Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[N:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([C:20](=[O:22])[CH3:21])=[C:13]3[NH:23][C:24]2[CH:25]=[N:26][C:27]([NH:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])=[CH:28][CH:29]=2)[CH:5]=[C:6](Cl)[C:7]=1[OH:8].[Cl:36]C1C=C(B2OC(C)(C)C(C)(C)O2)C=C([F:52])C=1O>>[ClH:1].[ClH:36].[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[N:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([C:20](=[O:22])[CH3:21])=[C:13]3[NH:23][C:24]2[CH:25]=[N:26][C:27]([NH:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])=[CH:28][CH:29]=2)[CH:5]=[C:6]([F:52])[C:7]=1[OH:8]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1Nc1ccc(NCCN(C)C)nc1
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1ccc(NCCN(C)C)nc1
Product: Cl
Yield: 195.8 %

Procedure:
Following general procedure II, 1-[6-(3,5-dichloro-4-hydroxyphenyl)-4-{6-[2-(dimethylamino)ethylamino]pyridin-3-ylamino}-1,5-naphthyridin-3-yl]ethanone (69 mg, 0.18 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (74 mg, 0.27 mmol) followed by formation of the trihydrochloride salt to afford the desired product (71 mg, 66%) as a yellow-orange solid: 1H NMR (500 MHz, CD3OD) δ 9.40 (s, 1H), 8.49 (d, J=9.0 Hz, 1H), 8.41 (d, J=9.1 Hz, 1H), 8.23 (d, J=2.5 Hz, 1H), 7.87 (dd, J=9.4, 2.5 Hz, 1H), 7.42 (br s, 2H), 7.06 (d, J=9.4 Hz, 1H), 3.91 (t, J=6.4 Hz, 2H), 3.47 (t, J=6.4 Hz, 2H), 2.99 (s, 6H), 2.85 (s, 3H); ESI MS m/z 495 [M+H]+; HPLC 98.9% (AUC), tR=8.97 min.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)=[O:8])=[CH:3][CH:2]=1.[C:27](#[N:29])[CH3:28].[NH2-].[Na+]>C1C=CC=CC=1>[OH:8][C:7]([C:4]1[CH:3]=[CH:2][C:1]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:6][CH:5]=1)([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)[CH2:28][C:27]#[N:29]
Reactant: O=C(c1ccc(-c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1
Reactant: CC#N
Agent: [NH2-]
Agent: [Na+]
Solvent: c1ccccc1
Product: N#CCC(O)(c1ccc(-c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1

Procedure:
Di-4-biphenylyl ketone was reacted with acetonitrile in benzene in the presence of sodamide by the method of Lettre and Wick (Annalen, 1957, 603, 194) to give 3-hydroxy-3, 3-di(4-biphenylyl) propionitrile, m.p. 168°-170° C, after recrystallisation from benzene. The nitrile (8.0 g.) dissolved in a mixture of tetrahydrofuran (80 ml.) and ether (80 ml.) was added over 30 minutes at room temperature under nitrogen to a stirred suspension of lithium aluminium hydride (2.88 g.) in ether (75 ml.). After stirring a further hour the mixture was decomposed by addition of water (2.8 ml.) and aqueous N sodium hydroxide (12 ml.) After filtration, the organic layer was separated and evaporated to give a solid which recrystallised from benzene/light petroleum (b.p. 80°-100° C), gave 1,1-di(4-biphenylyl)-3-aminopropan-1-ol, prisms, m.p. 176°-8° C,λmax (ethanol) = 260 nm. The carbinol (6.5 g.) boiled under reflux for 1 hour with glacial acetic acid (40 ml.) and concentrated hydrochloric acid (10 ml.) gave 1, 1-di-(4-biphenylyl)-3-aminoprop-1-ene hydrochloride, needles from n-propanol, m.p. 231°-232° C. The base, from ethanol, had m.p. 127°-8° C, λmax (ethanol) = 274 nm.
Reaction SMILES: C([CH:3]([C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:12](Cl)[N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#N.OO.[OH-:22].[K+].Cl.[OH2:25]>CC(C)=O>[C:3]([C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:12]([OH:25])[N:11]=1)(=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O
Reactant: [OH-]
Reactant: N#CC(c1ccccc1)c1nc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(c1ccccc1)c1nc(O)ccc1[N+](=O)[O-]
Temperature: 35 °C
Reaction time: 0.67 h

Procedure:
50 grams of 2-(α-cyanobenzyl)-3-nitro-6-chloropyridine were dissolved in 200 ml. of acetone, 70 ml. of 30% aqueous hydrogen peroxide added and then with stirring there was gradually dropped a solution of 39 grams of KOH in 50 ml. of water with stirring. The solution heated by itself to 35° C. After 40 minutes there was no blue coloration upon dropwise adding further potassium hydroxide solution. The yellow-red solution was diluted with water and acidified with hydrochloric acid. The 2-benzoyl-3-nitro-6-hydroxypyridine crystallized out and was filtered off with suction after an hour and dried.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:8]2[CH:9]=[CH:10][C:11]([N+:13]([O-])=O)=[CH:12][C:7]=2[NH:6][C:5](=[O:16])[CH:4]([NH:17][C:18](=[O:20])[CH3:19])[CH2:3]1.Cl[C:23]1[N:28]=[C:27]([NH:29][C:30]2[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:31]=2[C:32]([NH:34][CH3:35])=[O:33])[C:26]([Cl:41])=[CH:25][N:24]=1>>[C:18]([NH:17][CH:4]1[CH2:3][C:2]([CH3:21])([CH3:1])[C:8]2[CH:9]=[CH:10][C:11]([NH:13][C:23]3[N:28]=[C:27]([NH:29][C:30]4[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:31]=4[C:32]([NH:34][CH3:35])=[O:33])[C:26]([Cl:41])=[CH:25][N:24]=3)=[CH:12][C:7]=2[NH:6][C:5]1=[O:16])(=[O:20])[CH3:19]
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CC(=O)NC1CC(C)(C)c2ccc([N+](=O)[O-])cc2NC1=O
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)C(NC(C)=O)CC3(C)C)ncc1Cl

Procedure:
2-[2-(3-Acetylamino-5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-8-ylamino)-5-chloro-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide was prepared from N-(5,5-Dimethyl-8-nitro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-acetamide and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 1221d. (62 mg, 43%). HPLC purity=99%, LCMS 524 (M+H), 1H-NMR (DMSO-d6, 400 MHz) δ 9.53 (s, 1H), 9.39 (s, 1H), 9.35 (s, 1H), 8.51 (d, J=4.6 Hz, 1H), 8.19 (s, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.49-7.45 (m, 2H), 7.33-7.26 (m, 2H), 7.15 (s, 1H), 7.08 (d, J=9.0 Hz, 1H), 4.22-4.17 (m, 1H), 2.73 (d, J=4.4 Hz, 3H), 2.08-2.06 (m, 1H), 1.87-1.84 (m, 1H), 1.84 (s, 3H), 1.32 (s, 3H), 1.23 (s, 3H).
Reaction SMILES: [CH3:1][N+:2]([CH2:5][C@H:6]([NH2:11])[CH2:7][C:8]([O-:10])=[O:9])([CH3:4])[CH3:3].[C:12]([C:18]1[O:22][C:21]([C:23](ON2C(=O)CCC2=O)=[O:24])=[CH:20][CH:19]=1)#[C:13][CH2:14][CH2:15][CH2:16][CH3:17].CN(C=O)C.C(N(CC)CC)C>C(OCC)C>[C:12]([C:18]1[O:22][C:21]([C:23]([NH:11][C@@H:6]([CH2:5][N+:2]([CH3:3])([CH3:4])[CH3:1])[CH2:7][C:8]([O-:10])=[O:9])=[O:24])=[CH:20][CH:19]=1)#[C:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCC#Cc1ccc(C(=O)ON2C(=O)CCC2=O)o1
Reactant: C[N+](C)(C)C[C@H](N)CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCC#Cc1ccc(C(=O)N[C@H](CC(=O)[O-])C[N+](C)(C)C)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.9 %

Procedure:
(R)-aminocarnitine (20 mg, 0.12 mmol) and 2,5-dioxopyrrolidin-1-yl 5-(hex-1-ynyl)furan-2-carboxylate (68 mg, 0.23 mmol) were dissolved into DMF (1 mL). Triethylamine (50 μL, 0.36 mmol) was added and the solution was stirred at room temperature for 18 h. Diethyl ether (20 mL) was added and a white precipitate was collected. The powder was purified by silica gel chromatography (elution 10% MeOH/CH2Cl2 to 80% MeOH/CH2Cl2) to give the title compound as a white powder (16 mg, 40%). 1H NMR (400 MHz, D2O) δ 7.02 (d, 1H, J=3.7 Hz), 6.53 (d, 1H, J=3.6 Hz), 4.90-4.80 (m, 1H), 3.63-3.58 (m, 1H), 3.47-3.42 (m, 1H), 3.06 (s, 9H), 2.45-2.42 (m, 2H), 2.35 (t, 2H, J=6.9 Hz), 1.47-1.41 (m, 2H), 1.35-1.29 (m, 2H), 0.78 (t, 3H, J=7.3 Hz); MS ESI 335.2 [M+H]+, calcd for [C18H26N2O4+H]+ 335.19.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1>>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:13][CH:14]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=S(=O)(Nc1ccc(O)cc1)c1ccccc1
Yield: 97.3 %

Procedure:
The preparation is carried out as in Example 1(a) from 353 g (2 mol) of benzenesulphonyl chloride and 229.2 g of 4-aminophenol (2.1 mol). The amount obtained is 507.9 g, i.e. a yield of 97.3%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH2:59])=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1>C1COCC1.C(Cl)(Cl)Cl>[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH:59][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1
Reactant: O=C(O)c1ccccc1F
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccccc3F)nc12

Procedure:
From 2-fluorobenzoic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4)dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+20.0° (c=1.00, CHCl3), ES-MS m/e (%): 389 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C@@H:9]2[CH:16]3[CH2:17][N:12]4[CH2:13][CH:14]([CH2:18][CH:10]2[CH2:11]4)[CH2:15]3)=[CH:4][CH:3]=1.[NH:19]1[C:27]2[C:22](=[CH:23][C:24](B(O)O)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1>>[ClH:1].[ClH:1].[NH:19]1[C:27]2[C:22](=[CH:23][C:24]([C:2]3[N:7]=[CH:6][C:5]([O:8][C@@H:9]4[CH:16]5[CH2:17][N:12]6[CH2:13][CH:14]([CH2:18][CH:10]4[CH2:11]6)[CH2:15]5)=[CH:4][CH:3]=3)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: Clc1ccc(OC2C3CC4CC2CN(C4)C3)cn1
Product: Cl
Product: c1cc2cc(-c3ccc(OC4C5CC6CC4CN(C6)C5)cn3)ccc2[nH]1

Procedure:
Prepared from the product of Example 15B (165 mg, 0.623 mmol) and 1H-indol-5-ylboronic acid using the microwave Suzuki coupling Method G and the salt formation Method H to provide the titled compound: 1H NMR (300 MHz, methanol-D4) δ ppm 1.96 (s, 1H), 2.00 (s, 1H), 2.24 (s, 1H), 2.40 (s, 1H), 2.44 (s, 1H), 2.59 (s, 2H), 3.61 (s, 2H), 3.74 (s, 4H), 5.19 (t, J=3.2 Hz, 1H), 6.66 (dd, J=3.2, 0.8 Hz, 1H), 7.43 (d, J=3.4 Hz, 1H), 7.59-7.64 (m, 1H), 7.64-7.68 (m, 1H), 8.16 (dd, J=1.9, 0.8 Hz, 1H), 8.31-8.35 (m, 1H), 8.36-8.41 (m, 1H), 8.61 (d, J=2.0 Hz, 1H). MS (DCI/NH3) m/e=346 (M+H)+. Anal. calcd. for C22H23N3O.2HCl.H2O: C, 60.55; H, 6.24; N, 9.63. Found C, 60.71; H, 6.38; N, 9.39.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[CH:4][CH:3]=1.[N:19]1C=CC=CC=1.[O:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[C:30](Cl)=[O:31]>C(#N)C>[Cl:18][C:8]1[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:12]([Cl:13])[C:7]=1[N:6]1[C:2]([C:30]([CH:26]2[CH2:27][CH2:28][CH2:29][O:25]2)=[O:31])=[CH:3][C:4]([NH2:19])=[N:5]1
Reactant: Nc1ccnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: c1ccncc1
Reactant: O=C(Cl)C1CCCO1
Solvent: CC#N
Product: Nc1cc(C(=O)C2CCCO2)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Yield: 87 %

Procedure:
19.8 g (0.07 mol) of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-pyrazole and 7.1 g (0.09 mol) of pyridine are dissolved in 150 ml of acetonitrile, and 12.1 g (0.09 mol) of tetrahydrofuran-2-carboxylic acid chloride are added at 25°-30° C., with stirring. The mixture is stirred at room temperature for a further 24 hours. The reaction batch is then poured onto water and extracted with chloroform; the chloroform phase is washed with aqueous sodium bicarbonate solution, dried over sodium sulphate and concentrated. The oily residue is crystallized by trituration with petroleum ether. 24 g (87% of theory) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-5-(2-tetrahydrofuroyl)-amino-pyrazole of melting point 95°-97° C. are obtained.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([N:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)(=[O:35])[CH3:34]
Reactant: O=C(N[C@H]1CCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (S)-pyrrolidin-3-ylamide hydrochloride (example A143) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [N+:1]([C:4]1[C:12]([NH:13][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH2:8]2)([O-])=O.O>O1CCCC1.CO.[C].[Pd]>[NH2:1][C:4]1[C:12]([NH:13][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH2:8]2
Reactant: N#Cc1cccc(Nc2ccc3c(c2[N+](=O)[O-])CCC3)c1
Agent: [Pd]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cccc(Nc2ccc3c(c2N)CCC3)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.3 %

Procedure:
3-(4-Nitroindan-5-ylamino)benzonitrile (0.84 g, 3.00 mmol) was dissolved in tetrahydrofuran (84 mL)-methanol (21 mL). To the solution was added water-containing 5% palladium-carbon (0.08 g). The mixture was stirred under hydrogen atmosphere at room temperature for 16 hours. Insoluble was removed by filtration. The filtrate was concentrated under reduced pressure to give the titled compound as yellowish brown crystal (0.75 g, yield 100%).
Reaction SMILES: [CH3:1][S:2]([O-])(=O)=O.[O:6]=[C:7]1[CH2:12][N:11](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][C:9]2C=CS[C:8]1=2.[CH2:26](O)C.C1CCCCC1>>[OH:6][C:7]1[CH:12]=[N:11][CH:10]=[C:9]2[S:2][CH:1]=[CH:26][C:8]=12
Reactant: CS(=O)(=O)[O-]
Reactant: CCO
Reactant: Cc1ccc(S(=O)(=O)N2CC(=O)c3sccc3C2)cc1
Solvent: C1CCCCC1
Product: Oc1cncc2sccc12
Yield: 80 %

Procedure:
This compound is prepared according to the procedure of Example 1(c), from the methanesulfonate described in (b) above (Yield: 80%). White crystals; M.p.=206° C. (ethanol-cyclohexane)
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([NH2:25])[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:16]3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.Cl[C:36](OC1C=CC([N+]([O-])=O)=CC=1)=[O:37]>C1COCC1>[Cl:1][C:2]1[C:3]2[N:4]([C:36](=[O:37])[NH:25][C:8]=2[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:16]3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=c1[nH]c(-c2ccc3ccc(-c4ccccc4)nc3c2)c2c(Cl)nccn12
Temperature: 45 °C

Procedure:
C-(3-Chloro-pyrazin-2-yl)-C-(2-phenyl-quinolin-7-yl)-methylamine (2.0 g, 5.8 mmol) was dissolved in anhydrous THF (35.0 mL), followed by the addition of DIPEA (1.21 mL, 6.92 mmol) at rt. The dark brown solution was then charged with para-nitrophenyl chloroformate (1.28 g, 6.34 mmol) at rt, and warmed to 45° C. for 17 h. The crude reaction was concentrated in vacuo and dissolved with EtOAc and water. Yellow precipitate crashed out of solution and was filtered. The solid was washed with hexanes and dried under vacuum to yield the title compound as a yellow solid; MS (ES+): m/z 373.04 (100) [MH+], 375.00 (30) [MH+++]; HPLC: tR=3.15 min (OpenLynx, polar—5 min); 1HNMR (400 MHz, DMSO-d6) δ ppm 6.80-7.05 (m, 2H), 7.43-7.66 (m, 4H), 7.79 (dd, J=8.34, 1.77 Hz, 1H), 8.02-8.17 (m, 2H), 8.19-8.35 (m, 4H), 8.53 (d, J=8.59 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][CH3:8])[N:6]=1.[CH:9]1[C:22]2[CH:21]([C:23](Cl)=[O:24])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:14][C:13]=2[CH:12]=[CH:11][CH:10]=1>>[CH2:7]([N:5]1[N:4]=[N:3][C:2]([NH:1][C:23]([CH:21]2[C:22]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[O:14][C:15]3[C:20]2=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:24])=[N:6]1)[CH3:8]
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Reactant: CCn1nnc(N)n1
Product: CCn1nnc(NC(=O)C2c3ccccc3Oc3ccccc32)n1

Procedure:
The title compound, white solid, m.p. 228° C. (dec.) and MS: (neg. ions): m/e=320.0 (M+−H) was prepared in accordance with the general method of example 1 from 5-amino-2-ethyl-2H-tetrazole and 9H-xanthene-9-carbonyl chloride.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:4]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[CH:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].S(=O)(=O)(O)O>C(O)(=O)C.O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C>[CH3:10][O:9][C:7]([CH2:6][C:5]1[O:1][N:2]=[C:3]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:8]
Reactant: COC(=O)CC=C(C(=NO)c1ccc(OC)cc1)c1ccc(OC)cc1
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)Cc1onc(-c2ccc(OC)cc2)c1-c1ccc(OC)cc1
Yield: 89.7 %

Procedure:
A 3.7 g of methyl 5-hydroxyimino-4,5-bis(4-methoxyphenyl)-3-pentenoate in 40 ml of acetic acid was stirred at 60° C. for 24 hours while blowing air into the mixture in the presence of 0.4 g of cobalt acetate tetrahydrate. After completion of the reaction, 3N sulfuric acid was added to the solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous potassium carbonate solution and saturated brine in that order, and dried over anhydrous magnesium sulfate. The organic layer was then concentrated under reduced pressure and the residue was separated and purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to give 3.3 g (yield 90%) of 5-methoxycarbonylmethyl-3,4-bis(4-methoxyphenyl)isoxazole.
Reaction SMILES: N1C(C(O)=O)=CC(C(O)=O)=N1.[C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:24]=[CH:23][N:22]([CH2:25][C@H:26]([NH:28][C:29]([C:31]3[NH:35][N:34]=[C:33]([C:36]([OH:38])=O)[CH:32]=3)=[O:30])[CH3:27])[N:21]=2)=[CH:16][C:15]=1[CH3:39])#[N:13].[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1.ClC1C=C(C2OC(CCNC(C3NN=C(C(N4CCNCC4)=O)C=3)=O)=CC=2)C=CC=1Cl>>[C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:24]=[CH:23][N:22]([CH2:25][C@H:26]([NH:28][C:29]([C:31]3[NH:35][N:34]=[C:33]([C:36]([N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)=[O:38])[CH:32]=3)=[O:30])[CH3:27])[N:21]=2)=[CH:16][C:15]=1[CH3:39])#[N:13]
Reactant: Cc1cc(-c2ccn(C[C@@H](C)NC(=O)c3cc(C(=O)O)n[nH]3)n2)ccc1C#N
Reactant: C1COCCN1
Agent: O=C(NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1)c1cc(C(=O)N2CCNCC2)n[nH]1
Agent: O=C(O)c1cc(C(=O)O)[nH]n1
Product: Cc1cc(-c2ccn(C[C@@H](C)NC(=O)c3cc(C(=O)N4CCOCC4)n[nH]3)n2)ccc1C#N
Yield: 45 %

Procedure:
The title compound was synthesized using the method of Example 30, but replacing 5-pyridin-4-yl-4H-pyrazole-3-carboxylic acid with 3,5-pyrazoledicarboxylic acid. Thus obtained (R)-5-(1-(3-(4-cyano-3-methylphenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)-1H-pyrazole-3-carboxylic acid was coupled with morpholine according to synthesis of 5-(piperazine-1-carbonyl)-2H-pyrazole-3-carboxylic acid {2-[5-(3,4-dichlorophenyl)furan-2-yl]ethyl}amide, Example 1, but replacing piperazine with morpholine. Crude product was purified by chromatography (CombiFlash, 1st column silica, eluent: 0-10% MeOH/DCM; 2nd column C-18 RP eluent: 0-100% MeCN/water) to obtain 24 mg (45%) of the title compound. 1H-NMR (400 MHz; CDCl3): δ 1.25 (d, 3H), 2.60 (s, 3H), 3.79 (m, 8H), 4.29 (dd, 1H), 4.42 (dd, 1H), 4.60 (m, 1H), 6.61 (d, 1H), 7.02 (s, 1H), 7.47 (d, 1H), 7.63 (m, 2H), 7.72 (d, 1H), 7.79 (s, 1H), 11.09 (s, 1H).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:16]1[O:17][C:18]([C:25]2[C:33]3[C:28](=[C:29]([Br:34])[CH:30]=[CH:31][CH:32]=3)[NH:27][CH:26]=2)=[C:19]([C:21]([O:23][CH3:24])=[O:22])[N:20]=1)[CH:13]([CH3:15])[CH3:14])=O)C1C=CC=CC=1.Br.CC(OC)(C)C>C(O)(=O)C>[BrH:34].[NH2:11][C@H:12]([C:16]1[O:17][C:18]([C:25]2[C:33]3[C:28](=[C:29]([Br:34])[CH:30]=[CH:31][CH:32]=3)[NH:27][CH:26]=2)=[C:19]([C:21]([O:23][CH3:24])=[O:22])[N:20]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: COC(=O)c1nc([C@@H](NC(=O)OCc2ccccc2)C(C)C)oc1-c1c[nH]c2c(Br)cccc12
Agent: Br
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Product: COC(=O)c1nc([C@@H](N)C(C)C)oc1-c1c[nH]c2c(Br)cccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 198.2 %

Procedure:
Glacial acetic acid (25 mL) was added to methyl 2-((S)-1-(benzyloxycarbonylamino)-2-methylpropyl)-5-(7-bromo-1H-indol-3-yl)oxazole-4-carboxylate (9.99 g, 19.0 mmol) in a 500-mL round-bottom flask fitted with a mechanical stirrer. The suspension was stirred at 25° C. and 33% HBr in acetic acid (50 mL) was added in one portion. The mixture became homogeneous and then a precipitate formed in 5-10 min. After 1 h, MTBE (235 mL) was added and stirring was continued at 25° C. for another 1 h 20 min. The mixture was filtered and the precipitate was washed with MTBE (150 mL). The cream-colored powder was dried under vacuum to give methyl 2-((S)-1-amino-2-methylpropyl)-5-(7-bromo-1H-indol-3-yl)oxazole-4-carboxylate hydrobromide (8.91 g, 99% yield). 1H NMR (300 MHz, DMSO-d6): consistent with proposed structure. MS: m/z=392.0 (M+1).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][C:13](=[CH2:27])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([CH3:26])[CH:18]=1)=[O:15].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>ClCCCl>[CH3:26][C:19]1[CH:18]=[C:17]([NH:16][C:14]([C:13]2([CH3:12])[CH2:27][O:6]2)=[O:15])[CH:22]=[CH:21][C:20]=1[N+:23]([O-:25])=[O:24]
Reactant: C=C(C)C(=O)Nc1ccc([N+](=O)[O-])c(C)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: ClCCCl
Product: Cc1cc(NC(=O)C2(C)CO2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h

Procedure:
m-Chloroperoxybenzoic acid (6.7 g, 29.9 mmol) was added in portions at 60° C. to a solution of 2-methyl-N-(3-methyl-4-nitrophenyl)acrylamide (2.9 g, 13.2 mmol) and 2,6-di-tert-butyl-4-methylphenol (66 mg) in 1,2-dichloroethane (80 ml). The string was continued at 60° C. for 6 h, and the reaction mixture was allowed to cool to room temperature. The precipitated m-chlorobenzoic acid was filtered, and the filtrate was extracted with 1 M Na2CO3 (4×60 ml). The organic phase was dried over Na2SO4 and evaporated. The yield was 3.05 g. 1H NMR (DMSO-d6): 1.54 (3H, s), 2.51 (3H, s), 2.99 (1H, d, J=5.1 Hz), 3.05 (1H, d, J=5.1 Hz), 7.79 (2H, m), 8.01 (1H, m), 9.98 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][C:13]([N:16]3[CH2:21][CH2:20][O:19][C@H:18]([CH2:22][N:23]4[C:27]5=[N:28][C:29]([C:32]6[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=6)=[CH:30][N:31]=[C:26]5[N:25]=[N:24]4)[CH2:17]3)=[N:14][CH:15]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.CC(O)=O.[CH3:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1.C([O-])([O-])=O.[K+].[K+]>ClCCl>[F:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][C:13]([N:16]3[CH2:21][CH2:20][O:19][C@H:18]([CH2:22][N:23]4[C:27]5=[N:28][C:29]([C:32]6[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=6)=[CH:30][N:31]=[C:26]5[N:25]=[N:24]4)[CH2:17]3)=[N:14][CH:15]=2)[CH:7]=[CH:6][C:3]=1[CH2:4][N:46]1[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]1
Reactant: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(-c6ccc(C=O)c(F)c6)cn5)CCO4)c3n2)cn1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(-c3cnc(N4CCO[C@H](Cn5nnc6ncc(-c7cnn(C)c7)nc65)C4)nc3)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.8 %

Procedure:
(S)-2-fluoro-4-(2-(2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)-methyl)morpholino)pyrimidin-5-yl)benzaldehyde (41 mg, 0.09 mmol) was dissolved in dichloromethane (3 mL), and then AcOH (0.006 mL, 0.10 mmol) and 1-methylpiperazine (0.02 mL, 0.17 mmol) were added. The mixture was stirred at room temperature for 30 minutes, and then NaBH(OAC)3 (28 mg, 0.13 mmol) was added, followed by stirring at room temperature for 13 hours. When the reaction was completed, the reaction mixture was adjusted to pH 8 with 5% K2CO3, followed by extraction with dichloromethane and water two times or more. The organic layer was extracted with ethyl acetate and water, and the extra water was removed by sodium sulfate, followed by concentration under reduced pressure. PLC using 10% dichloromethane/methanol gave (S)-4-(5-(3-fluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)pyrimidin-2-yl)-2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholine (20 mg, 0.034 mmol) with a yield of 46%.