Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:56][CH:57]1[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1>CN(C=O)C>[O:60]1[CH2:61][CH2:62][CH:57]([NH:56][C:21]([C:17]2[S:16][C:15]([CH2:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][C:11]=3[CH3:24])=[N:19][C:18]=2[CH3:20])=[O:23])[CH2:58][CH2:59]1
Reactant: NC1CCOCC1
Reactant: Cc1nc(CCc2c(-c3ccc(F)cn3)noc2C)sc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(CCc2c(-c3ccc(F)cn3)noc2C)sc1C(=O)NC1CCOCC1
Reaction time: 1 h
Yield: 94.1 %

Procedure:
To a solution of 2-{2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl}-4-methyl-thiazole-5-carboxylic acid (69 mg, 0.20 mmol) in DMF (1.2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (71 mg, 0.22 mmol), N,N-diisopropyl ethyl amine (171 μL, 1.00 mmol) and 4-aminotetrahydropyran (22 mg, 0.22 mmol). The resulting reaction mixture was stirred for 1 h and then evaporated. Purification by chromatography (silica, heptane:ethyl acetate 4:1 to 0:1) afforded the title compound (81 mg, 94%) as an off white solid. MS: m/e=431.2 [M+H]+.
Reaction SMILES: Cl.[C:2]([C:6]1[O:10][C:9]([CH2:11][N:12]2[C:17]3[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[S:20][C:16]=3[C:15](=[O:27])[N:14]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[C:13]2=[O:34])=[N:8][N:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH2:35]([O:37][C:38]1[C:47]([O:48][CH3:49])=[CH:46][C:45]2[C:44]([C:50]3[CH:58]=[CH:57][C:53]([C:54](O)=[O:55])=[CH:52][CH:51]=3)=[N:43][C@@H:42]3[CH2:59][CH2:60][S:61][CH2:62][C@@H:41]3[C:40]=2[CH:39]=1)[CH3:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:2]([C:6]1[O:10][C:9]([CH2:11][N:12]2[C:17]3[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[S:20][C:16]=3[C:15](=[O:27])[N:14]([CH:28]3[CH2:29][CH2:30][N:31]([C:54]([C:53]4[CH:57]=[CH:58][C:50]([C:44]5[C:45]6[CH:46]=[C:47]([O:48][CH3:49])[C:38]([O:37][CH2:35][CH3:36])=[CH:39][C:40]=6[C@H:41]6[CH2:62][S:61][CH2:60][CH2:59][C@H:42]6[N:43]=5)=[CH:51][CH:52]=4)=[O:55])[CH2:32][CH2:33]3)[C:13]2=[O:34])=[N:8][N:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: CC(C)(C)c1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)o1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5nnc(C(C)(C)C)o5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(5-tert-butyl-1,3,4-oxadiazol-2-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (1.63 g; compound B98) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (1.39 g; compound C10) and HBTU (1.48 g) in DCM (40 ml) in the presence of DIPEA (2.38 ml) according to the procedure described in example 55 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluent: EtOAc/cyclohexane, 90/10 (v/v)] as a solid
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11]([O:16][C@@H:17]3[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[C@@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]3[O:19][C:20](=[O:22])[CH3:21])=[N:12][NH:13][C:14]=2[CH3:15])=[CH:5][CH:4]=1.[C:40](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]2[C:11]([O:16][C@@H:17]3[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[C@@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]3[O:19][C:20](=[O:22])[CH3:21])=[N:12][N:13]([CH3:40])[C:14]=2[CH3:15])=[CH:7][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(Cc2c(O[C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)n[nH]c2C)cc1
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COc1ccc(Cc2c(O[C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)nn(C)c2C)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 21.7 %

Procedure:
A suspension of 4-[(4-methoxyphenyl)methyl]-5-methyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-1H-pyrazole (18 mg), potassium carbonate (14 mg) and iodomethane (4.7 mg) in acetonitrile (2 mL) was stirred at 75° C. overnight. The reaction mixture was filtered through celite®, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by preparative thin layer chromatography (developing solvent:benzene/acetone=2/1) to give 4-[(4-methoxyphenyl)methyl]-1,5-dimethyl-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)pyrazole (4 mg).
Reaction SMILES: Br.[Br:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCCC1>[BrH:2].[O:5]=[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[CH2:3][N+:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(CBr)c1ccccn1
Reactant: c1ccncc1
Agent: Br
Solvent: C1CCOC1
Product: O=C(C[n+]1ccccc1)c1ccccn1
Temperature: 25 °C

Procedure:
5 g of 2-bromoacetylpyridine hydrobromide and 7 cm3 of pyridine are introduced into a three-necked flask containing 50 cm3 of tetrahydrofuran. The stirring is maintained for 2 days at room temperature and then the precipitate formed is filtered, washed with 30 cm3 of tetrahydrofuran and then dried at 40° C. under reduced pressure (90 Pa) to give 6.9 g of 1-[2-oxo-2-(2-pyridyl)ethyl]pyridinium hydrobromide in the form of a beige solid which is used as it is.
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:14]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([Cl:26])[CH:20]=2)[N:16]([CH3:27])[N:15]=1.C(=O)([O-])[O-].[K+].[K+].[F:34][C:35]1[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][C:36]=1[CH2:37]Cl>O>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C:14]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:37][C:36]3[CH:39]=[CH:40][C:41]([C:43]([F:44])([F:46])[F:45])=[CH:42][C:35]=3[F:34])=[C:21]([Cl:26])[CH:20]=2)[N:16]([CH3:27])[N:15]=1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(O)c(Cl)c1
Reactant: Fc1cc(C(F)(F)F)ccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(OCc2ccc(C(F)(F)F)cc2F)c(Cl)c1
Temperature: 25 °C
Yield: 49.6 %

Procedure:
To 20 ml of N,N-dimethylformamide are added 3-(2-chloro-6-fluorophenyl) 5-[3-chloro-4-hydroxyphenyl)-1-methyl-1H-1,2,4-triazole (0.90 g) and potassium carbonate (0.40 g) and 2-fluoro-4-trifluoromethylbenzyl chloride (0.50 g) is added thereto at room temperature with stirring, which is stirred at 120° C. for 5 hours. On completion of the reaction, the reaction solution is cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography to give 0.60 g of desired compound (melting point: 109.0°-111.0° C.).
Reaction SMILES: B(Br)(Br)Br.FC(F)(F)C(O)=O.[CH2:12]([N:14]([CH2:41][CH3:42])[C:15]([C:17]1[CH:18]=[CH:19][C:20]2[C:21](=[C:33]3[CH2:39][CH:38]4[NH:40][CH:35]([CH2:36][CH2:37]4)[CH2:34]3)[C:22]3[C:27]([O:28][C:29]=2[CH:30]=1)=[CH:26][C:25]([O:31]C)=[CH:24][CH:23]=3)=[O:16])[CH3:13].[OH-].[NH4+]>ClCCl>[CH2:41]([N:14]([CH2:12][CH3:13])[C:15]([C:17]1[CH:18]=[CH:19][C:20]2[C:21](=[C:33]3[CH2:39][CH:38]4[NH:40][CH:35]([CH2:36][CH2:37]4)[CH2:34]3)[C:22]3[C:27]([O:28][C:29]=2[CH:30]=1)=[CH:26][C:25]([OH:31])=[CH:24][CH:23]=3)=[O:16])[CH3:42]
Reactant: CCN(CC)C(=O)c1ccc2c(c1)Oc1cc(OC)ccc1C2=C1CC2CCC(C1)N2
Agent: BrB(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C(=O)c1ccc2c(c1)Oc1cc(O)ccc1C2=C1CC2CCC(C1)N2
Temperature: 0 °C

Procedure:
A 1.0 M solution of boron tribromide in dichloromethane (2.14 mL, 2.14 mmol) was added to a solution of the trifluoroacetic acid salt of 9-(8-aza-bicyclo[3.2.1]oct-3-ylidene)-6-methoxy-9H-xanthene-3-carboxylic acid diethylamide (0.285 g, 0.535 mmol) in dichloromethane (10 mL) at 0° C. The resultant mixture was stirred at room temperature for 2 h. The mixture was cooled to 0° C., and treated with 10% aqueous ammonium hydroxide (˜20 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo, and the residues was dissolved in DMSO and applied to reverse phase C18 column for purification via HPLC, using a gradient of acetonitrile (10% to 90%) in water with trifluoroacetic acid (0.1%) as the eluant. Fractions containing the title compound were combined and further purified via reverse phase HPLC to give the purified title compound (0.035 g). MS: m/z 405.1 (MH+). 1H NMR (DMSO-d6): δ 1.0-1.2 (br m, 6H), 1.29 (d, 12H, J=8.1 Hz), 1.7-1.8 (br m, 2H), 2.8-3.0 (br m, 4H), 3.1-3.5 (br m, 4H), 3.99 (br s, 2H), 6.63-6.65 (m, 2H), 7.13 (d, 1 H, J=7.9 Hz), 7.18-7.21 (m, 3H), 7.41 (d, 1H, J=7.9 Hz), 8.70 (br s, 1H), 9.01 br d, 1H) and 9.93 (br s 1H).
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[NH:15][C:16]4[C:21]([CH:22]=3)=[CH:20][C:19]([C:23]([N:25]3[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]3)=[O:24])=[CH:18][CH:17]=4)=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.[Cl:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1>>[Cl:34][C:35]1[CH:40]=[C:39]([N:15]2[C:16]3[C:21](=[CH:20][C:19]([C:23]([N:25]4[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]4)=[O:24])=[CH:18][CH:17]=3)[CH:22]=[C:14]2[C:12]([N:9]2[CH2:8][CH2:7][N:6]([C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[CH2:11][CH2:10]2)=[O:13])[CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(C(=O)C5CC5)CC4)cc3c2)CC1
Reactant: OB(O)c1cccc(Cl)c1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(C(=O)C4CC4)CC2)n3-c2cccc(Cl)c2)CC1
Yield: 53 %

Procedure:
The title compound was synthesized in analogy to example 5, after stirring for 6.5 days at 35° C., from (4-cyclopropanecarbonyl-piperazin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 25) and 3-chlorophenylboronic acid to afford the desired product as a colorless gum (53%). MS (ISP): 562.5 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH2:9])[CH:5]=[C:4]([Cl:10])[N:3]=1.CN(C)C=O.[CH3:16][O:17][CH2:18][CH2:19][O:20][C:21](Cl)=[O:22]>C(N(CC)CC)C>[NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][C:21]([O:20][CH2:19][CH2:18][O:17][CH3:16])=[O:22])[CH:5]=[C:4]([Cl:10])[N:3]=1
Reactant: Nc1cc(Cl)nc(N)[n+]1[O-]
Reactant: COCCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCOC(=O)Nc1cc(Cl)nc(N)[n+]1[O-]

Procedure:
5 G. of 2,4-diamino-6-chloropyrimidine-3-oxide are suspended in 50 ml. of dimethylformamide and 5 ml. of triethylamine and cooled to 0° C. while stirring. 4.3 G. of chloroformic acid 2-methoxyethyl ester are added dropwise to the cold suspension in the course of 15 minutes. The mixture is cooled for 2 hours and then stirred at room temperature for 16 hours. The solvent is distilled off at 25° C. in a high vacuum and the residue is digested with methylene chloride. The precipitate obtained is filtered off and washed with methylene chloride, methanol and water. The filtrate is washed with water and dried over sodium sulfate. By concentrating the solvent, there is obtained pure 2-methoxyethyl 2-amino-6-chloro-4-pyrimidinecarbamate-3-oxide having a melting point of 176°-178° C. Additional material is obtained by subjecting the mother liquor to chromatographical separation on silica gel.
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([N+:24]([O-])=O)[CH:18]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1.O.O.Cl[Sn]Cl>OS([O-])(=O)=O.[Na+].O1CCOCC1>[F:27][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[N:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([NH2:24])[CH:18]=3)=[N:12][CH:11]=2)=[CH:6][CH:5]=1
Reactant: Cc1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(Nc2ncc(-c3ccc(OC(F)F)cc3)cn2)cc1N
Temperature: 100 °C

Procedure:
A suspension of 5-(4-(difluoromethoxy)phenyl)-N-(4-methyl-3-nitrophenyl)pyrimidin-2-amine 28a (1.5 mmol) and SnCl2.2H2O (4.5 mmol) in 1N NaHSO4 (50 mL) and 1,4-dioxane (50 mL) is heated at 100° C. for 1 h. The solvent is removed under vacuum and the residue dissolved in 5% NaOH and extracted with DCM (3×50 mL). The organic layer is washed with 5% NaOH (1×50 mL), water (1×50 mL), brine, dried over Na2SO4 and concentrated to afford N1-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-yl)-4-methylbenzene-1,3-diamine 29a which is used without further purification. 1H NMR (400 MHz, d6-DMSO) δ 9.44 (s, 1H), 8.76 (s, 2H), 7.76 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.8 Hz, 2H), 7.30 (t, J=74.4 Hz, 1H), 7.07 (d, J=2.0 Hz, 1H), 6.90 (dd, J=2.0, 8.0 Hz, 1H), 6.82 (d, J=8.4 Hz, 1H), 4.95 (bs, 2H), 2.02 (s, 3H). MS (m/z) (M+1)+: 343.1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][O:14][CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: OCC1CCN(Cc2ccccc2)C1
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: c1ccc(CN2CCC(COC(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C
Yield: 48.8 %

Procedure:
A mixture of 1-benzylpyrrolidine-3-methanol (1.72 g) (J. Org. Chem., 1961, 26, 1521) and bromodiphenylmethane (4.94 g) in xylene (150 ml) was heated under reflux for 3 hours, allowed to cool to room temperature, diluted with ethyl acetate, washed with 10% aqueous sodium carbonate solution, dried over magnesium sulphate and evaporated. The residue was purified by chromatography on silica using dichloromethane plus 20% ethyl acetate plus 0-10% methanol as eluant. Appropriate fractions were combined and evaporated to give the title compound (1.57 g) as a pale brown oil which was charcterised by its 1H-NMR spectrum.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[Li+].CC([N-]C(C)C)C.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1COCC1>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][CH:6]1[CH2:5][CH2:4][N:3]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:2]1=[O:1])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Reactant: CCOC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1CCN(C(=O)OC(C)(C)C)C1=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
tert-Butyl 2-oxopyrrolidine-1-carboxylate (10 g, 54.0 mmol) was dissolved in THF (75 mL) and cooled to −78° C. LDA (1.8 M in THF/heptane, 30.0 mL, 54.0 mmol) was added and the solution was stirred for 1 h. Ethyl 2-bromoacetate (9.02 g, 54.0 mmol) was added and the mixture was stirred for 1 h and allowed to warm to room temperature and stirred for 16 h. The reaction mixture was partitioned between water and EtOAc. The aqueous layer was extracted two times with EtOAc and the combined extracts were dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by column chromatography to provide partially purified tert-butyl 3-(2-ethoxy-2-oxoethyl)-2-oxopyrrolidine-1-carboxylate. tert-Butyl 3-(2-ethoxy-2-oxoethyl)-2-oxopyrrolidine-1-carboxylate (4.72 g, 17.40 mmol) was dissolved in EtOH (30 mL) and TFA (10 mL). The reaction was stirred at room temperature for 2 h and 20 mL of TFA was added. After stirring for an additional 2 h, the reaction mixture was concentrated under reduced pressure and purified by column chromatography to provide the title compound (1.77 g). 1H NMR (400 MHz, CDCl3) δ ppm 1.26 (t, J=7.2 Hz, 3H), 1.81-1.93 (m, 1H), 2.35-2.49 (m, 2H), 2.75-2.85 (m, 1H), 2.88 (dd, J=16.4, 3.9 Hz, 1H), 3.31-3.40 (m, 2H), 4.09-4.21 (m, 2H), 5.96 (bs, 1H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10]1[N:14]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=2)[C:13]2[CH:23]=[C:24]([F:28])[CH:25]=[C:26]([F:27])[C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(=O)(O)[O-].[Na+]>Cl>[F:21][C:19]1[CH:20]=[C:15]([N:14]2[C:13]3[CH:23]=[C:24]([F:28])[CH:25]=[C:26]([F:27])[C:12]=3[N:11]=[C:10]2[CH:8]([NH2:7])[CH3:9])[CH:16]=[C:17]([F:22])[CH:18]=1
Reactant: CC(NC(=O)OC(C)(C)C)c1nc2c(F)cc(F)cc2n1-c1cc(F)cc(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(N)c1nc2c(F)cc(F)cc2n1-c1cc(F)cc(F)c1
Temperature: 25 °C

Procedure:
A solution of tert-butyl-1-(1-(3,5-difluorophenyl)-4,6-difluoro-1H-benzo[d]imidazol-2-yl)ethylcarbamate (0.4 g) was stirred in 2 N HCl (4 mL) at 120° C. for 4 h. The reaction mixture was cooled to rt and basified with satd. sodium bicarbonate solution (20 mL). The organic layer was extracted with EtOAc, dried over sodium sulfate and concentrated in vacuo to provide 1-(1-(3,5-difluorophenyl)-4,6-difluoro-1H-benzo[d]imidazol-2-yl]-ethanamine. The crude product was carried on without further purification.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7](F)=[C:8]([CH:24]=1)[CH2:9][N:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]([CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1)[OH:16]>>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[O:16][CH:15]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[C:11]3=[CH:12][CH:13]=[CH:14][N:10]3[CH2:9][C:8]=2[CH:24]=1
Reactant: CN1CCC(C(O)c2cccn2Cc2cc(Cl)ccc2F)CC1
Agent: [H-]
Agent: [Na+]
Product: CN1CCC(C2Oc3ccc(Cl)cc3Cn3cccc32)CC1
Temperature: 70 °C

Procedure:
To a suspension of sodium hydride (60% in oil, washed once with hexane) in 75 ml of 25% DMF/benzene mixture was added a solution of [1-(5-chloro-2-fluorobenzyl)-2-pyrryl]-[(1-methyl)piperidin-4-yl]methanol (83.7 g, 0.248 mole in 200 ml 25% DMF/benzene). This was heated at 70° C. for 3.5 hours.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:7]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:9]=1)[CH2:5]O.S(Cl)([Cl:19])=O>C1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([C:7]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:9]=1)[CH2:5][Cl:19]
Reactant: Cc1ccc(Sc2ccccc2)c(CO)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cc1ccc(Sc2ccccc2)c(CCl)c1
Reaction time: 1.5 h

Procedure:
570.7 g of 3-methyl-6-(phenylthio)-benzyl alcohol are dissolved in 1.5 litres of benzene and heated under reflux. There are added dropwise thereto within 45 minutes 352 ml of thionyl chloride and the mixture is boiled for a further 90 minutes. Then the mixture is concentrated under reduced pressure and there is obtained 3-methyl-6-(phenylthio)-benzyl chloride as a red-brown oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH2:13][NH2:14])=[CH:8][CH2:9][O:10]2)=[CH:5][CH:4]=1>[Ni].CO.CC(O)=O>[ClH:2].[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([CH2:13][NH2:14])[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: NCC1=CCOc2cc(Cl)ccc21
Agent: [Ni]
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: NCC1CCOc2cc(Cl)ccc21
Yield: 92 %

Procedure:
Hydrogenation of 1-(7-chloro-2H-chromen-4-yl)methanamine hydrochloride (500 mg, 2.6 mmol) was carried out in the presence of Raney Nickel (300 mg) in 2:1 MeOH/HOAc under 50 psi of H2 for 16 h at 30° C. The reaction was filtered through Celite and concentrated in vacuo. Precipitation from EtOAc and filtration gave 280 mg (56%) of the title compound as a white solid. [M+H] calc'd for C10H12ClNO, 198. Found 198.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].C1COCC1.Br[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>CS(C)=O>[N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: Brc1ccccn1
Reactant: N#Cc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2ccccn2)cc1
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 63.2 %

Procedure:
4-Hydroxybenzonitrile (1.00 g, 8.39 mmol) was dissolved in anhydrous DMSO (5.0 mL) and was slowly added a solution of potassium tert-butoxide in THF (1.0 M, 16.8 mmol). The solution was stirred for 2 hours 30 minutes. A solution of 2-bromopyridine (2.65 g, 16.8 mmol) in DMSO (5.0 mL) was then added to the reaction mixture the whole was heated at 160° C. for 115 hours. The cooled mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layers were dried with MgSO4, filtered and concentrated in vacuo. The crude solid was placed on a silica gel column and purified (EtOAc/Hex 1:6) to give the product as a light yellow solid (1.04 g, 63%). 1H NMR (500 MHz, CDCL3) δ(ppm): 7.01 (1H, d, J=8.2 Hz), 7.10 (1H, dd, J=7.2, 5.0 Hz), 7.24 (2H, d, J=9.0 Hz), 7.68 (2H, d, J=8.8 Hz), 7.77 (1H, ddd, J=8.3, 7.3, 2.0 Hz), 8.22 (1H, dd, J=5.0, 2.0 Hz). 13C NMR (125 MHz, CDCL3) δ(ppm): 108.0, 112.8 (CH), 118.9, 120.0 (CH), 121.6 (CH), 134.1 (CH), 140.2 (CH), 147.9 (CH), 158.2, 162.5. MS (FAB+): 197 (MH+). HRMS for C12H8N2O (MH+): calculated: 197.0713; found 197.0715.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.Cl[CH2:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][CH:17]=1.[OH-].[Na+]>CN(C=O)C.CCCCCC>[CH3:3][O:4][C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: ClCc1ccnc2ccccc12
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccnc3ccccc23)cc1
Temperature: 0 °C

Procedure:
Sodium hydride (430 mg, 60%, 10.75 mmol) was placed in a flask with hexane and stirred under nitrogen. After 10 minutes the hexane was discarded and 10 ml dry DMF was added. After cooling to 0° C., 4-hydroxy-benzoic acid methyl ester Q-2 (1.67 g, 11 mmol) was added and the mixture stirred for 15 minutes. 4-Chloromethyl-quinoline Q-1 (1.8 g, 10.1 mmol) was dissolved in 3 mL of DMF and added dropwise to the reaction mixture. The temperature was raised to 130° C. and the mixture stirred for a half hour. After cooling to room temperature the reaction mixture was poured into 50 mL 1N sodium hydroxide solution and extracted three times with 20 mL dichloromethane. The combined organic layers were washed twice with water, dried over sodium sulfate and concentrated in vacuo. The crude product (2.5 g) was recrystallized from ethyl ether to give 4-(quinolin-4-ylmethoxy)-benzoic acid methyl ester (1.6 g, 5.45 mM) as a white solid.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](\[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])/[C:5]([NH:7][CH3:8])=[O:6].C1C(=O)N([Br:23])C(=O)C1.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1/[C:4](=[N:3]\[O:2][CH3:1])/[C:5]([NH:7][CH3:8])=[O:6]
Reactant: CNC(=O)/C(=N/OC)c1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CNC(=O)/C(=N/OC)c1ccccc1CBr
Yield: 37.9 %

Procedure:
To (E)-2-methoxyimino-2-(2-methylphenyl)-N-methylacetamide (2.66 g, 0.01 mol), added were carbon tetrachloride (20 ml), NBS (1.96 g, 0.011 mol) and α,α'-azobis(isobutyronitrile) (0.16 g, 0.001 mol), and the reaction mixture was heated under reflux for 1 hour. After completion of the reaction, undissolved materials were removed and the remaining mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/toluene) to give (E)-2-(2-bromomethylphenyl)-2-methoxyimino-N-methylacetamide (1.08 g; yield, 37.7%) as an oil.