Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:13][C@H:14]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]1>C(O)C>[CH3:12][C:2]1[CH:3]=[CH:4][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[F:13][C@H:14]1[CH2:18][CH2:17][NH:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](F)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: F[C@H]1CCNC1
Reaction time: 8 h

Procedure:
Add p-toluenesulfonic acid monohydrate (0.50 g, 2.64 mmol) to tert-butyl (3S)-3-fluoropyrrolidine-1-carboxylate (See Intermediate 48) (0.50 g, 2.64 mmol) in ethanol (5 mL) at room temperature. Stir the resulting solution overnight. Concentrate the reaction mixture in vacuo to remove solvent and bi-products to give the title compound as an off-white solid (0.65 g): MS (m/e): 90 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[NH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.C(OCC)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Reactant: NCc1cccnc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCc1cccnc1
Temperature: 60 °C
Yield: 62.9 %

Procedure:
To a solution of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.2 g, 0.71 mmol) in N,N′-dimethylformamide is added 3-(aminomethyl)pyridine (0.073 mL, 0.71 mmol). The reaction mixture is heated at 60° C. under N2. After reaction is completed, diethyl ether is added, and the red precipitate is isolated and washed with methanol, ether, and hexane respectively to afford 0.16 g (63.2% yield) of orange solid: mp 299-300° C.; 1H NMR (DMSO-d6) δ 11.09 (s, 1H), 10.69 (m, 1H), 8.74 (d, J=9 Hz, 1H), 8.63 (s, 1H), 8.52 (d, J=3 Hz, 1H), 8.10 (s, 1H), 7.84 (m, 2H), 7.42 (m, 1H), 7.31 (d, J=9 Hz, 1H), 3.40 (d, J=4.8 Hz, 2H); MS (ESI) m/z 355.7 and 357.7 (M−H)−1, Analysis for C16H12BrN3O2, Calcd: C, 53.70; H, 3.38; N, 11.70. Found: C, 53.45; H, 3.23; N, 11.74.
Reaction SMILES: Cl.[CH2:2]([NH2:6])/[CH:3]=[CH:4]/[CH3:5].Br[CH2:8][C:9]([O:11][CH3:12])=[O:10].CCN(CC)CC>C(#N)C>[CH2:2]([NH:6][CH2:8][C:9]([O:11][CH3:12])=[O:10])/[CH:3]=[CH:4]/[CH3:5]
Reactant: COC(=O)CBr
Reactant: C/C=C/CN
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C/C=C/CNCC(=O)OC
Temperature: 25 °C
Yield: 19.7 %

Procedure:
A suspension of (E)-2-buten-1-amine HCl (5.37 g, 49.9 mmol) (Chem. Ber. 117, 1250(1984) in acetonitrile (100 mL) was treated with methyl bromoacetate (4.72 mL, 49.9 mmol) and Et3N (14.0 mL, 99.8 mmol) and stirred at room temperature for I hour. The suspension was then heated at reflux overnight. Solution occurred at reflux temperature. After cooling, the precipitated Et3N.HCl was filtered off and the solvent removed under reduced pressure leaving 5.0 g of the crude product. Chromatography on silica gel, eluting with CHCl3/MeOH (98/2) gave 1.41 g (19.8% yield) of the pure product as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][C:17]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:30]>C(Cl)Cl.C(OCC)C>[ClH:30].[ClH:30].[C:24]1([CH:20]2[C:18]3[N:19]=[C:15]([NH:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[S:16][C:17]=3[CH2:23][CH2:22][CH2:21]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3c(s2)CCCC3c2ccccc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: c1ccc(C2CCCc3sc(NC4CCNCC4)nc32)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-(4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.575 g, 3.8 mmol) in methylene chloride (13.8 mL) was added 2 M HCl solution in diethyl ether (6.9 mL). The reaction was stirred at room temperature over the weekend. The solvent was removed under reduced pressure and the residue was treated with diethyl ether and evaporated. The title compound was obtained as a light yellow solid (1.32 g, 90%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[OH:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[OH:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:12])[N:3]=2)=[CH:16][CH:15]=1
Reactant: Cc1nc(Cl)c2ccccc2n1
Reactant: Nc1ccc(O)cc1
Product: Cc1nc(Nc2ccc(O)cc2)c2ccccc2n1

Procedure:
The title compound was prepared from 4-chloro-2-methyl-quinazoline (818 mg, 4.58 mmol), 4-hydroxy-aniline (500 mg, 4.58 mmol) by a procedure similar to Example 1b to give 498 mg (43%) of off white solids. 1H NMR (DMSO-d6): 9.51 (s, 1H), 9.34 (s, 1H), 8.44 (d, J=7.8 Hz, 1H), 7.77 (t, J=8.4 Hz, 1H), 7.67-7.48 (m, 4H), 6.79 (d, J=7.8 Hz, 2H), 2.45 (s, 3H).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:21]=3[C:22]([F:25])([F:24])[F:23])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].Cl.[CH2:33]([NH2:35])[CH3:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH2:33]([NH:35][C:3](=[O:4])[CH:2]([OH:1])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:21]=3[C:22]([F:23])([F:25])[F:24])[O:14][N:13]=2)=[CH:8][CH:7]=1)[CH3:34]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCNC(=O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 77.8 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-VII, 35 mg, 0.081 mmol), ethanamine-HCl (9.95 mg, 0.122 mmol), HATU (40.2 mg, 0.106 mmol), and 4-methylmorpholine (32.9 mg, 0.325 mmol) were added to DMF (1 mL). It was stirred for 1 h and then was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 12 min, 20 mL/min, 220 nM, product retention=13.3 min) to provide (R/S)-N-ethyl-2-hydroxy-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (30 mg, 0.063 mmol, 77% yield): LCMS=458.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.46 (1 H, s), 8.11 (2 H, d, J=8.58 Hz), 7.51-7.72 (7 H, m), 5.09 (1 H, s), 3.24-3.30 (2 H, m), 1.14 (3 H, t, J=7.15 Hz); HPLC peak RT=7.9 min (Method A).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]1([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[S:7]([O:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCCCCCCCCCc1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCCCCCCCCCc2ccccc2)cc1
Reaction time: 16 h

Procedure:
4-Toluenesulphonyl chloride (2.6 g) was added in portions to a stirred solution of the product of step (a) (2.9 g) in pyridine (10 ml) at 0° C. The solution was stirred for 16 hours at 0°-5° C. then poured onto ice-hydrochloric acid and extracted with ether. The extract was washed with sodium bicarbonate and sodium chloride solutions, dried and evaporated. The residue was chromatographed on silica gel eluting with 1:1 dichloromethane:hexane to give the title compound as a colourless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][NH:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Br:17])[CH:16]=1)([CH3:4])([CH3:3])[CH3:2].[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][N:10]([C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Br:17])[CH:16]=1)[S:29]([C:20]1[CH:21]=[CH:22][C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=1)(=[O:31])=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)NCCNc1cncc(Br)c1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCCN(c1cncc(Br)c1)S(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of Example 386A (50 mg, 0.158 mmol) in pyridine (2 mL) was added 2-naphthalenesulfonyl chloride (72 mg, 0.316 mmol) at rt. The formed yellow solution was stirred at rt for 15 h. Pyridine was removed by blowing with nitrogen and the residual yellow solid was purified by flash chromatography (30-60% EtOAc in hexane) to the desired product (81 mg, 100%). MS (DCI) m/z 506, 508 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[NH:11][C:10]1=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:22]1([C:27]([CH2:29]Br)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23]1>>[N:22]1([C:27]([CH2:29][N:14]2[C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[N:11]([CH2:29][C:27]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:28])[C:10](=[O:21])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:15]2=[O:16])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(CBr)N1CCCC1
Reactant: CC(C)(C)OC(=O)NC1C(=O)Nc2ccccc2NC1=O
Product: CC(C)(C)OC(=O)NC1C(=O)N(CC(=O)N2CCCC2)c2ccccc2N(CC(=O)N2CCCC2)C1=O

Procedure:
Compound 14a is prepared in a manner similar to that used for preparation of Compound 14 h using previously prepared Compound 13 and pyrrolidinocarbonylmethyl bromide.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[N:13]([CH3:28])[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16](Cl)[N:15]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:29]([C:31]1[NH:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[N:32]=1)[CH3:30]>>[C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[N:13]([CH3:28])[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16]([N:32]2[C:33]4[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=4[N:35]=[C:31]2[CH2:29][CH3:30])[N:15]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(CN2CCN(C(C)(C)C)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CCc1nc2ccccc2[nH]1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)(C)C)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 4-(8-((4-tert-butylpiperazin-1-yl)methyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine and 2-ethyl-1H-benzo[d]imidazole were reacted to give 387. LCMS m/z: 518.3 (MH+)
Reaction SMILES: CN(C)C=O.[C:6]([C:8]1[C:13]([CH3:14])=[C:12](I)[C:11]([F:16])=[C:10]([O:17][CH3:18])[C:9]=1[NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])#[N:7].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>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.C(OCC)(=O)C>[C:6]([C:8]1[C:9]([NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[C:10]([O:17][CH3:18])[C:11]([F:16])=[C:12]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]=1[CH3:14])#[N:7]
Reactant: COc1c(F)c(I)c(C)c(C#N)c1NC(=O)C(C)(C)C
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1c(F)c(-c2ccccc2)c(C)c(C#N)c1NC(=O)C(C)(C)C
Temperature: 95 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (1.45 g, 1.26 mmol) was added to an N,N-dimethylformamide (50 ml) suspension of N-(2-cyano-5-fluoro-4-iodo-6-methoxy-3-methylphenyl)-2,2-dimethylpropionamide (I-69) (2.45 g, 6.28 mmol), phenylboronic acid (1.15 g, 9.42 mmol), potassium phosphate n-hydrate (74-78%, 3.60 g, 12.6 mmol), followed by stirring at 95° C. for 2 hours. The reaction liquid was cooled, then ethyl acetate (200 ml) was added, followed by washing with saturated brine (50 ml×3), drying over anhydrous magnesium sulfate, concentration under reduced pressure. The residue was purified twice by silica gel column chromatography (chloroform), (n-hexane:ethyl acetate=4:1) to obtain the entitled compound (2.06 g, 96%) as a yellow solid.
Reaction SMILES: [CH2:1]([SH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[CH:19]=[CH2:20]>C(N(CC)CC)C>[CH2:1]([S:17][CH2:20][CH2:19][C:18]([O:22][CH2:23][CH3:24])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCS
Reactant: C=CC(=O)OCC
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCSCCC(=O)OCC
Yield: 184.3 %

Procedure:
A solution of 15 g of hexadecylmercaptan, 3.0 g of ethyl acrylate and 2 ml of triethylamine is stirred at ambient temperature for 18 hours. The solvent is evaporated and the concentrate purified by high pressure liquid chromatography, to give 19.8 g of the desired product.
Reaction SMILES: [N:1]1([C:6]([NH:8][C:9]2[NH:10][C:11]([CH3:16])=[CH:12][C:13](=[O:15])[N:14]=2)=[O:7])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:17][NH:18][CH2:19][CH:20](N)N>ClCCl>[CH3:2][N:3]([CH2:4][CH2:5][NH:1][C:6]([NH:8][C:17]1[NH:18][C:19]([CH3:20])=[CH:12][C:13](=[O:15])[N:14]=1)=[O:7])[CH2:4][CH2:5][NH:1][C:6]([NH:8][C:9]1[NH:10][C:11]([CH3:16])=[CH:12][C:13](=[O:15])[N:14]=1)=[O:7]
Reactant: CNCC(N)N
Reactant: Cc1cc(=O)nc(NC(=O)n2ccnc2)[nH]1
Solvent: ClCCl
Product: Cc1cc(=O)nc(NC(=O)NCCN(C)CCNC(=O)Nc2nc(=O)cc(C)[nH]2)[nH]1

Procedure:
3 g of 2-(1-imidazolylcarbonylamino)-6-methyl-4[1H]-pyrimidinone (136 mmol) prepared according to the procedure described by Meijer et al., J. Am. Chem. Soc. 2003, 125, p. 6860 are added to a solution of 0.81 g of N-methyldiaminoethylamine (6.8 mmol) in 150 ml of dichloromethane. The solution is stirred at reflux for 4.5 hours. The product is precipitated from acetone, filtered off and washed with acetone, and then dried under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.Br.Br[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)=[O:28]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:26]=1[C:27]([C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)=[O:28]
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Reactant: O=C(CBr)c1ccncc1
Agent: Br
Product: COC(=O)Cc1c(C(=O)c2ccncc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 4-bromoacetylpyridine hydrobromide (L. W. Deady, M. S. Stanborough, Aust. J. Chem., 1981, 34, 1295).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:16]=[CH:15][C:14]3[CH:17]=[C:18]([C:24]4[CH:25]=[N:26][N:27](C(OC(C)(C)C)=O)[CH:28]=4)[N:19]([S:20]([CH3:23])(=[O:22])=[O:21])[C:13]=3[CH:12]=2)=[CH:6][CH:5]=1.ClC1N=CC2C=C(C3C=NN(C(OC(C)(C)C)=O)C=3)N(S(C)(=O)=O)C=2C=1>CCO>[F:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[N:16]=[CH:15][C:14]3[CH:17]=[C:18]([C:24]4[CH:25]=[N:26][NH:27][CH:28]=4)[N:19]([S:20]([CH3:23])(=[O:21])=[O:22])[C:13]=3[CH:12]=2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Nc4ccc(F)cc4)cc3n2S(C)(=O)=O)cn1
Agent: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Cl)cc3n2S(C)(=O)=O)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)n1c(-c2cn[nH]c2)cc2cnc(Nc3ccc(F)cc3)cc21
Temperature: 40 °C
Reaction time: 4 h
Yield: 44.9 %

Procedure:
Aqueous sodium hydroxide (127 μL, 1 M, 0.127 mmol) was added to a solution of tert-butyl 4-(6-(4-fluorophenylamino)-1-(methylsulfonyl)-1H-pyrrolo[3,2-c]pyridin-2-yl)-1H-pyrazole-1-carboxylate (Preparation 53, 20 mg, 0.042 mmol) (mixed with some tert-butyl 4-(6-chloro-1-(methylsulfonyl)-1H-pyrrolo[3,2-c]pyridin-2-yl)-1H-pyrazole-1-carboxylate) in EtOH (339 μL). The reaction mixture was stirred for 4 hours at 40° C. The reaction mixture was filtered on SCX-2 column and was then purified using preparative TLC eluting with DCM/MeOH, 95/5 to afford the title compound as a white solid (7 mg, 20%). 1H NMR (500 MHz, CD3OD): δ 3.02 (s, 3H), 6.73 (d, J=0.8 Hz, 1H), 7.00-7.07 (m, 2H), 7.45-7.49 (m, 2H), 7.51 (t, J=0.8 Hz, 1H), 7.90 (br s, 2H), 8.40 (d, J=0.8 Hz, 1H). ESI-HRMS Found 372.0936, calculated for C17H15FN5O2S [M+H]+: 372.0925. MPS1 IC50 (uM): 6.43
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]([OH:9])=O.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][C:43]=1[CH3:44])[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1>CN(C)C=O.CN(C)C(=O)C>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:41]=[CH:42][C:43]([CH3:44])=[C:22]([NH:21][C:7]([C:6]5[O:5][CH:4]=[N:3][C:2]=5[CH3:1])=[O:9])[CH:23]=4)=[N:31][N:30]3[CH:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: Cc1ncoc1C(=O)O
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)c1ocnc1C
Yield: 85.5 %

Procedure:
In the same manner as in Example 259 and using 4-methyl-1,3-oxazole-5-carboxylic acid (77 mg, 0.60 mmol), tetrahydrofuran (10 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (62 μL, 0.72 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.46 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (170 mg, 83%) was obtained as a white solid.
Reaction SMILES: [F:1][CH:2]([F:38])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH2:36][OH:37])[C:24]([N:26]4[CH2:31][CH2:30][NH:29][CH:28]([C:32]([F:35])([F:34])[F:33])[CH2:27]4)=[O:25])=[CH:19][CH:18]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1.F[CH:40](F)OC1C=CC(C2C=NC(NC3C=CC(C(CO)C(NCCF)=O)=CC=3)=NC=2)=CC=1.C=O.[O-]S([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[F:38][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH:23]([CH2:36][OH:37])[C:24]([N:26]4[CH2:31][CH2:30][N:29]([CH3:40])[CH:28]([C:32]([F:35])([F:34])[F:33])[CH2:27]4)=[O:25])=[CH:21][CH:22]=3)=[N:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: O=C(C(CO)c1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1)N1CCNC(C(F)(F)F)C1
Reactant: O=C(NCCF)C(CO)c1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1
Agent: C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(C(=O)C(CO)c2ccc(Nc3ncc(-c4ccc(OC(F)F)cc4)cn3)cc2)CC1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-1-(3-(trifluoromethyl)piperazin-1-yl)-3-hydroxypropan-1-one C37 (prepared as described for C1, 0.05 mmol), HCHO (0.15 mmol, 30% aqueous) and anhydrous Na2SO4 (1.5 mmol) in DCM (2 mL) is stirred at rt for 30 min. Then NaHB(OAc)3 (0.3 mmol) is added and the resulting mixture is stirred for 12 h. Purification by prep-HPLC (ACN gradient 10-70%) affords 2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenyl)-1-(3-(trifluoromethyl)-4-methylpiperazin-1-yl)-3-hydroxypropan-1-one C38. MS (m/z) (M+1)+: 552.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[N:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](O)=[O:35])=[CH:29][CH:28]=1.CCN=C=NCCCN(C)C>>[N:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:35])=[CH:29][CH:28]=1
Reactant: O=C(O)Cc1ccncc1
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)Cc4ccncc4)c3)c2c1
Yield: 4.4 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (250 mg, 0.74 mmol) with 4-pyridylacetic acid hydrochloride (0.15 g, 0.89 mmol) and EDCI (0.21 g, 1.11 mmol) furnished 12 mg (4% yield) of the title compound. 1H NMR (DMSOd6) δ 13.2 (br s, 1H), 10.2 (s, 1H), 8.6 (s, 1H), 8.5 (dd, 1H), 8.2 (s, 1H), 8.1 (br s, 1H), 7.9 (d, 1H), 7.75 (m, 2H), 7.6 (d, 1H), 7.5 (t, 1H), 7.4–7.1 (m, 2H), 3.8 (s, 2H); ES-MS (m/z) 372 [M+H]+.
Reaction SMILES: N#N.C(O[C:8]([NH:10][C@@H:11]([C:24]([OH:26])=O)[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH:22]=[O:23])[CH:14]=1)=[O:9])(C)(C)C.Cl.[CH2:28]([NH:35][C@H:36](C)[C:37](OCC1C=CC=CC=1)=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>ClCCl>[CH2:28]([N:35]1[C@H:36]([CH3:37])[C:8](=[O:9])[NH:10][C@H:11]([CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH:22]=[O:23])[CH:14]=2)[C:24]1=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)O
Reactant: C[C@@H](NCc1ccccc1)C(=O)OCc1ccccc1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1C(=O)N[C@H](Cc2cn(C=O)c3ccccc23)C(=O)N1Cc1ccccc1
Reaction time: 2 h
Yield: 57.5 %

Procedure:
To a mixture of N2 -(tert-butoxycarbonyl)-N1 -formyl-D-tryptophan (2.17 g) and benzyl (2R)-2-(N-benzylamino)propionate hydrochloride (2.0 g) in dichloromethane (30 ml) was added triethylamine (2.3 ml) under nitrogen atmosphere. To the mixture was added 2-chloro-1-methylpyridinium iodide (1.84 g) at room temperature, and the resulting mixture was stirred for 2 hours and left overnight. The reaction mixture was washed successively with dilute hydrochloric acid, aqueous sodium bicarbonate solution and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was dissolved in dichloromethane (30 ml). A solution of 4N hydrogen chloride in dioxane solution (10 ml) was added thereto at ice-bath temperature and-then the resulting mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between dichloromethane and aqueous saturated sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over magnesium sulfate and filtered. To the filtrate was added triethylamine (1 ml) and the resulting mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was purified on a silica gel column (60 g) eluting with a mixture of n-hexane and ethyl acetate (2:1) to give (3R,6R)-1-benzyl-3-(N-formyl-1H-indol-3-yl-methyl)-6-methylpiperazine-2,5-dione (1.3 g).