Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BrH:1].[Br:2][CH2:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]([NH2:14])=[NH:13])[S:9][CH:10]=1)=O.[NH2:15][C:16]([NH2:18])=[S:17]>CN(C)C=O>[BrH:2].[BrH:1].[NH:11]([C:8]1[S:9][CH:10]=[C:6]([C:4]2[N:15]=[C:16]([NH2:18])[S:17][CH:3]=2)[N:7]=1)[C:12]([NH2:14])=[NH:13]
Reactant: N=C(N)Nc1nc(C(=O)CBr)cs1
Reactant: NC(N)=S
Agent: Br
Solvent: CN(C)C=O
Product: N=C(N)Nc1nc(-c2csc(N)n2)cs1
Yield: 74 %

Procedure:
A solution of 688 mg (2.0 mmol) of 2-bromo-1-(2-guanidino-4-thiazolyl)ethanone hydrobromide and 183 mg of thiourea in 5 ml of dimethylformamide was stirred at room temperature. After a short time, a solid began to precipitate. After a total of four hours, the solid was collected by filtration, washed with ethyl acetate, and dried, thereby affording 595 mg (74%) of 2-guanidino-4-(2-amino-4-thiazolyl)thiazole dihydrobromide as a white powder; mp 320° (dec); mass spectrum parent of 240. This material could be converted to its free base by triturating with saturated sodium bicarbonate solution, stirring for 15 minutes, filtering the solid, and drying it under vacuum. In this way 2-guanidino-4-(2-amino-4-thiazolyl)thiazole was obtained as a crystalline solid, mp 274°. Calcd. for C7H8N6S2 : C, 34.99; H, 3.36; N, 34.97; found: C, 34.94; H, 3.41; N, 34.80.
Reaction SMILES: [I-:1].[K+].C(O[CH2:6][CH2:7][CH2:8][CH:9]1[C:15]2[CH:16]=[C:17]([I:20])[CH:18]=[CH:19][C:14]=2[CH:13]=[CH:12][C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]1=2)C>>[I:1][CH2:6][CH2:7][CH2:8][CH:9]1[C:15]2[CH:16]=[C:17]([I:20])[CH:18]=[CH:19][C:14]=2[CH:13]=[CH:12][C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]1=2
Reactant: [I-]
Reactant: CCOCCCC1c2ccccc2C=Cc2ccc(I)cc21
Agent: [K+]
Product: ICCCC1c2ccccc2C=Cc2ccc(I)cc21
Temperature: 25 °C

Procedure:
Phosphorus pentoxide (1.28 g.) and concentrated (85%) phosphoric acid (2.7 ml.) are mixed well and cooled to room temperature. Potassium iodide (6.6 g., 0.04 mole), finely powdered, and 5-(3-ethoxypropyl)-3-iodo-5H-dibenzo[a,d]cycloheptene (4.0 g., 0.01 mole) are added and the mixture stirred and heated in an oil bath at 110° for 16 hours.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH:20][C@H:21]2[C@@H:25]3[O:26][C:27]([CH3:30])([CH3:29])[O:28][C@@H:24]3[C@@H:23]([CH2:31][OH:32])[CH2:22]2)=[N:12][C:13]([S:18][CH3:19])=[N:14][C:15]=1[O:16]C.C(=O)([O-])[O-].[K+].[K+].C1(S)C=CC=CC=1>CN1C(=O)CCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:15](=[O:16])[NH:14][C:13]([S:18][CH3:19])=[N:12][C:11]=1[NH:20][C@H:21]1[C@H:25]2[C@H:24]([O:28][C:27]([CH3:30])([CH3:29])[O:26]2)[C@@H:23]([CH2:31][OH:32])[CH2:22]1
Reactant: COc1nc(SC)nc(N[C@@H]2C[C@H](CO)[C@H]3OC(C)(C)O[C@H]32)c1-c1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CSc1nc(N[C@@H]2C[C@H](CO)[C@H]3OC(C)(C)O[C@H]32)c(-c2nc3ccccc3s2)c(=O)[nH]1
Temperature: 190 °C

Procedure:
Compound 7 (800 mg, 1.686 mmol) and potassium carbonate (46.6 mg, 0.337 mmol) were suspended in NMP (843 μl) and thiophenol (208 μl, 2.023 mmol) was added. The reaction was sealed and heated to 190° C. for 20 min to consume all SM. The reaction was diluted with EtOAc, washed with water, brine, dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with CH2C2/MeOH to give the title compound as a white solid. 1H NMR (CD3OD) δ 7.80-7.77 (m, 2H), 7.35-7.31 (m, 1H), 7.23-7.19 (m, 1H), 4.61-4.56 (m, 2H), 4.43-4.04 (m, 1H), 3.76-3.74 (m, 2H), 2.54 (s, 3H), 2.57-2.46 (m, 1H), 2.35-2.31 (m, 1H), 1.82-1.77 (m, 1H), 1.44 (s, 3H), 1.27 (s, 3H); LCMS 2.29 min, 461 (M+H)
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH:9]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][CH2:7][CH2:6][NH:5]1.Br[CH2:19][C:20]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=1[F:28]>CN(C)C=O>[F:28][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:20]=1[CH2:19][N:5]1[CH2:6][CH2:7][CH2:8][CH:9]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[C:4]1=[O:3]
Reactant: CC(C)(C)OC(=O)NC1CCCNC1=O
Reactant: COc1cccc(F)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(F)c1CN1CCCC(NC(=O)OC(C)(C)C)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (82 mg, 2.054 mmol) was added to a solution of tert-butyl 2-oxopiperidin-3-ylcarbamate (200 mg, 0.933 mmol) in dimethylformamide (2 ml) at 23° C. and the resulting mixture was allowed to stir for 30 minutes. The mixture was then cooled to 0° C., and a solution of 2-(bromomethyl)-1-fluoro-3-methoxybenzene (214 mg, 0.977 mmol) in dimethylformamide (1.2 ml) added to the reaction mixture drop-wise. The resulting solution was allowed to stir for 90 minutes and was quenched with methanol. The mixture was then diluted with EtOAc, washed with water and brine, dried with magnesium sulfate, filtered and concentrated to afford tert-butyl 1-(2-fluoro-6-methoxybenzyl)-2-oxopiperidin-3-ylcarbamate. The crude product was progressed to the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([C:12]([CH3:36])([CH3:35])[C:13]([NH:15][C:16]1[O:20][N:19]=[C:18]([C:21]([CH3:34])([CH3:33])[CH2:22][O:23]CC2C=CC(OC)=CC=2)[CH:17]=1)=[O:14])(=[O:11])=[O:10]>ClCCCl.Cl.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([C:12]([CH3:36])([CH3:35])[C:13]([NH:15][C:16]1[O:20][N:19]=[C:18]([C:21]([CH3:34])([CH3:33])[CH2:22][OH:23])[CH:17]=1)=[O:14])(=[O:11])=[O:10]
Reactant: COc1ccc(COCC(C)(C)c2cc(NC(=O)C(C)(C)S(=O)(=O)c3ccc(F)cc3F)on2)cc1
Agent: Cl
Solvent: ClCCCl
Solvent: O
Product: CC(C)(CO)c1cc(NC(=O)C(C)(C)S(=O)(=O)c2ccc(F)cc2F)on1
Reaction time: 18 h
Yield: 109.1 %

Procedure:
To a solution of 21 mg (0.041 mmol) of 2-(2,4-Difluoro-benzenesulfonyl)-N-{3-[2-(4-methoxy-benzyloxy)-1,1-dimethyl-ethyl]-isoxazol-5-yl}-2-methyl-propionamide in DCE (1 ml) and 4M HCl solution (0.5 mL), a few drops of water are added and the reaction mixture stirred over night for 18 h. The solvents are removed to yield 18 mg of 2-(2,4-difluoro-benzenesulfonyl)-N-[3-(2-hydroxy-1,1-dimethyl-ethyl)-isoxazol-5-yl]-2-methyl-propionamide. Yield 100%, ES-MS: m/z 403 [M+H].
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[N:6][C:5]2[CH:17]=[CH:18][C:19]([C:21]#[C:22][C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)=[CH:20][C:4]=2[NH:3]1.[CH3:29][C:30](OC(C)=O)=[O:31]>C1COCC1>[C:30]([N:26]1[CH2:25][CH:24]=[C:23]([C:22]#[C:21][C:19]2[CH:18]=[CH:17][C:5]3[N:6]=[C:7]([C:9]4[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=4)[C:12]#[N:13])[CH2:8][C:2](=[O:1])[NH:3][C:4]=3[CH:20]=2)[CH2:28][CH2:27]1)(=[O:31])[CH3:29]
Reactant: N#Cc1cccc(C2=Nc3ccc(C#CC4=CCNCC4)cc3NC(=O)C2)c1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N1CC=C(C#Cc2ccc3c(c2)NC(=O)CC(c2cccc(C#N)c2)=N3)CC1
Yield: 96.3 %

Procedure:
Prepared from 3-[4-oxo-7-(1,2,3,6-tetrahydro-pyridin-4-ylethynyl)-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile (Example 140) (55 mg, 0.15 mmol) by treatment with Ac2O (0.017 mL, 0.165 mmol) in THF (3 mL) at 23° C. for 1 h. Obtained as a sand solid (59 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][NH:12][C:11](=[O:23])[C:10]=2[C:24]#[N:25])=[CH:5][CH:4]=1.[CH2:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([N:12]1[C:11](=[O:23])[C:10]([C:24]#[N:25])=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[N:13]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(-c2n[nH]c(=O)c(C#N)c2-c2ccc(OC)cc2)cc1
Reactant: ClCc1ccccc1
Product: COc1ccc(-c2nn(Cc3ccccc3)c(=O)c(C#N)c2-c2ccc(OC)cc2)cc1
Yield: 65.4 %

Procedure:
Using 5,6-bis(4-methoxyphenyl)-4-cyano-2H-pyridazin-3-one and benzyl chloride as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 65.4%.
Reaction SMILES: [N:1]([CH2:4][C:5]([C:7]1[C:17]2=[C:18]3[C:13](=[CH:14][CH:15]=[CH:16]2)[CH2:12][CH2:11][CH2:10][N:9]3[CH:8]=1)=[O:6])=[N+]=[N-].[O:19](C(OC(C)(C)C)=O)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=O.CO>C1COCC1.[Pd]>[C:23]([O:22][C:20](=[O:19])[NH:1][CH2:4][C:5]([C:7]1[C:17]2=[C:18]3[C:13](=[CH:14][CH:15]=[CH:16]2)[CH2:12][CH2:11][CH2:10][N:9]3[CH:8]=1)=[O:6])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: [N-]=[N+]=NCC(=O)c1cn2c3c(cccc13)CCC2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCC(=O)c1cn2c3c(cccc13)CCC2

Procedure:
A solution of 2-azido-1-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-ethanone (4.70 g, 19.58 mmol), (BOC)2O (4.48 g, 20.56 mmol), Pd/C (10%) in THF (30 mL)/MeOH (20 mL) was shaken under H2 (60 psi) overnight. The mixture was filtered through a pad of Celite and concentrated to give a residue that was purified by silica gel column chromatography (eluent, 2/1 hex/EtOAc). [2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester was obtained as a white solid (2.82 g, 46%). M.p.=175-177° C.; 1H NMR (400 MHz, DMSO-d6) δ: 8.35 (s, 1H), 7.86 (d, J=8.0 Hz, 1H), 7.12 (t, J=7.6 Hz, 1H), 6.99 (m, 2H), 4.27 (d, J=6.0 Hz, 2H), 4.23 (t, J=6.0 Hz, 2H), 2.94 (t, J=6.4 Hz, 2H), 2.14 (m, 2H), 1.41 (s, 9H). LCMS: m/e 315.21 [M+H], 259.17 [M-56].
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16](O)=[O:17])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:46][CH2:47][CH2:48][NH:49][C:50](=[O:56])[O:51][C:52]([CH3:55])([CH3:54])[CH3:53]>C1COCC1.C1COCC1.C(OCC)(=O)C>[C:1]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:46][CH2:47][CH2:48][NH:49][C:50](=[O:56])[O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:17])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCNC(=O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Reaction time: 8 h
Yield: 62.6 %

Procedure:
To a solution of (4-([1,1′-biphenyl]-4-ylmethoxy)phenyl)acetic acid (2.1 g) in THF (100 ml) were added WSC (1.4 g), HOBt (1 g), and t-butyl N-(2-aminoethyl)carbamate (1 g). After stirring overnight, the reaction mixture was diluted in THF-ethyl acetate, washed with 10% aqueous potassium carbonate, dried, and concentrated. The residue was recrystallized from ethanol to obtain the titled compound (1.8 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C:17]3[C@:8]([CH3:22])([C@H:9]4[C@@:13]([CH2:15][CH:16]=3)([CH3:14])[C@@H:12]([OH:21])[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.C1COCC1>[Pd].CO>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@:8]([CH3:22])([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@@H:12]([OH:21])[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CC[C@]1(C)C2=CC[C@@]2(C)[C@H]1CC[C@@H]2O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1)CC[C@@]1(C)[C@@H]3CC[C@H](O)[C@@]3(C)CC[C@H]21

Procedure:
75 mg of 3-methoxy-8β-methyl-estra-1,3,5(10),9(11)-tetraen-17β-ol (7a) was dissolved in a solvent mixture that consists of 3.5 ml of THF and 1.5 ml of methanol and stirred with 75 mg of palladium (10%, on magnesium carbonate) for 3.75 hours at room temperature under hydrogen atmosphere. Then, the reaction solution was filtered on Celite, the filtrate was evaporated to the dry state in a rotary evaporator, and the thus obtained TLC-uniform, foamy product (74 mg, 98%) was used without further purification in the next stage.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:12])=[CH:4][C:5]([Cl:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[BH4-].[Na+]>CO>[NH2:1][C:2]1[C:3]([Br:12])=[CH:4][C:5]([Cl:11])=[C:6]([CH:8]([OH:10])[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(N)c(Br)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1cc(N)c(Br)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
To a solution of 1-(5-amino-4-bromo-2-chloro-phenyl)-ethanone (0.25 g, 1.00 mmol) in methanol (5 ml) was added NaBH4 (0.076 g, 2.01 mmol). The mixture was stirred at room temperature for two hours, then quenched by addition of 2N HCl and taken to neutral pH with pH7 buffer. The mixture was extracted with dichloromethane, and the combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hex:EtOAc/7:3) gave 1-(5-amino-4-bromo-2-chloro-phenyl)-ethanol 0.195 g (77%) as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.CO>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([F:21])=[CH:23][CH:24]=3)[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CO
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)c4ccc(F)cc4)c3C2=O)C(=O)N1
Yield: 75.9 %

Procedure:
A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.1 g, 4.0 mmol) and 4-fluorobenzoyl chloride (0.95 mL, 8.0 mmol) in THF (40 mL) was heated to reflux for 15 h. To the mixture was added methanol (5 mL) to give a suspension. The suspension was filtered and washed with ether (2×10 mL) then methanol (5 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4-fluoro-benzamide as a yellow solid (1.2 g, 77% yield): mp, 283-285° C.; 1H NMR (DMSO-d6) δ 2.06-2.10 (m, 1H, CHH), 2.48-2.65 (m, 2H, CH2), 2.83-2.97 (m, 1H, CHH), 5.18 (dd, J=5.4, 12.6 Hz, 1H, NCH), 7.42-7.49 (m, 2H, Ar), 7.69 (d, J=7.2, Hz, 1H, Ar), 7.91 (t, J=8.2 Hz, 1H, Ar), 8.03-8.08 (m, 2H, Ar), 8.54 (d, J=8.3 Hz, 1H, Ar), 10.41 (s, 1H, NH), 11.15 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.10, 30.98, 49.29, 115.96 (d, JC-F=22 Hz); 118.03, 118.67, 128.09 (d, JC-F=235 Hz), 130.12, 131.49, 136.18, 136.75, 162.70, 164.08, 166.56, 168.22, 169.29, 172.27; Anal Calcd for C20H14N3O5F+0.2H2O: C, 60.21; H, 3.64; N, 10.53; F, 4.76; H2O, 0.90. Found: C, 60.17; H, 3.55; N, 10.47; F, 4.90; H2O, 0.95.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][N:7]2[N:10]=[C:11]([S:13]([NH:16][C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])(=[O:15])=[O:14])[N:12]=[C:6]2[N:5]=1.CS(O)(=O)=O>CS(C)=O>[CH3:3][CH:4]1[CH2:9][CH2:8][N:7]2[N:10]=[C:11]([S:13]([NH:16][C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])(=[O:15])=[O:14])[N:12]=[C:6]2[NH:5]1
Reactant: Cc1ccn2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2n1
Agent: CS(=O)(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1CCn2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2N1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 36.9 %

Procedure:
Sodium borohydride (0.6 g, 16 mmol) was added to a solution of 3.0 g (8.3 mmol) of 5-methyl-N-(2,6-dichlorophenyl)-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide in 25 ml of dry DMSO. An exothermic reaction occured and 2.0 ml (31 mmol) of methane sulfonic acid in 5 ml of DMSO was added at a rate to maintain the temperature of the reaction mixture at 60° C. After the addition was complete the reaction mixture was stirred for 10 minutes and carefully quenched with 0.5N aqueous NaOH. The clear yellow solution was filtered, and the filtrate was acidified with 3N aqueous HCl. The resulting precipitate was treated with dilute aqueous NaOH and filtered to remove insoluble material. The filtrate was acidified with aqueous HCl to precipitate a solid. The solid was collected by filtration and dried to yield 1.11 g (37%) of the desired product as a solid, m.p. 230°-235° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[NH:15][C:16](=[O:21])[CH2:17][CH2:18][CH2:19]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:22]([C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[NH:15][C:16](=[O:21])[CH2:17][CH2:18][CH2:19][N:38]1[CH2:39][CH2:40][CH:35]([C:32]2[CH:33]=[CH:34][C:29]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:30][CH:31]=2)[CH2:36][CH2:37]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Reactant: Cc1cccc(Cc2ccccc2)c1NC(=O)CCCCl
Product: Cc1cccc(Cc2ccccc2)c1NC(=O)CCCN1CCC(c2ccc(Oc3ccccc3)cc2)CC1

Procedure:
The compound (14) synthesized in Reference Example 14 and the compound (4) synthesized in Reference Example 4 were used to produce the above compound in the same way as Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18](O)=[O:19])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH3:22][NH:23][CH2:24][C:25]1[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][N:26]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[OH-].[Na+]>CCOC(C)=O>[CH3:22][N:23]([CH2:24][C:25]1[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][N:26]=1)[C:18]([CH:16]1[CH2:15][C:14]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][N:9]3[CH2:10][CH2:11][CH2:12][CH2:13]3)=[C:2]([Cl:1])[CH:3]=2)([OH:21])[CH2:17]1)=[O:19]
Reactant: CNCc1ncccc1C
Reactant: O=C(O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1cccnc1CN(C)C(=O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.7 %

Procedure:
To a solution of crude intermediate 17, 3-(3-chloro-4-((pyrrolidin-1-yl)methyl)phenyl)-3-hydroxycyclobutanecarboxylic acid (˜4.3 mL ˜0.65 mmol) was added methyl-(3-methyl-pyridin-2-ylmethyl)-amine (176 mg, 1.29 mmol) and T3P (50% solution in EtOAc, 0.62 ml, 0.97 mmol). The resulting reaction mixture was stirred at RT for 1 hr and then 25 ml of 1N NaOH and 100 ml of EtOAc were added and the layers were separated. The aqueous layer was subjected to EtOAc extraction (2×60 ml) again and the combined organic layers were dried over MgSO4 and evaporated. The residue was purified by flash column chromatography using a 40 g ISCO™ column, eluting with 5% MeOH/CH2Cl2 containing 0.25% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to give the title compound 127 mg, 46% yield). Rf=0.30 (15% MeOH/CH2Cl2+0.2% NH4OH); LRMS m/z Calcd for C24H30Cl N3 O2, 427.9, found, 428.2 (M+1) APCI; 400 MHz 1H NMR (CDCl3) 2:1 mixture of rotomers, diagnostic peaks, δ 4.72, 4.53 (s, 2H), 3.72 & 3.70 (s, 2H), 2.97, 2.93 (s, 3H), 1.76-1.74 (m, 4H); 100 MHz 13C NMR (CDCl3) 2:1 mixture of rotomers, diagnostic peaks δ 177.6, 175.7, 154.7, 153.6, 146.8, 146.6, 126.5, 126.4, 122.8, 122.7, 73.4, 73.2, 56.7, 56.6, 54.3, 54.2, 51.1, 41.4, 40.9, 35.6, 35.4, 28.9, 28.7, 23.7, 23.6, 18.3, 18.2.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:13][C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[N:6]=1)=[O:4].[H-].[Na+].Br[CH2:17][C:18]1[CH:22]=[C:21]([C:23]2[S:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[O:20][N:19]=1>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1[N:13]([CH2:17][C:18]2[CH:22]=[C:21]([C:23]3[S:24][C:25]([Cl:28])=[CH:26][CH:27]=3)[O:20][N:19]=2)[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[N:6]=1)=[O:4]
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Reactant: COC(=O)c1nc2cccnc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc2cccnc2n1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
100 mg (0.56 mmol) 3H-Imidazo[4,5-b]pyridine-2-carboxylic acid methyl ester were dissolved in 3 mL DMF. 22.6 mg (0.56 mmol) sodium hydride (60% in mineral oil) were added and the mixture was stirred 30 minutes at room temperature. 157.2 mg (0.56 mmol) 3-Bromomethyl-5-(5-Chloro-thiophen-2-yl)-isoxazole were added and the resulting mixture was stirred for 1 h at 80° C. The reaction mixture was cooled to room temperature and after the addition of a few drops of water concentrated under reduced pressure. HPLC-MS-analysis showed the presence of another isomer (ratio of isomers≈7:1). Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) gave pure 3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-3H-imidazo[4,5-b]pyridine-2-carboxylic acid methyl ester as a brown amorphous solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:15]=[C:16]([C:24]([CH3:30])([S:26]([CH3:29])(=[O:28])=[O:27])[CH3:25])[CH:17]=[C:18]3[C:23]=2[N:22]=[CH:21][CH:20]=[CH:19]3)[CH:9]=1.[C:31]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)([OH:33])=[O:32].C(Cl)Cl>CO>[CH3:30][C:24]([C:16]1[CH:17]=[C:18]2[C:23](=[C:14]([C:10]3[CH:9]=[C:8]([C:3]4[C:2]([C:37]5[CH:38]=[CH:39][C:34]([C:31]([OH:33])=[O:32])=[CH:35][CH:36]=5)=[CH:7][CH:6]=[CH:5][CH:4]=4)[CH:13]=[CH:12][CH:11]=3)[CH:15]=1)[N:22]=[CH:21][CH:20]=[CH:19]2)([S:26]([CH3:29])(=[O:28])=[O:27])[CH3:25]
Reactant: CC(C)(c1cc(-c2cccc(-c3ccccc3Br)c2)c2ncccc2c1)S(C)(=O)=O
Reactant: O=C(O)c1ccc(B(O)O)cc1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(c1cc(-c2cccc(-c3ccccc3-c3ccc(C(=O)O)cc3)c2)c2ncccc2c1)S(C)(=O)=O

Procedure:
Prepared according to the general procedure Coupling—1 using Arylbromide from step 1 and 4-carboxybenzeneboronic acid as starting materials. Flash chromatography (CH2Cl2:MeOH, 9:1) afforded the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:5]([F:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1>>[CH:20]1[C:21]2[CH:9]([NH:8][C:6]3[C:5]([F:22])=[CH:4][N:3]=[C:2]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=4)[N:7]=3)[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: Fc1cnc(Cl)nc1NC1c2ccccc2-c2ccccc21
Reactant: Nc1cccc(O)c1
Product: Oc1cccc(Nc2ncc(F)c(NC3c4ccccc4-c4ccccc43)n2)c1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-4-pyrimidinediamine, 2-chloro-N-(fluoren-9-yl)-5-fluoro-4-pyrimidineamine and 3-aminophenol were reacted to produce N4-(fluoren-9-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.85 (d, 1H, J=2.9 Hz), 7.74 (d, 2H, J=7.6 Hz), 7.64 (d, 2H, J=7.6 Hz), 7.41-7.28 (m, 6H), 7.14-7.05 (m, 2H), 6.56 (d, 1H, J=8.8 Hz), 5.28 (d, 1H, J=8.8 Hz); LCMS: ret. time: 23.27 min.; purity: 89%; MS (m/e): 385 (MH+).