Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[O:21][C:22]([F:25])([F:24])[F:23].[F:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1B(O)O>>[F:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[O:21][C:22]([F:25])([F:24])[F:23]
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: O=C(O)CCc1cccc(OCc2ccc(Cl)c(OC(F)(F)F)c2)c1
Product: COc1ccc(F)c(-c2ccc(COc3cccc(CCC(=O)O)c3)cc2OC(F)(F)F)c1

Procedure:
Compound 38 was synthesized using the procedure described above for preparing 13.3 using compound 37.3 and 2-fluoro-5-methoxyphenylboronic acid 38.1 (available from Aldrich). MS ESI (neg.) m/e: 463 (M−H). 1H NMR (400 MHz, CD3CN) δ ppm 7.47-7.54 (3H, m), 7.22 (1H, t, J=7.8 Hz), 7.12-7.17 (1H, m), 6.98 (1H, dt, J=9.0, 3.5 Hz), 6.90-6.93 (2H, m), 6.85 (2H, dd, J=8.0, 2.2 Hz), 5.16 (2H, s), 3.79 (3H, s), 2.86 (2H, s), 2.56-2.62 (2H, m).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9]P(=O)(OCC)OCC)[CH:6]=[CH:5]C=[CH:3][CH:2]=1.Cl.[NH2:19]CP(=O)(OCC)OCC>>[N:9]1[CH:5]=[CH:6][C:1]([CH2:2][CH2:3][NH2:19])=[CH:7][CH:8]=1
Reactant: CCOP(=O)(NCCc1ccccc1)OCC
Reactant: CCOP(=O)(CN)OCC
Agent: Cl
Product: NCCc1ccncc1
Yield: 47.5 %

Procedure:
Treatment of the phosphoramidate obtained in stage (d) with an aqueous solution of hydrochloric acid, under the conditions described in Example 1, gives, after rendering the mixture basic, 5.6 g. (yield: 47.5%, referred to the diethyl aminomethylphosphonate) of the desired amine in the form of a yellow oil which turns brown in air.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:22][C:23]1[C:24]([F:31])=[CH:25][C:26]([CH3:30])=[C:27]([OH:29])[CH:28]=1>>[ClH:1].[F:31][C:24]1[C:23]([NH:22][C:2]2[C:3]3[C:10]4[CH2:11][CH2:12][NH:13][CH2:14][C:9]=4[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:28][C:27]([OH:29])=[C:26]([CH3:30])[CH:25]=1
Reactant: Cc1cc(F)c(N)cc1O
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Product: Cc1cc(F)c(Nc2ncnc3sc4c(c23)CCNC4)cc1O
Product: Cl

Procedure:
The title compound was prepared in analogy to Example 65A from tert-butyl 4-chloro-5,8-dihydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7(6H)-carboxylate from Example 11A (2.20 g, 6.75 mmol) and 5-amino-4-fluoro-2-methylphenol (1.00 g, 7.09 mmol) to yield 2.69 g (100%).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:6]=[CH:7][CH:8]=1.[Br:13]CC1C(C(OC)=O)=CC=CC=1.[CH2:25]([P:29]([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH3:28].[Br-].[Na+]>O.C(#N)C>[Br-:13].[CH3:12][O:11][C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][P+:29]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:25][CH2:26][CH2:27][CH3:28])=[O:10]
Reactant: COC(=O)c1ccccc1CCl
Reactant: COC(=O)c1ccccc1CBr
Reactant: CCCCP(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCCC[P+](CCCC)(CCCC)Cc1ccccc1C(=O)OC

Procedure:
To a suitable vessel containing about 16.2 g of an approximate 50:50 mixture of methyl α-chloro-o-toluate and methyl α-bromo-o-toluate is added 100 ml of acetonitrile and 17.2 g (0.085 mol) of tributylphosphine and held at reflux under nitrogen for about 45 minutes. The solvent is removed under vacuum and the residue is dissolved in 370 ml of water. The aqueous solution is extracted twice with ether and added to a solution of 102 g (1.0 mol) of sodium bromide in 150 ml of water. This mixture is extracted with three 150 ml portions of chloroform. The chloroform extracts are combined, dried over calcium sulfate and concentrated under vacuum to 36.3 g of colorless oil. Two triturations of this oil with ether provides a white solid which upon recrystallization from ethyl acetate-ether yields approximately 24.6 g of o-methoxycarbonylbenzyltributylphosphonium bromide having a melting point of 65°-66°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1>CN(C=O)C>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[CH3:1])[CH:7]=[C:8]2[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:25][CH:24]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cc2cccc(C)c2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cccc(C)c2n1Cc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
ethyl 7-methyl-1H-indole-2-carboxylate (500 mg, 2.46 mmol) was dissolved in DMF (20 mL) and granular potassium carbonate (425 mg, 3.08 mmol) and p-chlorobenzylchloride (0.39 mL, 3.08 mmol) were added The mixture was stirred for 3 d at 60° C., after which time the incomplete reaction was terminated by dilution with ethyl acetate and subsequent washing with brine (3×). The organic phase was dried over magnesium sulfate, concentrated, and purified vial silica gel flash chromatography (80 g silica, 40% EtOAc/hexanes.) The title compound was obtained as white crystals. (Yield: 390 mg, 1.19 mmol, 46%) 1H NMR (400 MHz, CDCl3) 7.56, 7.41, 7.32-6.96, 6.78, 6.08, 4.31-4.25, 2.54, 1.34
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:26]N1C(=O)CCC1=O.[OH-].[Na+]>CN(C)C=O>[Cl:26][C:14]1[C:13]2[CH:12]=[C:11]([O:10][CH:7]3[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]3)[CH:19]=[CH:18][C:17]=2[N:16]2[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)N1CCC(Oc2ccc3c(c2)c(Cl)c2n3[C@H](C)CNC2=O)CC1
Reaction time: 18 h
Yield: 0 %

Procedure:
To the solution of 0.20 g (0.58 mmol) (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8) in 3 mL N,N-dimethylformamide, 86 μg (0.64 mmol) N-chlorosuccinimide were added and the solution was stirred for 18 hours. The reaction mixture was poured on 1M aqueous sodium hydroxide solution and was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash column chromatography on silica gel with dichloromethane: methanol:ammonia (9:1:0.1 v/v) as eluant to give 81 μg (37%) of the desired compound as a colorless oil.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH3:12][NH2:13]>CO>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([NH:13][CH3:12])=[O:10]
Reactant: COC(=O)c1ccccc1O
Reactant: CN
Solvent: CO
Product: CNC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
A solution of methyl salicylate (5.16 mL, 40 mmol) in methanol (10 mL) was added dropwise to aqueous 40% methylamine (18.1 mL, 210 mmol) at 0° C. After addition was complete the reaction mixture was kept on stirring at room temperature overnight. The volatiles were removed in vacuo to give the subtitled compound (5.48 g).
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.[C:14]([O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)(=[O:16])[CH3:15].S(Cl)([Cl:29])=O>ClCCl.C(OCC)C>[C:14]([O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([Cl:29])=[O:23])=[CH:20][CH:19]=1)(=[O:16])[CH3:15]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)Oc1ccc(C(=O)Cl)cc1
Temperature: 25 °C

Procedure:
1.1 ml (5.6 mmol) of dicyclohexylamine are added to 1 g (5.6 mmol) of 4-acetoxybenzoic acid placed in 10 ml of dichloromethane, and the solution is stirred at room temperature for minutes. 400 μl (5.6 mmol) of thionyl chloride are added and this mixture is stirred at room temperature for 2 hours. The reaction medium is diluted with ethyl ether. The precipitate is filtered off and rinsed with ethyl ether. Concentration of the filtrate gives the 4-acetoxybenzoyl chloride.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:50]=[CH:49][C:9]2[N:10]([CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23]3[C:28]([C:29]5[CH:34]=[CH:33][C:32](F)=[CH:31][CH:30]=5)=[CH:27][CH:26]=[C:25]([C:36]([N:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)=[O:37])[CH:24]=3)[CH:17]=[CH:16]4)=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[C:51](C1C=CC(B(O)O)=CC=1)([OH:53])=[O:52]>>[CH2:1]([O:3][C:4]([C:6]1[CH:50]=[CH:49][C:9]2[N:10]([CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23]3[C:28]([C:29]5[CH:34]=[CH:33][C:32]([C:51]([OH:53])=[O:52])=[CH:31][CH:30]=5)=[CH:27][CH:26]=[C:25]([C:36]([N:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)=[O:37])[CH:24]=3)[CH:17]=[CH:16]4)=[N:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4-c4ccc(F)cc4)ccc3c1)n2C1CCCCC1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4-c4ccc(C(=O)O)cc4)ccc3c1)n2C1CCCCC1

Procedure:
Prepared as described for Compound 549a using 4-carboxyphenylboronic acid instead of 4-fluorophenylboronic acid.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])O.[FH:13]>>[CH:11]1([F:13])[O:12][C@H:3]([CH2:2][OH:1])[C@@H:5]([OH:6])[C@H:7]([OH:8])[C@H:9]1[OH:10]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: F
Agent: *C(F)(F)C(*)(F)F
Product: OC[C@H]1OC(F)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 2.5 h
Yield: 94 %

Procedure:
In a distillation flask of polytetrafluoroethylene, a solution of 10 g of glucose in 100 g of hydrogen fluoride, prepared analogously to Example 1, was distilled under reduced pressure at an internal temperature of -30° C. The pressure was regulated between 100 and 130 mbar in such a way that steady distillation took place. After 2.5 hours, the residual HF content in the bottoms from the distillation was then only 5 g. The distillation was terminated, and the residue worked up in accordance with Example 1. 9.5 g of glucosyl fluoride were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH2:35](O)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH2:24][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH3:35])=[CH:18][CH:17]=1
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Yield: 54 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-octadecanol (70 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (54 mg, yield 51%).
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[CH:9]=2)[N:4]([S:22]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27](F)[CH:26]=2)(=[O:24])=[O:23])[CH2:3]1.[CH2:35]([OH:37])[CH3:36].[H-].[Na+].O>CN(C)C=O>[CH3:34][C:2]1([CH3:1])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[CH:9]=2)[N:4]([S:22]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([O:37][CH2:35][CH3:36])[CH:26]=2)(=[O:24])=[O:23])[CH2:3]1
Reactant: CC1(C)Cc2cc(-c3ccc(C(F)(F)F)cc3)ccc2N(S(=O)(=O)c2ccc(C#N)c(F)c2)C1
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(S(=O)(=O)N2CC(C)(C)Cc3cc(-c4ccc(C(F)(F)F)cc4)ccc32)ccc1C#N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
165 mg 4-[3,3-Dimethyl-6-(4-trifluoromethyl-phenyl)-3,4-dihydro-2H-quinoline-1-sulfonyl]-2-fluoro-benzonitrile and 30 ml ethanol were dissolved in 3 ml dimethylformamide. Then 10 mg sodium hydride were added and the reaction mixture stirred at room temperature for 4 hours. The mixture was then poured into 20 ml water and extracted five times with portions of 20 ml ethyl acetate. The combined organic extracts were dried over MgSO4 then evaporated in vacuo and the residue purified by chromatography on silica gel to obtain 40 mg 4-[3,3-Dimethyl-6-(4-trifluoromethyl-phenyl)-3,4-dihydro-2H-quinoline-1-sulfonyl]-2-ethoxy-benzonitrile.
Reaction SMILES: [C:1]([O:6][CH2:7][C:8]([F:11])([F:10])[F:9])(=[O:5])[C:2]([O-:4])=O.[CH2:12]([NH2:15])[CH2:13][NH2:14]>FC(F)(F)CO>[F:9][C:8]([F:11])([F:10])[CH2:7][O:6][C:1](=[O:5])[C:2]([NH:14][CH2:13][CH2:12][NH:15][C:2](=[O:4])[C:1]([OH:6])=[O:5])=[O:4]
Reactant: NCCN
Reactant: O=C([O-])C(=O)OCC(F)(F)F
Solvent: OCC(F)(F)F
Product: O=C(O)C(=O)NCCNC(=O)C(=O)OCC(F)(F)F
Reaction time: 18 h

Procedure:
A 500 mL 3-neck round bottom flask equipped with a magnetic stirbar, thermocouple, and argon inlet was charged with 2,2,2-trifluoroethyl oxalate (from Preparatory Example P7) (152.5 grams) and 2,2,2-trifluoroethanol (150 grams). The contents were cooled in an ice bath, and a mixture of ethylene diamine (EDA) (3.606 grans) in 2,2,2-trifluoroethanol (40 grams) was added dropwise over a period of 75 minutes. The cooling bath was removed, and the contents were stirred for 18 hours, after which time methyl tert-butyl ether (100 mL) was added, and the solids were then collected via filtration. The resulting 10.2 grams of solids was recrystallized from boiling 2,2,2-trifluoroethanol (416 grams) to obtain 9.23 grams of ethylene-bis-oxamic acid trifluoroethyl ester as white crystals having a melting point of 223° C. 1H NMR (300 MHz, d6-DMSO) δ 9.18 (brs, 2H), 4.92 (q, J=8.9 Hz, 4H), 3.31-3.29 (m, 4H).
Reaction SMILES: C[Al](C)C.CCCCCC.[Cl-].[NH4+:12].[C:13]([C:15]1[C:20]2[N:21]=[C:22]([C:24]([O:26]CC)=O)[O:23][C:19]=2[C:18]([F:29])=[C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:16]=1[CH3:36])#[N:14].Cl>O.ClCCl>[C:13]([C:15]1[C:20]2[N:21]=[C:22]([C:24]([NH2:12])=[O:26])[O:23][C:19]=2[C:18]([F:29])=[C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:16]=1[CH3:36])#[N:14]
Reactant: CCOC(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Reactant: [NH4+]
Agent: C[Al](C)C
Agent: Cl
Agent: [Cl-]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: O
Product: Cc1c(-c2ccccc2)c(F)c2oc(C(N)=O)nc2c1C#N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.9 %

Procedure:
At room temperature, trimethylaluminium (4.49 ml, 4.63 mmol, 1.03 M hexane solution was added to an anhydrous dichloromethane (6 ml) suspension of ammonium chloride (247 mg, 4.62 mmol), followed by stirring at room temperature for 20 minutes. A dichloromethane (4 ml) solution of ethyl 4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-2-carboxylate (I-111) (500 mg, 1.54 mmol) was added, followed by stirring for 4 hours and by heating under reflux in an oil bath at 45° C. for 48 hours. With cooling with ice, 1 N hydrochloric acid (10 ml) was added to the reaction liquid, then water (20 ml) was added, followed by extraction with chloroform (100 ml×2). The organic layer was washed with saturated brine (100 ml), then dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified in slurry with diethyl ether to obtain the entitled compound (368 mg, 80.8%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[N:18]=[C:17]2[CH:19]=[CH:20][CH:21]=[C:22]([Cl:23])[C:16]2=[N:15]1)[CH2:11][C:12]#[CH:13]>>[Cl:23][C:22]1[C:16]2[C:17](=[N:18][N:14]([CH2:10][CH2:11][C:12]#[C:13][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=3)[N:15]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCn1nc2cccc(Cl)c2n1
Product: FCc1cccc(C#CCCn2nc3cccc(Cl)c3n2)n1
Yield: 34 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (30 mg, 0.16 mmol) and 2-(but-3-ynyl)-4-chloro-2H-benzo[d][1,2,3]triazole (30 mg, 0.15 mmol, Example 146(B)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 16 mg (51 μmol, 35%) of 4-chloro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a brown oil.
Reaction SMILES: O.O.[Sn](Cl)Cl.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:16]=[N:17][CH:18]=[C:19]([O:21][CH3:22])[CH:20]=2)=[CH:9][C:8]=1[N+:23]([O-])=O.[OH-].[K+]>C(O)C.O1CCCC1>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:16]=[N:17][CH:18]=[C:19]([O:21][CH3:22])[CH:20]=2)=[CH:9][C:8]=1[NH2:23]
Reactant: COc1cncc(C#Cc2ccc(F)c([N+](=O)[O-])c2)c1
Agent: Cl[Sn]Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cncc(C#Cc2ccc(F)c(N)c2)c1
Temperature: 70 °C

Procedure:
Add tin (II) chloride dihydrate (1.41 g, 6.26 mmol) to a suspension of 3-(4-fluoro-3-nitrophenylethynyl)-5-methoxypyridine, (prepared as described in EXAMPLE 116), (190 mg, 0.69 mmol) in ethanol (20 mL) and tetrahydrofuran (17 mL) under nitrogen and heat at 70° C. for 2 h. Cool the reaction mixture, add a 50% aqueous solution of potassium hydroxide (100 mL), and extract with diethyl ether (2×100 mL). Wash the combined organic phases with an aqueous saturated solution of sodium chloride (100 mL), dry (sodium sulfate), filter, and concentrate. Purify the residue by silica gel chromatography, eluting with ethyl acetate to give the title compound as a yellow solid. Further purify the title compound by silica gel chromatography, eluting with 100% dichloromethane to 20:80 ethyl acetate:dichloromethane, to give the title compound as a white solid (143 mg, 86%).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:11]=3[N:12]=2)[CH2:4]1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][N:2]([CH3:18])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([NH:17][C:30]([C:29]4[CH:28]=[CH:27][C:26]([C:23]5[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=5)=[CH:34][CH:33]=4)=[O:31])=[CH:13][C:11]=3[N:12]=2)[CH2:4]1
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)cc1
Reactant: CN(C)C1CCN(c2nc3cc(N)ccc3o2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C1CCN(c2nc3cc(NC(=O)c4ccc(-c5ccc(F)cc5)cc4)ccc3o2)C1
Reaction time: 72 h
Yield: 77.2 %

Procedure:
Combine 2-(3-dimethylamino-pyrrolidin-1-yl)-benzooxazol-5-ylamine (0.100 g, 0.406 mmol), 4-(4-fluorophenyl)benzoic acid (0.073 g, 0.338 mmol), and HATU (0.129 g, 0.338 mmol) in CH2Cl2 and add DIEA (0.18 mL, 1.01 mmol). Shake the mixture in a shaker block at 40° C. for 72 h. Dilute the reaction mixture with CH2Cl2 (30 mL), and wash with saturated NaHCO3 (aqueous) (2×25 mL). Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate in vacuo. Subject the crude product to flash column chromatography (40 g column) eluting with 8% MeOH/CH2Cl2, to yield the title compound as a bluish-white solid (0.116 g, 65%). mass spectrum (m/e): 445.3 [M+1], 443.3 [M−1]. 1H NMR (400 MHz, DMSO-d6): δ 10.23 (s, 1H), 8.05 (d, 2H, J=8.4 Hz), 7.85-7.79 (m, 4H), 7.75 (d, 1H, J=2.2 Hz), 7.41-7.30 (m, 4H), 3.79 (dd, 1H, J=9.9, 7.1 Hz), 3.72 (m, 1H), 3.54 (m, 1H), 3.31 (m, 1H), 2.86 (m, 1H), 2.25-2.12 (m, 7H), 1.86 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:26][C:25]3[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COc1cccc(C2C(=O)Nc3cc(Cl)ccc32)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(CC2(c3cccc(OC)c3)C(=O)Nc3cc(Cl)ccc32)cc1
Temperature: 60 °C

Procedure:
A mixture of rac-6-chloro-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (0.16 g, 0.6 mmol) (from Example 6b supra), 4-methoxybenzyl chloride (0.15 g, 0.7 mmol) (Aldrich), potassium iodide (0.12 g, 0.71 mmol) and potassium carbonate (0.18 g, 1.3 mmol) in acetone (5 mL) was heated at 60° C. for 4 hours in a capped pressure tube. After cooling, mixture was diluted with ethyl acetate (50 mL) and extracted with water (2×50 mL) and brine (50 mL). Aqueous layers were back washed with ethyl acetate (50 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was recrystallized from dichloromethane-hexanes to give rac-6-chloro-3-(4-methoxy-benzyl)-3-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one as white needles. (Yield 0.19 g, 80.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:31][C:11]3[C:12](=[O:30])[N:13]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[N:18]=4)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C=O.[C:34](O)(=O)C>C(Cl)Cl.CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:31][C:11]3[C:12](=[O:30])[N:13]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH:24]5[CH2:25][CH2:26][N:27]([CH3:34])[CH2:28][CH2:29]5)[N:18]=4)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=c1c2sc(-c3ccc(Cl)cc3)cc2cnn1Cc1cccc(OC2CCNCC2)n1
Reactant: CC(=O)O
Agent: C=O
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(Oc2cccc(Cn3ncc4cc(-c5ccc(Cl)cc5)sc4c3=O)n2)CC1
Reaction time: 2 h

Procedure:
To a solution of 2-(4-chlorophenyl)-6-{[6-(piperidin-4-yloxy)pyridin-2-yl]methyl}thieno[2,3-d]pyridazin-7(6H)-one (0.16 g, 0.34 mmol) in DCM/MeOH (1:1, 10 mL) was added (polystyrylmethyl)trimethylammonium cyanoborohydride (0.25 g, 1.03 mmol), 36% aq. formaldehyde (0.05 mL, 0.69 mmol) and acetic acid (one drop). After 3 hours of stirring one additional amount of (polystyrylmethyl)trimethylammonium cyanoborohydride, formaldehyde and acetic acid added to the reaction mixture and stirred for two hours. The reaction mixture was filtrated, concentrated in vacuo and purified by flash chromatography using a gradient with EtOAc:MeOH:TEA (1:0.1:0.05) in n-heptane, which gave the product. Yield: 0.084 g (52%). 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.57-7.64 (m, 2H), 7.30-7.49 (m, 4H), 6.71 (d, 1H, J=7.31 Hz), 6.52 (d, 1H, J=8.16 Hz), 5.47 (s, 2H), 4.69-4.79 (m, 1H), 2.49-2.58 (m, 2H), 2.13 (s, 3H), 1.87-1.99 (m, 2H), 1.75-1.84 (m, 2H), 1.58-1.69 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 163.0, 157.4, 153.5, 152.3, 140.3, 139.3, 136.4, 136.0, 133.1, 131.3, 129.8, 128.1, 113.8, 110.1, 70.5, 55.6, 53.3, 46.4, 31.0 MS (ESI+) 467.08 (M+1H+).