Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([O:15][CH3:16])[C:7](F)=[C:8]([F:13])[CH:9]=2)[N:4]([CH:17]2[CH2:19][CH2:18]2)[C:3]1=[O:20].[C:21]([O:25][C:26](=[O:35])[NH:27][C@H:28]([C@@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)[CH3:29])([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C.CS(C)=O>O>[C:21]([O:25][C:26](=[O:35])[NH:27][C@@H:28]([C@H:30]1[CH2:34][CH2:33][N:32]([C:7]2[C:6]([O:15][CH3:16])=[C:5]3[C:10]([C:11](=[O:12])[N:2]([NH2:1])[C:3](=[O:20])[N:4]3[CH:17]3[CH2:19][CH2:18]3)=[CH:9][C:8]=2[F:13])[CH2:31]1)[CH3:29])([CH3:22])([CH3:23])[CH3:24]
Reactant: C[C@H](NC(=O)OC(C)(C)C)[C@@H]1CCNC1
Reactant: COc1c(F)c(F)cc2c(=O)n(N)c(=O)n(C3CC3)c12
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1c(N2CC[C@H]([C@@H](C)NC(=O)OC(C)(C)C)C2)c(F)cc2c(=O)n(N)c(=O)n(C3CC3)c12
Temperature: 25 °C
Yield: 96.3 %

Procedure:
A solution of 0.57 g (2.0 mmol) of 3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione (Example 24d), 0.64 g (3.0 mmol) of ((S)-(R)-1-pyrrolidin-3-ylethyl)carbamic acid tert-butyl ester (J. Het. Chem., 1992; 29:1481), 0.81 g (8.0 mmol) of triethylamine and 10 mL of dimethyl sulfoxide is heated at 110° C. for 4 hours. The reaction mixture is cooled to room temperature, poured into 150 mL of ice and water, and extracted with ethyl acetate (2×125 mL). The combined organic layers are washed with water, dried (MgSO4), filtered and evaporated in vacuo to give 1.1 g of crude product. Chromatography on flash grade silica gel (230–400 mesh) eluting with dichloromethane/ethanol (9:1) provided 0.92 g of the title compound, mp 96–98° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]#[N:12])[CH:10]=1)[C:5](O)=[O:6].C(Cl)(=O)C([Cl:16])=O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]#[N:12])[CH:10]=1)[C:5]([Cl:16])=[O:6]
Reactant: N#Cc1cc(F)cc(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: N#Cc1cc(F)cc(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
3-Fluoro-5-cyanobenzoic acid (2.5 g, 15.14 mmol) was treated with a solution of oxalyl chloride (30 mL of 2.5 M in dichloromethane, 75 mmol) and a catalytic amount of N,N-dimethylformamide. The reaction was stirred at ambient temperature for 2.5 hours. The excess oxalyl chloride was removed in vacuo to afford 3-fluoro-5-cyanobenzoyl chloride.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ONC(=O)CCC(N)=O.C(Cl)CCl.[NH2:41][CH2:42][C:43]1[CH:51]=[CH:50][C:46]([C:47]([OH:49])=[O:48])=[CH:45][CH:44]=1>ClCCl>[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([NH:41][CH2:42][C:43]4[CH:44]=[CH:45][C:46]([C:47]([OH:49])=[O:48])=[CH:50][CH:51]=4)=[O:24])=[CH:26][CH:27]=3)(=[O:17])=[O:18])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1
Reactant: NCc1ccc(C(=O)O)cc1
Agent: NC(=O)CCC(=O)NO
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(O)c1ccc(CNC(=O)c2ccc(S(=O)(=O)n3cc(-c4ccccc4)c4ccccc43)cc2)cc1
Yield: 48.1 %

Procedure:
Combine 4-(3-Phenyl-indole-1-sulfonyl)-benzoic acid (1.324 mmole) with N-hydroxy-succinamide (NHS− 1.457 mmoles), and EDC (1.324 mmoles) and stir in 20 ml dichloromethane for 15 hr. Condense the reaction to produce a solid. Isolate 0.613 g (yield=97.6%). React 1.05 mmole of residue with 4-aminomethyl-benzoic acid (1.05 mmole) in 3 ml dichloromethane for 15 hrs. Dilute reaction mixture and wash with 1 N HCl. Treat dichloromethane with MgSO4 and concentrate. Isolate a mixture of 4-(3-Phenyl-indole-1-sulfonyl)-benzoic acid and the title compound 0.258 g (48%): MS ES+5.10-77 MS ES−509.21.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[N:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:30]2[CH2:31][CH2:32][N:27]([C:22]3[N:21]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:28][CH2:29]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Reactant: c1cnc(N2CCNCC2)nc1
Product: COc1ccc2nc(OC)c(NC(=O)N3CCN(c4ncccn4)CC3)nc2c1
Yield: 80 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate and 1-(2-pyrimidyl)piperazine were reacted by the same way with the example 64 to obtain the titled compound (yield, 80%). 1H NMR (300 MHz, CDCl3): δ 3.72 (s, 3H), 3.87-3.96 (m, 7H), 4.12-4.15 (m, 4H), 6.54 (t, J=4.8 Hz, 1H), 6.92 (s, 1H), 7.04-7.36 (m, 3H), 7.62 (m, 1H), 8.34 (d, J=4.8 Hz, 2H).
Reaction SMILES: [Na].[Cl:2][C:3]1[NH:4][C:5]([Cl:9])=[C:6]([Cl:8])[N:7]=1.[H-].[Na+].[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18]Cl>CN(C)C=O.O>[Cl:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18][N:4]1[C:5]([Cl:9])=[C:6]([Cl:8])[N:7]=[C:3]1[Cl:2]
Reactant: ClCCCCOCCl
Reactant: Clc1nc(Cl)c(Cl)[nH]1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: ClCCCCOCn1c(Cl)nc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
To a solution of a sodium salt, prepared from 0.69 g of 2,4,5-trichloroimidazole and 0.16 g of 60% oil-based sodium hydride, in 5 ml of N,N-dimethylformamide was added dropwise 0.63 g of 4-chlorobutoxymethyl chloride at room temperature. After stirring at room temperature for 3 hours, 50 ml of water was added to the reaction mixture which was then extracted with three 30-ml portions of ether. The ether layer was dried over magnesium sulfate and concentrated. The oily product obtained was purified by column chromatography on silica gel to obtain 0.83 g of 1-(4-chlorobutoxymethyl)-2,4,5-trichloroimidazole.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][N:5]=1.[OH-].[Na+].[Cl:16][C:17]1[CH:26]=[CH:25][C:20]2[NH:21][C:22]([SH:24])=[N:23][C:19]=2[CH:18]=1>CO.O>[Cl:16][C:17]1[CH:26]=[CH:25][C:20]2[NH:21][C:22]([S:24][CH2:3][C:4]3[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][N:5]=3)=[N:23][C:19]=2[CH:18]=1
Reactant: Sc1nc2cc(Cl)ccc2[nH]1
Reactant: COc1ccnc(CCl)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccnc(CSc2nc3cc(Cl)ccc3[nH]2)c1OC

Procedure:
2-chloromethyl-3,4-dimethoxypyridine hydrochloride (896 mg, 0.004 mol) was dissolved in 25 ml MeOH and treated with NaOH (390 mg, 0.008 mol) dissolved in 1.5 ml H2O. 5-chloro-2-mercapto-1H-benzimidazole (812 mg, 0.0044 mol) was added and the resulting mixture allowed to react for 2h at room temperature. The solvent was evaporated and the residue partitioned between 50 ml 2.5 % NaOH and 75 ml CH2Cl2. The aqueous layer was separated and extracted twice with 25 ml CH2Cl2. The organic layers were combined, washed with 25 ml H2O, dried over MgSO4 and the solvent was evaporated.
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17](C)=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1C=CC=CC=1.C/C(/C(C)=O)=N\O.[F:28][C:29]([F:39])([F:38])C1C=C(C=CC=1)C=O>>[I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([C:29]([F:39])([F:38])[F:28])[CH:19]=2)[O:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: CC(=O)/C(C)=N/O
Product: Cc1oc(-c2cccc(C(F)(F)F)c2)nc1CI

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, diacetylmonoxime and 3-trifluoromethylbenzaldehyde gave 4-iodomethyl-5-methyl-2-(3-trifluoromethylphenyl)oxazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[CH:8]=[C:7]([CH2:12][CH2:13][CH2:14][C:15]#[N:16])[C:6]=2[CH:17]=1.[OH2:18]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9](=[O:11])[CH:8]=[C:7]([CH2:12][CH2:13][CH2:14][C:15]([NH2:16])=[O:18])[C:6]=2[CH:17]=1
Reactant: N#CCCCc1cc(=O)oc2ccc(Cl)cc12
Reactant: O
Agent: O=S(=O)(O)O
Product: NC(=O)CCCc1cc(=O)oc2ccc(Cl)cc12
Reaction time: 4 h
Yield: 93 %

Procedure:
4-(6-Chloro-2-oxo-2H-1-benzopyran-4-yl)-butyronitrile (100 mg, 0.4 mmol) is dissolved in conc. H2SO4 (2 mL) and is stirred for 4 hrs. Ice and then H2O (20 mL) is added to the reaction mixture, and the resulting precipitate is filtered and is washed with H2O and Et2O. The solid is dried in vacuo to give the title compound (100 mg, 93%) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 7.98 (1H, d, J=2 Hz), 7.68 (1H, dd, J=2, 9 Hz), 7.47 (1H, d, J=9 Hz), 7.32 (1H, broad s), 6.83 (1H, broad s), 6.43 (1H, s), 2.79 (2H, t, J=7 Hz), 2.20 (2H, t, J=7 Hz), 1.82 (2H, q, J=7 Hz); LCMS (MeCN—H2O, Luna 3μ C18(2) 30×4.6 mm) m/z (ES, Pos) calc. for C13H12ClNO3 m/z [M+H]=266, found 266.
Reaction SMILES: CN(C)C=O.[C:6]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[H-].[Na+].Cl[CH2:20][N:21]([N:23]1[C:32]2[C:27](=[CH:28][C:29]([F:35])=[C:30]([F:34])[C:31]=2[F:33])[C:26](=[O:36])[C:25]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:24]1)[CH3:22]>O.C(OCC)(=O)C>[F:35][C:29]1[CH:28]=[C:27]2[C:32](=[C:31]([F:33])[C:30]=1[F:34])[N:23]([N:21]([CH3:20])[CH2:22][CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6]([O:14][CH2:15][CH3:16])=[O:13])[CH:24]=[C:25]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:26]2=[O:36]
Reactant: CCOC(=O)c1cn(N(C)CCl)c2c(F)c(F)c(F)cc2c1=O
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cn(N(C)CC(C(=O)OCC)C(=O)OCC)c2c(F)c(F)c(F)cc2c1=O

Procedure:
To dimethylformamide (1.5 ml) solution of diethyl malonate (47.8 μl), was added sodium hydride (24.4 mg) with stirring under ice-cooling, and the mixture was stirred for 20 minutes with ice-cooling. To the solution was added ethyl 1-[N-(chloromethyl)-N-methylamino]-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (100 mg) with stirring under ice-cooling, and the mixture was stirred for 30 minutes at the same temperature. The reaction solution was added to a mixed solution comprising ethyl acetate (30 ml) and water (30 ml) for extraction. The organic layer was washed with water (30 ml×3) and a saturated brine(30 ml×3), dried over magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was subjected to column chromatography with silica gel (3 g), eluted with a mixed solvent of dichloromethane ethyl acetate (20/1 to 10/1) and concentrated to dryness under reduced pressure to obtain ethyl 6,7,8-trifluoro-1-[N-methyl-N-{2,2-bis(ethoxycarbonyl)ethyl}amino]-1,4-dihydro-4-oxoquinoline-3-carboxylate (49.1 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[Li]CCCC.[B:14](OC)([O:17]C)[O:15]C>CCOCC>[F:8][C:5]1[N:6]=[CH:7][C:2]([B:14]([OH:17])[OH:15])=[CH:3][CH:4]=1
Reactant: COB(OC)OC
Reactant: Fc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: CCOCC
Product: OB(O)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 583.8 %

Procedure:
To a mixture of 5-bromo-2-fluoro-pyridine (1.71 g, 6.20 mmol) in dry ether (100 mL) was added n-BuLi (1.6 M in hexane, 41.4 mL, 0.0663 mol) at −78° C. After 30 minutes, trimethyl borate (8.2 mL, 0.0722 mol) was added to the above mixture and the reaction was warmed to room temperature and stirred overnight. The reaction was quenched with water and brine and acidified with 10% HCl until pH=8. The mixture was extracted with EtOAc, washed with 50% brine, dried over MgSO4, filtered, concentrated to give 5.1 g (60%) of the desired product. The crude product was used in the next step without further purification.
Reaction SMILES: Cl[S:2]([C:5]1[C:6](=[O:22])[C:7]2[C:15](=[CH:16][CH:17]=1)[C:14]1[C:9](=[CH:10][C:11]([S:18](Cl)(=[O:20])=[O:19])=[CH:12][CH:13]=1)[CH:8]=2)(=[O:4])=[O:3].C(=O)(O)[O-].[Na+:27].S([O-])([O-])=O.[Na+:32].[Na+]>O>[Na:27][S:2]([C:5]1[C:6](=[O:22])[C:7]2[C:15](=[CH:16][CH:17]=1)[C:14]1[C:9](=[CH:10][C:11]([S:18]([Na:32])(=[O:20])=[O:19])=[CH:12][CH:13]=1)[CH:8]=2)(=[O:4])=[O:3]
Reactant: O=C1C2=Cc3cc(S(=O)(=O)Cl)ccc3C2=CC=C1S(=O)(=O)Cl
Reactant: [Na+]
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: O
Product: O=C1C2=Cc3cc(S(=O)(=O)[Na])ccc3C2=CC=C1S(=O)(=O)[Na]

Procedure:
Also, for example, 2,7-bis(chlorosulfonyl)-fluorenone can be mixed with a heated solution of sodium bicarbonate and sodium sulfite in water to yield 2,7-bis(sodiosulfonyl)fluorenone, which can be refluxed with n-butyl iodide in ethanol to yield 2,7-bis(n-butylsulfonyl)fluorenone, which in turn can be refluxed with malononitrile in methanol in the presence of piperidine to yield 2,7-bis(n-butyl sulfonyl)-9-(dicyanomethylene)fluorene.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:18][C:17](/[CH:26]=[C:27](\[CH3:33])/[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.B(Cl)(Cl)Cl.ClCCl>>[CH:20]1([C:19]2[N:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[N:16]=[C:17](/[CH:26]=[C:27](\[CH3:33])/[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:18]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CCOC(=O)/C(C)=C/c1cc(C2CCCCC2)n(-c2ccc(OCc3ccccc3)cc2)n1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)/C(C)=C/c1cc(C2CCCCC2)n(-c2ccc(O)cc2)n1
Yield: 100.6 %

Procedure:
According to the procedure for preparation of 4.3, debenzylation of 10.1 (440 mg, 0.99 mmol) with 1M BCl3 in dichloromethane (4.95 ml, 4.95 mmol) yielded 353 mg (100%) of 10.3. MS (ESI) 355.4 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][CH2:12][C:13]3=[O:18])=[C:5]([N+:19]([O-])=O)[CH:4]=1.P(OCC)(OCC)OCC>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3[C:10]4[CH2:11][CH2:12][C:13](=[O:18])[C:14]=4[CH:15]=[CH:16][C:17]=3[NH:19][C:5]=2[CH:4]=1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c([N+](=O)[O-])c1
Agent: CCOP(OCC)OCC
Product: COc1ccc2c(c1)[nH]c1ccc3c(c12)CCC3=O
Temperature: 90 °C
Reaction time: 72 h

Procedure:
Biphenyl 35 obtained (5.59 g) was divided into five portions (1.11 g each); then P(OEt)3 (per 7 mL) was added to each portion. The resulting mixture was subjected to argon blow in a flask, heated up to 90° C., kept at this temperature for 3 days, and cooled down. Carbazole was precipitated. Then the reaction mixture was diluted with ether; the precipitate was filtered off and washed with CH2Cl2. If the initial biphenyl remained in the filtrate (TLC monitoring, eluent: hexane-ethyl acetate, 1:1), this filtrate was evaporated and P(OEt)3 (per 1 mL into each flask) was added. The mixture was subjected to repeated cyclization for a day. The procedure repeated until the precipitation ceased and TLC data showed the absence of the initial biphenyl. Total yield of carbazole 36: 2.16 g.
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH2:10][O:11][C:12]1[CH:31]=[CH:30][C:15]([CH2:16][N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19]([CH2:28][OH:29])=[CH:18]2)=[CH:14][CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH3:1][N:2]([CH2:9][CH2:10][O:11][C:12]1[CH:31]=[CH:30][C:15]([CH2:16][N:17]2[CH:21]=[C:20]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:19]([CH:28]=[O:29])=[CH:18]2)=[CH:14][CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CN(CCOc1ccc(Cn2cc(CO)c(-c3ccccc3)c2)cc1)c1ccccn1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: CN(CCOc1ccc(Cn2cc(C=O)c(-c3ccccc3)c2)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
A mixture of [1-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]-4-phenyl-3-pyrrolyl]methanol (1.45 g), activated manganese dioxide (4.0 g), and tetrahydrofuran (60 ml) was stirred at room temperature for 3 hours. After the manganese dioxide was removed by filtration, the filtrate was concentrated to obtain 1-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]-4-phenylpyrrole-3-carbaldehyde (1.40 g, yield: 97%) as an oily substance.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH3:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>>[CH3:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([C:10]3[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=3)=[CH:8][CH:9]=2)=[O:33])=[CH:30][CH:29]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Product: COc1ccc(C(=O)NCCc2ccc(-c3ccc(C(C)CNS(=O)(=O)C(C)C)cc3)cc2)cc1

Procedure:
The title compound was prepared following the method of Example 147 and using 1 mL of a stock solution of 0.6 g (1.8 mmol) of material from Example 50 and 13 μL (0.11 mmol) 4-methoxybenzoyl chloride. NMR was consistent with the proposed compound.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([CH:10]([C:12]3[N:16]4[N:17]=[C:18]([C:21]5[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=5)[CH:19]=[CH:20][C:15]4=[N:14][CH:13]=3)[CH3:11])[CH:7]=[CH:6][C:5]=12.C1C(=O)N([Br:34])C(=O)C1>C(Cl)Cl>[Br:34][C:3]1[N:4]2[CH:9]=[C:8]([CH:10]([C:12]3[N:16]4[N:17]=[C:18]([C:21]5[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=5)[CH:19]=[CH:20][C:15]4=[N:14][CH:13]=3)[CH3:11])[CH:7]=[CH:6][C:5]2=[N:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(c1ccc2nccn2c1)c1cnc2ccc(-c3cnn(C)c3)nn12
Solvent: ClCCl
Product: CC(c1ccc2ncc(Br)n2c1)c1cnc2ccc(-c3cnn(C)c3)nn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(rac)-3-(1-Imidazo[1,2-a]pyridin-6-yl-ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazine (Example 293, 607 mg, 1.768 mmol) was dissolved in DCM (18 mL) and NBS (346 mg, 1.944 mmol) was added. It was stirred at rt for 30 min then the solvent was removed. The residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, 0 to 20% MeOH in DCM). Combined fractions were concentrated to give the title compound as a yellow solid (tR 0.7 min (conditions 2), MH+=422, 1H-NMR in DMSO-d6: 8.47 (s, 1H); 8.37 (s, 1H); 8.04 (m, 2H); 7.78 (s, 1H); 7.67 (s, 1H); 7.54 (d, 1H); 7.47 (d, 1H); 7.32 (d, 1H); 4.81 (q, 1H); 3.89 (s, 3H); 1.80 (d, 3H)).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[C:10]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:9](Cl)[N:8]=[C:7]([CH3:17])[N:6]=1>CO.COCCOC.C(OCC)C>[Cl:4][C:5]1[C:10]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:9]([O:2][CH3:1])[N:8]=[C:7]([CH3:17])[N:6]=1
Reactant: COC(=O)Cc1c(Cl)nc(C)nc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: COCCOC
Product: COC(=O)Cc1c(Cl)nc(C)nc1OC
Reaction time: 0.5 h

Procedure:
Sodium methylate in methanol (33 ml of a 5.4 molar solution) is added at room temperature to a solution of methyl 4,6-dichloro-2-methyl-pyrimidin-5-yl-acetate (35.5 g, 0.15 mol) in 1,2-dimethoxyethane (60 ml). After stirring for 30 minutes the mixture is diluted with diethyl ether and washed with water. Drying and distillation gives the methyl 4-chloro-6-methoxy-2-methyl-pyrimidin-5-yl-acetate as a colorless oil (30 g), b.p. 108°-110° C./0.5 torr.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:23])[N:6]([CH2:19][CH:20]2[CH2:22][CH2:21]2)[N:7]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][CH2:16][CH2:15][C:14]=3[CH:18]=2)[CH:9]=1)([OH:3])=[O:2].O1C2C=CC(C3C=C(C(OC)=O)C(=O)NN=3)=CC=2CC1.[F:44][C:45]1C=CC(CCl)=[CH:47][CH:46]=1>>[C:1]([C:4]1[C:5](=[O:23])[N:6]([CH2:19][C:20]2[CH:47]=[CH:46][C:45]([F:44])=[CH:21][CH:22]=2)[N:7]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][CH2:16][CH2:15][C:14]=3[CH:18]=2)[CH:9]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1cc(-c2ccc3c(c2)CCO3)nn(CC2CC2)c1=O
Reactant: Fc1ccc(CCl)cc1
Agent: COC(=O)c1cc(-c2ccc3c(c2)CCO3)n[nH]c1=O
Product: O=C(O)c1cc(-c2ccc3c(c2)CCO3)nn(Cc2ccc(F)cc2)c1=O
Yield: 54.7 %

Procedure:
The general procedure of Example 1 (3) was carried out by use of 6-(2,3-dihydro-1-benzofuran-5-yl)-4-methoxycarbonyl-2H-pyridazin-3-one and 4-fluorobenzyl chloride, to thereby yield the title compound as a yellow powder (yield: 54.7%).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH3:9][C:10]1[C:11](=[O:24])[O:12][C:13]2[C:18]([CH:19]=1)=[C:17]([O:20][CH2:21][O:22][CH3:23])[CH:16]=[CH:15][CH:14]=2.[NH4+].[Cl-]>CS(C)=O>[CH3:9][C:10]12[CH2:2][CH:19]1[C:18]1[C:17]([O:20][CH2:21][O:22][CH3:23])=[CH:16][CH:15]=[CH:14][C:13]=1[O:12][C:11]2=[O:24]
Reactant: COCOc1cccc2oc(=O)c(C)cc12
Reactant: C[S+](C)(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Product: COCOc1cccc2c1C1CC1(C)C(=O)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.7 %

Procedure:
To a solution of trimethylsulfoxonium iodide (4.52 g, 20.55 mmol) in dry dimethyl sulfoxide (50 ml) stirred under nitrogen at room temperature was added neat sodium hydride (60%, 0.822 g, 20.55 mmol). The reaction mixture was stirred at room temperature for 1 hour before adding 3-methyl-5-{[(methyloxy)methyl]oxy}-2H-chromen-2-one (Intermediate 113, 1.81 g) dissolved into 15 ml of DMSO. The reaction mixture turned yellow and was heated and stirred at 100° C. for 4 h. The reaction was then worked up by the addition of a saturated solution of NH4Cl and extracted with diethyl ether, washed with brine, dried over sodium sulphate, filtered and concentrated under vacuum. The residue obtained was purified by silica gel chromatography (Biotage system, with a gradient from pure cyclohexane to cyclohexane/ethyl acetate 5/1) to give the title compound as a white solid (360 mg).
Reaction SMILES: [CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2].[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][N:19]=1.[H-].[Na+]>CS(C)=O>[CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[N:7]([CH2:25][CH2:24][C:21]3[CH:20]=[N:19][C:18]([CH3:17])=[CH:23][CH:22]=3)[C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2]
Reactant: CCN1CCc2[nH]c3ccc(C)cc3c2C1
Reactant: C=Cc1ccc(C)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCN1CCc2c(c3cc(C)ccc3n2CCc2ccc(C)nc2)C1
Yield: 3 %

Procedure:
Preparation of the title compound was carried out according to General Method 2. 2-Ethyl-2,3,4,5-tetrahydro-8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole was prepared from 2-ethyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole (See Example 6) (214 mg, 1 mmol), 2-methyl-5-vinylpyridine (1 mL, 2.3 mmol) and NaH (120 mg, 3 mmol) in DMSO (4 ml) at 120° C. for 48 h to obtain 10 mg of 2-ethyl-2,3,4,5-tetrahydro-8-methyl-5-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[4,3-b]indole after purification.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11](=O)[C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=[C:14]([CH3:24])[C:13]=1[CH3:25]>C1COCC1>[CH3:25][C:13]1[C:14]([CH3:24])=[CH:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:17][C:12]=1[CH2:11][NH:10][C:3]1[C:2]([F:1])=[C:7]([OH:8])[CH:6]=[CH:5][C:4]=1[F:9]
Reactant: Cc1cc(-c2ccccc2)cc(C(=O)Nc2c(F)ccc(O)c2F)c1C
Solvent: C1CCOC1
Product: Cc1cc(-c2ccccc2)cc(CNc2c(F)ccc(O)c2F)c1C
Temperature: 60 °C
Yield: 58.9 %

Procedure:
To a solution of N-(2,6-difluoro-3-hydroxy-phenyl)-2,3-dimethyl-5-phenyl-benzamide (210 mg, 0.6 mmol, 1.0 eq) in THF (4 mL) at 0° C. was added dropwise a solution of BH3 (1M in THF, 3.6 mL, 3.6 mmol, 6.0 eq). The reaction mixture was heated at 60° C. for 5 h, then cooled and quenched by addition of water. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 100:0 to 10:1) to give the title compound as colorless oil (120 mg, 60%).