Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]I.[CH:3]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([CH:13]=[O:14])[C:7]=2[CH:6]=[CH:5][N:4]=1>CCOCC>[CH:3]1[C:12]2[C:7](=[C:8]([CH:13]([OH:14])[CH3:1])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: CI
Reactant: O=Cc1cccc2cnccc12
Solvent: CCOCC
Product: CC(O)c1cccc2cnccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To a mixture of Mg turnings (0.2 g, 7.9 mmol) in ether (10 mL) was added MeI (1.13 g, 7.9 mmol) slowly at RT under an inert atmosphere. After being stirred for 1 h at RT, the reaction mixture was cooled to −10° C. and a solution of isoquinoline-5-carbaldehyde (0.5 g, 3.18 mmol) in ether (10 mL) was added. The reaction mixture was then stirred for an additional hour at RT, quenched with saturated NH4Cl solution and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography using 30% ethyl acetate in hexanes to afford 1-(isoquinolin-5-yl)ethanol (0.53 g, 97%) as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[NH:20][N:21]=[C:22]([CH3:24])[CH:23]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.C[Si]([C:29]#[CH:30])(C)C.C(N(CC)CC)C>CN(C=O)C.[Cu]I.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>[C:29]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[NH:20][N:21]=[C:22]([CH3:24])[CH:23]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1)#[CH:30]
Reactant: Cc1cc(Nc2nc(-c3ccc(Br)cc3)nc3ccccc23)[nH]n1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#Cc1ccc(-c2nc(Nc3cc(C)n[nH]3)c3ccccc3n2)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
To a mixture of [2-(4-bromo-phenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (III-34) (114 mg, 0.3 mmol), and trimethylsilylacetylene (147 mg, 1.5 mmol) in DMF (2 mL) was added CuI (1.1 mg, 1:50 mol %), Pd(PPh3)2Cl2 (4.2 mg, 1:50 mol %) and triethylamine (121 mg, 0.36 mmol). The resulting mixture was heated at 120° C. overnight and the solvent evaporated. The residue was triturated in ethyl acetate and the resulting precipitate collected by filtration. The collected solid was suspended in THF (3 mL) and TBAF (1M in THF, 1.leq) was added. The reaction mixture was stirred at room temperature for 2 hours and the solvent evaporated. The residue was purified by flash chromatography (silica gel, gradient of DCM:MeOH) to afford III-48 as a white solid (68 mg, 70%): 1H NMR (DMSO) δ 2.34 (3H, s), 4.36 (1H, s), 6.74 (1H, s), 7.55 (1H, m), 7.65 (2H, d), 7.84 (2H, m), 8.47 (2H, d), 8.65 (1H, d), 10.43 (1H, s), 12.24 (1H, s); MS 326.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[NH:6][C:7](=[O:19])[C:8]3[CH:18]=[CH:17][CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[NH2:21][CH2:22][CH2:23][CH2:24][OH:25]>>[CH2:13]([N:10]1[C:9]2[N:15]=[CH:16][CH:17]=[CH:18][C:8]=2[C:7](=[O:19])[NH:6][C:5]2[C:4]([CH3:20])=[CH:3][C:2]([NH:21][CH2:22][CH2:23][CH2:24][OH:25])=[N:12][C:11]1=2)[CH3:14]
Reactant: NCCCO
Reactant: CCN1c2ncccc2C(=O)Nc2c(C)cc(Cl)nc21
Product: CCN1c2ncccc2C(=O)Nc2c(C)cc(NCCCO)nc21

Procedure:
The title compound, m.p. 222°-224° C., was synthesized from 2-chloro-5,11-dihydro-11-ethyl-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and 3-aminopropanol using procedures analogous to those described above, except that the mixture was heated in a pressure bottle at 210° C. for 40 min., and the product was crystallized from ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=O)[NH:11][CH2:10][CH:9]2[CH2:15]CC(O)=O)=[CH:4][CH:3]=1.B.[O:21]1CCCC1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[CH2:15][OH:21])=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: O=C(O)CCC1CNC(=O)CC1c1ccc(F)cc1
Agent: B
Product: OCC1CNCCC1c1ccc(F)cc1
Reaction time: 1 h
Yield: 80 %

Procedure:
Borane-tetrahydrofuran complex (1.0 molar solution in tetrahydrofuran (10.8 ml, 10.8 mmol) was added over 20 hours in 3 stages (in 3.6 mmol portions) at a rate of 7 ml/hour by means of a syringe pump to a solution of 4-(4-fluorophenyl)-3-carboxyethylpiperidin-6-one (0.53 g, 2 mmol, trans/cis˜1:1) in tetrahydrofuran (3 ml) at 26° C. The reaction mixture was stirred for 1 hour after addition of the last portion of the borane solution. then quenched with 3.5 ml 30% aqueous potassium carbonate solution. The phases were separated and the aqueous phase extracted with diethyl ether (25 ml). The organic phases were combined and evaporated to yield 0.43 g of the title compound. Yield 80%.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[N:6]2)=C.I([O-])(=O)(=O)=[O:14].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH:1]=[O:14])=[CH:12][CH:11]=2)[N:6]=[CH:7][CH:8]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1ccc2nccnc2c1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=Cc1ccc2nccnc2c1
Reaction time: 3 h
Yield: 68.3 %

Procedure:
To a mixture of 6-vinylquinoxaline (0.68 g,4.35 mMol) in dioxane (44 mL) and water (35 mL) was added osmium tetraoxide (2.5% wt in t-BuOH, 2.18 mL, 0.17 mMol) followed by sodium periodate (2.79 g, 13.1 mMol) and the reaction stirred for three hours. The solution was diluted with ethyl acetate (150 mL) and then washed with water (3×75 mL) followed by brine (75 mL). The organics were dried with magnesium sulfate, filtered, and concentrated to dryness on a rotary evaporator. Purification by flash column chromatography on silica gel using 10-20% ethyl acetate in dichloromethane as eluant yielded 470 mg (68% yield) of quinoxaline-6-carboxaldehyde as a white solid. 1H NMR (DMSO-d6): δ=10.30 (s, 1H), 9.11 (d, 2H, J=1.9 Hz), 8.74 (d, 1H, J=1.4 Hz), 8.26 (m, 2H). LC/MS (Method A), rt=0.69 mins., purity=94.8%, calculated mass=158, [M+H]+=159.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([NH2:10])=[N:7][C:6]=2[CH:11]=1.[CH3:12][O:13][CH2:14][CH2:15]Br>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[NH:10])[N:7]([CH2:15][CH2:14][O:13][CH3:12])[C:6]=2[CH:11]=1
Reactant: Nc1nc2cc(F)ccc2s1
Reactant: COCCBr
Product: COCCn1c(=N)sc2ccc(F)cc21

Procedure:
Commercially available 5-fluoro-benzothiazol-2-ylamine and 2-bromoethyl methyl ether were processed as described for Example 46A to afford the title compound. MS (ESI+) m/z 227 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][O:8][CH:9]([CH2:12]Br)[CH2:10]Br)=[CH:5][CH:4]=1.[CH3:16][NH2:17]>O>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][O:8][CH:9]2[CH2:12][N:17]([CH3:16])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(COC(CBr)CBr)cc1
Reactant: CN
Solvent: O
Product: COc1ccc(COC2CN(C)C2)cc1
Temperature: 90 °C

Procedure:
33.7 parts of 2-(p-methoxybenzyloxy)-1,3-dibromopropane, 70 parts of monomethylamine and 70 parts of water were added to in an autoclave, and the mixture was heated at 90° C. for 48 hours with agitation. The reaction mixture was cooled and treated in the same manner as in Example 29, followed by distillation under reduced pressure. As a result 11.7 parts of 3-(p-methoxybenzyloxy)-1-methylazetidine boiling at 85° - 87° C. under 2 mm Hg were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:27]3[CH2:32][CH2:31][C@H:30]([C:33](O)=[O:34])[CH2:29][CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.Cl.CN.C[CH2:40][N:41](C(C)C)C(C)C.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH3:40][NH:41][C:33]([C@H:30]1[CH2:31][CH2:32][C@H:27]([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]3=[C:10]([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)=[N:18]4)=[CH:13][CH:12]=3)[N:9]=2)[CH2:28][CH2:29]1)=[O:34]
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1nccn2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)nc2[C@H]1CC[C@H](C(=O)O)CC1
Agent: CN
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CNC(=O)[C@H]1CC[C@H](c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn32)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A DMF solution (3 mL) of trans-4-[8-amino-1-(2-phenylquinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid (260 mg, 0.56 mmol) and methylamine hydrochloride (379 mg, 5.6 mmol) in a sealed tube was charged with DIEA (0.98 mL, 5.6 mmol), 0.6M HOAt in DMF (0.93 mL, 0.56 mmol), and then EDC (161 mg, 0.84 mmol). The reaction mixture stirred at rt for 16 h. The reaction mixture was concentrated to solids, taken up in CH2Cl2, charged with silica, and concentrated to brown solids. The crude material was purified by silica gel column chromatography [Jones Flashmaster, 5 g/25 mL cartridge, eluting with 2%˜7N NH3 in MeOH/CH2Cl2]. The purified material was recrystallized from MeOH/CH2Cl2/diethyl ether to the desired product as a light yellow solid; 1H NMR (DMSO-d6, 400 MHz) δ 1.56-1.73 (m, 4H), 1.85-1.91 (m, 2H), 2.01-2.06 (m, 2H), 2.17-2.25 (m, 1H), 2.52 (d, 3H, J=4.4 Hz), 3.12-3.20 (m, 1H), 6.17 (s, 2H), 7.09 (d, 1H, J=4.8 Hz), 7.51-7.59 (m, 4H), 7.73 (d, 1H, J=4.8 Hz), 7.90 (dd, 1H, J=2.0 Hz, 8.4 Hz), 8.09 (d, 1H, J=8.4 Hz), 8.18 (d, 1H, J=8.8 Hz), 8.23 (s, 1H), 8.30 (d, 2H, J=7.6 Hz), 8.51 (d, 1H, J=8.4 Hz); MS (ES+): m/z 477.0 [MH+]; HPLC: tR=2.1 min (Micromass Platform II, polar—5 min).
Reaction SMILES: N(C[C@@H](C1C=CC(OCC2C=CC=CC=2)=C2C=1C=CC(=O)N2)O)=[N+]=[N-].[Si]([O:33][C@H:34]([C:68]1[CH:77]=[CH:76][C:75]([OH:78])=[C:74]2[C:69]=1[CH:70]=[CH:71][C:72](=[O:79])[NH:73]2)[CH2:35][NH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([NH:46][CH2:47][C:48]1[C:49]([NH:61][CH:62]2[CH2:67][CH2:66][O:65][CH2:64][CH2:63]2)=[C:50]2[CH:58]=[N:57][N:56]([CH2:59][CH3:60])[C:51]2=[N:52][C:53]=1[CH2:54][CH3:55])=[O:45])(C(C)(C)C)(C)C>>[CH2:59]([N:56]1[C:51]2=[N:52][C:53]([CH2:54][CH3:55])=[C:48]([CH2:47][NH:46][C:44](=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][NH:36][CH2:35][C@H:34]([OH:33])[C:68]3[CH:77]=[CH:76][C:75]([OH:78])=[C:74]4[C:69]=3[CH:70]=[CH:71][C:72](=[O:79])[NH:73]4)[C:49]([NH:61][CH:62]3[CH2:67][CH2:66][O:65][CH2:64][CH2:63]3)=[C:50]2[CH:58]=[N:57]1)[CH3:60]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12
Agent: [N-]=[N+]=NC[C@H](O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCCCCCCNC[C@H](O)c1ccc(O)c2[nH]c(=O)ccc12

Procedure:
The title compound was synthesized in a manner analogous to that described in Intermediate 3, using Intermediate 55 as substrate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:22]=[CH:21][C:12]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])=[CH:11][CH:10]=1.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[C:13]([C:12]1[CH:21]=[CH:22][C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:30]([NH:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:31])=[CH:10][CH:11]=1)(=[O:14])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccccc1Nc1ccc(C(=O)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)Nc1ccccc1Nc1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-(2-aminophenylamino)benzophenone (Compound 101, 0.58 g, 2 mmol) in toluene (10 ml) was added phenylisocyanate (0.22 ml, 2 mmol). The reaction mixture was heated for 20 hours on a steam bath. After cooling the reaction mixture to room temperature the resulting precipitate was collected by filtration and washed with toluene. The crude product was dissolved in hot isopropanol and crystallized on the addition of water to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[C:25]([Cl:27])[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([O:20]CC)=[O:19])[CH:8]=1)=[O:5].[Li+].[OH-].O.Cl>>[Cl:1][C:2]1[CH:26]=[C:25]([Cl:27])[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=[C:9]([C:18]([OH:20])=[O:19])[CH:8]=1)=[O:5]
Reactant: CCOC(=O)c1cc(NC(=O)c2cc(-c3ccccn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(NC(=O)c2cc(-c3ccccn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.3 %

Procedure:
To a solution of ethyl 5-(2,4-dichloro-5-(pyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylate (Example 124, 2.5 g, 5.19 mmol) in industrial methylated spirit (50 mL) was added a 1M LiOH solution in water (26 mL, 26 mmol) and the reaction was stirred at room temperature for 3 hours. The reaction was acidified with 2M HCl (aq) (13 mL, 26 mmol) to afford a precipitate that was filtered and washed with industrial methylated spirit to afford the title compound (1.96 g, 83%).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]=O)=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br.Br.Br.[CH2:18]([C:20]1[C:21]([C:28]2[CH:36]=[C:35]3[C:31]([C:32]([C:37]4[NH:38][C:39]5[CH2:44][CH2:43][NH:42][CH2:41][C:40]=5[N:45]=4)=[N:33][NH:34]3)=[CH:30][CH:29]=2)=[CH:22][C:23]([F:27])=[C:24]([OH:26])[CH:25]=1)[CH3:19]>>[CH2:18]([C:20]1[C:21]([C:28]2[CH:36]=[C:35]3[C:31]([C:32]([C:37]4[NH:38][C:39]5[CH2:44][CH2:43][N:42]([CH2:13][C:10]6[CH:11]=[CH:12][C:7]([N:1]7[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]7)=[N:8][CH:9]=6)[CH2:41][C:40]=5[N:45]=4)=[N:33][NH:34]3)=[CH:30][CH:29]=2)=[CH:22][C:23]([F:27])=[C:24]([OH:26])[CH:25]=1)[CH3:19]
Reactant: O=Cc1ccc(N2CCCCC2)nc1
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Agent: Br
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(Cc3ccc(N5CCCCC5)nc3)C4)n[nH]c2c1
Yield: 30.3 %

Procedure:
The title compound was prepared from 3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbaldehyde (38 mg, 198 μmol) and 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50 mg, 132 μmol) using the method of Example 22. The crude material was purified by HPLC Method A to afford 22.1 mg of the title compound.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH3:10])[C:6]=1[C:7](O)=[O:8].[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>[Cu].C(OCC)C>[F:11][C:12]1[CH:18]=[CH:17][C:15]2[NH:16][C:2]3[CH:3]=[N:4][N:5]([CH3:10])[C:6]=3[C:7](=[O:8])[C:14]=2[CH:13]=1
Reactant: Cn1ncc(I)c1C(=O)O
Reactant: Nc1ccc(F)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: Cn1ncc2[nH]c3ccc(F)cc3c(=O)c21
Temperature: 25 °C
Yield: 61 %

Procedure:
A mixture of 4-iodo-1-methyl-1H-pyrazole-5-carboxylic acid ((Manaev, Yu. A. et al., J. Gen. Chem. USSR (Engl. Transl.), 1982, 52 (11), 2291), 500 mg, 1.98 mmol), 4-fluoroaniline (0.94 ml, 9.90 mmol), copper powder (200 mg) and 5% aqueous sodium carbonate (10 ml) was stirred for 16 h at 100° C. After cooling to room temperature, 2N aqueous sodium hydroxide (100 ml) and diethyl ether (50 ml) were added to the mixture. The mixture was filtered through a pad of Celite. The water layer was separated, washed with diethyl ether (50 ml) and acidified with concentrated hydrochloric acid. The formed precipitate was collected by filtration and dried to give 282 mg (61%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][N:3]=1.Cl[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=2)[N:3]=1
Reactant: Cc1cc(-c2ccccc2)[nH]n1
Reactant: OCc1ccc(CCl)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccccc2)n(Cc2ccc(CO)cc2)n1
Temperature: 120 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
A mixture of 3-methyl-5-phenyl-1H-pyrazole (760 mg, 5.0 mmol), [4-(chloromethyl)phenyl]methanol (850 mg, 5.43 mmol), potassium carbonate (1.38 g, 10.0 mmol) and N,N-dimethylformamide (20 mL) was stirred at 120° C. for 1 hr. The reaction mixture was poured into 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried using a Presep Dehydration tube (manufactured by Wako Pure Chemical Industries, Ltd.) and concentrated. The residue was purified by silica gel column chromatography (10%-80% ethyl acetate/hexane) to give the title compound (850 mg, yield 61%) as colorless crystals. 1H NMR (CDCl3) δ: 2.21 (3H, s), 4.66 (2H, s), 5.33 (2H, s), 6.38 (1H, s), 7.13 (2H, d, J=8.1 Hz), 7.27-7.34 (3H, m), 7.34-7.42 (2H, m), 7.77-7.83 (2H, m).
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[C:12]([C:19]4[NH:27][C:26]5[CH2:25][CH2:24][NH:23][C:22](=[O:28])[C:21]=5[CH:20]=4)[CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].CO>[C:1]1([CH:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[C:12]([C:19]4[NH:27][C:26]5[CH2:25][CH2:24][NH:23][C:22](=[O:28])[C:21]=5[CH:20]=4)[CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(c1ccccc1)c1ccc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1
Agent: [Pd]
Solvent: CO
Product: CC(c1ccccc1)c1ccc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.6 %

Procedure:
A suspension of 2-(2-(1-phenylvinyl)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 113; 102.4 mg, 0.280 mmol) and palladium on carbon (10% w/w; 59.6 mg, 0.056 mmol) in MeOH (3.0 mL) was cycled under a H2 gas atmosphere (1 atm; 3 evacuation/H2 back-fill cycles) and then stirred at 25° C. for 1 d. The mixture was filtered through Celite, washing the filter cake with MeOH (10 mL). The combined filtrates were concentrated in vacuo to provide rac-2-(2-(1-phenylethyl)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (81.0 mg, 0.220 mmol, 79% yield) as a yellow-orange solid: 1H NMR (400 MHz, CDCl3) δ ppm 12.91 (1H, br. s.), 8.07-8.13 (2H, m), 7.60 (1H, dd, J=8.0, 1.0 Hz), 7.48-7.54 (1H, m), 7.35 (1H, d, J=6.8 Hz), 7.32-7.34 (2H, m), 7.29 (3H, d, J=6.8 Hz), 7.21 (1H, d, J=2.0 Hz), 5.38 (1H, br. s.), 4.54 (1H, q, J=7.0 Hz), 3.64 (2H, td, J=6.8, 2.5 Hz), 2.87-2.93 (2H, m), 1.87 (3H, d, J=7.0 Hz). m/z (ESI, +ve) 368.3 (M+H)+. Separation of this material by supercritical-fluid chromatography (Chiralcel OJ (250×21 mm, 10 μm), 50% liquid CO2/50% MeOH (+40 mM NH3), 50 mL/min) separately afforded 2-(2-(1-phenylethyl)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one, first-eluting enantiomer (115; 30.5 mg, 0.083 mmol) and 2-(2-(1-phenylethyl)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one, second eluting enantiomer (116; 27.6 mg, 0.075 mmol).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Br.[CH2:13]([O:15][P:16]([O:20]CC)[O:17][CH2:18][CH3:19])[CH3:14]>>[Br:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][P:16](=[O:20])([O:17][CH2:18][CH3:19])[O:15][CH2:13][CH3:14]
Reactant: CCOP(OCC)OCC
Reactant: BrCCCc1ccccc1CBr
Product: CCOP(=O)(Cc1ccccc1CCCBr)OCC
Yield: 83 %

Procedure:
In a round bottom flask equipped for distillation, 11.36 g (38.9 mmol) of 2-(3-bromopropyl)benzyl bromide and 6.46 (38.9 mmol) of freshly distilled triethylphosphite were heated with stirring at 100°-110° C. on an oil bath. When ethyl bromide ceased distilling off (about 2 h) the remaining volatile by-products and the triethylphosphite were removed from the mixture by distillation under vacuum. The remaining oil was chromatographed on a column of silica gel with hexame-ethyl acetate (1:1) as eluant. The combined fractions were concentrated under reduced pressure to yield 11.2 g (83%) of the product as a clear oil. IR(neat): 2985, 1496, 1450, 1391, 1252, 1162, 104, 967, 843, 802, 758 cm-1. 1H NMR(CDCl3) δ 1.2 (t, 6); 1.8-2.3 (m, 2H); 2.7-3.55 (m, 4H); 3.8-4.2 (m, 2H); 7.1-7.4 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[N:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O=S(Cl)Cl.[CH3:19]O>>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[N:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: COc1cc(C(=O)O)c(Cl)cc1C#N
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(OC)c(C#N)cc1Cl
Temperature: 0 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
2-chloro-4-cyano-5-methoxybenzoic acid (600 mg; 2.84 mmol; 1 eq.) was dissolved in MeOH (12 mL). The solution was cooled down to 0° C. SOCl2 (0.62 mL; 8.51 mmol; 3 eq.) was added dropwise. The reaction mixture was stirred at RT for 24 hours. The reaction mixture was concentrated and the residue was taken up in EtOAc. The organic layer was washed with a saturated aqueous solution of NaHCO3, then brine, dried over MgSO4, concentrated affording the title compound as a yellow solid (0.58 g, 90%). 1H NMR (DMSO-d6, 300 MHz) δ 8.09 (s, 1H), 7.57 (s, 1H), 3.96 (s, 3H), 3.89 (s, 3H). HPLC (Method A) Rt 4.08 min (Purity: 94.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[CH:11]1([CH:14]([OH:26])[CH2:15][CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH2:12]1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH:3]=1)[O:26][CH:14]([CH:11]1[CH2:12][CH2:13]1)[CH2:15][CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: CN(CCC(O)C1CC1)C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(Cl)cc1F
Product: CN(CCC(Oc1cc(Cl)ccc1C#N)C1CC1)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the method of Example 3 step (b) but using 4-chloro-2-fluorobenzonitrile and (3-cyclopropyl-3-hydroxypropyl)methylcarbamic acid, 1,1-dimethylethyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH2:6][C:5]([CH3:7])=[C:4]([CH3:8])[C:3]=1[CH3:9].[Li]CCCC.[Cl:15][Si:16](Cl)([CH3:18])[CH3:17]>C1COCC1>[Cl:15][Si:16]([CH3:18])([CH3:17])[CH:6]1[C:5]([CH3:7])=[C:4]([CH3:8])[C:3]([CH3:9])=[C:2]1[CH3:1]
Reactant: CC1=C(C)C(C)=C(C)C1
Reactant: C[Si](C)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=C(C)C([Si](C)(C)Cl)C(C)=C1C
Reaction time: 0.33 h

Procedure:
Under an argon atmosphere, to a solution of 48.0 g (0.393 mol) of tetramethylcyclopentadiene in 600 ml of THF, 157 ml of 2.5 M (0.393 mol) nBuLi in hexanes were added dropwise over 20 minutes at −80° C. This mixture was additionally stirred for 20 minutes at this temperature, and then for 0.5 hours at room temperature. The resulting mixture was added dropwise over 1.5 hours to a solution of 86.3 g (0.669 mol) of dichlorodimethylsilane in 150 ml of THF. The resulting mixture was stirred overnight at ambient temperature and then evaporated to dryness. Fractional distillation gave a yellow liquid, bp 52-56° C./1 mm Hg. Yield 48.3 g (57%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][NH:6]1)=[O:4].[Cl:20][C:21]1[N:25]=[C:24](Cl)[S:23][N:22]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:11])=[O:12])[CH2:7][N:6]1[C:24]1[S:23][N:22]=[C:21]([Cl:20])[N:25]=1)=[O:4]
Reactant: Clc1nsc(Cl)n1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1nc(Cl)ns1

Procedure:
In analogy to the procedure described in example 335a, (2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 253a) was reacted with 3,5-dichloro-[1,2,4]thiadiazole (CAS Reg. No. 2254-88-8) in a shaking reactor at 55° C. for 48 h to give the title compound as red oil. MS (ESI): m/z=422.0 [M+H]+.