Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[OH-].[K+].Cl.Cl[CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.O>C(O)C>[N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:16]=1[CH2:15][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(O)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCCc1ccc(OCc2ccc3ccccc3n2)cc1
Yield: 89 %

Procedure:
4-Hydroxybenzeneethanol (103.5 g) was stirred in ethanol (1.5 l), at room temperature. A solution of potassium hydroxide (84 g) in ethanol (1.5 l) was added dropwise, over a 1 hour period. 2-(Chloromethyl)quinoline monohydrochloride was added portionwise over a 25-minutes period. The reaction mixture was stirred and refluxed for 12 hours. The reaction mixture was poured out into water (5 l) and this mixture was stirred vigorously. The precipitate was filtered off, and washed with water (2 l). Toluene was added and azeotroped on the rotary evaporator. The residue was dried, yielding 187 g (89%) of 4-(2-quinolinylmethoxy)benzeneethanol (intermediate 1, mp. 144.8° C.).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.B1([O-])OO1.[OH2:15].[OH2:16].O.O.[Na+]>C(O)(C(F)(F)F)=O.CC(O)=O>[Br:1][C:2]1[CH:8]=[C:7]([F:9])[C:5]([N+:6]([O-:16])=[O:15])=[C:4]([F:10])[CH:3]=1
Reactant: O
Reactant: Nc1c(F)cc(Br)cc1F
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1c(F)cc(Br)cc1F
Temperature: 60 °C
Yield: 42 %

Procedure:
A solution of 4-bromo-2,6-difluoroaniline (4.75 g, 22.8 mmol) in TFA (50.2 mL) and AcOH (50.2 mL) was charged with sodium perborate tetrahydrate (16.0 g, 104 mmol). The reaction was warmed to 60° C. and heated for 24 h. The reaction was quenched with water (10 mL) and extracted with EtOAc (15 mL). The organic layer was washed with brine (10 mL) and dried over anhydrous Na2SO4. The organic layer was concentrated under reduced pressure to yield a yellow solid. The material was purified by silica gel chromatography on an ISCO combi-flash Rf system using Heptane/EtOAc (100:0→90:10) as eluent. The fractions containing product were combined and concentrated under reduced pressure to yield a white solid, 2.28 g (42% yield). 1H NMR (CDCl3, 400 MHz): δ=7.31-7.35 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.CN(C)C=O.F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:24]=1[F:32].C(=O)([O-])[O-].[Cs+].[Cs+]>ClCCl>[Br:1][C:2]1[C:3]([O:16][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:24]=2[F:32])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(Br)c(Oc3ccc([N+](=O)[O-])cc3F)c2CC[C@@H]1C
Temperature: 110 °C
Reaction time: 3 h
Yield: 86.4 %

Procedure:
A 50-mL round-bottom flask was purged and maintained with an inert atmosphere of nitrogen and charged with 1-[(2S)-6-bromo-5-hydroxy-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one (350 mg, 1.23 mmol), N,N-dimethylformamide (10 mL), 1,2-difluoro-4-nitrobenzene (415 mg, 2.61 mmol) and cesium carbonate (1.3 g, 3.99 mmol). The resulting mixture stirred for 3 h at 110° C. After cooling to room temperature, the reaction mixture was poured into dichloromethane (50 mL), washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 5:1, ethyl acetate/petroleum ether) to afford 1-[(2S)-6-bromo-5-(2-fluoro-4-nitrophenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-1-yl]ethan-1-one (450 mg, 86%) of as yellow oil. MS (ESI, neg. ion) m/z 421, 423[M−H].
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.[CH3:28][NH:29][CH2:30][CH3:31].C(N(C(C)C)C(C)C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>O1CCCC1>[CH2:30]([N:29]([CH3:28])[C:25]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]([NH:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:17]=[C:11]2[CH:10]=1)=[O:24])=[O:26])[CH3:31]
Reactant: CCNC
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCN(C)C(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Temperature: 70 °C
Yield: 89.4 %

Procedure:
A mixture of 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (150 mg, 0.404 mmole), N-methylethanamine (174 ul, 2.02 mmole), N-ethyldiisopropylamine (564 ul, 3.23 mmole) and 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate, 606 ul, 1.01 mmole) in tetrahydrofurane (7 ml) is stirred for at 70° C. The solvent is removed under reduced pressure and the residue is triturated for 1 hr with sat. aqueous sodium bicarbonate solution (30 ml). The solid is collected by filtration, washed with water and dried affording N4-ethyl-N4,1-dimethyl-N5-(2-morpholino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-4,5-dicarboxamide (149 mg, 89.4%) as a white solid. Mp.: 201-3° C. MS: m/z=413.3 (M+H+).
Reaction SMILES: O.[OH-].[Li+].[C:4]([S:7][C:8]1[N:9]=[C:10]([CH3:20])[N:11](C(OC(C)(C)C)=O)[CH:12]=1)(=O)[CH3:5].BrCC1[C:33]2[CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29][CH2:28][C:27]=2[CH:26]=[CH:25][C:24]=1[Cl:41]>CO>[C:37]([O:36][C:34]([N:30]1[CH2:31][CH2:32][C:33]2[C:5]([CH2:4][S:7][C:8]3[NH:9][C:10]([CH3:20])=[N:11][CH:12]=3)=[C:24]([Cl:41])[CH:25]=[CH:26][C:27]=2[CH2:28][CH2:29]1)=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(=O)Sc1cn(C(=O)OC(C)(C)C)c(C)n1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CBr)c2CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ncc(SCc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)[nH]1
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
Add lithium hydroxide hydrate (42 mg, 1 mmol) to a stirred solution of 4-acetylsulfanyl-1-tert-butoxycarbonyl-2-methyl-imidazole (290 mg, 1.13 mmol) and 6-bromomethyl-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (368 mg, 0.98 mmol) in methanol (12 mL) and stir the resulting mixture for 30 min. Partition the mixture between EtOAc and water and extract the aqueous phase three times with EtOAc. Dry the combined organic extracts over MgSO4, filter, and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel (40 g) eluting with hexane/EtOAc [100:0 (5 min), 19:1 (5 min), 85:15 (5 min), 4:1; flow rate: 50 mL/min] to give 3-tert-butoxycarbonyl-7-chloro-6-(2-methyl-3H-imidazol-4-ylthiomethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (310 mg, 54%). MS (ES+) m/z: 508 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Br)=[CH:10][CH:9]=1.[C:16]([O:20][C:21]([NH:23][C:24]1([CH2:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([OH:48])[CH:43]=3)=[CH:37][CH:36]=2)[CH2:29][O:28][C:27]([CH3:31])([CH3:30])[O:26][CH2:25]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C>[C:16]([O:20][C:21]([NH:23][C:24]1([CH2:32][CH2:33][CH2:34][C:35]2[CH:36]=[CH:37][C:38]([O:41][C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([O:48][CH2:12][C:11]4[CH:14]=[CH:15][C:8]([Cl:7])=[CH:9][CH:10]=4)[CH:43]=3)=[CH:39][CH:40]=2)[CH2:29][O:28][C:27]([CH3:31])([CH3:30])[O:26][CH2:25]1)=[O:22])([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)NC1(CCCc2ccc(Oc3cccc(O)c3)cc2)COC(C)(C)OC1
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(CCCc2ccc(Oc3cccc(OCc4ccc(Cl)cc4)c3)cc2)COC(C)(C)OC1
Temperature: 70 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
Potassium carbonate (150 mg) and p-chlorobenzyl bromide (103 mg) were added to a DMF solution (5 mL) of the compound of Example 105 (150 mg) and the mixture was stirred for 1 hour at 70° C. Subsequently, the mixture was decanted into water and was extracted with ethyl acetate. The organic phase was sequentially washed with water and a saturated aqueous solution of sodium chloride and was dried with anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the desired product (170 mg) as a colorless powder.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[N:19]1[N:27]2[C:22]([O:23][CH2:24][CH2:25][CH2:26]2)=[CH:21][C:20]=1[C:28](O)=[O:29]>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:28]([C:20]3[CH:21]=[C:22]4[O:23][CH2:24][CH2:25][CH2:26][N:27]4[N:19]=3)=[O:29])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=C(O)c1cc2n(n1)CCCO2
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc2n(n1)CCCO2

Procedure:
The title compound was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg, 0.767 mmol) and 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-2-carboxylic acid (168 mg, 0.997 mmol). The product was purified with flash-chromatography. Yield 251 mg (80%). 1H-NMR (400 MHz; CDCl3): δ 1.21 (d, 3H), 2.27-2.32 (m, 2H), 4.14-4.20 (m, 2H), 4.26-4.43 (m, 4H), 4.51-4.60 (m, 1H), 6.01 (s, 1H), 6.62 (d, 1H), 7.49 (d, 1H), 7.51 (d, 1H), 7.66 (d, 1H), 7.81-7.84 (m, 1H), 8.03 (d, 1H).
Reaction SMILES: Cl.[CH:2]1([C@H:8]2[CH2:13][NH:12][CH2:11][C@@H:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)[CH:23]=[C:22]([CH3:32])[N:21]=1.ClC1N=C(NC2NN=CC=2)C=C(C)N=1>>[CH:2]1([C@H:8]2[CH2:13][N:12]([C:20]3[N:21]=[C:22]([CH3:32])[CH:23]=[C:24]([NH:26][C:27]4[S:28][CH:29]=[CH:30][N:31]=4)[N:25]=3)[CH2:11][C@@H:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:9]2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Cc1cc(Nc2nccs2)nc(Cl)n1
Reactant: COC(=O)C[C@@H]1CNC[C@H](C2CCCCC2)C1
Agent: Cc1cc(Nc2ccn[nH]2)nc(Cl)n1
Agent: Cl
Product: COC(=O)C[C@H]1C[C@@H](C2CCCCC2)CN(c2nc(C)cc(Nc3nccs3)n2)C1

Procedure:
The title compound was prepared by the similar manner described in Example 1 using methyl (cis-5-cyclohexylpiperidine-3-yl)acetate hydrochloride prepared in Step 3 of Example 22 instead of (S)-3-(tert-butoxycarbonylamino)piperidine, and 2-chloro-6-methyl-N-(1,3-thiazol-2-yl)pyrimidin-4-amine prepared in Referential Example 3 instead of 2-chloro-6-methyl-N-(1H-pyrazol-5-yl)pyrimidin-4-amine.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.CN(C)[C:15]1[CH:23]=CC(C(Cl)=O)=C[CH:16]=1.C(Cl)C=C.CN(C)C1C=CC(C([O-])=O)=CC=1.[Na+]>CN(C)C=O>[CH2:23]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([N:2]([CH3:12])[CH3:1])=[CH:4][CH:5]=1)[CH:15]=[CH2:16]
Reactant: CN(C)c1ccc(C(=O)O)cc1
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccc(C(=O)[O-])cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C=CCCl
Product: C=CCOC(=O)c1ccc(N(C)C)cc1
Yield: 60 %

Procedure:
Esters of p-dimethylaminobenzoic acid can be prepared by several methods. U.S. Pat. No. 2,202,865 describes the preparation of esters by reacting p-dimethylaminobenzoyl chloride with alcohols. Another method is by reacting an alkali salt of p-dimethylaminobenzoic acid with an alkene halide. Either method can be used but the latter is preferred. For example, if allyl chloride is added to sodium p-dimethylaminobenzoate in a suitable solvent such as dimethylformamide using a quaternary ammonium salt catalyst, allyl-p-dimethylaminobenzoate is obtained in yield of about 60%.
Reaction SMILES: [CH2:1]([N:10]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:21])=[CH:17][C:18]=2[Cl:20])[NH:13][C:12]=1[C:22]([O:24]CC)=[O:23])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].O.[OH-].[Li+].Cl>O1CCCC1.O>[CH2:1]([N:10]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:21])=[CH:17][C:18]=2[Cl:20])[NH:13][C:12]=1[C:22]([OH:24])=[O:23])[C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1N(CC(=O)c1ccccc1)Cc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CN(Cc1ccccc1)c1c(C(=O)O)[nH]c2cc(Cl)cc(Cl)c12)c1ccccc1

Procedure:
Dissolve 3-[(phenacyl)benzylamino]-2-carbethoxy-4,6-dichloroindole (0.5 g, 1.07 mmol) in tetrahydrofuran (10 mL) and water (10 mL). Add lithium hydroxide monohydrate (0.16 g, 3.74 mmol) and stir for 24 hours. Heat at reflux for 6 hours and pour into 1N hydrochloric acid (100 mL). Extract into ethyl acetate, dry (MgSO4) and evaporate the solvent in vacuo. Recrystallize (ethyl acetate/hexane) to give the title compound; mp 266°-7° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:21]=C)=[C:4]([CH:9]=[C:10]([CH2:13][C:14]2[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].CC(C)=[O:25].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[CH:21]([C:3]1[C:2]([CH3:1])=[C:11]([CH3:12])[C:10]([CH2:13][C:14]2[CH:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])=[O:25]
Reactant: CC(C)=O
Reactant: C=Cc1c(C(=O)OC)cc(Cc2ccc(C)nc2)c(C)c1C
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc(Cc2ccc(C)nc2)c(C)c(C)c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3,4-dimethyl-5-((6-methylpyridin-3-yl)methyl)-2-vinylbenzoate (0.49 g) in a mixed solvent of acetone (6.10 mL)-acetonitrile (6.10 mL)-water (6.10 mL) were added osmium oxide (fixed catalyst I) (0.21 g) and sodium periodate (1.79 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.47 g) as a crude product. This compound was used in the next step without an additional purification.
Reaction SMILES: [CH2:1]([S:3]([NH:6][CH2:7][CH2:8][C:9]([O:11]C)=O)(=[O:5])=[O:4])[CH3:2].[Cl:13][C:14]1[CH:32]=[CH:31][C:17]2[O:18][C:19]3[CH:30]=[CH:29][CH:28]=[CH:27][C:20]=3[CH2:21][N:22]([C:23]([NH:25][NH2:26])=[O:24])[C:16]=2[CH:15]=1>>[CH2:1]([S:3]([NH:6][CH2:7][CH2:8][C:9]([NH:26][NH:25][C:23]([N:22]1[CH2:21][C:20]2[CH:27]=[CH:28][CH:29]=[CH:30][C:19]=2[O:18][C:17]2[CH:31]=[CH:32][C:14]([Cl:13])=[CH:15][C:16]1=2)=[O:24])=[O:11])(=[O:4])=[O:5])[CH3:2]
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: CCS(=O)(=O)NCCC(=O)OC
Product: CCS(=O)(=O)NCCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-[(ethylsulfonyl)amino]-1-oxopropyl]hydrazide (22) was prepared from N-(ethylsulfonyl)-β-alanine, methyl ester (21), prepared as described above in Example 21, and 8-chlorodibenz[-b,f][1,4]-oxazepine-10(11H)-carboxylic acid, hydrazide (1), prepared as described above in Example 1, in the manner described in Example 18 above on a 2.0 mmol scale to yield 0.25 g (28%) of product. Analysis calculated for C19H21NO5SCl 0.75 H2O (M.W. 466.43): C, 48.93; H, 4.86; N, 12.01; Cl, 7.60; S, 6.87. Found: C, 49.05; H, 4.61; N, 11.78; Cl, 8.34; S, 6.69.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C:10]([O:12]C)=[O:11])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[CH3:2].[OH-].[Li+]>C1COCC1.O>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[CH3:2]
Reactant: CCOc1cc(C(=O)OC)ccc1-c1ccccc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(C(=O)O)ccc1-c1ccccc1C
Reaction time: 24 h
Yield: 93.2 %

Procedure:
To a stirred solution of methyl 2-ethoxy-2′-methyl-1,1′-biphenyl-4-carboxylate (11 g, 40.6 mmol) in a mixture of THF (100 mL) and water (10 mL) was added lithium hydroxide (6.82 g, 162.7 mmol) in portions. After 24 hours at RT, the reaction mixture was evaporated and the residue was taken up with water. The aqueous layer was acidified with a concentrated aqueous solution of HCl and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4) and concentrated under vacuum to afford of the title compound as pale yellow solid (9.7 g, 93%). LC/MS, M−(ESI): 255.0. 1H NMR (DMSO-d6, 400 MHz) δ 13.02 (1H, bs), 7.57 (2H, m), 7.18-7.25 (4H, m), 7.09 (1H, d), 4.05 (2H, q), 2.05 (3H, s), 1.18 (3H, t).
Reaction SMILES: O=[C:2]1[CH:8]([CH2:9][C:10]([OH:12])=O)[CH2:7]C[S:5][C:4]2[S:13][CH:14]=[CH:15][C:3]1=2.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][NH2:24])=[CH:19][CH:18]=1>C(O)C>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:10](=[O:12])[CH2:9][CH:8]3[CH2:7][S:5][C:4]4[S:13][CH:14]=[CH:15][C:3]=4[C:2]3=[N:24]2)=[CH:19][CH:18]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: O=C(O)CC1CCSc2sccc2C1=O
Solvent: CCO
Product: O=C1CC2CSc3sccc3C2=NN1c1ccc(Cl)cc1
Yield: 33.2 %

Procedure:
A mixture of 3.7 g of 4-oxo-4,5,6,7-tetrahydrothieno[2,3-b]thiepin-5-acetic acid and 2.6 g of 4-chlorophenylhydrazine in 50 ml of ethanol is refluxed under heating for 6.5 hours. Then, the reaction mixture is concentrated under reduced pressure. The resulting residue is dissolved in 40 ml of acetic acid and the mixture is further refluxed under heating for 1.5 hours. After cooling, the mixture is concentrated under reduced pressure, and the residue is subjected to column chromatography on silica gel and eluted with chloroform. The crystals obtained from the fraction are recrystallized from a mixed solvent of chloroform and ethanol to give 1.7 g of 2-(4-chlorophenyl)-4,4a,5,6-tetrahydrothieno[2',3':2,3]thiopyrano[4,5-c]pyridazin-3(2H)-one as pale brown crystals, melting at 134°-135° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][C:12]3[C:17]([F:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=3[F:20])=[CH:8][C:7]([CH3:21])=[CH:6][N:5]2[C:22]=1[C:23]([O:25]CC)=[O:24].[OH-].[Li+].Cl>C1COCC1.CO>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][C:12]3[C:17]([F:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=3[F:20])=[CH:8][C:7]([CH3:21])=[CH:6][N:5]2[C:22]=1[C:23]([OH:25])=[O:24]
Reactant: CCOC(=O)c1c(C)nc2c(OCc3c(F)ccc(F)c3F)cc(C)cn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCc2c(F)ccc(F)c2F)c2nc(C)c(C(=O)O)n2c1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
6.9 g (17.51 mmol) of ethyl 2,6-dimethyl-8-[(2,3,6-trifluorobenzyl)oxy]imidazo[1,2-a]pyridine-3-carboxylate from Example 145A were dissolved in 374 ml of THF/methanol (5/1), 87.5 ml (87.5 mmol) of 1 N aqueous lithium hydroxide solution were added and the mixture was stirred at 40° C. for 5 hours. After cooling, the mixture was acidified, with ice-cooling, with 6 N aqueous hydrochloric acid, and the organic solvent was then removed on a rotary evaporator. The solid formed was filtered off with suction, washed with water and then dried under high vacuum. This gave 6.7 g of the target compound (108% of theory).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:9]=2)=[CH:6][CH:5]=[C:4]([O:34][CH2:35][CH2:36][O:37][CH3:38])[N:3]=1.[F:39][C:40]1[CH:41]=[C:42]([NH2:48])[CH:43]=[N:44][C:45]=1[O:46][CH3:47]>>[F:39][C:40]1[CH:41]=[C:42]([NH:48][C:2]2[C:7]([C:8]3[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=3)=[CH:6][CH:5]=[C:4]([O:34][CH2:35][CH2:36][O:37][CH3:38])[N:3]=2)[CH:43]=[N:44][C:45]=1[O:46][CH3:47]
Reactant: COc1ncc(N)cc1F
Reactant: COCCOc1ccc(-c2nc(C)nc(N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)n2)c(F)n1
Product: COCCOc1ccc(-c2nc(C)nc(N)n2)c(Nc2cnc(OC)c(F)c2)n1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 254 using 4-(2-fluoro-6-(2-methoxyethoxy)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine and 5-fluoro-6-methoxypyridin-3-amine (Anichem), and was isolated as yellow amorphous powder (4.9%). m/z (ESI, +ve ion) 402.0 (M+H)+. 1H NMR (400 MHz, d4-MeOH) δ 12.15 (1H, br. s.); 8.77 (1H, d, J=8.6 Hz); 8.32 (1H, br. s.); 8.15 (1H, br. s.); 6.30 (1H, s); 3.98 (3H, s); 3.72 (2H, br. s.); 3.37 (4H, s); 2.44 (4H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([O-:3])=[O:2].Br[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1>O1CCOCC1>[N+:1]([C:4]1[CH:11]=[C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([O-:3])=[O:2]
Reactant: CC1(C)OB(c2ccc(C=O)c([N+](=O)[O-])c2)OC1(C)C
Reactant: Brc1ccccn1
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2ccccn2)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared by the procedure as described in Example 101 (Step C) using 2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde and 2-bromopyridine in dioxane (reflux).
Reaction SMILES: CO[C:3](=O)[C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[H-].C([Al+]CC(C)C)C(C)C.C1(P(=[CH:47][C:48]([O:50][CH3:51])=[O:49])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:13]([O:12][C:10]([N:5]1[CH2:6][CH2:7][CH2:8][CH2:9][C@H:4]1[CH:3]=[CH:47][C:48]([O:50][CH3:51])=[O:49])=[O:11])([CH3:14])([CH3:15])[CH3:16]
Reactant: COC(=O)[C@@H]1CCCCN1C(=O)OC(C)(C)C
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: COC(=O)C=C[C@@H]1CCCCN1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
A stirred solution of (S)-N-(t-butoxycarbonyl)-pipecolinic acid methyl ester (2.04 g, 8.39 mmol) in methylene chloride (75 mL) at −78° C. under nitrogen was treated with diisobutylaluminum hydride (1.0 M in toluene, 14.2mL, 14.2 mmol). After 1.25 h a second aliquot of diisobutylaluminum hydride (2.00 mL, 2.00 mmol) was added. The mixture was stirred for an additional 30 min. and then quenched by the addition of a 20% aqueous Rochelle's salt solution (100 mL) followed by vigorous stirring for 1 h. The aqueous layer was extracted with methylene chloride and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The crude aldehyde was dissolved in methylene chloride (100 mL) and treated with methyl (triphenylphosphoranylidene)acetate (4.00 g, 12.0 mmol). After 15 hours (h) the reaction mixture was concentrated and purified by flash chromatography to give the desired product (1.46 g, 65%).
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C2C(COC([NH:35][CH2:36][C:37]([NH:39][CH2:40][CH:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)=[O:38])=O)C3C(=CC=CC=3)C=2C=CC=1.C(N(CC)CC)C>C(#N)C>[NH2:35][CH2:36][C:37]([NH:39][CH2:40][CH:41]1[CH2:42][CH2:43][N:44]([CH2:14][C:13]2[CH:16]=[CH:17][C:10]([C:8](=[O:9])[NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:11][CH:12]=2)[CH2:45][CH2:46]1)=[O:38]
Reactant: O=C(CNC(=O)OCC1c2ccccc2-c2ccccc21)NCC1CCNCC1
Reactant: O=C(Nc1ccccc1)c1ccc(CCl)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NCC(=O)NCC1CCN(Cc2ccc(C(=O)Nc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 30.2 %

Procedure:
An acetonitrile (100 mL) solution of 4-(N-phenylcarbamoyl)benzyl chloride (800 mg, 3.26 mmol) was dropped into a mixture of 4-[[N-(9-fluorenylmethyloxycarbonyl)glycyl]aminomethyl]piperidine (1.27 g, 2.96 mmol) with triethylamine (1.25 mL, 8.88 mmol), KI (50 mg, 0.30 mmol) and acetonitrile (200 mL). The resulting mixture was stirred at room temperature for 19 hours and stirred at 60° C. for another 5 hours. After concentrating, the obtained crude product was purified by column chromatography (SiO2, 5% methanol/dichloromethane-triethylamine/methanol/dichloromethane=2:2:96) to provide 4-[(glycylamino)methyl]-1-[4-(N-phenylcarbamoyl)benzyl]piperidine (340 mg, 30%).