Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([CH3:9])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][N:30]=2)C=[CH:24]1.C(N(CC)CC)C>C(Cl)Cl>[C:1]1([S:7][C:9]2[C:26]3[C:31](=[N:30][CH:29]=[CH:28][CH:27]=3)[NH:23][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)c1ccccc1
Reactant: c1cnc2[nH]ccc2c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: c1ccc(Sc2c[nH]c3ncccc23)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl phenyl sulfoxide (8.33 g, 59.4 mmol) in CH2Cl2 is chilled to −78° C. and treated dropwise with trifluoroacetic anhydride (4.1 mL, 5.3 mmol). After stirring for 30 min at −78° C., a solution of 7-azaindole (5.2 g, 44.0 mmol) in CH2Cl2 is added. After 30 min at −78° C., triethylamine (74 mL, 534 mmol) is added and the reaction is allowed to reach ambient temperature. After stirring for 3.5 days, the reaction is concentrated in vacuo, treated with saturated aqueous NaHCO3 and extracted with CH2Cl2. The organic extracts are combined and concentrated in vacuo. The resultant residue is crystallized from methanol/H2O and recrystallized from CH2Cl2/hexane to afford the title compound as an off-white solid, 1.26 g, mp 188–189° C., characterized by mass spectral analyses and HNMR analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][OH:10])=[CH:4][CH:3]=1.[NH:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH2:13]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:13][NH:12][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9][OH:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)NN
Reactant: O=C(CO)c1ccc(Cl)cc1
Solvent: CCO
Product: CCOC(=O)NN=C(CO)c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
A mixture of the compound obtained in Step A (195 mmoles) and ethyl hydrazinecarboxylate (224 mmoles) in ethanol is stirred at reflux for 18 hours. The reaction mixture is cooled to 0° C. and the precipitate formed is filtered off, washed with ethyl ether and dried in vacuo to yield the title product, which is used directly in the next Step.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:46])[O:5][C:6]1[CH:7]=[C:8]([CH:20]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[O:29][C@@H:30]([CH3:45])[C@@H:31]([CH2:33][O:34][Si](C(C)C)(C(C)C)C(C)C)[N:32]=3)=[CH:26][CH:27]=2)[CH:22]=1)[O:9][C:10]1[CH:11]=[CH:12][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[N:14][CH:15]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH3:1][O:2][CH2:3][C@H:4]([CH3:46])[O:5][C:6]1[CH:22]=[C:21]([C:23]2[NH:24][C:25]([C:28]3[O:29][C@@H:30]([CH3:45])[C@@H:31]([CH2:33][OH:34])[N:32]=3)=[CH:26][CH:27]=2)[CH:20]=[C:8]([O:9][C:10]2[CH:15]=[N:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=2)[CH:7]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C3=N[C@H](CO[Si](C(C)C)(C(C)C)C(C)C)[C@H](C)O3)[nH]2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C3=N[C@H](CO)[C@H](C)O3)[nH]2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{5-[(4R,5S)-5-methyl-4-{[(triisopropylsilyl)oxy]methyl}-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)-2-(methylsulfonyl)pyridine (901 mg, 1.34 mmol) synthesized in Example (91c) was dissolved in tetrahydrofuran (15 mL), and tetrabutylammonium fluoride (1 mol/L tetrahydrofuran solution, 1.54 mL, 1.54 mmol) was added at 0° C., followed by stirring at room temperature for 1 hour under nitrogen atmosphere. Water (20 mL) was added, and extraction was carried out with ethyl acetate (40 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=80%-100%) to afford the desired compound (578 mg, yield 84%) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.[NH:21]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([C:4]2[C:3]([CH2:2][N:21]3[CH2:27][CH2:26][CH2:25][N:24]([CH2:2][C:3]4[C:4]([C:9]5[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=5)=[N:5][CH:6]=[CH:7][CH:8]=4)[CH2:23][CH2:22]3)=[CH:8][CH:7]=[CH:6][N:5]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: COc1cc(-c2ncccc2CCl)cc(OC)c1OC
Reactant: C1CNCCNC1
Product: COc1cc(-c2ncccc2CN2CCCN(Cc3cccnc3-c3cc(OC)c(OC)c(OC)c3)CC2)cc(OC)c1OC

Procedure:
3-Chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (311 mg) and homopiperazine (53 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([CH2:22][CH2:23][CH3:24])[C:8]3[O:15][C:14]([C:16]([O:18]CC)=[O:17])=[CH:13][C:12](=[O:21])[C:9]=3[CH:10]=2)[N:5]=[C:4]([C:25]([O:27]CC)=[O:26])[CH:3]=1.[NH2:30][C:31]([NH2:33])=[O:32].S(=O)(=O)(O)O>>[NH:30]([C:2]1[C:11]2[C:6](=[C:7]([CH2:22][CH2:23][CH3:24])[C:8]3[O:15][C:14]([C:16]([OH:18])=[O:17])=[CH:13][C:12](=[O:21])[C:9]=3[CH:10]=2)[N:5]=[C:4]([C:25]([OH:27])=[O:26])[CH:3]=1)[C:31]([NH2:33])=[O:32]
Reactant: CCCc1c2nc(C(=O)OCC)cc(Cl)c2cc2c(=O)cc(C(=O)OCC)oc12
Reactant: NC(N)=O
Agent: O=S(=O)(O)O
Product: CCCc1c2nc(C(=O)O)cc(NC(N)=O)c2cc2c(=O)cc(C(=O)O)oc12
Temperature: 0 °C
Yield: 16.3 %

Procedure:
Diethyl 6-chloro-4-oxo-10-propyl-4H-pyrano[3,2-g]quinoline-2,8-dicarboxylate (1 g) and urea (50 g) were fused together at 175° C. for 6 hours. The solid after cooling was added to 70% sulphuric acid (200 ml) and heated on a steambath for 8 hours. The mixture was poured into ice-water (2 liters) and the precipitate was collected and washed well with water to afford the sub-title compound (0.15 g): identified by NMR spectroscopy.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1.Cl.[NH2:16][OH:17]>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][C:11](=[N:16][OH:17])[CH2:10][CH2:9]1
Reactant: NO
Reactant: O=C1CCN(CCCCCCO)CC1
Agent: Cl
Product: OCCCCCCN1CCC(=NO)CC1

Procedure:
1-(6-Hydroxyhexyl)-4-piperidone oxime is prepared from 1-(6-hydroxyhexyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:47])[CH:4]([N:12]([S:33]([C:36]1[C:41]([CH3:42])=[CH:40][C:39]([O:43][CH3:44])=[C:38]([CH3:45])[C:37]=1[CH3:46])(=[O:35])=[O:34])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Sn](CCCC)(CCCC)CCCC)=[CH:16][CH:15]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:48][O:49][C:50]([C:52]1[S:53][C:54](Br)=[CH:55][CH:56]=1)=[O:51]>C1(C)C=CC=CC=1>[CH3:48][O:49][C:50]([C:52]1[S:53][C:54]([C:17]2[CH:18]=[CH:19][C:14]([CH2:13][N:12]([CH:4]([C:3]([O:2][CH3:1])=[O:47])[CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[S:33]([C:36]3[C:41]([CH3:42])=[CH:40][C:39]([O:43][CH3:44])=[C:38]([CH3:45])[C:37]=3[CH3:46])(=[O:35])=[O:34])=[CH:15][CH:16]=2)=[CH:55][CH:56]=1)=[O:51]
Reactant: COC(=O)c1ccc(Br)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(CN(C(Cc2ccccc2)C(=O)OC)S(=O)(=O)c2c(C)cc(OC)c(C)c2C)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccc(CN(C(Cc3ccccc3)C(=O)OC)S(=O)(=O)c3c(C)cc(OC)c(C)c3C)cc2)s1
Yield: 41 %

Procedure:
To a stirred solution of 2-[(4-Methoxy-2,3,6-trimethyl-benzenesulfonyl)-(4-tributylstannanyl-benzyl)-amino]-3-phenyl-propionic acid methyl ester (100 mg. 0.13 mmol.) in toluene (3 ml.) were added P(Ph3)4Pd (6 mg. 0.039eq.), CuBr (2 mg.) and 5-Bromo-thiophene-2-carboxylic acid methyl ester (26.5 mg, 0.12 mmol.) under nitrogen. The reaction mixture was stirred and heated to reflux during 5 hrs. The progress of the reaction was monitored by TLC. Filtration and removal of the solvent under reduced pressure on a rotary evaporator followed by silica plate for purification using 80% hexane 20% EtOAc afforded 5-(4-{[(1-Methoxycarbonyl-2-phenyl-ethyl)-(4-methoxy-2,3,6-trimethyl-benzenesulfonyl)-amino]-methyl}-phenyl)-thiophene-2-carboxylic acid methyl ester in 41% yield: 1HNMR (Varian 400 MHz, CDCl3) δ8.67(d, 1H, HPh), 8.35 (d, 2H, thiopheneH), 8.10(m, 6H, HPh), 8.00(d, 2H, thiopheneH), 7.38(s, 1H, MTRH), 5.72(m, 3H, NCH2Ph, CHCH2), 4.82(s, 3H, OCH3), 4.68(s, 3H, COOCH3), 4.29(s, 3H, COOCH3), 4.10 (m, 1H, CHCH2), 3.85 (m, 1H, CHCH2), 3.57(s, 3H, ArCH3), 3.40(s, 3H, ArCH3), 3.0(s, 3H, ArCH3) ppm. MS 622.6 (M+).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)[NH:8][CH:7]=1)=O)C.F[P-](F)(F)(F)(F)F.FC(N(C)C)=[N+:29](C)C.C(N(CC)C(C)C)(C)C.N>C(#N)C>[NH:13]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:19]2[C:11]([C:9]2[NH:8][CH:7]=[C:6]([C:4]([NH2:29])=[O:3])[CH:10]=2)=[N:12]1
Reactant: CCOC(=O)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Reactant: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-(1H-pyrazolo[3,4-b]pyridin-3-yl)-1H-pyrrole-3-carboxylic acid (80 mg, 0.35 mmol) (from Example 11) and fluoro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (92.7 mg, 0.35 mmol) (Aldrich, Milwaukee, Wis.) in acetonitrile (6 mL) at 0° C. was added N,N-diisopropylethylamine (DIPEA) (54.28 mg, 0.42 mmol). The mixture was allowed to warm up to room temperature and stirred for one hour. The mixture was then cooled in an ice-bath and charged with ammonia gas. After stirring at room temperature for overnight, the reaction was concentrated, diluted with water and extracted with DCM. The organic layer was concentrated and triturated with DCM to give the titled compound.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.O.[NH2:14][NH2:15]>O1CCCC1>[NH:14]([C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1)[NH2:15]
Reactant: NN
Reactant: CCOC(=O)c1sc(Br)nc1C
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(NN)nc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 137.4 %

Procedure:
A To a stirred solution of ethyl 2-bromo-4-methylthiazole-5-carboxylate (10.00 g, 40.00 mmol) in tetrahydrofuran (125 mL), was added hydrazine monohydrate (6.01 g, 120.0 mmol). The reaction mixture was stirred at ambient temperature for 18 hours, concentrated in vacuo to dryness. The residue was purified by column chromatography to afford ethyl 2-hydrazinyl-4-methylthiazole-5-carboxylate as a white solid (11.06 g, 91%): 1H NMR (300 MHz, DMSO-d6) δ 5.02 (s, 2H), 4.13 (q, J=6.0 Hz, 2H), 2.33 (s, 3H), 1.18 (t, J=6.0 Hz, 3H); MS (ES+) m/z 202.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][NH:10][C@@H:11]2[C:20]3[N:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14][CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:21][O:22][C:23](=[O:34])[C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=1[CH2:32]Br.CCN(C(C)C)C(C)C>CC#N>[CH3:21][O:22][C:23](=[O:34])[C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=1[CH2:32][N:10]([CH2:9][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=1)[CH:11]1[C:20]2[N:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:14][CH2:13][CH2:12]1
Reactant: Cc1cnc(CN[C@H]2CCCc3cccnc32)c(C)c1
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1cc(C#N)ccc1CN(Cc1ncc(C)cc1C)C1CCCc2cccnc21

Procedure:
Using General Procedure A: Reaction of (S)-(3,5-dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine in CH3CN with 2-Bromomethyl-5-cyano-benzoic acid methyl ester, DIPEA and KI gave 5-cyano-2-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8yl)-amino]-methyl}-benzoic acid methyl ester as a red oil. 1H NMR (CDCl3) δ 1.76 (m, 1H), 2.06 (m, 2H), 2.16 (s, 3H), 2.27 (s, 3H), 2.28 (m, 1H), 2.75 (m, 2H), 3.86 (m, 2H), 3.90 (s, 3H), 4.15 (m, 1H), 4.29 (m, 2H), 6.99 (d, 2H, J=15.8 Hz), 7.35 (d, 1H, J=6.6 Hz), 7.46 (d, 1H, J=7.9 Hz), 7.88 (s, 1H), 8.01 (s, 2H), 8.51 (s, 1H).
Reaction SMILES: [CH2:1]1[N:5]2[C:6]3[C:11]([NH:12][C:13](=O)[C@@H:4]2[CH2:3][CH2:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O>O1CCCC1>[CH2:1]1[N:5]2[C:6]3[C:11]([NH:12][CH2:13][C@@H:4]2[CH2:3][CH2:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: O=C1Nc2ccccc2N2CCC[C@@H]12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: c1ccc2c(c1)NC[C@@H]1CCCN21
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.7 %

Procedure:
A solution of 1.04 g of (3aS)-1,2,3,3a,4,5-hexahydro-pyrrolo[1,2-a]quinoxalin-4-one prepared in Reference Example 9 in 30 ml of anhydrous tetrahydrofuran was dropwise added, with ice-cooling, to a suspension of 0.53 g of lithium aluminum hydride in 30 ml of anhydrous tetrahydrofuran over 30 minutes. After the dropwise addition, the mixture was refluxed with heating for 2 hours. The reaction solution was ice-cooled, then 100 ml of ethyl acetate was gradually added thereto and the mixture was further stirred at room temperature for 15 hours. Water was added to the reaction liquid and the separated insolubles were filtered off through a Celite layer. The resulting organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated. The resulting residue was subjected to silica gel column chromatography treatment and eluted with chloroform/ethyl acetate (99/1) to give 0.95 g (yield 98.1%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:14])[CH:8]=2)[N:3]=1.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].N1C=CC=CC=1>ClCCl>[CH3:13][O:12][C:11]1[C:2]([NH:1][C:16](=[O:17])[O:18][CH2:19][CH3:20])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([CH3:14])=[CH:6][CH:5]=2
Reactant: CCOC(=O)Cl
Reactant: COc1nc2cc(C)ccc2nc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.1 %

Procedure:
2-Amino-3-methoxy-6-methylquinoxaline (1.15 g, 6.08 mmol) and ethyl chloroformate (1.32 g, 12.2 mmol) were dissolved in dichloromethane (30 ml) at room temperature and thereto pyridine (0.96 g, 12.2 mmol) was added. The resulting mixture was stirred at room temperature for 24 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (3:1) mixture and concentration gave 1.59 g of the titled compound (yield, 100%).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[CH3:18][S:19]([CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27](OC)=[O:28])=[CH:25][CH:24]=1)(=[O:21])=[O:20].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C(OCC)(=O)C.O.CO>[CH3:18][S:19]([CH2:22][C:23]1[CH:32]=[CH:31][C:26]([CH2:27][OH:28])=[CH:25][CH:24]=1)(=[O:20])=[O:21]
Reactant: COC(=O)c1ccc(CS(C)(=O)=O)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: CS(=O)(=O)Cc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.2 %

Procedure:
A 1.0 M solution of diisobutylaluminum hydride in toluene (44 mL, 44 mmol) was added slowly drop-wise to a 0° C. solution of methyl 4-(methanesulfonylmethyl)benzoate (4.00 g, 17.5 mmol) and toluene (220 mL). After the addition was complete, the reaction mixture was warmed to room temperature, then stirred at room temperature for 16 hours. After this time, thin-layer chromatography indicated some starting material to remain. The reaction mixture was cooled to 0° C., then additional 1.0 M diisobutylaluminum hydride in toluene (44 mL, 44 mmol) was added slowly drop-wise to the cold reaction mixture. The reaction mixture was warmed to room temperature, and then stirred for 20 minutes. The reaction mixture was again cooled to 0° C. Ethyl acetate (50 mL) was added followed by methanol (1 mL). The reaction mixture was allowed to stand for 6 minutes at 0° C., during which time the mixture became cloudy and thick. A saturated aqueous solution of sodium potassium tartrate was added, and the heterogeneous mixture was warmed to room temperature. Water and additional ethyl acetate (50 mL) were added. The organic phase was separated, dried over MgSO4, filtered, and concentrated to give 2.18 g (62%) of (4-methane-sulfonylmethyl-phenyl)-methanol as a white solid.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[CH:9]12[CH2:16][C:15](=O)[CH2:14][CH:13]1[CH2:12][C:11](=O)[CH2:10]2>>[OH:7][C:4]1[CH:5]=[CH:6][C:1]([C:11]2([C:1]3[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=3)[CH2:12][CH:13]3[CH:9]([CH2:16][C:15]([C:1]4[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=4)([C:1]4[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=4)[CH2:14]3)[CH2:10]2)=[CH:2][CH:3]=1
Reactant: O=C1CCC(=O)CC1
Reactant: O=C1CC2CC(=O)CC2C1
Product: Oc1ccc(C2(c3ccc(O)cc3)CC3CC(c4ccc(O)cc4)(c4ccc(O)cc4)CC3C2)cc1

Procedure:
Compound [I-c] was synthesized in the same manner as in Synthesis Example (5) except that 1,4-cyclohexanedione was replaced by 27.6 g (0.2 mole) of bicyclo[3.3.0]octane-3,7-dione (m.p. 85° C.).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[CH:9][N:8]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:13])[C:6]=2[N:7]=1.[CH2:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][N:21]1[CH2:30][CH:31]([OH:49])[CH2:32][NH:33][C:34]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[CH:36][N:35]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][N:21]1[CH2:30][CH:31]([OH:49])[CH2:32][NH:33][C:34]1[CH:39]=[C:38]([C:2]2[N:3]=[CH:4][C:5]3[CH:10]=[CH:9][N:8]([CH2:11][C:12]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)=[O:13])[C:6]=3[N:7]=2)[CH:37]=[CH:36][N:35]=1
Reactant: O=C(Cn1ccc2cnc(Cl)nc21)N1CCOCC1
Reactant: CC1(C)OB(c2ccnc(NCC(O)CN3CCc4ccccc4C3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(Cn1ccc2cnc(-c3ccnc(NCC(O)CN4CCc5ccccc5C4)c3)nc21)N1CCOCC1
Temperature: 100 °C
Yield: 50.5 %

Procedure:
To a solution of 2-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-morpholinoethanone (60 mg, 0.268 mmol) in dioxane/H2O (10 mL) was added 1-(3,4-dihydroisoquinolin-2(1H)-yl)-3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)amino)propan-2-ol (120.5 mg, 0.15 mmol), Pd(dppf)Cl2 (10 mg) and K2CO3 (72.86 mg, 0.15 mmol). The reaction mixture was heated at 100° C. under microwave conditions for 40 min. The mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water and the organic layer dried concentrated and the residue purified by pre-HPLC to give the desired compound (40 mg, Yield 29%). 1H NMR (400 MHz, MeOD) δ 9.01 (s, 1H), 8.07 (d, J=5.2 Hz, 1H), 7.61 (s, 1H), 7.57 (d, J=5.2 Hz, 1H), 7.50 (s, 1H), 7.09-7.02 (m, 4H), 6.72 (s, 1H), 5.31 (s, 1H), 4.13 (br.s, 1H), 3.77-3.40 (m, 12H), 2.91-2.85 (m, 4H), 2.74-2.62 (m, 2H). LCMS (m/z): 528.2 (M+1).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)=O.[N:13]#[C:14][C:15]#[N:16].CN(C)C1C=CC=CC=1>CN(C)C=O>[C:14]([C:15]1[NH:2][CH:3]=[C:4]([C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=2)[N:16]=1)#[N:13]
Reactant: Cc1ccc(C(=O)CN)cc1
Reactant: N#CC#N
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN(C)c1ccccc1
Product: Cc1ccc(-c2c[nH]c(C#N)n2)cc1
Temperature: 100 °C
Yield: 70 %

Procedure:
15 g (81 mmol) of 2-amino-4'-methylacetophenone hydrochloride was measured out in a 200-ml four-necked flask. To the material was then added 121 ml (121 mmol) of a 1 mol/l N,N-dimethylformamide solution of cyanogen. The mixture was then stirred. To the mixture was then added 29.4 g (243 mmol) of N,N-dimethylaniline. The mixture was then heated at a temperature of 100° C. with stirring for 3 hours. N,N-dimethylaniline was then distilled off from the reaction mixture under a pressure of 30 mmHg. The reaction mixture was then allowed to cool to room temperature. 200 ml of water was then poured into the reaction mixture. The reaction mixture was acidified with hydrochloric acid, and a precipitate was recovered by filtration. The filtration residue was dissolved in 200 ml of a 5% aqueous solution of sodium hydroxide, and the solution was filtered. The filtrate was then acidified with hydrochloric acid. 2-Cyano-4-(p-tolyl)imidazole as a desired compound was then recovered by filtration. The material was then dried to obtain 12.43 g of a desired compound with a purity of 83.4% (yield: 70.0%).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([C:20]1[N:25]=[CH:24][C:23](Br)=[CH:22][N:21]=1)[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[F:19].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].[NH:63]1[CH2:68][CH2:67][CH:66]([C:69]([O:71][CH2:72][CH3:73])=[O:70])[CH2:65][CH2:64]1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[NH:63]1[CH2:68][CH2:67][CH:66]([C:69]([O:71][CH:72]([C:23]2[CH:22]=[N:21][C:20]([N:7]([CH2:6][C:5]3[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=[C:3]([C:2]([F:35])([F:34])[F:1])[CH:4]=3)[CH2:8][C:9]3[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=[CH:11][C:10]=3[F:19])=[N:25][CH:24]=2)[CH3:73])=[O:70])[CH2:65][CH2:64]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Fc1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(OC(=O)C1CCNCC1)c1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2F)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-(2-fluoro-5-trifluoromethyl-benzyl)-amine (300 mg) is dissolved in toluene (5 ml) and thereto are added tris(dibenzylideneacetone)dipalladium (48 mg), 2-(di-tert-butylphosphino)biphenyl (62 mg), sodium tert-butoxide (75 mg) and ethyl piperidine-4-carboxylate (120 μl) and the mixture is stirred under nitrogen atmosphere at room temperature overnight. To the reaction solution are added a saturated aqueous sodium bicarbonate solution and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane:ethyl acetate=19:1→9:1) to give 1-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-fluoro-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yl}-ethyl piperidine-4-carboxylate (111 mg). MS (m/z): 653 [M+H]+
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5](B(O)O)[C:4]=2[CH:3]=[CH:2]1.Br[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH:1]1[C:9]2[C:4](=[C:5]([C:14]3[CH:15]=[C:16]([NH2:17])[CH:18]=[CH:19][CH:20]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Nc1cccc(Br)c1
Reactant: OB(O)c1cccc2[nH]ccc12
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Nc1cccc(-c2cccc3[nH]ccc23)c1
Temperature: 25 °C
Yield: 78 %

Procedure:
Indole-4-boronic acid (0.140 g, 0.872 mmol) and 3-bromoaniline (0.063 mL, 0.581 mmol) were combined in dioxane (2 mL) in a flame-dried, round-bottom flask. K3PO4 (1.27M, 0.778 mL, 0.99 mmol), PCy3 (0.004 g, 0.014 mmol), and Pd2(dba)3 (0.005 g, 0.006 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash silica column chromatography (5-60% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.094 g in 78% yield.