Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:6]([O:8][CH2:9][CH:10]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7])[CH2:2][C:3](O)=[O:4].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.[CH3:52][O:53][C:54](=[O:74])[CH:55]([NH2:73])[CH:56]([C:61]1[CH:66]=[CH:65][C:64]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)=[CH:63][CH:62]=1)[C:57]([O:59][CH3:60])=[O:58]>CN(C)C=O>[CH3:60][O:59][C:57](=[O:58])[CH:56]([C:61]1[CH:62]=[CH:63][C:64]([C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)=[CH:65][CH:66]=1)[CH:55]([NH:73][C:3](=[O:4])[CH2:2][NH:1][C:6]([O:8][CH2:9][CH:10]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[C:17]2[C:22]1=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:7])[C:54]([O:53][CH3:52])=[O:74]
Reactant: COC(=O)C(N)C(C(=O)OC)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C(NC(=O)CNC(=O)OCC1c2ccccc2-c2ccccc21)C(C(=O)OC)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 54 %

Procedure:
A solution of Fmoc-Gly-OH (from Bachem) (1.66 g., 5.6 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (from Aldrich, 39391) (1.1 g., 5.7 mmol), 1-hydroxybenzotriazole (from Aldrich, 54804) (0.76 g., 5.6 mmol) and triethylamine (0.4 mL, 2.8 mmol) in dimethylformamide (50 mL) was stirred at room temperature for 1 hour. A solution of 2-amino-3-biphenyl-4-yl-succinic acid dimethyl ester hydrochloride (0.98 g., 2.8 mmol) in dimethylformamide (10 mL) was added and the reaction mixture was stirred at room temperature for a further 14 hours. The solvent was removed in vacuo and the residue partitioned between ethylacetate (100 mL) and sodium bicarbonate (100 mL, saturated solution in water). The aqueous layer was washed with ethylacetate (2×100 mL), the organics combined, dried over magnesium sulphate and concentrated in vacuo to afford a crude residue. The crude product was purified using flash chromatography (SiO2) eluting with ethylacetate/isohexane (3:1) to afford 2-biphenyl-4-yl-3-[2-(9H-fluoren-9-ylmethoxycarbonylamino)-acetylamino]-succinic acid dimethyl ester as a white crystalline solid (0.89 g., 54% yield). 1HNMR (CDCl3) δH(ppm); 3.71-3.73 (m, 7H), 3.81 0.2H (d, CH J=5.6 Hz), 3.86, 0.3H (d, CH J=5.8 Hz), 3.9, 0.3H (d, CH J=5.3 Hz), 3.94, 0.2H (d, CH J=5.8 Hz), 4.13-4.24 (m, 1H), 4.28-4.44 (m, 2.5H), 4.5 (d, 0.5H J=4.4 Hz), 5.1-5.4 (m, 2H), 6.4 (d, NH J=8.5 Hz), 7.19 (d, NH J=9.4 Hz), 7.23-7.34, 5H (m, Ar—H), 7.35-7.42, 4H (m, Ar—H), 7.47-7.60, 6H (m, Ar—H), 7.74, 2H (d, Ar—H J=7.6 Hz); LCMS analysis (solvent MeCN/H2O/0.1% HCO2H, 5-95% gradient/H2O 2.5 min, 95% 4 min., Phenomenex C18 reverse phase, flow rate 1 mL/min.) HPLC retention times 5.33 and 5.47 min. (diastereoisomers).; mass found 593 (M+H).
Reaction SMILES: [C:1]([C:9]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[C:1]([C:9]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:11][N:12]([CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:13][CH2:14]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)C1(c2ccccc2)CCNCC1
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: O=C(c1ccccc1)C1(c2ccccc2)CCN(CCCc2ccccc2)CC1

Procedure:
3 g 4-benzoyl-4-phenylpiperidine was taken up in 200 ml n-butanol with 1.5 ml 1-bromo-3-phenylpropane and 10 g sodium carbonate, and refluxed for 4 hours. The resulting mixture was filtered and the filtrate concentrated in vacuo, taken up in ethyl acetate and washed with water. The ethyl acetate layer was dried over potassium carbonate and eluted through a short silica plug with 1:1 hexane/ethyl acetate. The eluted product was concentrated to dryness overnight, giving 3.14 g of product, melting point: 185°-186° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([CH3:14])([CH3:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.IC.[C:23](=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:23])[C:10](=[O:12])[C:9]([CH3:13])([CH3:14])[CH2:8][N:7]([CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19]3)[C:6]=2[N:20]=1
Reactant: CC1(C)CN(C2CCCC2)c2nc(Cl)ncc2NC1=O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
To a solution of 18.43 g (0.187 mole) of 2-chloro-9-cyclopentyl-7,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-38) and 500 mL of dimethylformamide was added 26.6 g (0.187 mole) of iodomethane and 30.6 g (0.0939 mole) of cesium carbonate. The mixture was stirred overnight at ambient temperature. The mixture was then filtered and concentrated under reduced pressure. The residue was partitioned between 500 mL of ethyl acetate and 200 mL of water. The aqueous layer was extracted twice with 200 mL of ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 18.47 g of 2-chloro-9-cyclopentyl-5,7,7-trimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-38) as an off-white solid.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][C:13](=[O:15])[O:12][N:11]=2)=[CH:6][CH:5]=1.Cl[CH2:17][O:18][CH3:19]>C1COCC1>[I:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:14]=[C:13]([O:15][CH2:17][O:18][CH3:19])[O:12][N:11]=2)=[CH:8][CH:9]=1
Reactant: COCCl
Reactant: O=C1CC(c2ccc(I)cc2)=NO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1cc(-c2ccc(I)cc2)no1
Temperature: 0 °C
Reaction time: 2 h
Yield: 41.6 %

Procedure:
Sodium hydride (360 mg, 9.0 mmol, 60% in mineral oil) was added into a solution of 3-(4-iodophenyl)isoxazol-5(4H)-one (2.0 g, 6.97 mmol) in anhydrous THF (20 mL) at 0° C. The mixture was stirred at 0° C. for 2 h. Chloro(methoxy)methane (1.12 g, 14 mmol) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 2 h, poured into ice-water, and extracted with EtOAc (3×60 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified on a silica gel column using EtOAc in petroleum ether (1:20) to afford the title compound as pale solid (960 mg, 42%). 1H NMR (DMSO-d6, 400 MHz): δ 7.96 (d, 2H), 7.45 (d, 2H), 5.99 (s, 1H), 4.95 (s, 2H), 3.27 (s, 3H). LCMS: 332 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:8]=[N:9][N:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][C@H:23]3[CH3:27])=[CH:14][CH:13]=2)[CH:11]=1)=[O:6].[C:28]([Si:32](Cl)([CH3:34])[CH3:33])([CH3:31])([CH3:30])[CH3:29].N1C=CN=C1.CN(C)C=O>[Cl-].[Na+].O>[Si:32]([O:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:8]=[N:9][N:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][C@H:23]3[CH3:27])=[CH:14][CH:13]=2)[CH:11]=1)=[O:6])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(=O)NCCO)cn2)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(=O)NCCO[Si](C)(C)C(C)(C)C)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
A mixture of N-(2-hydroxyethyl)-1-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrazole-4-carboxamide prepared in Example 66 (0.500 g), tert-butylchlorodimethylsilane (0.303 g), imidazole (0.273 g) and N,N-dimethylformamide (5.0 mL) was stirred overnight at room temperature. The reaction mixture was diluted with brine and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=1:1) to give the titled compound (0.550 g) as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[NH2:15][C:16]1[S:17][C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[C:19]([OH:21])[N:20]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:28][C:24]1[CH:23]=[C:22]([CH:18]2[S:17][C:16]([NH:15][C:12]([C:3]3[C:2]([OH:1])=[C:11]4[C:6]([CH:7]=[CH:8][CH:9]=[N:10]4)=[CH:5][CH:4]=3)=[O:14])=[N:20][C:19]2=[O:21])[CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)c1ccc2cccnc2c1O
Reactant: Nc1nc(O)c(-c2cccc(Cl)c2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC1=NC(=O)C(c2cccc(Cl)c2)S1)c1ccc2cccnc2c1O
Temperature: 25 °C
Reaction time: 168 h
Yield: 30.5 %

Procedure:
To a solution of 8-hydroxyquinoline-7-carboxylic acid (0.284 g,) of Preparation 1 and 2-amino-5-(3-chlorophenyl)-4-hydroxy-1,3-thiazole (0.340 g) in 20 mL DMF is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.305 g) and 1-hydroxybenzotriazole monohydrate (0.217 g). The mixture is stirred at room temperature for 7 days. The solution is then poured into 30 mL ice-water. The resulting solid is collected and dried. The crude product is triturated with hot EtOAc, then with hot i-PrOH to yield 0.182 g of the title product as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([Li])CCC.Cl[C:24]([O:26]C)=[O:25]>C1COCC1>[F:1][C:2]1[C:3]([CH2:18][C:24]([OH:26])=[O:25])=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cl
Reactant: [Li]CCCC
Reactant: Fc1cccc(-c2nccc3ccccc23)c1
Solvent: C1CCOC1
Product: O=C(O)Cc1c(F)cccc1-c1nccc2ccccc12
Temperature: -78 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
50.0 g (0.224 mol) of 1-(3-fluorophenyl)isoquinoline were dissolved in 1000 ml of THF and admixed dropwise at −78° C. with 134.4 ml (0.336 mol, 1.50 eq.) of n-butyllithium (2.5 M in hexane). After the addition had ended, the mixture was stirred at −78° C. for a further 3 h and the red-brown lithium organyl was subsequently transferred via a tube at −78° C. to a solution of 190.8 ml (2.47 mol, 11.0 eq.) of methyl chloroformate in 2000 ml of THF. The mixture was stirred at −78° C. up to −20° C. for a further 18 h. The reaction solution was quenched with EtOH with external ice cooling and concentrated to a third of the volume. Subsequently, the reaction solution was admixed with 300 ml of dichloromethane and washed three times each with 100 ml of NH4Cl solution and NaHCO3 solution and water, dried over MgSO4 and concentrated under reduced pressure. The resulting highly viscous oil was crystallized from heptane. 44.68 g of a crystalline solid were obtained, corresponding to 70.4% of theory, with a purity of 98%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]([CH2:18][C:19](O)=[O:20])[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:34]([NH:36][CH2:37][CH3:38])[CH3:35]>O1CCCC1>[OH2:2].[CH2:34]([N:36]([CH2:37][CH3:38])[C:19](=[O:20])[CH2:18][N:17]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[N:10]=[C:9]1[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH3:35]
Reactant: COc1ccc(-c2nc3cccnc3n2CC(=O)O)cc1
Reactant: CCNCC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCN(CC)C(=O)Cn1c(-c2ccc(OC)cc2)nc2cccnc21
Product: O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.2 g, 0.015 mole) and 1,1'-carbonyldiimidazole (2.43 g, 0.015 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 3 hours. The diethylamine (2.19 g, 0.03 mole) was added and the reaction mixture was allowed to stir at room temperature overnight, then heated to reflux for 3 hrs. The tetrahydrofuran was evaporated to dryness. The residue was treated with hot water, filtered through a Celite pad, and allowed to crystallize upon cooling. The solid was collected by filtration, washed with water, and dried under high vacuum at 50°-60° C. overnight to give 1.0 g, mp (softens at 55° C., resolidified) 133°-35° C. Total yield in 2 crops was 1.9 g (38%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:24]1[CH:25]=[C:26]([CH2:30][NH:31][C:32](=[O:35])[CH2:33][CH3:34])[CH:27]=[N:28][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1[C:24]1[CH:25]=[C:26]([CH2:30][NH:31][C:32](=[O:35])[CH2:33][CH3:34])[CH:27]=[N:28][CH:29]=1
Reactant: CCC(=O)NCc1cncc(Br)c1
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)c(F)cc21
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(=O)NCc1cncc(-c2cc3c(cc2F)N(C)C(=O)CC3)c1
Temperature: 110 °C
Yield: 17.6 %

Procedure:
To a mixture of 7-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-22, 168 g, 0.55 mmol) and N-(5-bromo-pyridin-3-ylmethyl)-propionamide (122 mg, 0.5 mmol) in DMF (3 mL), purged with argon for 1 min, was added bis(triphenylphosphine)palladium (II)chloride (38 mg, 0.054 mmol) and 1 N aq. Na2CO3 (2.5 mL). Then, the resulting reaction mixture was heated in a microwave at 110° C. for 45 min. After cooling to room temperature, it was diluted with EtOAc (5 mL) and poured into a satd. aq. solution of NaHCO3 (10 mL). The aqueous layer was extracted with EtOAc (3×5 mL) and combined organics were washed with water and brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was then purified by prep-HPLC to afford the title compound (30 mg, 18%) as a white solid. MS: 342.1 (M+H+)+.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:36])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[C:14]4[CH:26]=[CH:25][C:24](=[O:27])[N:23]([C:28]5[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=5[F:35])[C:15]=4[N:16]=[C:17](S(C)(=O)=O)[N:18]=3)[CH:7]=2)[CH2:3][CH2:2]1.[CH2:37]([NH:40][CH2:41][CH2:42][NH2:43])[CH2:38][CH3:39]>>[CH:1]1([NH:4][C:5](=[O:36])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[C:14]4[CH:26]=[CH:25][C:24](=[O:27])[N:23]([C:28]5[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=5[F:35])[C:15]=4[N:16]=[C:17]([NH:43][CH2:42][CH2:41][NH:40][CH2:37][CH2:38][CH3:39])[N:18]=3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CCCNCCN
Product: CCCNCCNc1nc(-c2cc(C(=O)NC3CC3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1

Procedure:
The title compound is prepared from N-cyclopropyl-3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzamide and N-propyl-1,2-ethanediamine following the General Procedure for Sulfoxide/Sulfone Displacement, disclosed above. The concentrated reaction mixture is purified via reversed-phase HPLC. The desired product is obtained as a yellow solid (m.p. 120-134) >95% pure by HPLC (65 mg, 61%): LC-MS m/z 533 (M+H)+, 1.84 min (ret time).
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14](Cl)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[NH2:18][C:19]1[N:24]=[C:23]([C:25]2[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=2)[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:22]([CH3:38])=[CH:21][N:20]=1>N1C=CC=CC=1>[F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:18][C:19]4[N:24]=[C:23]([C:25]5[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=5)[C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[C:22]([CH3:38])=[CH:21][N:20]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: Cc1cnc(N)nc1-c1cccc(C(=O)OC(C)(C)C)c1
Solvent: c1ccncc1
Product: Cc1cnc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C(=O)OC(C)(C)C)c1
Temperature: 90 °C

Procedure:
To 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (91 mg, 0.35 mmol) and tert-butyl 3-(2-amino-5-methylpyrimidin-4-yl)benzoate (50 mg, 0.175 mmol), pyridine (2 mL) was added. The reaction was heated at 90° C. for twenty four hours. The pyridine was evaporated under reduced pressure. The resulting mixture was dissolved in ethyl acetate and filtered. The filtrate was washed with saturated aqueous NaHCO3 (×3). The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to yield tert-butyl 3-(2-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-5-methylpyrimidin-4-yl)benzoate. ESI-MS m/z calc. 509.18, found 510.5 (M+1)+. Retention time 2.22 minutes
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:3]=1.O.[NH2:27][NH2:28]>C(O)C>[NH2:13][C:12]1[C:11]2[C:10](=[CH:9][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH:5]=3)=[CH:15][CH:14]=2)[NH:28][N:27]=1
Reactant: N#Cc1ccc(-c2cc(NCc3ccccc3Cl)nc(N)n2)cc1F
Reactant: NN
Solvent: CCO
Solvent: O
Product: Nc1nc(NCc2ccccc2Cl)cc(-c2ccc3c(N)n[nH]c3c2)n1
Temperature: 100 °C
Yield: 18.2 %

Procedure:
To 4-(2-amino-6-{[(2-chlorophenyl)methyl]amino}-4-pyrimidinyl)-2-fluorobenzonitrile (800 mg, 2.27 mmol) in ethanol (2 mL) was added hydrazine monohydrate (3 mL, 74 mmol), and the reaction mixture was heated to 100° C. for 1 hour in a BiotageInitiator® microwave synthesizer. Upon cooling, the reaction mixture was concentrated in vacuum and purified by RPHPLC (BiotageSP1) (gradient: 30% CH3CN/H2O to 60% CH3CN/H2O) to afford the title compound (151 mg) as an off-white solid. LC-MS (ES) m/z=366 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 4.61 (d, J=5.6 Hz, 2H), 5.37 (s, 2H), 6.07 (s, 2H), 6.40 (s, 1H), 7.34-7.27 (m, 2H), 7.46-7.41 (m, 4H), 7.70 (d, J=8.8 Hz, 1H), 7.84 (s, 1H), 11.52 (s, 1H).
Reaction SMILES: C(#N)C.Br[C:5]1[CH:6]=[C:7]([C:11]2[C:12]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:21]([O:30][CH3:31])=[CH:20][C:13]=3[N:14]([CH3:19])[C:15](=[O:18])[CH2:16][N:17]=2)[CH:8]=[CH:9][CH:10]=1.[C:32]1(C#C)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cu](I)I.Cl[Pd]Cl.C(N(CC)CC)C>[C:37]([C:5]1[CH:6]=[C:7]([C:11]2[C:12]3[CH:23]=[C:22]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:21]([O:30][CH3:31])=[CH:20][C:13]=3[N:14]([CH3:19])[C:15](=[O:18])[CH2:16][N:17]=2)[CH:8]=[CH:9][CH:10]=1)#[C:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: C#Cc1ccccc1
Reactant: COc1cc2c(cc1-c1ccccc1)C(c1cccc(Br)c1)=NCC(=O)N2C
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCC#Cc1cccc(C2=NCC(=O)N(C)c3cc(OC)c(-c4ccccc4)cc32)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To 10 mL of degazed acetonitrile, 5-(3-bromo-phenyl)-8-methoxy-1-methyl-7-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one Example 62 (200 mg, 0.46 mmol), phenylacetylene (715 μL, 2.30 mmol), copper iodide (15 mg, 0.08 mmol), triphenylphosphine (30 mg, 0.11 mmol), PdCl2 (10 mg, 0.06 mmol) and triethylamine (0.9 mL) were added. The mixture was stirred for 16 hours at 50° C. under nitrogen atmosphere. The working solution was evaporated under vacuum. The residue was partitioned from water and ethyl acetate and extracted two more times with ethyl acetate. The organic phase was dried over Na2SO4 and concentrated until dryness. The residue was purified by chromatography (eluant: Hexane/EtOAc: 1/1). The title compound was crystallised from ether/pentane to afford 134 mg of the title compound: beige solid, yield=90%.
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7](SC)=[N:6][C:5]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)=[CH:15][CH:14]=1)(=[O:3])[NH2:2].C1C=C(Cl)C=C(C(OO)=O)C=1.CCN(C(C)C)C(C)C.Cl.[CH3:53][O:54][C:55]1[CH:69]=[CH:68][C:58]([C:59]([NH:61][C@@H:62]2[CH2:67][CH2:66][CH2:65][NH:64][CH2:63]2)=[O:60])=[CH:57][CH:56]=1>CN1C(=O)CCC1.C(Cl)(Cl)Cl>[CH3:53][O:54][C:55]1[CH:56]=[CH:57][C:58]([C:59]([NH:61][C@@H:62]2[CH2:67][CH2:66][CH2:65][N:64]([C:7]3[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([CH:19]5[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]5)=[CH:15][CH:14]=4)[N:6]=3)[CH2:63]2)=[O:60])=[CH:68][CH:69]=1
Reactant: CSc1nnc(C(N)=O)c(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)n1
Reactant: COc1ccc(C(=O)N[C@@H]2CCCNC2)cc1
Agent: Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)N[C@@H]2CCCN(c3nnc(C(N)=O)c(Nc4ccc(C5CCNCC5)cc4)n3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To ethyl 5-chloro-3-(methylthio)-1,2,4-triazine-6-carboxylate (1) (1.20 g, 5.15 mmol) in acetonitrile (40 mL) was added tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (2.14 g, 7.73 mmol) and then DIEA (1350 μL, 7.73 mmol). The mixture was stirred at RT for 1 hour. To the mixture was then added ammonia (7.0 N solution in methanol, 30 mL). The mixture turned cloudy in 10 min and then into a suspension. The mixture was stirred for 8 hours, and the solid was isolated by filtration. It was washed with cold acetonitrile (10 mL×2) and then washed with hexane (10 mL×3). The solid was dried in a vacuum oven to afford tert-butyl 4-(4-(6-carbamoyl-3-(methylthio)-1,2,4-triazin-5-ylamino)phenyl)piperidine-1-carboxylate (490) (1.82 g, 79% yield) in high purity. Compound 490 (600 mg, 1.35 mmol) was dissolved in 20 mL NMP. To it were added dry mCPBA (77% strength, 840 mg, 3.38 mmol). The mixture was stirred at RT for 1 hour. To the mixture was added DIEA (2.10 mL, 12.1 mmol) and (R)-4-methoxy-N-(piperidin-3-yl)benzamide hydrochloride (489) (550 mg, 2.03 mmol). The mixture was stirred at 70° C. for 30 min. The mixture was cooled to RT, diluted with 200 mL chloroform, washed with 1N NaOH (aq) ×2 and water, dried, concentrated in vacuo to dryness for crude (R)-tert-butyl 4-(4-(6-carbamoyl-3-(3-(4-methoxybenzamido)piperidin-1-yl)-1,2,4-triazin-5-ylamino)phenyl)piperidine-1-carboxylate (491) (740 mg, 87%). It was treated with 35 mL commercial 4N HCl in dioxane at RT for 45 min. The mixture was concentrated in vacuo to dryness to afford crude (R)-3-(3-(4-methoxybenzamido)piperidin-1-yl)-5-(4-(piperidin-4-yl)phenylamino)-1,2,4-triazine-6-carboxamide (492). A small amount of crude 492 was purified using reverse phase prep HPLC to isolate as HCl salt. LC-MS (ESI): m/z (M+1) 531.1. UV: λ=255 nm.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[C:11]1[N:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=1.O>CN(C=O)C.CCOC(C)=O>[N:5]1[CH:6]=[CH:7][C:2]([S:1][C:11]2[N:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=2)=[CH:3][CH:4]=1
Reactant: Sc1ccncc1
Reactant: O=Cc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Sc2ccncc2)nc1
Reaction time: 0.33 h
Yield: 75.5 %

Procedure:
To a solution of 4-mercaptopyridine (5.59 g, 50.3 mmol) in DMF (100 mL) was added NaH (60% dispersion in oil, 1.99 g, 49.7 mmol) in portions and the mixture was stirred for 20 min. 6-Bromo-3-pyridine carboxaldehyde (9.22 g, 49.6 mmol) was added and the resultant mixture was stirred for 1 h. Water was added followed by the addition of EtOAc. The phases were separated and the aqueous layer was extracted with EtOAc (2×). The organic extracts were combined, dried over Na2SO4, filtered and concentrated in vacuo to give a crude product, which was purified by recrystallization from EtOAc. The resultant colored solid was filtered through a silica gel column (eluent: MTBE). Evaporation of the filtrate and further recrystallization from MTBE gave the product as a white solid (8.1 g, 76% yield).