Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:5][C:6]2[CH:7]=[C:8]([C:16]3[N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]4[CH:20]=[N:21][NH:22][C:23](=[O:24])[C:18]=4[C:17]=3I)[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:4][CH2:3][CH2:2]1.BrC1N(COCC[Si](C)(C)C)C2C=NNC(=O)C=2C=1.[C:54]1(B(O)O)[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>>[CH:1]1([O:5][C:6]2[CH:7]=[C:8]([C:16]3[N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]4[CH:20]=[N:21][NH:22][C:23](=[O:24])[C:18]=4[C:17]=3[C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)c1ccccc1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CCC3)c2)c(I)c2c(=O)[nH]ncc21
Agent: C[Si](C)(C)CCOCn1c(Br)cc2c(=O)[nH]ncc21
Product: C[Si](C)(C)CCOCn1c(-c2ccc(OC(F)F)c(OC3CCC3)c2)c(-c2ccccc2)c2c(=O)[nH]ncc21
Yield: 55.1 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 1-(a) except for using 299 mg (0.495 mmol) of 2-(3-cyclobutoxy-4-difluoromethoxyphenyl)-3-iodo-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo-[2,3-d]pyridazin-4-one obtained in Example 34-(a) in place of 2-bromo-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one, and using 95 mg (0.779 mmol) of phenylboronic acid in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane obtained in the following Reference example 1-(a), whereby 151 mg of the title compound was obtained as a pale beige solid. (Yield: 89%)
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C1CCC(N=C=NC2CCCCC2)CC1.CO.[NH2:38][C@H:39]([CH2:43][OH:44])[CH:40]([CH3:42])[CH3:41]>N1C=CC=CC=1.C(OCC)(=O)C>[C:1]([NH:38][C@H:39]([CH2:43][OH:44])[CH:40]([CH3:42])[CH3:41])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CC(C)[C@H](N)CO
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CO
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N[C@H](CO)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a round bottom flask, oleic acid (1) (1.53 g, 5.33 mmol) was dissolved in 20 ml of dry pyridine (over KOH). To the solution TEA (0.74 ml, 5.33 mmol), DCC (1.1 g, 5.33 mmol), and NHS (0.55 g, 4.85 mmol) were added. The mixture was stirred at room temperature for overnight. After confirming the total conversion of the acid to the NHS intermediate using TLC (5% MeOH), L-Valinol (0.5 g, 4.85 mmol) was added and the mixture was stirred for additional 24 hours. After completion of the reaction (TLC: 100% Ethyl acetate), volatiles were removed under reduced pressure to dryness. The gum was dissolved in 5 ml DCM and the desired product oleoyl-valinol (10) was obtained using column chromatography (dichloromethane/ethyl acetate=1:1, v/v)). Colorless viscous oil (0.94 g, 46.8 yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[CH3:13][S:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O)(=[O:16])=[O:15].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH2:51]=[C:52]([CH3:54])[CH3:53]>C(#N)C>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][CH:20]([C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([S:14]([CH3:13])(=[O:16])=[O:15])[CH:18]=1)[CH2:51][C:52]2([CH3:54])[CH3:53])=[O:12])[CH3:2]
Reactant: C=C(C)C
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)c1cccc(C=O)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(S(C)(=O)=O)c1)N2
Temperature: 0 °C
Reaction time: 12 h
Yield: 42.6 %

Procedure:
A mixture of 4-aminobenzoic acid ethyl ester (3.3 g, 20 mmol), 3-methanesulfonyl benzaldehyde (3.68 g, 20 mmol) and ytterbium(III) triflate hydrate (1.86 g, 3 mmol) in acetonitrile (150 mL) was cooled to 0° C. in a sealed reaction bottle. Then a cooled solution of isobutene (5.6 g, 100 mmol) was added into. The reaction mixture was heated to 90° C. and stirred for 12 h. The solvent was removed in vacuo and the residue was purified on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (10% ethyl acetate/hexanes) to afford 2-(3-methanesulfonyl-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.3 g, 43%) as a white solid: MS (ESI) M+1=388.3.
Reaction SMILES: [O:1]1[CH2:5]CCC1.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=O)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[C:22](N1C=CN=C1)([N:24]1C=CN=C1)=O.C(N(CC)CC)C>CCOCC>[C:6]([O:10][C:11]([N:13]1[CH2:14][CH2:15][CH:16]([C:19]([N:24]([O:1][CH3:5])[CH3:22])=[O:21])[CH2:17][CH2:18]1)=[O:12])([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 500 ml round bottom flask was added 150 ml tetrahydrofuran and 24.8 g 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (108 mmol). Carbonyldiimidazole (CDI) (18.4 g, 114 mmol) was added in portions. The reaction mixture was stirred at room temperature for 1 hour. Methylmehoxy amine hydrochloride salt (14.8 g, 151 mmol) was added followed by 22.6 ml triethylamine. The reaction mixture was heated at 55° C. for 1 hour. It was cooled with ice bath and diluted with 200 ml ether. The resulting mixture was washed sequentially twice with 150 ml of saturated ammonium chloride solution, 150 ml 5% KOH solution and 100 ml brine. The organic layers were dried over sodium sulfate, filtered and concentrated. The residue was dissolved in 50 ml toluene and then reconcentrated under vacuum to give 29 g colorless oil which was used for next step without further purification.
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:28])[C:7]([CH3:27])([CH3:26])[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([OH:25])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH3:24])([CH3:23])[C:18]([O:20]CC)=[O:19])C>O.C(O)C>[OH:25][CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([CH3:24])([CH3:23])[C:18]([OH:20])=[O:19])[CH2:11][CH2:10][CH2:9][CH2:8][C:7]([CH3:27])([CH3:26])[C:6]([OH:28])=[O:5]
Reactant: CCOC(=O)C(C)(C)CCCCC(O)CCCCC(C)(C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(CCCCC(O)CCCCC(C)(C)C(=O)O)C(=O)O
Yield: 94.8 %

Procedure:
To a homogeneous solution of potassium hydroxide (3.45 g, 61 mmol) in water (3.3 mL) and ethanol (11.1 mL) was added 7-hydroxy-2,2,12,12-tetramethyltridecanedioic acid diethyl ester (8.2 g, 22 mmol) and the mixture was heated at reflux for 4 h. The mixture was concentrated in vacuo and the residue was extracted with diethyl ether (3×50 mL). The water layer was acidified with concentrated hydrochloric acid (6 mL) to pH 1. The product was extracted with diethyl ether (3′ 100 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica, dichloromethane: methanol=90:10) to give the pure product (6.6 g, 95%) as a colorless oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 8.10 (br., 3H), 3.58 (br., 1H), 1.62-1.22 (m, 16H), 1.18 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 184.3, 71.8, 42.1, 40.5, 36.9, 25.9, 25.0, 24.9. HRMS (LSIMS, gly): Calcd. for C17H33O5 (MH+): 317.2328. found 317.2330. HPLC: 90.4% purity.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([NH2:8])=[O:7])=[N:2]1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:23]([CH2:28][CH3:29])([CH2:26][CH3:27])[CH2:24][CH3:25])(=O)=O>ClCCCl.ClCCl>[CH2:24]([Si:23]([CH2:28][CH3:29])([CH2:26][CH3:27])[NH:8][C:6]([C:3]1[N:4]=[CH:5][NH:1][N:2]=1)=[O:7])[CH3:25]
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Reactant: NC(=O)c1nc[nH]n1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: Cc1cccc(C)n1
Product: CC[Si](CC)(CC)NC(=O)c1nc[nH]n1
Temperature: 50 °C
Yield: 67.7 %

Procedure:
A stirred mixture of 1H-1,2,4-triazole-3-carboxamide (500 mg, 4.46 mmol) in 1,2-dichloroethane (4.46 mL) treated at room temperature with 2,6-lutidine (2.08 mL, 17.84 mmol) and triethylsilyl trifluoromethanesulfonate (3.03 mL, 13.38 mmol) and heated under a nitrogen atmosphere at 50° C. After 4 hours of heating the reaction solution allowed to cool to room temperature and diluted with dichloromethane (25 mL), washed with water (25 mL), 0.5M hydrochloric acid (25 mL), water (25 mL), dried over MgSO4, filtered, and evaporated to solid. The solid was flash chromatographed (silica gel, 10-65% ethyl acetate:hexane) to give the product as a white solid (683 mg).
Reaction SMILES: [C:1]1([CH:7]([C:15]2NCCN[N:16]=2)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(C#N)C1C=CC=CC=1.C(Cl)C1C=CC=CC=1>>[C:1]1([CH:7]([CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:15]#[N:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(CC(C2=NNCCN2)c2ccccc2)cc1
Solvent: N#CCc1ccccc1
Solvent: ClCc1ccccc1
Product: N#CC(Cc1ccccc1)c1ccccc1

Procedure:
A process for preparing 3-(1,2-diphenylethyl)-1,4,5,6-tetrahydro-1,2,4-triazine which comprises reacting benzyl cyanide with benzyl chloride to produce 2,3-diphenylpropionitrile and cyclizing the 2,3-diphenylpropionitrile with 2-aminoethylhydrazine in the presence of a catalytic amount of elemental sulfur to give 3-(1,2-diphenylethyl)-1,4,5,6-tetrahydro-1,2,4-triazine.
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)=[C:2]=[O:3].[CH2:13]([N:20]1[CH2:24][CH2:23][C:22]2([CH2:28][CH2:27][NH:26][CH2:25]2)[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH2:29][C:30]1[CH:31]=[C:32]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:33]=[CH:34][C:35]=1[NH:36]C(=O)OC(C)(C)C.C(N(C(C)C)CC)(C)C>ClCCl>[NH2:36][C:35]1[CH:34]=[CH:33][C:32]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:31][C:30]=1[NH:29][C:8]([C:7]1[CH:11]=[CH:12][C:4]([NH:1][C:2]([N:26]2[CH2:27][CH2:28][C:22]3([CH2:23][CH2:24][N:20]([CH2:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:21]3)[CH2:25]2)=[O:3])=[CH:5][CH:6]=1)=[O:9]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1N
Reactant: c1ccc(CN2CCC3(CCNC3)C2)cc1
Reactant: O=C=Nc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(-c2ccccc2)cc1NC(=O)c1ccc(NC(=O)N2CCC3(CCN(Cc4ccccc4)C3)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of stirring 4-isocyanatobenzoyl chloride (50 mg, 0.275 mmol) in 3 mL of dichloromethane was added 2-benzyl-2,7-diazaspiro[4,4]nonane (60 mg, 0.275 mmol) slowly over a period of 10 minutes. The reaction mixture was allowed to stir for 30 min. at room temperature. Tert-butyl (3-aminobiphenyl-4-yl)carbamate (78.2 mg, 0.275 mmol) was then added, followed by the addition of diisopropylethylamine (48 μL, 0.275 mmol). The reaction mixture was allowed to stir for 1 hour at room temperature. Argonaut W-Carbonate scavenging resin (285 mg, 0.825 mmol) was then added and stirred overnight at room temperature. The mixture was then filtered from scavenging resin and concentrated. Added dichloromethane (1 mL) and stirred, then treated with trifluoroacetic acid (1 mL). The reaction mixture was concentrated after 2 hours of stirring at room temperature and the crude residue was purified by reverse-phase chromatography (5-50-95% acetonitrile/water with 0.1% formic acid). The appropriate fractions were combined and lyophilized. MS (ESI+): cal'd [4+H]+ 546.3, obs'd 546.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[CH:4][CH:3]=1.[ClH:11].[Cl-].C(C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC)(=O)CCCCCCC>ClC1C=CC=CC=1>[Cl:11][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: Cl
Reactant: OCCc1ccc(F)cc1
Agent: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: Fc1ccc(CCCl)cc1

Procedure:
A mixture of 7 g 2-(4-fluoro-phenyl)-ethanol, 25 mL of chlorobenzene, 42 mL of 37% HCl, and 0.9 g of Aliquot® 336 (tricaprylylmethyl ammonium chloride) was heated to reflux for 3 days, cooled and extracted into 3×100 mL of hexane. The combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. The resulting oil was mainly 1-(2-chloro-ethyl)-4-fluoro-benzene:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[C:6](=[O:18])[C:5]=2[NH:4][N:3]=1.[C:19](=[O:22])([O-])[O-].[K+].[K+].ClC[CH2:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[C:40]([CH3:42])[C:39]([CH3:43])=[CH:38][C:37]=2[CH3:44])[CH2:32][CH2:31]1)=O>>[NH2:1][C:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[C:6](=[O:18])[C:5]=2[N:4]([C:19](=[O:22])[CH2:27][CH2:28][N:30]2[CH2:35][CH2:34][N:33]([C:36]3[CH:41]=[C:40]([CH3:42])[C:39]([CH3:43])=[CH:38][C:37]=3[CH3:44])[CH2:32][CH2:31]2)[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(N2CCc3c(N)n[nH]c3C2=O)cc1
Reactant: Cc1cc(C)c(N2CCN(C(=O)CCCl)CC2)cc1C
Agent: [K+]
Product: Cc1ccc(N2CCc3c(N)nn(C(=O)CCN4CCN(c5cc(C)c(C)cc5C)CC4)c3C2=O)cc1

Procedure:
A target compound (107.5 mg, 0.214 mmol, 53.7%) was yielded as solid in the same manner as Example 1 by reacting 3-amino-5,6-dihydro-6-N-(p-tolyl)-1H-pyrazolo[3,4-c]pyridin-7(4H)-one (97 mg, 0.4 mmol) with potassium carbonate (82.9 mg, 0.6 mmol) and 3-chloro-1-{4-(2,4,5-trimethylphenyl)piperazin-1-yl}propan-1-one (129.7 mg, 0.44 mmol).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[CH:15]=[C:14]([C:16]4[S:17][C:18]5[C:24]([C:25]6[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=6)=[C:23]([C@H:32]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:22]([CH3:43])=[CH:21][C:19]=5[N:20]=4)[CH:13]=[CH:12][N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:51][CH3:52]>CN(C=O)C>[C:39]([O:38][C@@H:32]([C:23]1[C:22]([CH3:43])=[CH:21][C:19]2[N:20]=[C:16]([C:14]3[CH:13]=[CH:12][N:11]=[C:10]([C:6]4[CH:5]=[C:4]5[C:9](=[CH:8][CH:7]=4)[N:1]([CH2:51][CH3:52])[N:2]=[CH:3]5)[CH:15]=3)[S:17][C:18]=2[C:24]=1[C:25]1[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=1)[C:33]([O:35][CH2:36][CH3:37])=[O:34])([CH3:42])([CH3:41])[CH3:40]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5[nH]ncc5c4)c3)sc2c1-c1ccc(Cl)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5c(cnn5CC)c4)c3)sc2c1-c1ccc(Cl)cc1

Procedure:
To a solution of (S)-ethyl 2-(2-(2-(1H-indazol-5-yl)pyridin-4-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (32 mg, 0.052 mmol) in DMF (1 mL), was added Cs2CO3 (34 mg, 0.104 mmol), iodoethane (5 μL, 0.062 mmol). The reaction was reacted at room temperature. After the reaction finished, the reaction mixture was washed by water, extracted by EtOAc, the organic phase was dried over MgSO4, filtered, concentrated down, purified by silica gel column, eluting by 0-100% EtOAc in hexanes to give (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-(1-ethyl-1H-indazol-5-yl)pyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate. LCMS-ESI+: calc'd for C36H35ClN4O3S: 639.2 (M+H+). found: 639.4;
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:26])[N:5]([CH2:12][CH:13]([C:20]1([CH3:25])OCC[O:21]1)[C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])[C:6]2=[O:11].C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1>CC(C)=O.O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:26])[N:5]([CH2:12][CH:13]([C:20](=[O:21])[CH3:25])[C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])[C:6]2=[O:11]
Reactant: C=CCOC(=O)C(CN1C(=O)c2cccc(F)c2C1=O)C1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: CC(C)=O
Solvent: O
Product: C=CCOC(=O)C(CN1C(=O)c2cccc(F)c2C1=O)C(C)=O
Temperature: 80 °C

Procedure:
Allyl 3-(4-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (331 mg, 0.91 mmol) was dissolved in a a solvent mixture of acetone/water (v/v=5/1), and catalyst amount of p-toluenesulfonic acid anhydride was added to the obtained solution. The resulting mixture was refluxed at 80° C. for 18 hours. After the reaction was completed, the reaction mixture was washed with water, and then acetone was removed by distilling under a reduced pressure. The residue was extracted with dichloromethane. The combined organic layer was dried with anhydrous sulfate and distilled under a reduced pressure. The desired product was obtained (131.2 mg, 31%) by performing column chromatography (eluent: n-hexane/ethyl acetate=2/1).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([S:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[NH:27][CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:33][C:34]1[C:39]([C:40]#[N:41])=[C:38](Cl)[N:37]=[CH:36][N:35]=1.CCN(C(C)C)C(C)C>C(O)(C)(C)C>[NH2:33][C:34]1[C:39]([C:40]#[N:41])=[C:38]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([S:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[NH:27][CH2:28][CH2:29][N:30]([CH3:31])[CH3:32])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:37]=[CH:36][N:35]=1
Reactant: C[C@H](N)c1nn2ccc(Sc3ccccc3NCCN(C)C)c2c(=O)n1-c1ccccc1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nn2ccc(Sc3ccccc3NCCN(C)C)c2c(=O)n1-c1ccccc1
Yield: 2.9 %

Procedure:
(S)-2-(1-Aminoethyl)-5-((2-((2-(dimethylamino)ethyl)amino)phenyl)thio)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (267 mg, 0.54 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (123 mg, 0.81 mmol) and DIEA (280 μl, 1.61 mmol) in 10 ml of tert-BuOH were stirred overnight at 80° C. After evaporation of the solvent under reduced pressure, the residue was purified using SP1® Purification System (0% to 20%, DCM-MeOH) to obtain 9 mg of the title compound as a solid. Purity 99%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-])=O)[C:5]([CH3:11])=[C:6]([CH:10]=1)C(O)=O.CN([CH:18]([O:21]C)[O:19][CH3:20])C.[CH3:23]N(C=O)C>C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:10]=[C:6]([C:18]([O:19][CH3:20])=[O:21])[C:5]2[CH:11]=[CH:23][NH:12][C:4]=2[CH:3]=1
Reactant: CN(C)C=O
Reactant: COC(OC)N(C)C
Reactant: Cc1c(C(=O)O)cc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)cc2[nH]ccc12
Temperature: 115 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
To a stirred solution of 5-bromo-2-methyl-3-nitro-benzoic acid (140 g, 538.4 mmol) in DMF (550 ml) was added DMF-DMA (599 mL, 4846 mmol) at room temperature. The reaction mixture was stirred at 115° C. for 18 h. The reaction mixture was then concentrated in vacuo. The residual contents (176 g, 536.5 mmol) were dissolved in acetic acid (696 mL) and added to a suspension of iron (329.2 g, 5902 mmol) in acetic acid (1.4 L) at 50° C. After completion of addition, the reaction mixture was stirred at 80-90° C. for 4 h. The reaction mixture was then filtered through a Celite pad. The filtrate was poured onto ice water (1 L) and extracted with diethyl ether (3×700 ml). The combined organic layers were washed with sat NaHCO3, brine, and dried over anhydrous Na2SO4, filtered, and evaporated under vacuum. The crude product was purified by silica gel chromatography (eluent: 10% ethyl acetate in pet ether) and afforded the title compound as a solid (80 g, 59%). 1H NMR (DMSO-d6, 400 MHz) δ: 3.980 (s, 3H), 7.168 (d, J=3.2 Hz, 1H), 7.334 (d, J=3.2 Hz, 1H), 7.734 (s, 1H), 8.017 (s, 1H), 8.384 (brs, 1H); LCMS (ES−) m/z=251.9 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][C:11]1[O:12][CH2:13][C:14]([CH3:17])([CH3:16])[N:15]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:10][C:11]2[O:12][CH2:13][C:14]([CH3:17])([CH3:16])[N:15]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: CC1=NC(C)(C)CO1
Product: CC1(C)COC(C=Cc2cccc(Cl)c2)=N1

Procedure:
2-(2-m-Chlorophenylethenyl)-4,4-dimethyl-2-oxazoline (P-1895) was prepared by reacting m-chlorobenzaldehyde with 2,4,4-trimethyl-2-oxazoline.
Reaction SMILES: Cl.C(Cl)(=O)[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[C:11](=[O:14])(O)[O-].[Na+].[CH3:16][NH:17][CH2:18][CH2:19][CH2:20][N:21]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH2:29][CH2:28][C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]1=2.Cl>C(Cl)Cl>[CH3:16][N:17]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)[CH2:18][CH2:19][CH2:20][N:21]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=2[C:28](=[C:11]=[O:14])[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]1=2
Reactant: CNCCCN1c2ccccc2CCc2ccccc21
Reactant: O=C([O-])O
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CN(CCCN1c2ccccc2CC(=C=O)c2ccccc21)c1cccnc1
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 62 %

Procedure:
Freshly prepared nicotinoyl chloride hydrochloride (0.55 g, 0.003 mol) was suspended in methylene chloride (12 ml) cooled to 5° C. and sodium bicarbonate (0.053 g, 0.0063 mol) was added. After 5 minutes, desipramine hydrochloride (0.75 g, 0.0025 mol) was added and the mixture was stirred for 3 hours at 5° C. The sodium chloride was removed by filtration and the organic solution was extracted with aqueous sodium bicarbonate, dried over sodium sulfate, filtered through Celite™ and concentrated. Ethyl ether (5 ml) was added to the oily residue and white crystals formed. Yield 62% (0.58 g), m.p. 84°-86° C. The product has the formula: ##STR1553##
Reaction SMILES: [NH2:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[N:13]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[N:14]=[C:15]([NH:16][CH:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)[C:8]=23)=[C:4]([F:35])[CH:3]=1.CCN(C(C)C)C(C)C.[C:45]1([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH:50]=[CH:49][CH:48]=[C:47]([C:51](Cl)=[O:52])[CH:46]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[F:35][C:4]1[CH:3]=[C:2]([NH:1][C:51]([C:47]2[CH:46]=[C:45]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH:50]=[CH:49][CH:48]=2)=[O:52])[CH:34]=[CH:33][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[N:13]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[N:14]=[C:15]([NH:16][CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[C:8]=12
Reactant: O=C(Cl)c1cccc(-c2ccccc2)c1
Reactant: COc1ccc(Cn2nc(NC3CCN(C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2nc(NC3CCN(C)CC3)c3c(Oc4ccc(NC(=O)c5cccc(-c6ccccc6)c5)cc4F)ccnc32)cc1
Temperature: 25 °C
Yield: 58.6 %

Procedure:
To a stirred solution of 1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-N-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine (12 mg, 0.026 mmol) (prepared in Example 101, step A) in 260 μL dichloromethane at 0° C. under nitrogen was added DIEA (14 μL, 0.078 mmol) followed by biphenyl-3-carbonyl chloride (7 mg, 0.031 mmol). The reaction was allowed to warm to room temperature overnight. The reaction was diluted to 10 mL with dichloromethane and stirred rapidly with 10% sodium carbonate solution for 5 minutes. The organics were isolated and dried (MgSO4). The organics were filtered and concentrated to a residue that was loaded onto a Biotage 12S column with dichloromethane and eluted with 4/1 EtOAc/hexanes. The product containing fractions were pooled and concentrated to a yellow oil (10 mg, 59% yield).