Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]COCC.[CH3:6][N:7]([CH3:21])[C:8]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:6][N:7]([CH3:21])[C:8]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][C:11](=[CH2:1])[CH2:10][CH2:9]1
Reactant: CCOCC
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CCC(c2ccccc2)(N(C)C)CC1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Tert-BuOK (0.550 g, 4.74 mmol) was provided in abs. ether (10 mL) in argon and methyl triphenyl phosphonium bromide (1.89 g, 4.74 mmol) added. The mixture was then heated to 40° C. for 30 min. After this reaction time 4-dimethylamino-4-phenylcyclohexanone (1.00 g, 4.60 mmol) dissolved in abs. THF (10 mL) was carefully added in drops and the reaction solution was heated to 50° C. for 5 h. The reaction batch was stirred overnight at room temperature and concentrated in a vacuum until dry. The residue was taken up in dioxan (50 mL) and mixed with HCl/dioxan (5 mL). The precipitated solid was aspirated and washed with ether. The isolated hydrochloride was basified with 2 N NaOH and extracted with dichloromethane (2×80 mL). The organic phase was dried over Na2SO4, filtered and concentrated to low volume in a vacuum.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([Cl:38])[C:7]([NH:25][C@@H:26]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]2)=[C:13]([CH3:24])[CH:12]=1)(=[O:3])[NH2:2].[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl>[C:1]([C:4]1[N:5]=[C:6]([Cl:38])[C:7]([NH:25][C@@H:26]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:27]2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][CH:20]([N:43]3[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]3)[CH2:19][CH2:18]2)=[C:13]([CH3:24])[CH:12]=1)(=[O:3])[NH2:2]
Reactant: CN1CCNCC1
Reactant: Cc1cc(Nc2nc(N[C@@H]3CCN(C(=O)OC(C)(C)C)C3)c(Cl)nc2C(N)=O)ccc1N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: Cc1cc(Nc2nc(N[C@@H]3CCN(C(=O)OC(C)(C)C)C3)c(Cl)nc2C(N)=O)ccc1N1CCC(N2CCN(C)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of tert-butyl (3R)-3-[(5-carbamoyl-3-chloro-6-{[3-methyl-4-(4-oxopiperidin-1-yl)phenyl]amino}pyrazin-2-yl)amino]pyrrolidine-1-carboxylate (578 mg), 1-methylpiperazine (175 μL), and 1,2-dichloroethane (8.67 mL) was added sodium triacetoxyborohydride (338 mg), followed by stirring at room temperature for 3 hours. To the reactant was added 1-methylpiperazine (82 μL), followed by stirring at room temperature for 4 hours. To the reactant were added chloroform and a saturated aqueous sodium hydrogen carbonate solution, and followed by liquid separation. The organic phase was dried over anhydrous magnesium sulfate and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-300:10:1) to obtain tert-butyl (3R)-3-{[5-carbamoyl-3-chloro-6-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazin-2-yl]amino}pyrrolidine-1-carboxylate (560 mg) as a yellow amorphous substance.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:4]([CH3:20])([CH3:19])[CH2:3]1.Cl[P:22]1[N:26]([CH3:27])[CH2:25][CH2:24][N:23]1[CH3:28]>>[CH3:28][N:23]1[CH2:24][CH2:25][N:26]([CH3:27])[P:22]1[O:1][CH:2]1[CH2:7][C:6]([CH3:8])([CH3:9])[N:5]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:4]([CH3:19])([CH3:20])[CH2:3]1
Reactant: CCCCCCCCON1C(C)(C)CC(O)CC1(C)C
Reactant: CN1CCN(C)P1Cl
Product: CCCCCCCCON1C(C)(C)CC(OP2N(C)CCN2C)CC1(C)C

Procedure:
The title compound is prepared from 4-hydroxy-1-octyloxy-2, 2,6,6-tetramethylpiperidine and 2-chloro-1,3-dimethyl-1,3,2-diazaphospholidine according to the procedure of Example 6.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9](=O)[CH3:10].[NH2:12][C:13]([NH2:15])=[S:14]>>[NH2:15][C:13]1[S:14][CH:10]=[C:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[N:12]=1
Reactant: CC(=O)c1cc(F)ccc1F
Reactant: NC(N)=S
Product: Nc1nc(-c2cc(F)ccc2F)cs1
Yield: 77.8 %

Procedure:
Using 2′,5′-difluoroacetophenone and thiourea as the raw materials, the same operation as the Example 395(1) gave the title compound.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]([OH:14])=[C:8]([C:11](=[O:13])[CH3:12])[C:9]=1[OH:10])(=O)[CH3:2].[OH:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>CO>[C:11]([C:8]1[C:7](=[O:14])[O:6][C:5](=[O:15])[C:4](=[C:1]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[OH:16])[CH3:2])[C:9]=1[OH:10])(=[O:13])[CH3:12]
Reactant: Nc1ccccc1O
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Solvent: CO
Product: CC(=O)C1=C(O)C(=C(C)Nc2ccccc2O)C(=O)OC1=O

Procedure:
To a boiling solution of 4.24 g. (0.02 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 200 ml. of methanol is added 2.18 g. (0.02 m.) of o-hydroxyaniline. The resulting mixture is refluxed overnight and filtered to yield 5-acetyl-4-hydroxy-3-[1-(o-hydroxyphenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 210° -212° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[O:6][CH2:7][C:8]#[N:9].[NH:15]([C:17]([C@@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=O)[NH2:16].C([O-])([O-])=O.[K+].[K+]>C(O)CCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[O:6][CH2:7][C:8]1[NH:9][C:17]([C@@H:19]2[CH2:23][CH2:22][CH2:21][N:20]2[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:15][N:16]=1
Reactant: COc1ccc(OCC#N)cc1OC
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: COc1ccc(OCc2nnc([C@@H]3CCCN3C(=O)OC(C)(C)C)[nH]2)cc1OC
Temperature: 160 °C
Yield: 31.9 %

Procedure:
To a n-butanol (10 ml) solution of 2-(3,4-dimethoxyphenoxy)acetonitrile (1.26 g) and (S)-t-butyl 2-(hydrazinecarbonyl)pyrrolidine-1-carboxylate (500 mg), K2CO3 (150 mg) was added. The resulting mixture was stirred at 160° C. for an hour under microwave irradiation. After distilling off the solvent under reduced pressure, water was added, followed by extraction with ethyl acetate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography and NH-form silica gel chromatography to give the titled compound (281 mg).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCC)C.[CH3:37][Si:38]([C:41]#[CH:42])([CH3:40])[CH3:39]>[Cu](I)I.CN(C=O)C>[CH3:12][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:42]#[C:41][Si:38]([CH3:40])([CH3:39])[CH3:37])=[CH:3][CH:4]=2)[N:9]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccc2ccc(Br)cc2n1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: Cc1ccc2ccc(C#C[Si](C)(C)C)cc2n1
Temperature: 110 °C
Yield: 80.8 %

Procedure:
In a sealed tube were introduced 7-bromo-2-methyl-quinoline (500 mg, 2.25 mmol, 1.0 eq), PdCl2(PPh3)3 (79 mg, 0.11 mmol, 5% mol), copper iodide (21 mg, 0.11 mmol, 5% mol), and triphenylphosphine (106 mg, 0.39 mmol, 20% mol). Then, DMF (5 mL) was added followed by diethylamine (3.5 mL, 34 mmol, 15 eq) and trimethylsilylacetylene (350 μL, 2.5 mmol, 1.1 eq). The mixture was heated at 110° C. overnight. After cooling down the solvent was evaporated and the crude product was purified by column chromatography (Florisil, Cyclohexane-EtOAc 95:5) to afford 2-methyl-7-trimethylsilanylethynyl-quinoline as a white solid (435 mg, 81%).
Reaction SMILES: [Br:1]Br.[OH:3][C:4]([CH3:30])([CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][CH:17]=1)[CH2:5][C:6]([O:8]CC)=[O:7].[OH-].[Na+]>C(O)C>[OH:3][C:4]1([CH3:30])[CH:11]([Br:1])[CH:12]([CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:18][CH:17]=2)[O:8][C:6](=[O:7])[CH2:5]1
Reactant: CCOC(=O)CC(C)(O)C=CCCCc1ccc(OCc2ccccc2)cc1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(O)CC(=O)OC(CCCc2ccc(OCc3ccccc3)cc2)C1Br

Procedure:
According to the method described in Example 25 (b), the reaction was carried out by using 0.13 ml of bromine and 0.74 g of the carboxylic acid which was prepared from 0.80 g of ethyl 3-hydroxy-3-methyl-8-(p-benzyloxyphenyl)-4-octenoate, 8 ml of ethanol and 1 ml of 4 N sodium hydroxide, and the product was recrystallized from ethyl ether to give 0.32 g of the desired compound melting at 100°-101° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[O:38]1[CH2:42][CH2:41][O:40][CH:39]1[CH2:43][NH:44][CH3:45]>>[O:38]1[CH2:42][CH2:41][O:40][CH:39]1[CH2:43][N:44]([CH3:45])[C:21]1[N:20]=[C:19]([O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:29]=[C:30]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[CH:31]=[C:2]([F:1])[CH:3]=3)=[CH:9][CH:10]=2)[CH:24]=[CH:23][N:22]=1
Reactant: CNCC1OCCO1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: CN(CC1OCCO1)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and [1,3]dioxolan-2-ylmethyl-methylamine according to conditions described in general procedure C. Mp: 111-112° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.75-3.96 (m, 8 H), 3.27 (m, 4 H), 3.80 (m, 4H), 4.75-5.0 (m, 2 H), 6.27 (d, J=5.1Hz, 1 H), 7.05 (d, J=12.5 Hz, 1 H), 7.28 (d, J=8.8 Hz, 1 H), 7.42-7.62 (m, 5 H), 7.84 (d, J=7.7 Hz, 1 H), 7.99-8.01 (m, 1 H), 8.28 (d, J=5.5 Hz, 1 H), 10.47 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:19])[N:4]([CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:5]=[CH:6][C:7]=1Cl.[CH2:20]([NH2:23])[CH2:21][CH3:22]>>[Cl:1][C:2]1[C:3](=[O:19])[N:4]([CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:5]=[CH:6][C:7]=1[NH:23][CH2:20][CH2:21][CH3:22]
Reactant: CC1(C)CC(n2ncc(Cl)c(Cl)c2=O)CC(C)(C)C1
Reactant: CCCN
Product: CCCNc1cnn(C2CC(C)(C)CC(C)(C)C2)c(=O)c1Cl

Procedure:
4-Chloro-5-n-propylamino-2-(3,3,5,5-tetramethylcyclohexyl)pyridazin-3-one was prepared from 4,5-Dichloro-2-(3,3,5,5-tetramethylcyclohexyl)pyridazin-3-one in a similar manner using n-propylamine (4 equivalents). 1H NMR (300 MHz CDCl3) 7.6 (s, 1H), 5.3 (m, 1H), 4.65 (brs, 1H), 3.5 (q, 2H, J=7 Hz), 1.72 (q, 2H, J=7 Hz), 1.55 (m, 4H), 1.3 (m, 1H), 1.15 (m, 1H), 1.15 (s, 6H), 1.04 (t, 3H, J=7 Hz), 0.95 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[CH:26]=[N:25][CH:24]=[CH:23][N:22]=2)=[N:10]1.C1C(=O)N([Br:34])C(=O)C1>>[Br:34][CH2:20][C:13]1[NH:12][C:11]([C:21]2[CH:26]=[N:25][CH:24]=[CH:23][N:22]=2)=[N:10][CH:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Cl:1])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C1=C(C)NC(c2cnccn2)=NC1c1ccc(F)cc1Cl
Product: CCOC(=O)C1=C(CBr)NC(c2cnccn2)=NC1c1ccc(F)cc1Cl
Yield: 65 %

Procedure:
Ethyl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(pyrazin-2-yl)-1,4-dihydropyrimidine-5-carboxylate (5.02 g, 13.4 mmol) was reacted with NBS (2.87 g, 16.1 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (3.95 g, 65%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@:5]1([CH3:9])[CH2:8][CH2:7][NH:6]1)=[O:4].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH3:1][O:2][C:3]([C@@:5]1([CH3:9])[CH2:8][CH2:7][N:6]1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: COC(=O)[C@@]1(C)CCN1
Solvent: C1CCOC1
Product: COC(=O)[C@@]1(C)CCN1Cc1ccccc1
Temperature: 50 °C

Procedure:
To a solution of (R)-2-methyl-azetidine-2-carboxylic acid methyl ester (1 eq.) in THF were added TEA (2 eq.) and benzyl bromide (1 eq.). The reaction was heated at 50° C. for 15 h. The solvent was concentrated under reduced pressure, the crude was purified by chromatography on silica gel (elution with heptane/EtOAc 1/0 to 1/1) to afford (R)-1-benzyl-2-methyl-azetidine-2-carboxylic acid methyl ester.
Reaction SMILES: [CH2:1]([C@@:8]1([OH:32])[C@H:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:11]([CH2:21][OH:22])[O:10][C@H:9]1[N:23]1[CH:30]=[C:29]([Br:31])[C:27](=[O:28])[NH:26][C:24]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:33][CH:34]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:35](O)=[O:36].CN(C)C=O.C1(N=C=NC2CCCCC2)CCCCC1>C1CCCCC1>[SH:33][CH:34]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:35]([O:22][CH2:21][C@H:11]1[O:10][C@@H:9]([N:23]2[CH:30]=[C:29]([Br:31])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[C@:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([OH:32])[C@@H:12]1[O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:36]
Reactant: CCCCCCCCCCCCCCCCC(S)C(=O)O
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](OCc3ccccc3)[C@]2(O)Cc2ccccc2)cc1Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCCCC1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCC(S)C(=O)OC[C@H]1O[C@@H](n2cc(Br)c(=O)[nH]c2=O)[C@@](O)(Cc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
10 mmol of 2',3'-O-dibenzyl-5-bromouridine and 20 mmol of 2-mercaptostearic acid were added to 400 ml of dimethylformamide containing 40 ml of N,N'-dicyclohexylcarbodiimide, and the mixture was stirred for 3 hours. The resulting reaction mixture was then concentrted at 0.2 atm. at a temperature of 60° C. 200 ml of cyclohexane was added to the residue, and the mixture was heated at a temperature of 80° C for 2 hours while refluxing. The reaction mixture was filtered to recover the residue, and the residue was washed three times with cyclohexane. The resulting residue was then added to 100 ml of dimethylformamide followed by heating at a temperature of 80° C to dissolve the residue. The solution was allowed to cool to room temperature and 100 ml of water was added to the solution. The white precipitate formed was collected by filtration and air-dried to obtain 5.6 mmol (56% yield) of 5'-O-(2-mercaptostearoyl)-2',3' -O-dibenzyl-5-bromouridine as a white powder.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5](=[O:11])[N:6]([CH:8]([CH3:10])[CH3:9])[CH:7]=1.[CH:12]([C:14]1[S:18][C:17](B(O)O)=[CH:16][CH:15]=1)=[O:13].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH:8]([N:6]1[C:5](=[O:11])[CH:4]=[CH:3][C:2]([C:17]2[S:18][C:14]([CH:12]=[O:13])=[CH:15][CH:16]=2)=[CH:7]1)([CH3:10])[CH3:9]
Reactant: O=Cc1ccc(B(O)O)s1
Reactant: CC(C)n1cc(I)ccc1=O
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: Cc1ccccc1
Solvent: CCO
Product: CC(C)n1cc(-c2ccc(C=O)s2)ccc1=O
Temperature: 100 °C
Yield: 53.5 %

Procedure:
To a stirred solution of 5-iodo-1-isopropylpyridin-2(1H)-one (0.41 g, 1.55 mmol) in toluene (5 mL) and ethanol (2 mL) was added 5-formylthiophen-2-yl boronic acid (0.289 g, 1.87 mmol), 2M Na2CO3 (0.495 g, 4.67 mmol), and Pd(PPh3)4 (0.09 g, 0.07 mmol). The mixture was purged with argon and heated at 100° C. for about 2 h. The mixture was concentrated, diluted with water (50 mL), and extracted with ethyl acetate (2×200 mL). The combined organic extracts were washed with brine solution (20 mL), dried over Na2SO4 and concentrated under vacuum to obtain crude product. The crude product was purified by flash chromatography (silica gel, 60-120μ) using 20% ethyl acetate in hexane as eluent to afford 5-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-carbaldehyde as an off-white solid (0.205 g, 53.3% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.18 (s, 1H), 7.99 (d, 1H), 7.78 (d, 1H), 7.62 (d, 1H), 7.58 (d, 1H), 7.53 (d, 1H), 5.08-5.01 (m, 1H), 1.21 (t, 6H), LC-MS m/z calcd for [M+H]+ 248.07. found 248.1.
Reaction SMILES: [CH:1]1([CH2:11][C:12]([OH:14])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[OH-].[Na+].[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[S:27](Cl)(=[O:29])=[O:28]>O1CCOCC1.O>[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[S:27]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]1[CH2:11][C:12]([OH:14])=[O:13])(=[O:28])=[O:29]
Reactant: O=C(O)CC1NCCc2ccccc21
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CC1c2ccccc2CCN1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.91 g of (1,2,3,4-tetrahydro-1-isoquinolyl)acetic acid (Preparation 2.18) are suspended in 25 ml of dioxane, 10 ml of 1N NaOH are added, followed by portionwise addition of 2.3 g of 2-naphthalenesulphonyl chloride, and the mixture is maintained at pH=10.5-12 by addition of 1N NaOH. The mixture is kept stirring as a constant pH for 2 hours at RT. The reaction medium is diluted with 100 ml of water and is then washed twice with EtOAc and brought to pH=1.2 by addition of 6N HCl in the presence of EtOAc. This mixture is extracted with EtOAc, washed with saturated NaCl solution, dried over Na2SO4 and evaporated to dryness. The expected product crystallizes from heptane, and is drained, washed with heptane and then dried to give 3.14 g, m.p=132° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:17]([O:19]C)=O)[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:21])[O:4][N:3]=1.[CH:22]1([Mg]Cl)[CH2:26][CH2:25][CH2:24][CH2:23]1>C1COCC1>[CH:22]1([C:17]([C:9]2[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=[C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:21])[CH:8]=2)=[O:19])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Cl[Mg]C1CCCC1
Reactant: COC(=O)c1cc(-c2c(C)noc2C)cc2[nH]c(=O)[nH]c12
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1cc(C(=O)C2CCCC2)c2[nH]c(=O)[nH]c2c1

Procedure:
To a mixture containing methyl 6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate (60 mg, 0.21 mmol, 1 equiv.) and THF (3 mL) is added cyclopentyl magnesium chloride (0.88 mL, 1.46 mmol, 7 equiv.) at 0° C. for 5 min. After completion, the reaction was quenched and extracted with EtOAc and washed with water, saturated NH4Cl. After drying with MgSO4, it was filtered and concentrated to dryness. Purification was carried out by reverse phase HPLC.
Reaction SMILES: S([O:6][CH3:7])(OC)(=O)=O.[CH:8]1[C:13](O)=[CH:12][CH:11]=[C:10]([Br:15])[CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[Br:15][C:10]1[CH:11]=[CH:12][C:13]([O:6][CH3:7])=[CH:8][CH:9]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(Br)cc1

Procedure:
25 g (0.20 mol) of dimethyl sulphate are run over the course of 45 minutes into a refluxing suspension of 34.4 g (0.20 mol) of p-bromophenol and 27.5 g (0.20 mol) of potassium carbonate in 150 ml of acetone. The reflux is maintained for a further hour, the inorganic salts are removed by filtration and the filtrate is evaporated to dryness under reduced pressure. The residue is dissolved in diethyl ether, the ether solution is washed with dilute sodium hydroxide solution and water and is dried over dry sodium sulphate, and the solvent is evaporated to give 37.2 g of a slightly yellow oil which is insoluble in water.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])(C)(C)C.C(O[C:23](=[O:40])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[C:37]([NH2:39])[N:36]=[CH:35][N:34]=2)[CH:28]=1)=O)(C)(C)C>>[NH2:39][C:37]1[N:36]=[CH:35][N:34]=[C:33]([C:29]2[CH:28]=[C:27]([C:25]3[CH2:24][C:23](=[O:40])[NH:16][C:9]4[CH:10]=[C:11]([Cl:15])[C:12]([CH3:14])=[CH:13][C:8]=4[N:7]=3)[CH:32]=[CH:31][CH:30]=2)[CH:38]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cc(N)ncn2)c1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: Cc1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3cc(N)ncn3)c1)=N2

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (103 mg, 0.4 mmol) and 3-[3-(6-amino-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K53) (138 mg, 0.44 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (126 mg).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].Br[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)=[O:9].[ClH:23]>CC(O)C>[ClH:23].[O:16]([C:13]1[CH:12]=[CH:11][C:10]([C:8](=[O:9])[CH2:7][NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:15][CH:14]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(CBr)c1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)N
Agent: Cl
Solvent: CC(C)O
Product: CC(C)(C)NCC(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Tert-butylamine (15 ml) was added with stirring to a solution of 2-bromo-4′-phenoxyacetophenone (12.7 g, prepared by bromination of 4′-phenoxyacetophenone according to Tetrahedron Letters, 1993, 34, 3177) in propan-2-ol and the mixture heated at 80° C. for 3 hours. The mixture was cooled to 0C and concentrated hydrochloric acid (10 ml) added. The suspension was stirred at ambient temperature for 18 hours and the solid collected by filtration to give 4′-phenoxy-2-(tert-butylamino)acetophenone hydrochloride (3.75 g), m.p. 210-212° C.
Reaction SMILES: [CH3:1][C:2]([S:5](/[N:7]=[CH:8]/[C:9]1[CH:10]=[N:11][NH:12][C:13]=1[CH3:14])=[O:6])([CH3:4])[CH3:3].[CH3:15][Mg+].[Br-]>C1COCC1>[CH3:4][C:2]([S:5]([NH:7][CH:8]([C:9]1[CH:10]=[N:11][NH:12][C:13]=1[CH3:14])[CH3:15])=[O:6])([CH3:1])[CH3:3]
Reactant: C[Mg+]
Reactant: Cc1[nH]ncc1/C=N/S(=O)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1[nH]ncc1C(C)NS(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (E)-2-methyl-N-((5-methyl-1H-pyrazol-4-yl)methylene)propane-2-sulfinamide (Step A9B) (2.1 g, 9.29 mmol) in THF (45 ml) was added a 1M solution of MeMgBr in THF (27.9 ml, 27.9 mmol) at −48° C. under nitrogen. After being stirred for 60 min, the reaction mixture was allowed to warm to rt and then heated at 90° C. for 4 hours.