Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19](O)=[O:20])[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:55]([NH2:64])(=[O:63])[C:56]1[C:57](=[CH:59][CH:60]=[CH:61][CH:62]=1)[NH2:58]>ClCCl.CC#N>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:13][CH2:14][N:15]([CH2:18][C:19]([NH:58][C:57]3[CH:59]=[CH:60][CH:61]=[CH:62][C:56]=3[C:55]([NH2:64])=[O:63])=[O:20])[CH2:16][CH2:17]2)(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: NC(=O)c1ccccc1N
Reactant: COc1ccc(S(=O)(=O)N2CCN(CC(=O)O)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(S(=O)(=O)N2CCN(CC(=O)Nc3ccccc3C(N)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of [4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-acetic acid (1.10 g, 3.5 mmol), HATU (1.33 g, 3.5 mmol) and DIEA (1.22 mL, 7 mmol) in dichloromethane (40 mL) was added anthranilamide (714 mg, 5.25 mmol). The reaction was stirred at room temperature for 1 hour and then the reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (50-100% ethyl acetate-hexanes) to yield the pure product. (1.18 g, 78%). 1H NMR (400 MHz, CDCl3) δ 11.82 (s, 1H), 8.66 (d, J=8.0 Hz, 1H), 7.77 (d, J=7.0 Hz, 2H), 7.51 (m, 2H), 7.11 (t, J=7.6 Hz, 1H), 7.05 (d, J=7.1 Hz, 2H), 6.10 (br s, 1H), 5.51 (br s, 1H), 3.92 (s, 3H), 3.24 (m, 6H), 2.76 (t, J=4.7 Hz, 4H); HPLC ret. time 2.46 min, 10-99% CH3CN, 5 min run; ESI-MS m/z 433.1 (M+1)+.
Reaction SMILES: [CH:1]1([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.II.[CH2:20]([O:22][C:23](=[O:26])[CH2:24]Br)[CH3:21].Cl>C1C=CC=CC=1.[Zn]>[OH:17][C:15]([C:12]1[CH:11]=[CH:10][C:9]([CH:1]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:14][CH:13]=1)([CH3:16])[CH2:24][C:23]([O:22][CH2:20][CH3:21])=[O:26]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)c1ccc(C2CCCCCCC2)cc1
Agent: Cl
Agent: II
Agent: [Zn]
Solvent: c1ccccc1
Product: CCOC(=O)CC(C)(O)c1ccc(C2CCCCCCC2)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a refluxing mixture of 4′-cyclooctylacetophenone (30 g), I2 (5 mg) and Zn (17.2 g) in benzene (300 ml) was added ethylbromoacetate (18 ml) dropwise during 30 minutes. The mixture was refluxed for 2 h and then cooled to room temperature. It was acidified with 10% HCl (200 ml), benzene layer was separated out. The organic layer was washed with water, dried (Na2SO4) and concentrated. The crude product was purified by column chromatography on silica gel to give 39.4 g (95% yield) of ethyl 3-hydroxy-3-(4′-cyclooctylphenyl)-butanoate (2d, formula 2, R=cyclooctyl) as viscous oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Al](C)C.CO[C:13]([C:15]1[CH:16]=[C:17]([NH2:30])[C:18]2[N:19]([N:21]=[C:22]([C:24]3[O:25][C:26]([Br:29])=[CH:27][CH:28]=3)[N:23]=2)[CH:20]=1)=[O:14].Cl>O1CCOCC1.C1(C)C=CC=CC=1>[NH2:30][C:17]1[C:18]2[N:19]([N:21]=[C:22]([C:24]3[O:25][C:26]([Br:29])=[CH:27][CH:28]=3)[N:23]=2)[CH:20]=[C:15]([C:13]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:14])[CH:16]=1
Reactant: COC(=O)c1cc(N)c2nc(-c3ccc(Br)o3)nn2c1
Reactant: C1CCNCC1
Agent: C[Al](C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Nc1cc(C(=O)N2CCCCC2)cn2nc(-c3ccc(Br)o3)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.9 %

Procedure:
A solution of 20 mg (0.24 mmol) piperidine in 1 ml dioxane was treated with 0.24 ml (0.24 mmol) trimethylaluminum in toluene and stirred for 1 h at room temperature. 20 mg (0.06 mmol) 8-Amino-2-(5-bromo-furan-2-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylic acid methyl ester in 1 ml dioxane was added and the mixture was heated to 90° C. for 72 h. 0.5 ml 1N HCl aq. was added and the volatiles were removed. The residue was taken up in 1.5 ml formic acid and 0.5 ml methanol and purified by reversed phase preparative HPLC eluting with a gradient of acetonitrile and water. The elution solvents were evaporated to obtain 7 mg (29%) of the title compound.
Reaction SMILES: Cl[C:2]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[C:12]([CH3:17])=[N:13][O:14][C:15]=3[CH3:16])[CH:9]=2)[NH:4][C:3]1=[O:18].N1C=CC=CC=1.[CH2:31]([OH:34])[CH2:32][OH:33]>C1COCC1.O>[CH3:17][C:12]1[C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][C:3](=[O:18])[C:2]3([O:33][CH2:32][CH2:31][OH:34])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:15]([CH3:16])[O:14][N:13]=1
Reactant: OCCO
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(Cl)(c1ccccc1)C(=O)N2
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: Cc1noc(C)c1-c1ccc2c(c1)C(OCCO)(c1ccccc1)C(=O)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 15.6 %

Procedure:
30 mg (0.088 mmol) of 3-chloro-5-(3,5-dimethylisoxazol-4-yl)-3-phenylindolin-2-one and 139 mg (0.176 mmol) of pyridine were dissolved in 5 ml of THF. After the addition of 54 mg (0.88 mmol) of ethane-1,2-diol, the reaction solution was stirred for 5 h at room temperature. Subsequently, the solution was diluted with water. The aqueous phase was extracted with 2×25 mL of EtOAc. The combined organic phases were washed with aqueous NaHCO3 and with water, dried and concentrated in vacuo. The resulting residue was purified by Pre-TLC (eluent: Hexane/EtOAc=1/1) to give product (5 mg, 15%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.77 (s, 1H), 7.32-7.35 (m, 6H), 7.20 (s, 1H), 7.04 (d, J=8.0 Hz, 1H), 4.65 (t, J=5.6 Hz, 1H), 3.23-3.52 (m, 4H), 2.35 (s, 3H), 2.18 (s, 3H). MS (ESI) m/e [M+1]+ 365.
Reaction SMILES: [Cl:1][C:2]1[S:17][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=O)[CH:19]=1>>[Cl:1][C:2]1[S:17][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]3[CH2:12][CH2:13][N:14]([CH2:24][C:20]4[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=4)[CH2:15][CH2:16]3)[C:4]=2[CH:3]=1
Reactant: O=Cc1cccnc1
Reactant: Clc1cc2c(NC3CCNCC3)ncnc2s1
Product: Clc1cc2c(NC3CCN(Cc4cccnc4)CC3)ncnc2s1

Procedure:
The title compound was prepared (338 mg, 94%) from 6-chloro-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine (341 mg, 1.0 mmol) and 3-pyridinecarboxaldehyde (107 mg, 1.0 mmol) by following the general procedure described for Preparation 11. 1H NMR (400 MHz, CDCl3): 8.57 (d, 1H), 8.52 (dd, 1H), 8.43 (s, 1H), 7.68-7.65 (m, 1H), 7.29 (d, 1H), 7.02 (s, 1H), 5.14 (d, 1H), 4.21-4.17 (m, 1H), 3.54 (s, 2H), 2.88 (d, 2H), 2.43 (t, 2H), 2.10-2.07 (m, 2H), 1.62-1.52 (m, 2H); MS (ESI) m/z: Calculated: 359.88; Observed: 360.2 (M++1).
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH:14]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.Cl>[OH-].[Na+]>[CH:14]1([C:20]([NH:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]2[CH:5]=[CH:6][C:7]([O:10][C:20]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:21])=[CH:8][CH:9]=2)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: O=C(Cl)C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(N[C@@H](Cc1ccc(OC(=O)C2CCCCC2)cc1)C(=O)O)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.1 %

Procedure:
(L)-Tyrosine (61.6 g., 0.34 mole) was dissolved in 190 mL of 2 N sodium hydroxide. Cyclohexanoyl chloride (49.32 mL, 0.34 mole) was added dropwise to the mixture. Additional aqueous 2 N sodium hydroxide was added, and the reaction mixture was allowed to stir at room temperature for 2 hours. The mixture was then acidified to pH 9.5 with aqueous (4:1) hydrochloric acid. A precipitate formed which was separated by vacuum filtration. The solids were dissolved in 2 N sodium hydroxide and dried by lyophilization to furnish 33.5 g of N,O-dicyclohexanoyl-(L)-tyrosine. The product was purified by column chromatography on silica gel using butanol/acetic acid/water as the eluent system. The pure product was a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.[Br:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH3:13])([CH3:14])[C:6]=3[CH:15]=2)=[CH:19][CH:18]=1
Reactant: CN1C(=O)OC(C)(C)c2cc(N)ccc21
Reactant: OB(O)c1ccc(Br)cc1
Product: CN1C(=O)OC(C)(C)c2cc(Nc3ccc(Br)cc3)ccc21

Procedure:
Prepared from 6-amino-1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 4-bromophenyl boronic acid according to the coupling procedure described in example 1. MS (ESI) m/z 361/363 ([M+H]+); MS (ESI) m/z 359/361 ([M−H]−); Anal. calcd for C17H17BrN2O2: C, 56.52; H, 4.74; N, 7.75. Found: C, 56.98; H, 4.34; N, 7.30.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:9]=[C:10]([C:13]([OH:15])=O)[S:11][CH:12]=2)[N:4]([CH3:16])[N:3]=1.[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:9]=[C:10]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=3)[CH2:19][N:20]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:30])=[O:15])[S:11][CH:12]=2)[N:4]([CH3:16])[N:3]=1
Reactant: Cc1c(Cl)nn(C)c1-c1csc(C(=O)O)c1
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1c(Cl)nn(C)c1-c1csc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(3-chloro-1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (291 mg, 1.13 mmol) [prepared according to the procedure of Example 176], 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (409 mg, 1.22 mmol) [prepared according to the procedure of Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (5.03 g, 17.8 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (654 mg, 1.39 mmol) in chloroform (10 mL). DIEA (1 mL, 5.73 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (427 mg, 0.76 mmol, 67%): LC-MS (ES) m/z=537 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([NH2:17])=[S:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:19][C:20](=O)[C:21]([F:24])([F:23])[F:22]>C(O)C>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[S:16][CH:19]=[C:20]([C:21]([F:24])([F:23])[F:22])[N:17]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: NC(=S)NC1CCN(Cc2ccccc2)CC1
Solvent: CCO
Product: FC(F)(F)c1csc(NC2CCN(Cc3ccccc3)CC2)n1
Yield: 89.3 %

Procedure:
To a stirred solution of (1-benzyl-piperidin-4-yl)-thiourea (0.5 g, 2.0 mmol) (prepared by a procedure similar to that described in WO 03/062215) in ethanol (15 ml) was added 3-bromo-1,1,1-trifluoroacetone (0.22 ml, 2.1 mmol) and the reaction mixture was heated at reflux for 1 h. After evaporation of the solvent, the crude product was crystallized from acetonitrile to yield D8 (0.61 g, 88%) as a white solid. C16H18F3N3S.HBr free base requires 341. Found 342 (MH+).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:12][CH2:13][C:14]1[O:15][C:16]([CH3:19])=[CH:17][CH:18]=1)=[N:7]2.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1>O1CCOCC1>[CH3:19][C:16]1[O:15][C:14]([CH2:13][NH:12][C:6]2[CH:5]=[CH:4][C:3]3[C:2]([NH:20][CH:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=2)=[CH:18][CH:17]=1
Reactant: CN1CCC(N)CC1
Reactant: Cc1ccc(CNc2ccc3c(Br)cccc3n2)o1
Solvent: C1COCCO1
Product: Cc1ccc(CNc2ccc3c(NC4CCN(C)CC4)cccc3n2)o1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
(5-Bromo-quinolin-2-yl)-(5-methyl-furan-2-ylmethyl)-amine (150 mg, 0.47 mmol) was dissolved in 2 mL dioxane. Argon was bubbled through the solution for 2 minutes to remove oxygen. 4-Amino-1-methyl-piperidine (165 mg, 1.45 mmol), sodium tert.-butylate (117 mg, 1.22 mmol), 1,1′-bis(diphenylphosphin)ferrocen (41 mg, 0.074 mmol) and 1,1′-bis(diphenylphosphin)ferrocen-palladium(II)chloride (19 mg, 0.023 mmol) were added. The reaction mixture was stirred in a sealed tube at 120° C. overnight. The solvent was evaporated and the residue purified by flash chromatography on silica gel (dichloromethane/methanol/ammonia 100:0:0->90:10:1 gradient). The title compound was obtained as a brown solid (36 mg, 22%), MS: m/e=351.3 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([CH3:22])=[N:16][C:17]=3[O:19][CH2:20][CH3:21])[NH:12][C:11]([CH3:23])=[C:10]2[C:24]([OH:26])=O)=[C:5]([O:27][CH3:28])[CH:4]=1)#[N:2].C(OCC)(=O)C.C(N1C=CN=C1)([N:37]1C=CN=C1)=O.N>ClCCl.CO.C1CCCCC1.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([CH3:22])=[N:16][C:17]=3[O:19][CH2:20][CH3:21])[NH:12][C:11]([CH3:23])=[C:10]2[C:24]([NH2:37])=[O:26])=[C:5]([O:27][CH3:28])[CH:4]=1)#[N:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOc1nc(C)cc2c1C(c1ccc(C#N)cc1OC)C(C(=O)O)=C(C)N2
Agent: N
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOc1nc(C)cc2c1C(c1ccc(C#N)cc1OC)C(C(N)=O)=C(C)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
640 mg (1.69 mmol) of the compound from Example 27A are introduced into 30 ml of ethyl acetate and, after addition of 342 mg (2.11 mmol) of 1,1′-carbonyldiimidazole, stirred at room temperature overnight. A TLC check (silica gel; mobile phase: cyclohexane/ethyl acetate 1:1 or dichloromethane/methanol 9:1) shows complete conversion. The volatile components are removed in a rotary evaporator, and the residue is taken up in 20 ml of DMF. Then 2.36 ml of ammonia (28% by weight solution in water, 16.87 mmol) are added, and the reaction mixture is heated at 50° C. for 8 h. The solvent is distilled out under reduced pressure, and the residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 368 mg (58% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[S:4][N:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[N:26]3[N:27]=[C:28]([NH2:30])[N:29]=[C:25]3[CH2:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.NC1C=CC=C(Br)N=1>>[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[N:26]3[N:27]=[C:28]([NH:30][CH:10]4[CH2:11][CH2:12][N:7]([C:5]5[S:4][N:3]=[C:2]([CH3:1])[N:6]=5)[CH2:8][CH2:9]4)[N:29]=[C:25]3[CH2:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Reactant: Nc1nc2n(n1)C(c1ccc(F)cc1)CCC2
Agent: Nc1cccc(Br)n1
Product: Cc1nsc(N2CCC(Nc3nc4n(n3)C(c3ccc(F)cc3)CCC4)CC2)n1

Procedure:
Prepared in analogy to example 1 step h) starting from 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one (example 1c) and 5-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine. The latter compound can be prepared in analogy to example 1 steps d-g) starting from 2-amino-6-bromo-pyridine. The title compound was obtained as a white solid (yield=30%).
Reaction SMILES: CC1C=CC=CC=1[CH2:4][CH2:5][Si:6]([CH3:21])([CH3:20])[O:7][Si:8]([CH3:19])([CH3:18])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1C.C[Si](C)(C)O[Si](C)(C)C>>[CH3:4][CH2:5][Si:6]([CH3:21])([CH3:20])[O:7][Si:8]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:18])[CH3:19]
Reactant: Cc1ccccc1CC[Si](C)(C)O[Si](C)(C)CCc1ccccc1C
Solvent: C[Si](C)(C)O[Si](C)(C)C
Product: CC[Si](C)(C)O[Si](C)(C)CCc1ccccc1
Reaction time: 2 h

Procedure:
The following were charged to a 1 L roundbottom flask equipped with a stirrer and thermometer: 200 g 1,3-di(2-methylphenethyl)tetramethyldisiloxane as prepared in Example 3, 600 g hexamethyldisiloxane, and 5 g thoroughly dehydrated activated clay. This was followed by heating to 80° to 85° C. and stirring for 2 hours. The reaction mixture was then filtered and the filtrate was heated in vacuo to afford 170 g 2- (methylphenethylpentamethyldisiloxane.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:11](=[O:12])[CH2:10][CH2:9][C@H:5]1[C:6]([OH:8])=O)[CH3:3].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N1CCOCC1)C.[Cl:43][C:44]1[C:49]([C:50]([F:53])([F:52])[F:51])=[CH:48][CH:47]=[CH:46][C:45]=1[CH2:54][NH2:55].C(=O)([O-])O.[Na+]>ClCCl>[Cl:43][C:44]1[C:49]([C:50]([F:52])([F:53])[F:51])=[CH:48][CH:47]=[CH:46][C:45]=1[CH2:54][NH:55][C:6](=[O:8])[C@@H:5]1[CH2:9][CH2:10][C:11](=[O:12])[N:4]1[CH:2]([CH3:1])[CH3:3]
Reactant: NCc1cccc(C(F)(F)F)c1Cl
Reactant: CC(C)N1C(=O)CC[C@H]1C(=O)O
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)N1C(=O)CC[C@H]1C(=O)NCc1cccc(C(F)(F)F)c1Cl
Reaction time: 48 h

Procedure:
1-(1-Methylethyl)-5-oxoproline (0.100 g, 0.58 mmol) was dissolved in dichloromethane (20 ml) and to this was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.111 g, 0.58 mmol), 1-Hydroxybenzotriazole (0.078 g, 0.58 mmol), and N-ethyl morpholine (0.223 ml, 1.75 mmol). Finally {[2-chloro-3-(trifluoromethyl)phenyl]methyl}amine was added to the mixture and stirring continued for ˜48 hrs. The mixture was then treated with saturated aqueous sodium hydrogen carbonate (20 ml) and stirred vigorously. The aqueous layer was removed using a phase separator and then the solvent was removed from the organic layer using an argon blow-down unit. The resulting residue was treated with a mixture of water and ethylacetate (25 ml, 1:1) and the aqueous layer was subsequently discarded. The organic layer was filtered through a phase separator and evaporated to give an oil. This was triturated with diethyl ether to give a solid and this was subsequently purified by mass-directed automated HPLC to give N-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-1-(1-methylethyl)-5-oxoprolinamide (0.097 g) as a white solid. LC/MS [M+H]+=363, retention time=2.48 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].Cl[Sn]Cl.O.[CH3:15][CH2:16][O:17]C(C)=O>ClCCCl>[C:16]([C:5]1[NH:4][C:3]([C:7]([O:9][CH3:10])=[O:8])=[C:2]([Cl:1])[CH:6]=1)(=[O:17])[CH3:15]
Reactant: COC(=O)c1[nH]ccc1Cl
Reactant: CCOC(C)=O
Agent: Cl[Sn]Cl
Solvent: O
Solvent: ClCCCl
Product: COC(=O)c1[nH]c(C(C)=O)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 26 %

Procedure:
A solution of methyl 3-chloro-1H-pyrrole-2-carboxylate (0.100 g, 0.627 mmol) in DCE (3 mL) was added to a suspension of SnCl2 (0.238 g, 1.25 mmol) and methyl 3-chloro-1H-pyrrole-2-carboxylate (0.100 g, 0.627 mmol) in DCE (3 mL) at 0° C. The reaction was stirred for 10 min. at 0° C. then warmed to room temp over 2 hours. The reaction mixture was poured into water and EtOAc and the organic layer was separated, then washed with 1N sodium hydroxide, dried over MgSO4, filtered and evaporated to a residue. Purification was accomplished on silica with EtOAc and hexanes to afford the title compound (0.034 g, 26%) as a solid, along with methyl 4-acetyl-3-chloro-1H-pyrrole-2-carboxylate (0.047 g, 37%) as a solid. 1H NMR (400 MHz, CDCl3) δ ppm 9.90 (br. s., 1H), 6.79 (s, 1H), 3.89 (s, 3H), 2.43 (s, 3H). LCMS: m/z 200.0 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([N+:30]([O-])=O)[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[C:10]2=[CH:11][C:12]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:15]=3)=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1.[NH4+].[Cl-]>C1COCC1.CO.[Zn]>[F:1][C:2]1[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[C:10]2=[CH:11][C:12]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[CH:15]=3)=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ncnn3cc(-c4ccnc(N5CCOCC5)c4)cc23)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(Oc2ncnn3cc(-c4ccnc(N5CCOCC5)c4)cc23)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
To a solution of 4-(2-fluoro-4-nitrophenoxy)-6-(2-morpholinopyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazine (54 mg, 0.12 mmol) in a mixture of THF (2.0 mL) and MeOH (2.0 mL) were added NH4Cl (127 mg, 2.4 mmol) and Zn dust (78 mg, 1.2 mmol). The reaction mixture was stirred at room temperature for 3 h, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to provide the desired product (40 mg, 82% yield). MS(ESI) m/z 407.19 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4](S(C)(=O)=O)[N:3]=1.[C:23]1([CH2:29][CH2:30][CH2:31][NH2:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([NH:32][CH2:31][CH2:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N
Reactant: NCCCc1ccccc1
Solvent: COCCOC
Product: N#Cc1c(NCCCc2ccccc2)nc(N)nc1-c1ccc2c(c1)OCO2

Procedure:
From 2-amino-4-benzo [1,3]dioxol-5-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile and 3-phenylpropylamine in DME. ES-MS m/e (%): 374 (M+H+, 100).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][NH:5][C:6]1[N:11]=[C:10]2[NH:12][CH:13]=[C:14]([C:15]#[N:16])[C:9]2=[CH:8][CH:7]=1.[C:18]([C:22]1[CH:23]=[C:24]2[C:29](=[C:30]([F:32])[CH:31]=1)[C:28](=[O:33])[N:27]([C:34]1[C:42]3[CH2:41][O:40]B(O)[C:38]=3[CH:37]=[CH:36][CH:35]=1)[N:26]=[CH:25]2)([CH3:21])([CH3:20])[CH3:19].N1C=CC=CC=1.[NH4+].[Cl-]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCCl>[C:18]([C:22]1[CH:23]=[C:24]2[C:29](=[C:30]([F:32])[CH:31]=1)[C:28](=[O:33])[N:27]([C:34]1[C:42]([CH2:41][OH:40])=[C:38]([N:12]3[C:10]4=[N:11][C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:17])[CH3:1])=[CH:7][CH:8]=[C:9]4[C:14]([C:15]#[N:16])=[CH:13]3)[CH:37]=[CH:36][CH:35]=1)[N:26]=[CH:25]2)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc4c3COB4O)ncc2c1
Reactant: CN(C)CCNc1ccc2c(C#N)c[nH]c2n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CN(C)CCNc1ccc2c(C#N)cn(-c3cccc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)c2n1
Temperature: 45 °C
Reaction time: 48 h
Yield: 3.5 %

Procedure:
In a 25 mL round-bottomed flask, 6-(2-(dimethylamino)ethylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (211 mg, 920 μmol), 6-tert-butyl-8-fluoro-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-4-yl)phthalazin-1(2H)-one (324 mg, 920 μmol, Eq: 1.00) and copper acetate (226 mg) were combined with 1,2-Dichloroethane (6.73 ml) to give a blue suspension. Pyridine (146 mg, 149 μl, 1.84 mmol, Eq: 2) was added. The reaction mixture was heated to 45° C. and stirred for 2 d. Mixture was poured into 20 mL sat NH4Cl and extracted with EtOAc (3×20 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 5% to 10% MeOH in DCM), then by HPLC to give 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-6-(2-(dimethylamino)ethylamino)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (18 mg, 3.5%)