Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:13]C)=[N:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=O)[CH3:2].F[B-](F)(F)F.O=C1C=CC=CN1OC(N(C)C)=[N+](C)C.O.OC1C2N=NNC=2C=CC=1.[C:46]([O:50][C:51](=[O:58])[NH:52][CH2:53][C:54]([NH:56][NH2:57])=[O:55])([CH3:49])([CH3:48])[CH3:47].C(N(C(C)C)C(C)C)C>ClCCl.O>[C:46]([O:50][C:51](=[O:58])[NH:52][CH2:53][C:54]([NH:56][NH:57][C:8]([C:7]1[CH:11]=[C:3]([CH2:1][CH3:2])[C:4](=[O:13])[NH:5][C:6]=1[CH3:12])=[O:10])=[O:55])([CH3:49])([CH3:47])[CH3:48]
Reactant: CCc1cc(C(=O)O)c(C)nc1OC
Reactant: CC(C)(C)OC(=O)NCC(=O)NN
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CCc1cc(C(=O)NNC(=O)CNC(=O)OC(C)(C)C)c(C)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
Under a nitrogen atmosphere in a round bottom flask, 5-ethyl-6-methoxy-2-methyl-nicotinic acid (500 mg, 2.56 mmol) of Step 2, Example 14 is dissolved in dichloromethane (60 mL). O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (838 mg, 2.82 mmol) is added, followed by hydroxybenzotriazole hydrate (392 mg, 2.56 mmol). The resulting mixture is stirred at rt for 30 min to give a suspension, which is treated with hydrazinocarbonylmethyl-carbamic acid tert-butyl ester (509 mg, 2.69 mmol) followed by N-ethyl-diisopropylamine (1.16 mL, 6.66 mmol). The resulting solution is stirred at rt for 135 hr, LC/MS shows the reaction to be complete. The reaction is diluted with water and the mixture is extracted with five portions of dichloromethane, the combined extract is washed with saturated aqueous sodium bicarbonate (30 mL), then dried over magnesium sulfate, filtered and evaporated. The crude product is purified by flash chromatography on a 10-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (3:1). Fractions containing the product are combined and evaporated and repurified by flash chromatography on a 10-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (3:1 increasing to 1:1) to obtain {2-[N′-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridine-3-carbonyl)-hydrazino]-2-oxo-ethyl}-carbamic acid tert-butyl ester (686 mg, 73% yield) as a white solid. MS: m/e 755 (100%) (2M+Na), 367 (70%) (M+H); 1H NMR (300 MHz, CDCl3, δ, ppm): 8.97 (1H, br.s), 8.22 (1H, br.s), 7.44 (1H, s), 5.21 (1H, br.t), 3.96 (5H, m), 2.59 (3H, s), 2.53 (2H, q), 1.48 (9H, s), 1.18 (3H, t).
Reaction SMILES: [CH2:1]([CH:4]1[C:9]2[C:10](=[O:19])[C:11]3[C:16]([C:17](=[O:18])[C:8]=2[CH2:7][CH:6]([C:20]([O:22][CH3:23])=[O:21])[O:5]1)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:2][CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N12CCN(CC1)CC2>>[CH2:1]([CH:4]1[C:9]2[C:10](=[O:19])[C:11]3[C:16]([C:17](=[O:18])[C:8]=2[CH:7]=[C:6]([C:20]([O:22][CH3:23])=[O:21])[O:5]1)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:2][CH3:3]
Reactant: CCCC1OC(C(=O)OC)CC2=C1C(=O)c1ccccc1C2=O
Agent: C1CN2CCN1CC2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCC1OC(C(=O)OC)=CC2=C1C(=O)c1ccccc1C2=O
Yield: 70 %

Procedure:
The 1-propyl-3-methoxycarbonyl-3,4,5,10-tetrahydro-5,10-dioxo-1H-naphtho-[2,3-c]-pyran described in step 4 (50 mg, 0.159 mmol) was stirred with triphenylphosphine (166.6 mg, 0.636 mmol) and 1,4-diaza bicyclo-[2,2.2]-octane (19.6 mg, 0.175 mmol) in presence of air for a few hours at room temperature until the starting material was entirely consumed. The reaction mixture was evaporated to dryness. The crude product obtained was chromatographed (toluene/ethyl acetate=10/1, v/v) to give the titled compound (35 mg, 70%).
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.F[C:16]1[N:21]=[C:20]([C:22]2[NH:31][C:30](=[O:32])[C:29]3[C:24](=[CH:25][C:26]([O:35][CH3:36])=[CH:27][C:28]=3[O:33][CH3:34])[N:23]=2)[CH:19]=[CH:18][CH:17]=1.CN(C)C(N(C)C)=N>CS(C)=O.O>[CH3:34][O:33][C:28]1[CH:27]=[C:26]([O:35][CH3:36])[CH:25]=[C:24]2[C:29]=1[C:30](=[O:32])[NH:31][C:22]([C:20]1[N:21]=[C:16]([N:6]3[CH2:7][CH2:8][N:3]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:4][CH2:5]3)[CH:17]=[CH:18][CH:19]=1)=[N:23]2
Reactant: COC(=O)CCN1CCNCC1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(F)n3)nc2c1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)CCN1CCN(c2cccc(-c3nc4cc(OC)cc(OC)c4c(=O)[nH]3)n2)CC1
Temperature: 85 °C
Yield: 66.5 %

Procedure:
To a stirred suspension of methyl 3-(piperazin-1-yl)propanoate dihydrochloride (0.358 g, 1.46 mmol) and 2-(6-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.220 g, 0.73 mmol) in dry DMSO (1.5 mL) was added 1,1,3,3-tetramethylguanidine (0.336 g, 2.92 mmol). The resulting mixture was heated at 85° C. for 5 h. After that time the reaction was cooled to rt, diluted with water (20 mL) and extracted with ethyl acetate (3×25 mL). The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/methanol to 97:3 dichloromethane/methanol) to give methyl 3-(4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)propanoate (0.220 g, 66%) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 10.31 (s, 1H), 7.85 (d, J=7.42 Hz, 1H), 7.62-7.70 (m, 1H), 6.79-6.85 (m, 2H), 6.48 (d, J=2.34 Hz, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 3.72 (s, 3H), 3.59-3.67 (m, 4H), 2.75-2.83 (m, 2H), 2.54-2.66 (m, 6H); ESI MS m/z 454 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>CO.CCOC(C)=O>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:6][CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: O=Cc1cccc(O)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: OCc1cccc(O)c1Cl
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-3-hydroxybenzaldehyde (8.10 g, 51.7 mmol) in MeOH was added NaBH4 (1.96 g, 51.7 mmol) at 0° C. The reaction was allowed to stir for 30 minutes. TLC showed clean conversion to a more polar spot. The reaction was diluted with EtOAc (400 mL), washed with water and brine, dried over sodium sulfate, and concentrated. The crude product was used in Step B without further purification.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5]([C:7]1[C:8]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=2[O:28]CC=C)=[C:9]2[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=3[S:14][C:10]2=[N:11][C:12]=1[CH3:13])[OH:6])C.I[CH2:34][CH3:35]>CC#N.[Ag]=O.[Ag-]=O>[CH2:34]([O:6][CH:5]([C:7]1[C:8]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=2[OH:28])=[C:9]2[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=3[S:14][C:10]2=[N:11][C:12]=1[CH3:13])[C:4]([OH:3])=[O:32])[CH3:35]
Reactant: C=CCOc1cc(C)ccc1-c1c(C(O)C(=O)OCC)c(C)nc2sc3c(c12)CCCC3
Reactant: CCI
Agent: O=[Ag-]
Agent: O=[Ag]
Solvent: CC#N
Product: CCOC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1O)CCCC3
Temperature: 60 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
To a stirred solution of [4-(2-Allyloxy-4-methyl-phenyl)-2-methyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-b]pyridin-3-yl]-hydroxy-acetic acid ethyl ester (100 mg, 221 μmols, 1 eq) in MeCN (5 mL) was added silver oxide (102 mg, 442 μmols, 2 eq) followed by iodoethane (172 mg, 89 uL, 5 eq) and the reaction was stirred for 16 hours at 60° C. Additional iodoethane (1 mL, 50 eq) and silver (I) oxide (102 mg, 2 eq) was added and the reaction was continued to be heated at 60° C. for 16 hours. The reaction was diluted with MeCN (5 mL), and filtered. The filtrate was then concentrated in vacuo. The residue was purified using ISCO Companion with a Redisep silica gel 12 g cartridge and a gradient of heptane and ethyl acetate (0% to 30%). Fractions containing (4-(2-allyloxy-4-methyl-phenyl)-2-methyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-b]pyridin-3-yl)-ethoxy-acetic acid ethyl ester were combined and concentrated in vacuo to give the desired product as a pale orange oil, 22 mg (22% yield). LC-MS (12 min acidic) 7.55 mins 100% pure by UV, ES+/APCI+ 480.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([O:14]CC)=[O:13])=[CH:7]2.[OH-].[Na+]>O1CCOCC1>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([OH:14])=[O:13])=[CH:7]2
Reactant: CCOC(=O)c1ccc2c(N)cccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1cccc2cc(C(=O)O)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.8 %

Procedure:
A mixture of ethyl 5-amino-2-naphthoate (7.0 g, 0.0325 mol), dioxane (40 ml), and 1N NaOH (39 mL) was stirred at room temperature for 16 hours. The dioxane was removed under reduced pressure, H2O (50 mL) was added, and the mixture was neutralized with acetic acid (2.23 mL). The resulting brown solid precipitate was collected by filtration to give the desired product (5.4 g, 89%), m.p. 231°-234° C.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.Cl.[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[C:20](Cl)=[O:21]>[OH-].[Na+]>[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[C:20]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])=[CH:13][CH:14]=1)=[O:21]
Reactant: CC(C)(Oc1ccc(N)cc1)C(=O)O
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(Oc1ccc(NC(=O)c2cc(Cl)cc(Cl)c2)cc1)C(=O)O
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of 0.5 g 2-(4-aminophenoxy)-2-methylpropionic acid in 5 ml 2N NaOH, 0.70 ml 3,5-dichlorobenzoyl chloride was dropwise added with stirring 5 ml additional 2N NaOH was gradually added to keep the PH strongly alkaline during the reaction. After 1 hour stirring, the reaction product was acidified with HCl. The white precipitate was recrystallized from aqueous isopropanol to give 1.4 g (76%) of fine crystals MP 206-207°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20](=[O:21])[C:11]2=[CH:12][NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1.I[CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH2:23]([N:13]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[C:10]2=[N:9][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:20](=[O:21])[C:11]2=[CH:12]1)[CH3:24]
Reactant: CCI
Reactant: O=c1c2c[nH]c3ccccc3c-2nn1-c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCn1cc2c(=O)n(-c3ccccc3F)nc-2c2ccccc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2-(2-Fluorophenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (51 mg, 0.18 mmol) was dissolved in dimethylsulfoxide (1 mL) and treated with iodoethane (0.018 mL, 0.22 mmol, 1.2 equiv) and potassium carbonate (30 mg, 0.22 mmol, 1.2 equiv). The mixture was stirred at ambient temperature for 14 hours, filtered and purified by preparative reverse phase HPLC (82:20 to 5:95; water containing 0.1% trifluoroacetic acid:acetonitrile containing 0.1% trifluoroacetic acid), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.78 (1H, s), 8.48 (1H, dd, J=8.0, 1.5 Hz), 7.74-7.58 (4H, m), 7.42-7.36 (1H, m), 7.29-7.23 (2H, m), 4.44 (1H, q, J=7.4 Hz), 1.64 (3H, t, J=7.2 Hz) ppm; low resolution mass spectrometry (ES+) m/z 308.0 [(M+H)+; calculated for C18H15FN3O: 308.1].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:16][C:17]1[S:21][C:20]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[N:19][C:18]=1[CH3:29]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([O:14][CH2:16][C:17]2[S:21][C:20]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[N:19][C:18]=2[CH3:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1CCl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Product: Cc1nc(-c2ccc(Cl)cc2)sc1CO[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Yield: 78.5 %

Procedure:
In an argon atmosphere, (R)-1-(tert-butoxycarbonyl)-3-hydroxypiperidine (604 mg, 3.00 mmol) and 5-chloromethyl-2-(4-chlorophenyl)-4-methylthiazole (775 mg, 3.00 mmol) were reacted in the same manner as in Step 6a of Example 6 to give 996 mg (78%) of the desired compound as a yellow oil.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][CH2:21][CH2:22][O:23][N:24]=[C:25]([CH:55]1[CH2:57][CH2:56]1)[C:26]1[C:34]2[CH:33]=[CH:32][C:31]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:30][C:29]=2[N:28](COCC[Si](C)(C)C)[N:27]=1>O1CCCC1>[CH3:19][O:20][CH2:21][CH2:22][O:23][N:24]=[C:25]([CH:55]1[CH2:57][CH2:56]1)[C:26]1[C:34]2[CH:33]=[CH:32][C:31]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH2:30][C:29]=2[NH:28][N:27]=1
Reactant: COCCON=C(c1nn(COCC[Si](C)(C)C)c2c1C=CC(c1ccccc1)(c1ccccc1)C2)C1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COCCON=C(c1n[nH]c2c1C=CC(c1ccccc1)(c1ccccc1)C2)C1CC1
Temperature: 20 °C
Reaction time: 96 h

Procedure:
1.47 cm3 of a commercial 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran are added to a solution of 0.32 g of the E isomer of cyclopropyl(6,6-diphenyl-1-(2-trimethylsilanylethoxymethyl)-6,7-dihydro-1H-indazol-3-yl)methanone O-(2-methoxyethyl)oxime in 50 cm3 of tetrahydrofuran, and the mixture is stirred in the region of 20° C. for 4 days. The solution is concentrated to dryness under reduced pressure and the residue is taken up in 50 cm3 of ethyl acetate; the solution is washed with three times 30 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (13 kPa). After flash chromatography on a column of silica [eluent: dichloromethane/ethyl acetate (90/10 by volume)], 0.073 g of the E isomer of cyclopropyl(6,6-diphenyl-6,7-dihydro-1H-indazol-3-yl)methanone O-(2-methoxyethyl)oxime, corresponding to Example 6-7B, is thus obtained in the form of a resin, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([OH:12])[CH:8]=[C:7]2[C:3]=1[C:4](=[O:18])[C:5]1([CH2:17][CH2:16][CH2:15][CH2:14]1)[C:6]2=[O:13].Cl[CH2:20][C:21]#[N:22].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[O:13]=[C:6]1[C:7]2[C:3](=[C:2]([Cl:1])[C:10]([CH3:11])=[C:9]([O:12][CH2:20][C:21]#[N:22])[CH:8]=2)[C:4](=[O:18])[C:5]21[CH2:17][CH2:16][CH2:15][CH2:14]2
Reactant: Cc1c(O)cc2c(c1Cl)C(=O)C1(CCCC1)C2=O
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(OCC#N)cc2c(c1Cl)C(=O)C1(CCCC1)C2=O
Temperature: 65 °C

Procedure:
A stirred mixture of 4'-chloro-5'-methyl-6'-hydroxyspiro(cyclopentane-1,2'-indan)-1' ,3'-dione (9.3 g., 0.035 mole), chloroacetonitrile (2.83 g., 0.0375 mole), potassium carbonate (5.2 g., 0.0375 mole) and potassium iodide (6.2 g., 0.0375 mole) in dimethylformamide (100 ml.) is heated at 65°C. for 21/2 hours, cooled, then poured into water (1.5 1.) affording 10.7 g. of [1' ,3'-dioxo-4'-chloro-5'-methylspiro(cyclopentane-1,2'-indan)-6'-yloxylacetonitrile which melts at 137°-9°C. after recrystallization from ethanol-water.
Reaction SMILES: [NH2:1][C@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([CH3:6])([OH:5])[CH3:4].[Cl:13][C:14]([Cl:19])([Cl:18])[C:15](Cl)=[O:16]>N1C=CC=CC=1>[OH:5][C:3]([CH3:6])([CH3:4])[C@H:2]([NH:1][C:15](=[O:16])[C:14]([Cl:19])([Cl:18])[Cl:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CC(C)(O)[C@H](N)c1ccccc1
Solvent: c1ccncc1
Product: CC(C)(O)[C@H](NC(=O)C(Cl)(Cl)Cl)c1ccccc1
Reaction time: 0.17 h
Yield: 67 %

Procedure:
To a solution of (13) (1.413 g, 8.56 mmol) in pyridine (24 ml) at 0° C. was added trichloroacetyl chloride (1.05 ml, 9.41 mmol). After stirring at this temperature for 10 minutes the reaction mixture was stirred overnight at room temperature. The reaction was quenched by the addition of saturated aqueous sodium chloride solution, after which the product was extracted with dichloromethane and the combined organic extracts were washed with hydrochloric acid (1M). Concentration in vacuo and purification by flash column chromatography using 30% ethyl acetate/40-60 petroleum ether as eluant furnished the title compound (14) (1.782 g, 65%) as a solid which was recrystallised from ether/40-60 petroleum ether; mp 97° C.; νmax (CHCl3) 1716 cm-1 ; [α]D24 (c 1 in CHCl3)=-55.5; (Found: C, 46.41; H, 4.26; N, 4.49. C12H14Cl3NO2 requires C, 46.40; H, 4.54; N, 4.51%); δH (200 MHz; CDCl3) 1.06 (3H, s, C(CH3)2), 1.39 (3H, s, C(CH3)2), 1.94 (1H, s, OH), 4.70 (1H, d, J=8.5, CHCH), 7.29-7.39 (5H, m, ArCH); δC (125 MHz; CDCl3) 27.70 (CH3), 27.86 (CH3), 63.06 (CH), 75.52 (C), 92.97 (CCl3), 128.13 (ArCH), 128.35 (ArCH), 128.71 (ArCH), 137.88 (C), 161.51 (CO); m/z (CI-, NH3) 310 (M+).
Reaction SMILES: [N:1]1[CH2:5][CH2:4][CH2:3][C:2]=1[CH2:6][CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:19])=[CH:10][CH:9]=1.C([BH3-])#N.[Na+].Cl.[OH-].[Na+]>CO>[N:20]1([C:18]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([CH2:7][CH2:6][CH:2]3[CH2:3][CH2:4][CH2:5][NH:1]3)=[CH:9][CH:10]=2)=[O:19])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: O=C(c1ccc(CCC2=NCCC2)c2ccccc12)N1CCOCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C(c1ccc(CCC2CCCN2)c2ccccc12)N1CCOCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
6.4 1 g of {4-[2-(4,5-dihydro-3H-pyrrol-2-yl)ethyl]naphthalen-1-yl)morpholin-4-ylmethanone is dissolved in 50 ml of methanol, and 0.26 g of sodium cyano borohydride is added. A pH of 2 inset at 0° C. using methanolic HCl. The mixture is subsequently allowed to left to stir at RT for a further 6 h and then subjected to aqueous work-up. A pH of 9 is set using aqueous NaOH, and the mixture is extracted with ethyl acetate. The dried and evaporated organic phase is purified by chromatography, giving 460 mg of morpholin-4-yl-[4-(2-pyrrolidin-2-ylethyl)naphthalen-1-yl]methanone; Rt.: 1.420 min; [M+H]+339.2.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:12][O:13][C:14](=[O:33])[CH:15]([NH:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])P(OC)(OC)=O.CN(C)C(N(C)C)=N>O1CCCC1>[CH2:26]([O:25][C:23]([NH:22]/[C:15](=[CH:8]\[C:7]1[CH:10]=[CH:11][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)/[C:14]([O:13][CH3:12])=[O:33])=[O:24])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)c1ccc(C=O)cc1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1ccc(C(C)C)cc1)NC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 72 h

Procedure:
4-Isopropylbenzaldehyde (2.00 g, 13.50 mmol) and methyl{[(benzyloxy)carbonyl]amino}-(dimethoxyphosphoryl)acetate (3.58 g, 10.80 mmol, 0.8 equivalent) are dissolved in tetrahydrofuran (20 ml) and cooled to −78° C. At −78° C., N,N,N′,N′-tetramethylguanidine (27.92 g, 0.24 mol, 11.5 equivalents) is added dropwise and then stirred at −78° C. for 3 h and subsequently at room temperature 3 days. The mixture is then extracted by shaking with ethyl acetate (twice 100 ml) and water, and the combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulphate. After concentration, the crude product is chromatographed (Biotage 40M, cyclohexane/ethyl acetate 5/1). 3.47 g (73% of theory) of the title compound are obtained.
Reaction SMILES: [CH:1]1([CH2:5][N:6]2[C:10]3[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:9]=3[N:8]=[N:7]2)[CH2:4][CH2:3][CH2:2]1.[Br-:16].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:16][C:14]1[C:9]2[N:8]=[N:7][N:6]([CH2:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)[C:10]=2[CH:11]=[CH:12][C:13]=1[OH:15]
Reactant: [Br-]
Reactant: Oc1ccc2c(c1)nnn2CC1CCC1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: Oc1ccc2c(nnn2CC2CCC2)c1Br

Procedure:
A solution of 1-(cyclobutylmethyl)-1H-benzotriazol-5-ol (3-4, 280 mg, 1.38 mmol, 1 equiv) and pyridinium tribromide (551 mg, 1.72 mmol, 1.25 equiv) in chloroform (20 mL) was stirred at 23° C. for 4 h. The mixture was concentrated and the residue partitioned between saturated aqueous sodium bicarbonate solution (100 mL) and ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate and concentrated to give 4-bromo-1-(cyclobutylmethyl)-1H-benzotriazol-5-ol (3-5) as an orange solid. 1H NMR (300 MHz, CDCl3) δ 7.38 (d, 1H, J=8.9 Hz), 7.25 (d, 1H, J=8.9 Hz), 5.92 (br s, 1H), 4.60 (d, 2H, J=7.0 Hz), 2.96 (p, 1H, J=7.6 Hz), 2.06 (m, 2H), 1.89 (m, 4H) ppm. LRMS m/z (M+H) 283.9 found, 284.0 required.
Reaction SMILES: [CH3:1][N:2]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C=O.[NH3:20]>[Cl-].[Zn+2].[Cl-].CO>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([NH:2][CH3:1])=[C:6]([CH:7]=1)[C:12](=[NH:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(C=O)c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CO
Product: CNc1ccc(Cl)cc1C(=N)c1ccccc1
Yield: 75.7 %

Procedure:
A mixture of 41.1 g (0.15 mole) of N-methyl-N-(2-benzoyl-4-chlorophenyl)formamide, 90 ml methanol, 90 g anhydrous ammonia, and 0.5 g zinc chloride was heated in a sealed 360 ml Hastelloy® tube at 150° for 15 hr. and then cooled and vented. The solid portion of the residue was collected on a filter and recrystallized from methanol to give 27.8 g (76%) of 5-chloro-2-methylaminobenzophenone imine as long yellow needles: mp 93°-95°; 1H nmr (CDCl3) δ 2.92 ppm (d, J = 5.5 Hz, 3H), 6.65 ppm (d, J = 9 Hz, 1H) 7.4 ppm (m, 7H) and 9.4 ppm (broad, 2NH).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([OH:24])=[C:21]([C:25]#[N:26])[C:20](=[O:27])[NH:19][C:18]=3[S:17][CH:16]=2)=[CH:11][CH:10]=1)=O.C(O)(=O)C.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][NH2:42])=[CH:36][CH:35]=1.C([BH3-])#N>CO.ClCCl>[OH:24][C:22]1[C:23]2[C:15]([C:12]3[CH:13]=[CH:14][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[CH2:1][NH:42][CH2:41][CH2:40][C:37]4[CH:36]=[CH:35][C:34]([C:33]([F:32])([F:43])[F:44])=[CH:39][CH:38]=4)=[CH:10][CH:11]=3)=[CH:16][S:17][C:18]=2[NH:19][C:20](=[O:27])[C:21]=1[C:25]#[N:26]
Reactant: N#Cc1c(O)c2c(-c3ccc(-c4ccccc4C=O)cc3)csc2[nH]c1=O
Reactant: NCCc1ccc(C(F)(F)F)cc1
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1c(O)c2c(-c3ccc(-c4ccccc4CNCCc4ccc(C(F)(F)F)cc4)cc3)csc2[nH]c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-(2′-formyl-1,1′-biphenyl-4-yl)-4-hydroxy-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile (0.025 g, 0.067 mmol) in MeOH (1 mL) and dichloromethane (1 mL, with 2% v/v acetic acid) was added 2-(4-trifluoromethyl phenyl)ethyl amine (0.025 g, 0.13 mmol) and shaken at room temperature for 10 min. MP-cyanoborohydride (0.09 g, 0.2 mmol) was then added to the reaction mixture and shaken at room temperature for 24 h. The reaction was filtered, concentrated and purified by RP-HPLC to give the title compound. MS (ESI) m/e 546 (M+H)+; 1H NMR (500 MHz, DMSO-d6): δ ppm 11.11 (br s, 1H), 8.97 (br s, 2H), 7.66–7.70 (m, 3H), 7.58 (d, 2H), 7.50–7.54 (m, 2H), 7.46 (d, 2H), 7.37–7.40 (m, 1H), 7.30 (d, 2H), 6.76 (s, 1H), 4.24 (s, 2H), 3.17 (br s, 2H), 2.95 (t, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[S:8][C:9]([C:11]([O:13]C)=[O:12])=[CH:10][C:3]=12.O.[OH-].[Li+].CO.Cl>C1COCC1.O>[F:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[S:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:3]=12
Reactant: COC(=O)c1cc2c(F)cncc2s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2c(F)cncc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of methyl 4-fluorothieno[2,3-c]pyridine-2-carboxylate (0.942 g, 4.46 mmol) in THF (23 mL) was added a solution of lithium hydroxide monohydrate (0.384 g, 9.14 mmol) in water (23 mL). Methanol (2.8 mL) was then added until the solution was transparent. The reaction mixture stirred 2 h at room temperature. The reaction was then adjusted to pH ˜4 by addition of 2 N aqueous HCl, causing formation of a white precipitate. THF and methanol were removed by rotary evaporation, and then the residual solid was collected by vacuum filtration, washing with water (2×25 mL). The collected white solid was dried in an oven at 50° C. to afford 765 mg (87%) of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 14.15 (br. s., 1 H), 9.23 (s, 1 H), 8.54 (s, 1 H), 8.14 (s, 1 H); MS (ESI): 198.05 [M+H]+; HPLC tR=2.40 min (ZQ3, polar—4 min).