamine and 30 mL of methanol was stirred for 2 hours at ambient temperature. Then 681 mg (18.0 mmol) of sodium borohydride was added and stirring was continued for one hour at ambient temperature. The mixture was stirred into 500 mL of ice water and carefully acidified with 10% hydrochloric acid. The solution obtained was washed twice with 50 mL of tert-butylmethylether, then made alkaline with 20% sodium hydroxide solution and extracted exhaustively with tert-butylmethylether. The final extracts obtained were combined, washed twice with 20 mL of water, dried over magnesium sulfate and evaporated down in vacuo. The colorless oil remaining was used in the next step without any further purification. Yield: 3.2 g (54% of theoretical). IR (KBr): no C═O; MS: M+=355.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]([OH:18])=[O:17])[C:10]1=[O:19])=O)(C)(C)C.Cl.[CH2:21](O)[CH3:22]>>[NH2:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C:16]([O:18][CH2:21][CH3:22])=[O:17])[C:10]1=[O:19]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(CC(=O)O)C1=O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)CN1CCC[C@H](N)C1=O
Reaction time: 1 h

Procedure:
To a solution of compound 21 (5.45 g, 0.020 mol) in 20 mL of dry ethanol at 0° was added ethanolic 12N HCl (50.0 mL, 0.60 mol). The solution was stirred at 0° for one hr and then allowed to stir at ambient temperature for 3 hrs. The solvent was evaporated, the residue was twice redissolved in a mixture of ethanol, acetonitrile: 1,1 and reevaporated. After vacuum pumping at <1 mm Hg for 24 hrs, 4.84 g (~quantitative crude yield) of product 22 was obtained as a sticky light brown foam. TLC (silica; CH2Cl2, methanol, conc NH4OH: 27, 3, 1): Rf=0.35.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8]3[CH:14]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=4)[CH:12]=[N:11][C:9]=3[NH:10][C:6]=2[CH:5]=[N:4][C:3]=1[C:21]#[N:22].[H-].[Na+].Cl[CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31]>CN(C=O)C.O>[Br:1][C:2]1[C:7]2[C:8]3[CH:14]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=4)[CH:12]=[N:11][C:9]=3[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:6]=2[CH:5]=[N:4][C:3]=1[C:21]#[N:22]
Reactant: Cn1cc(-c2cnc3[nH]c4cnc(C#N)c(Br)c4c3c2)cn1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2cnc3c(c2)c2c(Br)c(C#N)ncc2n3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53.9 %

Procedure:
To a solution of 5-bromo-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (547 mg, 1.55 mmol) in DMF (25 ml) under a flow of nitrogen was added sodium hydride (93 mg, 60% dispersion in mineral oil, 2.39 mmol). After 20 min, a yellow solution had formed and (2-chloromethoxyethyl)-trimethyl-silane (358 μL, 2.02 mmol) was added. The reaction mixture was stirred at ambient temperature for 3 days, then diluted with water and sonicated. The resultant solid was collected by filtration and triturated with methanol to afford the title compound as a yellow solid (404 mg, 54%). 1H NMR (CDCl3, 300 MHz): δ 9.13 (s, 1H), 9.04 (d, J=2.2 Hz, 1H), 8.95 (d, J=2.1 Hz, 1H), 7.93-7.88 (m, 1H), 7.83-7.77 (m, 1H), 6.06 (s, 2H), 4.06 (s, 3H), 3.70-3.59 (m, 2H), 1.03-0.92 (m, 2H), -0.03 (s, 9H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:8][C:9]1[S:10][C:11]([CH:14]2[CH2:16][CH2:15]2)=[N:12][N:13]=1.[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:40]1[N:41]=[CH:42][NH:43][CH:44]=1)([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C>[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:40]1[N:41]=[CH:42][N:43]([CH2:8][C:9]2[S:10][C:11]([CH:14]3[CH2:16][CH2:15]3)=[N:12][N:13]=2)[CH:44]=1)([C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:23])([CH3:19])([CH3:20])[CH3:18]
Reactant: ClCc1nnc(C2CC2)s1
Reactant: CCOC(=O)C(CCCCNC(=O)OC(C)(C)C)(C(=O)OCC)c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCCCNC(=O)OC(C)(C)C)(C(=O)OCC)c1cn(Cc2nnc(C3CC3)s2)cn1
Yield: 17.9 %

Procedure:
Together with 1.97 g (6.04 mmol) of cesium carbonate and 0.29 g (1.66 mmol) of 2-chloromethyl-5-cyclopropyl-1,3,4-thiadiazole, a solution of 0.60 g (1.51 mmol) of diethyl 2-(4-tert-butoxycarbonylaminobutyl)-2-(1H-imidazol-4-yl)malonate in 12 ml of DMF was heated at 75° C. for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was taken up in ethyl acetate and washed with water. The organic phase was dried over Na2SO4, filtered and concentrated. Chromatographic purification of the residue on silica gel (CH2Cl2:MeOH:water:acetic acid 95:5:0.5:0.5) gave 0.145 g (18%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=NO)[C:10]=2[CH:11]=1.C([O-])([O-])=[O:15].[Na+].[Na+]>CC(C)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:15])[C:10]=2[CH:11]=1
Reactant: ON=C1CCCc2cnc(Cl)cc21
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C1CCCc2cnc(Cl)cc21
Temperature: 60 °C

Procedure:
3-Chloro-7,8-dihydro-6H-isoquinolin-5-one oxime (9.10 g; 46.3 mmol) dissolved in acetone (105 ml) and HClconc (105 ml) is heated at 60° C. for 1 hour. The reaction mixture is poured on 2N Na2CO3 and extracted with ethyl acetate three times, the organic phases are combined, dried over Na2SO4 and evaporated to dryness. Chromatography (SiO2; Hexanes/acetone 85:15) yields the desired ketone as yellowish crystals. 1H-NMR (400 MHz; DMSO-d6): 8.57 (s, 1H); 7.66 (s, 1H); 2.96 (m, 2H); 2.71 (m, 2H); 2.10 (m, 2H). MS (m/z) ES+: 182 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][C:20]1=[O:24].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=[C:2]([N:19]2[CH2:23][CH2:22][CH2:21][C:20]2=[O:24])[CH:7]=1
Reactant: O=C1CCCN1
Reactant: C[C@H](Nc1nc(Cl)cc(Cl)n1)c1ccc(F)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@H](Nc1nc(Cl)cc(N2CCCC2=O)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
100 mg of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyrimidine-2-amine (Reference Example 1), 33 mg of 2-pyrrolidone, 20 mg of 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 149 mg of tripotassium phosphate and 19 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 3 ml of degassed 1,4-dioxane, and the mixture was stirred at 100° C. for 3 hours under argon atmosphere. The reaction solution was filtrated to remove precipitates, and the solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 106 mg of the objective compound as yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[OH:10][C:11]1[CH:16]=[CH:15][N:14]([C:17]2[S:18][C:19]([C:23](O)=[O:24])=[C:20]([CH3:22])[N:21]=2)[C:13](=[O:26])[CH:12]=1>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:23]([C:19]2[S:18][C:17]([N:14]3[CH:15]=[CH:16][C:11]([OH:10])=[CH:12][C:13]3=[O:26])=[N:21][C:20]=2[CH3:22])=[O:24])=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)O
Product: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccc(F)cc1
Yield: 37 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 4-fluorobenzylamine in place of benzylamine to react with 2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 37% yield: mp 280-282° C. (methanol/ethyl acetate); 1H NMR (300 MHz, DMSO-d6) δ 8.74 (t, J=5.9 Hz, 1H), 8.56 (d, J=8.0 Hz, 1H), 7.34-7.29 (m, 2H), 7.12 (t, J=8.9 Hz, 2H), 6.22 (dd, J=8.0, 2.5 Hz, 1H), 5.75 (d, J=2.5 Hz, 1H), 4.35 (d, J=5.8 Hz, 2H), 2.52 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 167.9, 162.0, 161.6, 154.1, 150.2, 139.9, 132.6, 128.7, 127.7, 127.2, 123.6, 104.4, 98.0, 43.1, 17.5; MS (ES+) m/z 360.1 (M+1).