Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[Li]CCCC.Cl[Si](CC)(CC)CC.[Cl:20][C:21]1[N:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:38]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)=[O:39])[CH:27]=2)[N:22]=1>C1COCC1.O>[Cl:20][C:21]1[N:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:38]([C:6]3[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=3)([C:40]3[CH:41]=[CH:42][C:43]([CH3:46])=[CH:44][CH:45]=3)[OH:39])[CH:27]=2)[N:22]=1
Reactant: Cc1ccc(C(=O)c2ccc3nc(Cl)nc(-c4cccc(Cl)c4)c3c2)cc1
Reactant: Cn1ccnc1
Agent: CC[Si](Cl)(CC)CC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(O)(c2ccc3nc(Cl)nc(-c4cccc(Cl)c4)c3c2)c2cncn2C)cc1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
1-Methyl-1H-imidazole (0.0507 mol) was added at −70° C. to THF (90 ml) under N2 flow. nBuLi (31.5 ml) was added dropwise. The mixture was stirred at −70° C. for 15 minutes. Chlorotriethyl-silane (0.0522 mol) was added dropwise. The mixture was stirred at −70° C. for 15 minutes. nBuLi (28 ml) was added. The mixture was stirred at −70° C. for 15 minutes. A mixture of intermediate 23 (0.029 mol) in THF (115 ml) was added dropwise. The mixture was stirred at −70° C. for 1 hour, poured out into water and extracted with DCM. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (15-35 μm) (eluent: DCM/MeOH/NH4OH; 96/4/0.1). The pure fractions were collected and the solvent was evaporated, yielding 9 g (65%). A sample (0.3 g) was crystallized from 2-propanone, The precipitate was filtered off and dried, yielding 2-chloro-4-(3-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-α-(4-methylphenyl)-6-quinazolinemethanol (intermediate 24), mp. 220° C.
Reaction SMILES: ClC1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[CH3:15])[N:5]=[C:4]([NH2:16])[N:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH3:25])=[CH:20][CH:19]=1.[CH:26](N(C(C)C)CC)(C)C>O1CCCC1>[Cl:14][C:12]1[CH:11]=[CH:10][C:9]([CH3:15])=[C:8]([C:6]2[N:7]=[C:25]([N:24]([C:21]3[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=3)[CH3:26])[N:3]=[C:4]([NH2:16])[N:5]=2)[CH:13]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(Cl)cc1-c1nc(N)nc(Cl)n1
Reactant: CNc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: Cc1ccc(Cl)cc1-c1nc(N)nc(N(C)c2ccc(Cl)cc2)n1
Temperature: 40 °C
Yield: 21.8 %

Procedure:
A mixture of 4-chloro-6-(5-chloro-2-methyl-phenyl)-[1,3,5]triazin-2-yl-amine (106 mg, 0.42 mmol), (4-chloro-phenyl)-methyl-amine (0.15 ml, 1.25 mmol), tetrahydrofuran (5 ml), and diisopropylethylamine (0.75 ml, 4.2 mmol) was heated at 40° C. for 72 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane (25 ml). The solution was washed with hydrochloric acid (1 M, 25 ml) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 2% methanol-dichloromethane followed by 5% methanol-dichloromethane. Recrystallization (ethyl acetate-hexane) provided the title compound (33 mg, 22% yield). 1H NMR (DMSO-d6) 7.78 (s, 1H), 7.37-7.46 (m, 4H), 7.26 (d, J=8.4 Hz, 1H), 7.10 (br s, 2H), 3.43 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:15]2[C:10](C(C(O)=O)=CC=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li][CH3:27].[CH2:28]1[CH2:32][O:31][CH2:30][CH2:29]1>>[CH2:1]([N:8]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:15]2[C:10]([C:28]([C:32](=[O:31])[CH3:27])=[CH:29][CH:30]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: O=C(O)c1cccc2c(-c3ccccc3)n(Cc3ccccc3)nc12
Reactant: [Li]C
Product: CC(=O)c1cccc2c(-c3ccccc3)n(Cc3ccccc3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Benzyl-3-phenyl-2H-indazole-7-carboxylic acid (0.5 mmol, 160 mg, see preparation of Example 518) was dissolved in 5 ml of dry THF at 0° C. Two milliliters (2 ml) of MeLi (1.6M solution in THF) were added dropwise and the mixture was stirred overnight at room temperature. The reaction mixture was quenched with aq NH4Cl solution and the product was extracted with EtOAc, and then flash column chromatography (SiO2, dichloromethane as an eluant) afforded 1-(2-benzyl-3-phenyl-2H-indazol-7-yl)ethanone in 61% yleld.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:17]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31]CC3C=CC=CC=3)[CH:24]=2)[N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])C1C=CC=CC=1>C1COCC1.CO.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:17]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([OH:31])[CH:24]=2)[N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1ccc(C(c2ccc(OC)c(OCc3ccccc3)c2)n2cncn2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C(c2ccc(OC)c(O)c2)n2cncn2)cc1O

Procedure:
10% Pd/C (80 mg) was added to a solution of 1-[bis-(3-benzyloxy-4-methoxyphenyl)methyl]-1H-[1,2,4]triazole (1.65 g, 3.25 mmol) in THF/MeOH (1:1, 200 mL). The solution was stirred under an atmosphere of H2 (provided by addition from a balloon) overnight. The excess H2 was removed and the reaction mixture was filtered through Celite® washing with THF and MeOH, then the solvent was removed in vacuo. The crude product was purified using Flashmaster II (EtOAc/Hexane) to give the title compound STX1003 (0.86 g, 81%, mp 217.5-219° C.) as a white solid; δH (270 MHz, d6-DMSO) 9.08 (2H, s, 2×OH), 8.47 (1H, s, NCHN), 8.03 (1H, s NCHN), 6.88 (2H, d, J=8.4, ArH), 6.76 (1H, s, CH), 6.64 (2H, s, ArH), 6.57 (2H, d, J=8.4, ArH), 3.74 (6H, s, 2×CH3); δC (68 MHz, d6-DMSO) 151.8 (CH), 147.3 (2×C), 146.3 (2×C), 144.0 (CH), 130.1 (2×C), 118.8 (2×CH), 115.3 (2×CH), 111.9 (2×CH), 64.9 (CH), 55.6 (2×Ch3); LCMS (ES−) 326.2 ([M−H]−, 100%), 255.9 (70), 240.4 (60), 211.4 (70); HRMS (FAB+) Found 327.1226, C17H17N3O4 requires 327.1219; HPLC (CH3CN/H2O, 90:10) tR=1.57 min 99+%); Found: C, 62.10%, H, 5.26%; N, 12.80%, C17H17N3O4 requires: C, 62.38%; H, 5.23%; N, 12.84%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:29]([F:32])([F:31])[F:30])[O:13][N:12]=[C:11]([C:14]3[CH:27]=[CH:26][C:17]([C:18]([NH:20][N:21]4[CH:25]=[CH:24][CH:23]=[N:22]4)=[O:19])=[C:16]([CH3:28])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].[Na+].[H][H].[C:37](Cl)(=[O:39])[CH3:38]>O1CCCC1>[C:37]([N:20]([N:21]1[CH:25]=[CH:24][CH:23]=[N:22]1)[C:18](=[O:19])[C:17]1[CH:26]=[CH:27][C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)([C:29]([F:30])([F:32])[F:31])[O:13][N:12]=2)=[CH:15][C:16]=1[CH3:28])(=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: [H][H]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nn1cccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N(C(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C)n1cccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 26.7 %

Procedure:
In a solution of 0.20 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-N-(1-pyrazolyl)benzoic acid amide in 3 mL of tetrahydrofuran, 0.027 g of 60% oily sodium hydride was added and stirred at room temperature for 10 minutes. After ceasing the generation of hydrogen gas, 0.049 g of acetyl chloride was added under cooling with ice and with stirring, and continued to stir at the same temperature further for 10 minutes. After the completion of the reaction, the reaction mixture was poured in 10 mL of ice water, extracted with ethyl acetate (10 mL×1), the organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (2:3) to obtain 0.058 g of the aimed product as yellow resinous substance.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH2:15][CH3:16])[CH2:12][OH:13])=[N:8][C:7]([S:17]CC3C=CC=CC=3)=[N:6][C:5]=2[N:25]=1.[Na]>N>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH2:15][CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:17])=[N:6][C:5]=2[N:25]=1
Reactant: CCC[C@H](CO)Nc1nc(SCc2ccccc2)nc2nc(N)sc12
Agent: N
Agent: [Na]
Product: CCC[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Temperature: -33 °C
Reaction time: 0.01 h
Yield: 80.3 %

Procedure:
A round-bottomed flask was equipped with a dry ice-ethanol condenser and immersed in a dry ice-ethanol cooling bath. Ammonia (250 mL) was condensed into the flask followed by addition of (2R)-2-{[2-amino-5-(benzylthio)[1,3]thiazolo[4,5-d]pyrimidin-7-yl]amino}pentan-1-ol (6.8 g, 18.1 mmol). The resulting mixture was allowed to warm to −33° C. and sodium metal was added in small pieces until a blue colour appeared and persisted for 30 seconds. The reaction was then quenched by addition of a spoonful of solid ammonium chloride. The ammonia was evaporated off and water (250 mL) was added to the residue. The resulting mixture was neutralized with 1M HCl (aq). The precipitated product was collected by filtration, washed with water and dried in vacuo to yield 4.15 g (80% yield) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH2:10].C(N(CC)CC)C.C1C=[CH:20][C:21](=[O:34])[C:22]2C=1C(C(Cl)=O)=C1C=2C=CC=C1>ClCCl>[CH:21]([O:34][CH:7]([CH3:6])[CH3:2])([CH3:22])[CH3:20].[NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH-:10]
Reactant: O=C(Cl)C1=c2ccccc2=C2C(=O)C=CC=C12
Reactant: Nc1cc(F)c(F)cc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(C)C
Product: [NH-]c1cc(F)c(F)cc1N
Temperature: 25 °C
Reaction time: 20 h
Yield: 282 %

Procedure:
The procedure used in stage 1 of Example 1 is followed, but starting from 1 g of 1,2-diamino-4,5-difluorobenzene, 1.9 ml of triethylamine and 1.7 g of fluoren-4-one-9-carboxylic acid chloride in 50 ml of dichloromethane. After stirring for 20 hours at room temperature, the precipitate that formed is filtered off, and washed with dichloromethane, with water, then with a 10% saturated aqueous solution of sodium hydrogen carbonate and, finally, with water. After formation of a paste with diisopropyl ether, in this way we obtain 1.4 g of (2-amino-4,5-difluorophenyl)amide of 9-oxo-9H-fluorene-4-carboxylic acid, in the form of a yellow powder, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[C:11]1(=[O:20])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1.C(OCC)(=O)C>C(Cl)Cl.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Sc+3]>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[O:20])[CH2:12]1
Reactant: O=C1C=Cc2ccccc21
Reactant: Fc1cccc2cc[nH]c12
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C1CC(c2c[nH]c3c(F)cccc23)c2ccccc21
Temperature: 25 °C
Yield: 82 %

Procedure:
Triethylamine (4.5 mL; 32 mmol; 1.2 equiv.) was added to 3-bromo-indan-1-one (5.6 g; 27 mmol) in 100 mL THF at 0° C. and stirred 1 h at r.t. The reaction mixture was filtered to remove triethylammonium bromide and concentrated in vacuo to give inden-1-one. 7-Fluoroindole (3.3 g, 22 mmol ) and Sc(OTf)3 (550mg, 5 mol %) were added to inden-1-one in 100 mL CH2Cl2 at 0° C. The reaction mixture was allowed to warm to room temperature over night. 100 mL ethyl acetate was added and the mixture was filtered through a silica gel plug and concentrated in vacuo. After flash chromatography (heptane/ethyl acetate, silica gel) 5.9 g 3-(7-fluoro-1H-indol-3-yl)-indan-1-one (82%) was isolated.
Reaction SMILES: [OH:1][C@@:2]1([CH3:15])[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:3]1[CH3:14].O.I([O-])(=O)(=O)=[O:18].[Na+]>C(OCC)(=O)C.O.[Ru](=O)=O>[OH:1][C@@:2]1([CH3:15])[CH2:6][C:5](=[O:18])[N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:3]1[CH3:14]
Reactant: C[C@@H]1N(C(=O)OC(C)(C)C)CC[C@]1(C)O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru]=O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H]1N(C(=O)OC(C)(C)C)C(=O)C[C@]1(C)O
Temperature: 25 °C
Reaction time: 40 h
Yield: 34.2 %

Procedure:
To a solution of tert-butyl(2S,3S)-3-hydroxy-2,3-dimethylpyrrolidine-1-carboxylate (3.05 g) in ethyl acetate (45 mL) were successively added water (68 mL), ruthenium dioxide monohydrate (566 mg) and sodium periodate (4.57 g) at room temperature. The mixture was stirred at room temperature for 40 hr, the organic layer and the aqueous layer were separated, and the aqueous layer was extracted with ethyl acetate. The obtained organic layers were mixed, isopropanol (0.7 mL) was added, and the mixture was stirred at room temperature for 5 min. The reaction solution was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/10→4/10) to give the title compound as a white powder (yield: 1.11 g, 34%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1F)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(Cc1cc([N+](=O)[O-])ccc1F)C(=O)OC(C)(C)C
Reactant: C1CCNC1
Product: CC(C)(C)OC(=O)N(Cc1cc([N+](=O)[O-])ccc1N1CCCC1)C(=O)OC(C)(C)C
Yield: 80 %

Procedure:
Using the compound obtained in Example 263 as a starting material and also using pyrrolidine as a reagent, the same procedure of Example 264 gave the titled compound (yield, 80%).
Reaction SMILES: C12N(C3C=NC4C(=CC=CC=4)N=3)CC1CCNC2.[CH:19]12[CH2:25][NH:24][CH:23]1[CH2:22][N:21]([C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35])=[O:27])[CH2:20]2.Cl[C:37]1[N:42]=[C:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:40]=[CH:39][N:38]=1>>[CH3:35][O:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:26]([N:21]1[CH2:22][CH:23]2[CH:19]([CH2:25][N:24]2[C:37]2[N:42]=[C:41]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH:40]=[CH:39][N:38]=2)[CH2:20]1)=[O:27]
Reactant: COc1ccccc1C(=O)N1CC2CNC2C1
Reactant: Clc1nccc(-c2ccccc2)n1
Agent: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Product: COc1ccccc1C(=O)N1CC2CN(c3nccc(-c4ccccc4)n3)C2C1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, Step A, using Intermediate 22 and 2-chloro-4-phenyl-pyrimidine. MS (ESI) mass calcd. for C23H22N4O, 386.46; m/z found, 387.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH:9]([CH3:16])[CH2:8][N:7]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[C:6]=2[CH:25]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=2)O1.C(=O)([O-])[O-].[K+].[K+].O1CCCC1>C(OCC)(=O)C.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.O>[NH2:40][C:37]1[N:38]=[CH:39][C:34]([C:2]2[CH:3]=[CH:4][C:5]3[N:11]4[C:12]([CH3:15])=[N:13][N:14]=[C:10]4[CH:9]([CH3:16])[CH2:8][N:7]([C:17]4[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=4)[C:6]=3[CH:25]=2)=[CH:35][CH:36]=1
Reactant: Cc1nnc2n1-c1ccc(Br)cc1N(c1ccc(C#N)cc1)CC2C
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nnc2n1-c1ccc(-c3ccc(N)nc3)cc1N(c1ccc(C#N)cc1)CC2C
Temperature: 100 °C
Yield: 59.4 %

Procedure:
A mixture of 4-(8-bromo-1,4-dimethyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-6(5H)-yl)benzonitrile (244 mg, 0.62 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (274 mg, 1.24 mmol), tetrakis(triphenylphosphine)palladium(0) (50 mg) and potassium carbonate (350 mg, 2.53 mmol) in a mixed solution of tetrahydrofuran (10 mL) and water (1 mL) was heated at 100° C. for 30 minutes under microwave (pressure: 17.2 bar, equipment power: 150 W). The reaction mixture was diluted with ethyl acetate (20 mL) and washed with brine (10 mL*3). The organic phase was separated, dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated to give a crude product, which was purified by column chromatography (silica gel, dichloromethane/methanol=12:1) to afford 4-(8-(6-aminopyridin-3-yl)-1,4-dimethyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-6(5H)-yl)benzonitrile as a light yellow solid (150 mg, 59.4%). LRMS (M+H)+: calcd 407.19. found 407.
Reaction SMILES: [CH2:1]([OH:6])[CH:2]([OH:5])[CH:3]=[CH2:4].[CH3:7][C:8]([CH3:10])=O.COC(OC)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:7][C:8]1([CH3:10])[O:5][CH:2]([CH:3]=[CH2:4])[CH2:1][O:6]1
Reactant: C=CC(O)CO
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: COC(C)(C)OC
Product: C=CC1COC(C)(C)O1
Reaction time: 3 h
Yield: 56.7 %

Procedure:
3-Butene-1,2-diol (5.00 g, 56.7 mmol), acetone (9.88 g, 170 mmol), 2,2-dimethoxy propane (17.7 g, 170 mmol), and p-toluene sulfonic acid (1.62 g, 8.5 mmol) were added to benzene (100 mL). After 16 hours of reflux, starting material was observed by TLC. 2,2-Dimethoxy propane (9.99 g, 95.1 mmol) and acetone (1.58 g, 27.3 mmol) were then added, followed by an additional 3 hour reflux. The mixture was washed with saturated aqueous NaHCO3 and extracted with EtOAc (3×40 mL). The organic extracts were dried over MgSO4, filtered, concentrated and purified by column chromatography (5% ethyl acetate in hexanes) to provide the titled compound (4.12 g, 57%) as a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[N:6][CH:7]=1.S(Cl)(Cl)=O.[CH3:16]O>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:16])=[O:10])[CH:5]=[N:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)Cc1cncc(Br)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-(5-bromopyridin-3-yl)acetic acid (5 g, 23.14 mmol) in MeOH (100 mL) was added thionyl chloride (1.858 mL, 25.5 mmol) at 0° C., and the mixture was stirred at 0° C. for 2 h. The mixture was concentrated in vacuo, re-dissolved in DCM (100 mL) and MeOH (10 mL), and saturated NaHCO3 in water (5 mL) was added, followed with NaHCO3 (10 g). To the mixture was added silica gel (10 g) and the mixture was concentrated. The residue was purified by silica chromatography eluting with 0-50% EtOAc-heptane to give methyl 2-(5-bromopyridin-3-yl)acetate. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.64 (s, 3H), 3.80 (s, 2H), 8.01 (dd, J=2.0 Hz, 1H), 8.48 (d, J=1.8 Hz, 1H), 8.61 (d, J=2.3 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[O:14][CH2:15][CH:16]1[CH2:18][CH2:17]1.C1C(=O)N([Cl:26])C(=O)C1>C(Cl)(Cl)(Cl)Cl.O>[NH2:1][C:2]1[C:3]([O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][C:7]=1[Cl:26]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)Cc1ccc(N)c(OCC2CC2)c1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)Cc1cc(Cl)c(N)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.3 %

Procedure:
To a stirred solution of ethyl 2-(4-amino-3-(cyclopropylmethoxy)phenyl)acetate (1.2 g, 4.0 mmol) in dry CCl4 (60 mL), NCS (0.427 g, 3.2 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 h at room temperature to complete the reaction. The reaction mixture was diluted with water, extracted with DCM (2×50 mL), the combined organic solvents was dried over Na2SO4, filtered and concentrated in vacuo. The crude reaction mixture was purified by column chromatography to yield Ethyl 2-(4-amino-3-chloro-5-(cyclopropylmethoxy)phenyl)acetate (920 mg) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:41])[CH2:10][NH:11][C:12]([C:14]2[N:15]=[C:16]3[N:31]([CH2:32][C:33](=[O:40])[N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)[CH:30]=[CH:29][N:17]3[C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=O)=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[CH2:21]([O:20][C:19]1[C:18](=[O:28])[N:17]2[CH:29]=[CH:30][N:31]([CH2:32][C:33](=[O:40])[N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[C:16]2=[N:15][C:14]=1[C:12]1[O:41][C:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:10][N:11]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(CNC(=O)c1nc2n(CC(=O)N3CCCCC3)ccn2c(=O)c1OCc1ccccc1)Cc1ccc(F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Cn1ccn2c(=O)c(OCc3ccccc3)c(-c3ncc(Cc4ccc(F)cc4)o3)nc12)N1CCCCC1
Reaction time: 3 h
Yield: 20.7 %

Procedure:
To a solution of the product of example 5 (200 mg, 0.357 mmol) in acetonitrile (3 ml), carbon tetrachloride (330 mg, 2.1 mmol), triethylamine (180 mg, 1.78 mmol) and triphenylphosphine (470 mg, 1.79 mmol) were added successively at room temperature. The mixture was stirred for 3 hours. The product was purified by column chromatography (CH2Cl2/MeOH=150/1) to give the titled product (40 mg, 21% yield).
Reaction SMILES: CN(C)[C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[C:9]([CH2:11][CH3:12])[CH:8]=[CH:7][C:6]=1[NH:13][C:14]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[C:16]([F:22])[C:15]=1[F:23].[OH-].[Na+].CCCC[OH:32].Cl>C1(C)C=CC=CC=1>[CH2:11]([C:9]1[CH:8]=[CH:7][C:6]([NH:13][C:14]2[C:19]([F:20])=[C:18]([F:21])[CH:17]=[C:16]([F:22])[C:15]=2[F:23])=[C:5]([CH2:4][C:3]([OH:24])=[O:32])[CH:10]=1)[CH3:12]
Reactant: CCc1ccc(Nc2c(F)c(F)cc(F)c2F)c(CC(=O)N(C)C)c1
Reactant: CCCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCc1ccc(Nc2c(F)c(F)cc(F)c2F)c(CC(=O)O)c1
Temperature: 25 °C

Procedure:
N,N-Dimethyl-5-ethyl-2-(2′,3′,5′,6′-tetrafluoroanilino)phenylacetamide (26 g, 0.073 mol) and 6N NaOH (150 ml) are stirred as a two phase solution with n-BuOH (150 ml) at reflux temperature for 14 hours. After cooling to room temperature, the reaction is poured over ice (500 ml). Toluene (500 ml) is added and the mixture transferred to a separatory funnel. The aqueous phase is brought to a pH of 1 with 3 N HCl. The organic layer is separated and the aqueous phase re-extracted with toluene (250 ml). The combined organic layers are dried (MgSO4) and concentrated under high vacuum (35-50 mbar) on a rotovap taking care not to warm above 50°. Small white needles are obtained by crystallization of the residue from hexane, m.p. 164-166°. Recrystallization from cyclohexane gives 5-ethyl-2-(2′,3′,5′,6′-tetrafluoroanilino)phenylacetic acid a white solid, m.p. 165-169°.