Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([P:6](Cl)[C:7]([CH2:10][CH3:11])([CH3:9])[CH3:8])([CH2:4][CH3:5])([CH3:3])[CH3:2].[CH:13]1(Cl)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[Mg].S(=O)(=O)(O)O>O1CCCC1.[Cu]Cl.C1(C)C=CC=CC=1>[C:1]([P:6]([C:7]([CH2:10][CH3:11])([CH3:9])[CH3:8])[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: ClC1CCCCC1
Reactant: CCC(C)(C)P(Cl)C(C)(C)CC
Agent: Cl[Cu]
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCC(C)(C)P(C1CCCCC1)C(C)(C)CC
Reaction time: 6 h
Yield: 96.7 %

Procedure:
In a 300 ml four-necked flask thoroughly purged with nitrogen, 10.4 g (0.05 mol) of di-tert-amylphosphinous chloride, 0.10 g (0.001 mol (corresponding to 2% by mol)) of copper(I) chloride and 30 ml of tetrahydrofuran were placed. To the contents of the flask, a Grignard reagent solution previously prepared from 8.3 g (0.060 mol) of cyclohexyl chloride and 2.0 g (0.08 mol) of metallic magnesium in 50 ml of tetrahydrofuran was dropwise added over a period of 1 hour with maintaining the temperature at 25° C. to 30° C. After the dropwise addition was completed, stirring was conducted at a temperature of 35° C. to 40° C. for 6 hours. After the temperature of the reaction solution was returned to room temperature, 20 ml of toluene and 20 ml of a 5% sulfuric acid aqueous solution were added to the reaction solution to perform liquid separation. Then, the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent and a low-boiling component were distilled off under reduced pressure to obtain 12.4 g (purity: 94.9%) of the aimed di-tert-amylcyclohexylphosphine as an oily substance. The yield was 90.2%.
Reaction SMILES: [I:1][C:2]1[C:6]([C:7](=[O:9])[CH3:8])=[CH:5][N:4]([CH:10]([CH3:12])[CH3:11])[N:3]=1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[CH3:15][N:16]([CH3:18])[CH:17]=[CH:8][C:7]([C:6]1[C:2]([I:1])=[N:3][N:4]([CH:10]([CH3:12])[CH3:11])[CH:5]=1)=[O:9]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cn(C(C)C)nc1I
Product: CC(C)n1cc(C(=O)C=CN(C)C)c(I)n1
Temperature: 155 °C

Procedure:
A mixture of Intermediate 1-(3-iodo-1-isopropyl-1H-pyrazol-4-yl)ethanone (5.0 g, 18.0 mmol) and N,N-dimethylformamide dimethyl acetal (50 mL) was heated at 155° C. for 20 h. The mixture was concentrated under vacuum to provide the crude title compound. MS m/z 334.0 (M+1).
Reaction SMILES: [CH2:1]([S:8][CH:9]([CH:34](OC)[O:35]C)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[C:20]([CH3:23])[CH:19]=[CH:18][C:17]=2[N:24]([CH3:33])[S:25]([C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)(=[O:27])=[O:26])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O>O>[CH2:1]([S:8][CH:9]([CH:34]=[O:35])[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[C:20]([CH3:23])[CH:19]=[CH:18][C:17]=2[N:24]([CH3:33])[S:25]([C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)(=[O:27])=[O:26])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)C(CNC(=O)c1cc2c(C)ccc(N(C)S(=O)(=O)c3cccs3)c2[nH]1)SCc1ccccc1
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(=O)NCC(C=O)SCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 100.7 %

Procedure:
A mixture of N-[2-(benzylthio)-3,3-dimethoxypropyl]-4-methyl-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (4.75 g), Amberlyst (registered trade mark) 15 ion exchange resin (1.0 g), acetone (100 mL) and water (0.4 mL) was stirred at room temperature for 20 hr. Amberlyst (registered trade mark) 15 ion exchange resin was filtered off, and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=2:3-3:2) to give the title compound (4.4 g, yield: 100%) as a colorless amorphous solid. MS: 528 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.Cl.[CH3:20][O:21][C:22](=[O:31])[C@H:23]([CH2:25][C:26]1[N:30]=[CH:29][NH:28][CH:27]=1)[NH2:24]>CO.C(Cl)Cl>[CH3:20][O:21][C:22](=[O:31])[C@H:23]([CH2:25][C:26]1[N:30]=[CH:29][NH:28][CH:27]=1)[NH:24][C:15](=[O:17])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2) and L-histidine methyl ester dihydrochloride (Sigma), the title compound was prepared as a solid (mp=195-197° C.). The reaction was monitored by tlc (Rf=0.29 in 10% CH3OH/CH2Cl2).
Reaction SMILES: C[C:2]1[O:3]C(=O)C2SC=C[C:6]=2[N:7]=1.[NH2:12][C:13]1C(C)=CC=CC=1>C(O)(=O)C>[CH3:2][N:7]([C:13]([N:12]=[N:12][C:2]([N:7]([CH3:6])[CH3:13])=[O:3])=[O:3])[CH3:6]
Reactant: Cc1ccccc1N
Reactant: Cc1nc2ccsc2c(=O)o1
Solvent: CC(=O)O
Product: CN(C)C(=O)N=NC(=O)N(C)C
Yield: 45.9 %

Procedure:
2-Methyl-thieno[3,2-d][1,3]oxazin4-one (12.7 g, 76 mmol) and o-toluidine (16.2 mL, 152 mmol) were combined in acetic acid (175 mL) and refluxed for 3 hours. The reaction was concentrated and the residue was partitioned between ethyl acetate and water. The two phase mixture was treated with sodium bicarbonate until the aqueous layer was basic and the phases were then separated. The aqueous phase was extracted with ethyl acetate and the combined organic layer was washed with water and brine, dried over sodium sulfate and concentrated to leave a black oil. This residue was purified by flash chromatography on silica gel (60×200 mm). Elution with 20% ethyl acetate/hexane gave 16.2 g of impure product and 3 g of uncyclized diamide biproduct. The impure product was chromatographed a second time as above but with 10% and 15% ethyl acetate/hexane elution. In this fashion 9.2 g (47%) of 2-methyl-3-(2-methylphenyl)-3H-thieno[3,2-d]pyrimidin-4-one was isolated as a light yellow solid. NMR δ7.70 (d, J=5.3 Hz, 1H), 7.39-7.30 (m, 3H), 7.29 (d, J=5.3 Hz, 1H), 7.13 (d, J=7.8 Hz, 1H), 2.15 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:5](=O)[C:4]([NH:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[C:3]1[O:16]CC.[F:19][C:20]([F:27])([C:23]([F:26])([F:25])[F:24])[CH2:21][NH2:22]>C(O)C>[O:1]=[C:2]1[C:3](=[O:16])[C:4]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=2)=[C:5]1[NH:22][CH2:21][C:20]([F:27])([F:19])[C:23]([F:26])([F:25])[F:24]
Reactant: NCC(F)(F)C(F)(F)F
Reactant: CCOc1c(Nc2ccc(C#N)cc2)c(=O)c1=O
Solvent: CCO
Product: N#Cc1ccc(Nc2c(NCC(F)(F)C(F)(F)F)c(=O)c2=O)cc1
Yield: 71 %

Procedure:
4-(3,4-Dioxo-2-ethoxy-cyclobut-1-enylamino)-benzonitrile (1 g, 4.1 mmol) and 2,2,3,3,3-pentafluoropropylamine (3 mL) in ethanol were refluxed for 24 hours. The reaction mixture was filtered and the resulting solid was triturated with diethyl ether to give 1.0 g (71% ) of 4-[3,4-dioxo-2-(2,2,3,3,3-pentafluoro-propylamino)-cyclobut-1-enylamino]-benzonitrile as a yellow solid: mp 272°-275° C. (dec); 1H NMR (DMSO-d6): δ 10.15 (br s, 1H), 8.19 (br s, 1H), 7.81 (d, 2H), 7.79 (d, 2H), 4.54 (dt, 2H). IR (KBr): 3185. 2239, 1804, 1672, 1608, 1565, 1548 cm-1 ; MS (m/z) 346([M+H]+).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:9]([CH2:10][CH3:11])=[N:8][C:7]2[N:12]([CH2:15][CH3:16])[N:13]=[CH:14][C:6]=2[C:5]=1[NH:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[CH3:24][C:25]([CH3:32])([C:29](O)=[O:30])[C:26]([OH:28])=[O:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[CH2:15]([N:12]1[C:7]2=[N:8][C:9]([CH2:10][CH3:11])=[C:4]([CH2:3][NH:2][C:29](=[O:30])[C:25]([CH3:32])([CH3:24])[C:26]([OH:28])=[O:27])[C:5]([NH:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[C:6]2[CH:14]=[N:13]1)[CH3:16]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: CC(C)(C(=O)O)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)C(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.5 %

Procedure:
A mixture of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine hydrochloride (400 mg, 1.18 mmol), dimethylpropanedioic acid (156 mg, 1.18 mmol), HBTU (535 mg, 1.41 mmol) and Et3N (0.82 mL, 5.89 mmol) in DCM (8 mL) was stirred at room temperature overnight. It was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with water followed by a brine wash. The organic layers were dried over sodium sulfate, filtered, concentrated and purified with CombiFlash eluting with 10% methanol in DCM. The product fractions were combined and concentrated to give 3-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-2,2-dimethyl-3-oxopropanoic acid as a solid (165 mg, 34%). LC-MS m/z 418 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](Cl)=[N:15][N:14]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][C:6]=2[CH3:11])=[N:15][N:14]=1
Reactant: Clc1nnc(Cl)c2ccccc12
Reactant: Cc1cc2cc(Cl)ccc2[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1[nH]c2ccc(Cl)cc2c1-c1nnc(Cl)c2ccccc12
Temperature: 65 °C
Yield: 87.6 %

Procedure:
5-Chloro-2-methylindole (0.74 g, 2.26 mmol) and 1,4-dichloro-phthalazine (0.45 g, 2.26 mmol) were treated with 30 mL of 1,2-dichloroethane and 3.2 mmol of AlCl3 (427 mg). The resulting suspension was heated to 65° C. overnight. The reaction was cooled and quenched with 3 mL water. The resultant precipitate was filtered and dried under vacuum to give 0.65 g of the sub-title compound. MS: ESI (negative): 326, 328 (M−H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)([OH:9])[CH3:8])=[N:4][CH:3]=1.O.[NH2:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[NH2:24][C:25]1[CH:30]=[C:29]([C:2]2[S:6][C:5]([C:7]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)([OH:9])[CH3:8])=[N:4][CH:3]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(C)(O)c2ncc(Br)s2)CC1
Reactant: Nc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(C(C)(O)c2ncc(-c3cccc(N)c3)s2)CC1
Yield: 91.9 %

Procedure:
The product of Step 2 (87 mg, 0.222 mmol), 3-aminophenylboronic acid monohydrate (41.3 mg, 0.267 mmol), Pd(Ph3P)4 (12.85 mg, 0.011 mmol) and Na2CO3 (0.333 mL, 0.667 mmol) were stirred in DME at 100° C. overnight under N2. The reaction mixture was filtered through a pre-pack pad of celica with dichloromethane. The filtrate was concentrated and the residue was purified by flash chromatography to give tert-butyl 4-{1-[5-(3-aminophenyl)-1,3-thiazol-2-yl]-1-hydroxyethyl}piperidine-1-carboxylate (82.4 mg, 0.204 mmol, 92%) as a yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].[I-:16].[Na+]>CC(C)=O>[I:16][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: [I-]
Reactant: CCOC(=O)N1CCN(C(=O)CCl)CC1
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)N1CCN(C(=O)CI)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.3 %

Procedure:
A mixture of ethyl 4-(2-chloroacetyl)piperazine-1-carboxylate (2.36 g, 10.06 mmol) and sodium iodide (3 g, 20.11 mmol) in acetone (45 mL) was stirred at room temperature for 24 h to give a suspension containing white solids. The solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was extracted with CH2Cl2 and H2O. The organic layer then dried over MgSO4, filtered and concentrated to give ethyl 4-(2-iodoacetyl)piperazine-1-carboxylate (2.47 g, 75% yield). C9H151N2O3; brown oil; IR vmax (neat) 2981, 2927, 2864, 1697, 1642, 1464, 1434, 1385, 1286, 1232, 1133, 1073, 1030, 989, 767 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.14 (2H, q, J=7.0 Hz), 3.75 (2H, s), 3.58 (4H, m), 3.43 (4H, m), 1.26 (3H, t, J=7.0 Hz); 13C NMR (100 MHz, CDCl3) δ 166.6, 155.1, 61.8, 47.0, 43.1 (2×), 42.0 (2×), 14.7; ESI-HRMS calcd for C9H161N2O3: 327.0206. found: m/z 327.0215 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:8]1([CH3:13])[O:12][CH2:11][CH2:10][O:9]1)[C:4]([O:6][CH3:7])=[O:5].[Br:14][C:15]1[CH:16]=[C:17]2[C:22](=O)[O:21][C:19](=[O:20])[C:18]2=[CH:24][CH:25]=1>>[Br:14][C:15]1[CH:16]=[C:17]2[C:18](=[CH:24][CH:25]=1)[C:19](=[O:20])[N:1]([CH2:2][CH:3]([C:8]1([CH3:13])[O:9][CH2:10][CH2:11][O:12]1)[C:4]([O:6][CH3:7])=[O:5])[C:22]2=[O:21]
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Reactant: COC(=O)C(CN)C1(C)OCCO1
Product: COC(=O)C(CN1C(=O)c2ccc(Br)cc2C1=O)C1(C)OCCO1

Procedure:
Methyl 3-(5-bromo-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.48 g, 57 mmol) in the same manner as described in the above example 5 (1) from methyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.62 g, 2.75 mmol) and 4-bromophthalic anhydride (0.62 g, 2.75 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: C(N1C(C2C=CC=CC=2)CC(C)(C)[N:10]2[N:22]=CC(C(=O)CC3C=CC(C)=CC=3)=C12)C1C=CC=CC=1.C(O[CH:38]=[C:39]([S:42]([CH2:45][C:46]1[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=1)(=[O:44])=[O:43])[C:40]#[N:41])C.O.NN>C(O)C>[C:49]1([CH3:52])[CH:50]=[CH:51][C:46]([CH2:45][S:42]([C:39]2[CH:38]=[N:22][NH:10][C:40]=2[NH2:41])(=[O:44])=[O:43])=[CH:47][CH:48]=1
Reactant: CCOC=C(C#N)S(=O)(=O)Cc1ccc(C)cc1
Reactant: Cc1ccc(CC(=O)c2cnn3c2N(Cc2ccccc2)C(c2ccccc2)CC3(C)C)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1ccc(CS(=O)(=O)c2cn[nH]c2N)cc1

Procedure:
7,7-Dimethyl-3-(4-methylbenzyl)sulfonyl)-5-phenyl-4,7-dihydropyrazolo[1,5-a]pyrimidine (4): A slurry of 1.9 g (7.2 mmol) of 3 in 25 mL of ethanol was treated with 0.38 mL (7.9 mmol) of hydrazine monohydrate and heated to reflux for 3 h. The reaction was concentrated in vacuo to give crude 4-p-tolylmethanesulfonyl-2H-pyrazol-3-ylamine as a tan solid. The crude pyrazole, 1.3 g (7.9 mmol) of 3-methyl-1-phenyl-but-2-en-1-one and 2.8 mL (36 mmol) of trifluoroacetic acid was dissolved in 25 mL of 2-methoxyethanol and heated to reflux for 3 days. The reaction was then cooled to room temperature, concentrated in vacuo and dissolved in AcOEt. This solution was washed successively with saturated sodium bicarbonate, water and brine before being dried over sodium sulfate. The solution was filtered, concentrated in vacuo and the resulting crude material was purified by flash chromatography eluting with a 75 to 33% hexanes/AcOEt gradient to give 1.25 g (44%) of the title compound as a powder. 1H NMR (CDCl3) δ 1.67 (s, 6H), 2.13 (s, 3H), 4.26 (s, 2H), 4.81 (d, J=2.0 Hz, 1H), 6.39 (s, 1H), 7.05 (dd, J=8.0, 18.5 Hz, 4H), 7.20 (dd, J=3.7, 7.4 Hz, 2H), 7.36-7.39 (m, 3H), 7.52 (s, 1H). MS Calcd.: 393. Found: 394 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]1.C(Cl)Cl.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(=O)([O-])[O-].[Na+].[Na+]>C(N(CC)CC)C>[CH3:22][S:23]([O:18][CH2:17][CH2:16][CH2:15][N:12]1[CH2:11][CH2:10][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:14][CH2:13]1)(=[O:25])=[O:24]
Reactant: COc1ccccc1N1CCN(CCCO)CC1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(CCCOS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3-[4-(2-methoxyphenyl)piperazin-1-yl]-1-propanol (24 g, 95.87 mmol), prepared as in Example 10, in 25 mL of triethylamine and 300 mL of methylene chloride was cooled to approximately 0° C. and then methanesulfonyl chloride (8.8 mL) was added dropwise. The mixture was stirred at approximately 0° C. for 1 hour and then at room temperature for 0.5 hours. The mixture was poured into saturated sodium carbonate and stirred for 15 minutes. The organic phase was separated, washed with saturated sodium carbonate (2×150 mL), dried (MgSO4) and concentrated to give 3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl methanesulfonate (21 g, 63.63 mmol).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[O:11][N:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)[CH:4]=[N:3]1.C1C=CC2N(O)N=NC=2C=1.N=C=N.[NH2:28][CH2:29][CH2:30][N:31]1[CH:35]=[CH:34][C:33]([C:36]2[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[C:38]([Cl:44])[CH:37]=2)=[N:32]1.C(O)C(N)(CO)CO>CN(C=O)C.C(Cl)Cl>[Cl:44][C:38]1[CH:37]=[C:36]([C:33]2[CH:34]=[CH:35][N:31]([CH2:30][CH2:29][NH:28][C:12]([C:9]3[CH:8]=[C:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)[O:11][N:10]=3)=[O:14])[N:32]=2)[CH:43]=[CH:42][C:39]=1[C:40]#[N:41]
Reactant: Cn1cc(-c2cc(C(=O)O)no2)cn1
Reactant: N#Cc1ccc(-c2ccn(CCN)n2)cc1Cl
Agent: N=C=N
Agent: NC(CO)(CO)CO
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1cc(-c2cc(C(=O)NCCn3ccc(-c4ccc(C#N)c(Cl)c4)n3)no2)cn1
Reaction time: 0.17 h
Yield: 19 %

Procedure:
5-(1-methyl-1H-pyrazol-4-yl)isoxazole-3-carboxylic acid (57.9 mg, 0.3 mmol), HOBt (46 mg, 0.340 mmol) and PS-carbodiimide (364 mg), DCM (4 ml) and DMF (0.4 ml) were mixed in a glass vial. The mixture was shaken for 10 min. 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (49 mg, 0.20 mmol) was added and the mixture was stirred for 24 h. The solids were filtered off. PS-Trisamine (333 mg, 1.0 mmol) was added to the filtrate. The mixture was shaken for 4 h and filtered. The filtrate was concentrated and purified by flash chromatography (gradient of DCM:MeOH) to give 16 mg of the title compound. 1H-NMR (400 MHz; d6-DMSO): 3.70 δ (m, 2H), 3.91 (s, 3H), 4.38 (m, 2H), 6.89 (m, 1H), 6.97 (d, 1H), 7.85 (m, 1H), 7.94-8.00 (m, 3H), 8.10 (d, 1H), 8.36 (s, 1H), 8.86-9.13 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N+:26]([O-:28])=[O:27])(=[O:19])=[O:18])=[CH:12][C:11]=1[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31].[CH:34]1([CH:37]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50]O)[CH:45]=2)[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:36][CH2:35]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[CH:34]1([CH:37]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([CH2:50][N:16]([C:13]3[CH:14]=[CH:15][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:11]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:12]=3)[S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N+:26]([O-:28])=[O:27])(=[O:18])=[O:19])[CH:45]=2)[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:36][CH2:35]1
Reactant: CCOC(=O)CC(c1cccc(CO)c1)C1CC1
Reactant: COc1ccc(F)c(-c2ccc(NS(=O)(=O)c3ccccc3[N+](=O)[O-])cc2CC(C)(C)C)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1cccc(CN(c2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])c1)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To a solution of N-(2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl)-2-nitrobenzenesulfonamide (892 mg), ethyl 3-cyclopropyl-3-(3-(hydroxymethyl)phenyl)propanoate (445 mg) and triphenylphosphine (990 mg) in THF (19 mL) was added a 40% solution of diethyl azodicarboxylate in toluene (1.49 mL) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (1.22 g) as a colorless gummy substance.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH2:4][CH2:3]1.Br[C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[C:20]([Br:22])[CH:21]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[Br:22][C:20]1[CH:21]=[C:16]([NH:14][C:11]2[CH:10]=[CH:9][C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[CH:13][N:12]=2)[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=1
Reactant: CN1CCN(c2ccc(N)nc2)CC1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CC1
Temperature: 120 °C
Yield: 27.8 %

Procedure:
To 5-(4-Methyl-piperazin-1-yl)-pyridin-2-ylamine (1.06 g, 5.53 mmol), 3,5-Dibromo-1-methyl-1H-pyridin-2-one (1.23 g, 4.61 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (400 mg, 0.691 mmol), and cesium carbonate (4.50 g, 13.8 mmol) was added 45 mL 1,4-dioxane and tris(dibenzylidineacetone)dipalladium(0) (422 mg, 0.461 mmol). This was heated in a a 120° C. oil bath for 6 hours under argon. This ws partitioned between ethylacetate and dilute aqueous sodium bicarbonate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution with 2 to 5% methanol/dichloromethane) to yield 5-Bromo-1-methyl-3-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-1H-pyridin-2-one (484 mg, 1.28 mmol). MS (ESI) 380.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][CH:17]=[C:18](I)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O1CCOCC1.[CH3:26][O:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[O:34][CH3:35].C([O-])([O-])=O.[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][CH:17]=[C:18]([C:31]4[CH:30]=[CH:29][C:28]([O:27][CH3:26])=[C:33]([O:34][CH3:35])[CH:32]=4)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2nn3c(I)cnc3s2)cc1OC
Reactant: COc1ccc(B(O)O)cc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2nn3c(-c4ccc(OC)c(OC)c4)cnc3s2)cc1OC
Temperature: 120 °C
Yield: 21.8 %

Procedure:
A mixture of 2-(3,4-dimethoxy-phenyl)-5-iodo-imidazo[2,1-b][1,3,4]thiadiazole (0.10 g, 0.3 mmol, 1 eq), dioxane (5 mL), 3,4-dimethoxyphenylboronic acid (0.12 g, 0.6 mmol, 2.5 eq), Pd(Ph3P)2Cl2 (0.018 g, 0.1 eq), K2CO3 (0.178 g, 1.3 mmol, 5 eq) and water (2 mL) was heated in the microwave oven (120° C., 30 min). The reaction mixture was concentrated, and the residue was purified by column chromatography (SiO2, cyclohexane/5-100% EtOAc). The obtained product was triturated with MeOH/Et2O to give the desired product (yellow solid, 0.026 g, 26%). HPLC-MS: (5-100% B in 10 min, 0.6 mL/min, 50° C.): tR=7.24 min, [M+H]+ m/z 398.1; 1H NMR (300 MHz, DMSO) δ/ppm 7.74 (s, 1H), 7.70 (d, J=2.0, 1H), 7.61 (dd, J=2.0, 8.4, 1H), 7.57-7.50 (m, 2H), 7.17 (d, J=8.2, 1H), 7.09 (d, J=8.5, 1H), 3.88 (s, 6H), 3.86 (s, 3H), 3.81 (s, 3H).