Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]=2[S:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18](N)=[O:19])=[CH:16][C:3]1=2.[OH-:21].[K+].O.CO>C(O)(=O)C>[O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]=2[S:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:19])=[O:21])=[CH:16][C:3]1=2
Reactant: [OH-]
Reactant: NC(=O)Cc1ccc2c(c1)C(=O)Cc1cccnc1S2
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc2c(c1)C(=O)Cc1cccnc1S2
Temperature: 0 °C
Yield: 29.9 %

Procedure:
A mixture of 50 mg of (5,6-dihydro-6-oxo benzo[b]pyrido-[3,2-f]thiepin-8-yl)-acetamide, 200 mg of potassium hydroxide, 2 ml of water and 15 ml of methanol was refluxed under a nitrogen atmosphere for 4 hours. After the completion of the reaction, the solvent was distilled off to obtain a residue, to which was added ice water. The mixture was acidified with acetic acid and extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation to obtain an oil, which was chromatographed over silica gel and eluted with chloroform/ethanol (200/1) to obtain a solid. This solid was recrystallized from ethanol to give 15 mg (yield: 30%) of (5,6-dihydro-6-oxo benzo[b]pyrido[3,2-f]thiepin-8-yl)-acetic acid as colorless needle crystals having a melting point of 212°-213.5° C.
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].O.Cl.[NH:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1.C(#N)C.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[CH3:8][C:2]([N:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1)([CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: O=C1CCNCC1
Reactant: CCOC(=O)C(C)(C)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOCC
Product: CCOC(=O)C(C)(C)N1CCC(=O)CC1
Reaction time: 20 h

Procedure:
A mixture of ethyl 2-bromo-2-methylpropanoate (48.3 ml, 5 equiv), 4-piperidone hydrochloride monohydrate (100 g, 1 equiv), acetonitrile (1216 ml) and potassium carbonate (353 g, 4 equiv) was heated at reflux under nitrogen with mechanical stirring for 20 h then cooled in an ice bath before adding diethyl ether (approx. 1400 ml). The mixture was filtered through celite, evaporated in vacuo, then excess bromoester distilled off (50° C. still head temperature/10 Torr). Flash chromatography (silica, 5-30% ethyl acetate in hexane) and evaporation of the product fractions gave the crude product as a yellow oil. To remove some remaining bromoester contaminant this was partitioned between ethyl acetate and 2M aqueous hydrochloric acid. The organic layer was discarded and the aqueous layer was basified with sodium carbonate, saturated with sodium chloride and extracted with ethyl acetate. Drying and evaporation of the organic extracts gave the desired product as a yellow oil (54.7 g).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:15]([OH:17])=O)[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:18]([O:20][C:21](=[O:28])[CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][NH:24]1)[CH3:19]>>[CH2:18]([O:20][C:21](=[O:28])[CH2:22][C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:15](=[O:17])[C@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:19]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)O
Reactant: CCOC(=O)CC1CCCN1
Product: CCOC(=O)C[C@@H]1CCCN1C(=O)[C@H](CCCCN)NC(=O)OC(C)(C)C

Procedure:
N-α-CBZ, N- -BOC-L-lysine and ethyl-2-pyrrolidineacetate are condensed by the procedure of Example 1, Step C to give N-α-CBZ, N- -BOC-L-lysyl-(S)-2-pyrrolidine acetic acid ethyl ester. The N-α-CBZ group is removed by hydrogenolysis in ethanol containing one equivalent of acetic acid over 10% palladium on charcoal utilizing the procedure of P. G. Katsoyannis and G. P. Schwartz, Methods in Enzymology, 47, 546 (1974), to give N- -BOC-L-lysyl-(S)-2-pyrrolidineacetic acid ethyl ester.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:11]=2)[CH:6]=[C:5]([C:21]([O:23][CH3:24])=[O:22])[CH:4]=1)=[CH2:2].[OH-:25].[Na+].OO.Cl>C1COCC1.O>[OH:25][CH:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][CH:11]=2)[CH:6]=[C:5]([C:21]([O:23][CH3:24])=[O:22])[CH:4]=1)[CH3:2]
Reactant: [OH-]
Reactant: C=Cc1cc(C(=O)OC)cc2cc(OCc3ccccc3)ccc12
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(C(C)O)c2ccc(OCc3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.3 g (0.9 mmol) of 1-vinyl-3-carbomethoxy-6benzyloxynaphthalene and 0.9 ml (0.9 mmol) of 1.0M BH3.THF complex in 15 ml of THF is stirred at 25° C. for 2 hours. To this is added 1 ml of H2O, 1 ml of 1N NaOH and 1 ml of 30% H2O2 which is then stirred at 25° C. for 2 hours. The mixture is acidified to pH ~1 using 1N HCl and extracted with ethyl acetate. The organics are dried (MgSO4) and concentrated in vacuo. Purification by flash silica gel chromatography using 15% ethyl acetate in hexanes as an eluent affords 0.08 g of 1-hydroxyethyl-3-carbomethoxy-6-benzyloxynaphthalene in the form a yellow oil which is used directly in the next step.
Reaction SMILES: BrC1C=C(F)C(F)=CC=1O.C(O[CH:14](OCC)[CH2:15][O:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[Br:25])C>>[F:23][C:21]1[C:22]2[CH:14]=[CH:15][O:16][C:17]=2[C:18]([Br:25])=[CH:19][C:20]=1[F:24]
Reactant: CCOC(COc1cc(F)c(F)cc1Br)OCC
Agent: Oc1cc(F)c(F)cc1Br
Product: Fc1cc(Br)c2occc2c1F

Procedure:
Beginning with 5 gm (23.9 mMol) 2-bromo-4,5-difluorophenol, 7.05 gm (91%) 2-(2-bromo-4,5-difluorophenoxy)-acetaldehyde diethyl acetal were prepared essentially as described in Preparation IV.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[F:10][C:11]1[CH:12]=[C:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:14]=[CH:15][C:16]=1[C:17]1[C:18]([NH2:23])=[N:19][CH:20]=[CH:21][CH:22]=1.O>C1COCC1.CCCCCC>[F:10][C:11]1[CH:12]=[C:13]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:14]=[CH:15][C:16]=1[C:17]1[C:18]2=[N:23][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:19]2[CH:20]=[CH:21][CH:22]=1
Reactant: Nc1ncccc1-c1ccc(-c2ccccc2)cc1F
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=CC=C(c3ccc(-c4ccccc4)cc3F)C2=N1
Yield: 79.1 %

Procedure:
To a suspension of 60% sodium hydride (0.76 g) in THF (20 mL) was added 2-chloroethanesulfonyl chloride (1.85 g) under ice-cooling. The reaction mixture was stirred under ice-cooling for 5 min, and a solution of 3-(3-fluorobiphenyl-4-yl)pyridin-2-amine (1.0 g) in THF (20 mL) was added. The reaction mixture was stirred at room temperature overnight, and water and hexane were added under ice-cooling. The resulting solid was collected by filtration, washed with diisopropyl ether, and dried under reduced pressure to give the title compound (1.06 g).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Br:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:18][OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](Cl)(=[O:22])[CH3:21]>>[C:20]([O:19][CH2:18][C:9]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:16]2[C:11]([CH:10]=1)=[CH:12][C:13]([Br:17])=[CH:14][CH:15]=2)(=[O:22])[CH3:21]
Reactant: OCc1cc2cc(Br)ccc2n1Cc1ccccc1
Reactant: CC(=O)Cl
Product: CC(=O)OCc1cc2cc(Br)ccc2n1Cc1ccccc1

Procedure:
The title compound was prepared from (1-benzyl-5-bromo-1H-indol-2-yl)methanol and acetyl chloride in substantially the same manner, as described in step 4 of Example 1. The product was obtained as a semi-solid. Mass spectrum (ESI, [M−H]−) m/z 356. 1H NMR (400 MHz, DMSO-d6) δ 7.78 (d, 1H, J=2.13 Hz), 7.38 (d, 1H, J=8.86 Hz), 7.29–7.20 (m, 4H), 6.94 (d, 2H, J=7.17 Hz), 6.64 (s, 1H), 5.47 (s, 2H), 5.21 (s, 2H), and 1.79 ppm (s, 3H).
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:16][CH:15]2[CH:11]([CH2:12][NH:13][CH2:14]2)[CH2:10]1)=[O:8].Cl[C:24]1[N:29]=[C:28]([C:30]2[O:31][CH:32]=[CH:33][CH:34]=2)[CH:27]=[CH:26][N:25]=1>>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:10][CH:11]2[CH:15]([CH2:14][N:13]([C:24]3[N:29]=[C:28]([C:30]4[O:31][CH:32]=[CH:33][CH:34]=4)[CH:27]=[CH:26][N:25]=3)[CH2:12]2)[CH2:16]1)=[O:8]
Reactant: Clc1nccc(-c2ccco2)n1
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNCC2C1
Product: O=C(c1ccccc1-c1ccccc1)N1CC2CN(c3nccc(-c4ccco4)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 17 and 2-chloro-4-furan-2-yl-pyrimidine. MS (ESI) mass calcd. for C27H24N4O2, 436.52; m/z found, 437.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.CCN(CC)CC.[S:20](Cl)([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21].O>C(Cl)Cl>[F:24][C:23]([F:26])([F:25])[S:20]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2)(=[O:22])=[O:21]
Reactant: O=C1NCCc2cc(O)ccc21
Reactant: O=S(=O)(Cl)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1NCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reaction time: 2 h
Yield: 0.1 %

Procedure:
To a suspension of 6-hydroxy-3,4-dihydroisoquinolin-1(2H)-one (1.60 g, 9.81 mmol) and Et3N (1.37 mL, 0.992 g, 9.81 mmol) in CH2Cl2 (100 mL) was added triflic chloride (1.65 g, 9.81 mmol). After 2 h of stirring, H2O (100 mL) was added and the mixture was extracted with CH2Cl2 (3×100 mL), dried (MgSO4), concentrated and purified via column chromatography to yield 1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate (1.70 mg, 59% yield) as a colorless solid. 1H NMR (400 MHz, CDCl3): δ8.19 (d, J=8.4 Hz, 1H), 7.27 (dd, J=8.4, and 2.4 Hz, 1H), 7.19 (d, J=2.4 Hz, 1H), 6.58 (brs, 1H), 3.64 (dt, J=6.8, and 2.4 Hz, 2H), 3.08 (t, J=6.6 Hz, 2H); MS (ESI) m/z: 296.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([CH:19]([OH:26])[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:27]([F:30])([F:29])[F:28].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[O:26])=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:27]([F:30])([F:28])[F:29]
Reactant: O=S(=O)(Nc1cc(Cl)cnc1C(O)c1ccncc1)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: O=C(c1ccncc1)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-chloro-N-[5-chloro-2-(hydroxy-pyridin-4-yl-methyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (15 mg, 0.03 mmol) and PCC (15 mg) was stirred at room temperature for 2 h. It was then treated with small amount of silica gel and filtered. The filtrate was concentrated under reduced pressure to provide the crude ketone. 1H NMR (400 MHz, CDCl3) δ 10.90 (br s, 1 H), 8.78 (dd, J=4.4, 1.6 Hz, 2 H), 8.35 (d, J=2.0 Hz, 1 H), 8.19-8.17 (m, 2 H), 7.98 (dd, J=8.4, 2.0 Hz, 1 H), 7.65-7.61 (m, 3 H). MS m/z: 476.0 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[C@@H:5]([NH:7][C@H:8]([C:23](=[O:40])[N:24]([C:26]1[N:30](CC2C=CC(OC)=CC=2)[N:29]=[N:28][N:27]=1)[CH3:25])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:12][CH:11]=1)[CH3:6])[CH3:2].C(Cl)Cl>C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4](=[O:41])[C@@H:5]([NH:7][C@H:8]([C:23](=[O:40])[N:24]([CH3:25])[C:26]1[NH:30][N:29]=[N:28][N:27]=1)[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[CH:14][CH:15]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)[C@H](C)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)N(C)c1nnnn1Cc1ccc(OC)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H](C)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)N(C)c1nnn[nH]1
Yield: 58.2 %

Procedure:
Next, (S)-2-((S)-2-(3′-chloro-biphenyl-4-yl)-1-{[1-(4-methoxy-benzyl)-1H-tetrazol-5-yl]-methyl-carbamoyl}-ethylamino)-propionic acid ethyl ester (260 mg, 0.451 mmol) was dissolved in TFA (5 mL) and DCM (5 mL) and stirred at 50° C. for 12 hours and at 75° C. for 5 hours. The reaction mixture was concentrated under reduced pressure to give (S)-2-{(S)-2-(3′-chloro-biphenyl-4-yl)-1-[methyl-(1H-tetrazol-5-yl)-carbamoyl]-ethylamino}-propionic acid ethyl ester (120 mg). MS: m/z (MH+) 457; HPLC retention time 0.95 min (HPLC condition C).
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=O.[CH:24]([C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][N:27]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.CO>[C:16]1([C@@H:14]2[CH2:15][C@H:13]2[NH:5][CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([CH2:24][C:26]3[CH:35]=[CH:34][C:29]([C:30]([OH:32])=[O:31])=[CH:28][N:27]=3)[CH2:11][CH2:12]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Reactant: COC(=O)c1ccc(C=O)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CO
Product: O=C(O)c1ccc(CN2CCC(CN[C@@H]3C[C@H]3c3ccccc3)CC2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.6 %

Procedure:
To a solution 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (130 mg, 0.398 mmol) in 1,2-dichloroethane (DCE) (2 mL) were added methyl 6-formylnicotinate (86 mg, 0.518 mmol) and sodium triacetoxyborohydride (127 mg, 0.598 mmol), and the reaction mixture was stirred at room temperature for 18 h. The mixture was quenched with water (2 mL) and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated to give a crude product. The product was dissolved in methanol (2.000 mL) and sodium hydroxide (3M, 0.664 mL, 1.992 mmol) was added. The mixture was stirred at room temperature for 3 h and concentrated. The residue was treated with methanol and filtered. The filtrate was purified using reverse-phase HPLC under the acidic conditions to give 110 mg of product as pale yellow solid (HCl salt). MS: (M+H)+=366.4. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.24 (m, 1H),1.54-1.73 (m, 3H), 1.98-2.12 (m, 3H), 2.59-2.72 (m, 1H), 2.94 (m, 4H), 3.45 (br. s., 2H), 4.54 (br. s., 2H), 7.16-7.25 (m, 3H), 7.27-7.35 (m, 2H), 7.81 (d, J=8.08 Hz, 1H), 8.38 (dd, J=8.08, 2.27 Hz, 1H), 9.12 (d, J=1.52 Hz, 1H), 9.78 (br. s., 2H), 10.72 (br. s., 1H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C@H:11]1[C@@H:17]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:16][C@H:15]2[N:25]([CH3:26])[C@@H:12]1[CH2:13][CH2:14]2)(OC)=[O:8]>C(OCC)C>[OH:8][CH2:7][C@H:11]1[C@@H:17]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH2:16][C@H:15]2[N:25]([CH3:26])[C@@H:12]1[CH2:13][CH2:14]2
Reactant: COC(=O)[C@H]1[C@@H](c2ccc(F)cc2)C[C@@H]2CC[C@H]1N2C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CN1[C@H]2CC[C@@H]1[C@@H](CO)[C@@H](c1ccc(F)cc1)C2
Reaction time: 0.17 h

Procedure:
To a suspension of lithium aluminum hydride (0.8 g, 21 mmol) in diethyl ether (30 ml), at room temperature, was slowly added a solution of (1R,2S,3S)-2-carbomethoxy-3-(4-fluorophenyl)tropane (5 g, 18 mmol) in 100 ml diethyl ether. The reaction completed after stirring for 10 minutes and was quenched by addition of 0.8 ml water, 0.8 ml sodium hydroxide (15%) and 2 ml water. The aluminum salts were removed by filtration and the solvent was removed in vacuo leaving oil. The title compound precipitated upon trituration with pentane as white crystals, m.p. 79°-80° C.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:27])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23](N)=[CH:22][N:21]=1)([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].N([O-])=O.[Na+].[ClH:32].[C:33]([O:37][CH2:38][CH3:39])(=[O:36])[CH:34]=[CH2:35]>O.CC(C)=O>[C:1]([O:4][C:5]1[C:6]([CH3:27])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:35][CH:34]([Cl:32])[C:33]([O:37][CH2:38][CH3:39])=[O:36])=[CH:22][N:21]=1)([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: Cl
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(COc1ccc(N)cn1)O2
Reactant: C=CC(=O)OCC
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CCc3c(C)c(OC(C)=O)c(C)c(C)c3O2)nc1

Procedure:
Following the same procedure as described in Preparation 18, 4.5 g of 6-acetoxy-2-(5-aminopyridin-2-yloxymethyl)-2,5,7,8-tetramethylchroman (prepared as described in Preparation 37), 1.1 g of sodium nitrite, 5 ml of concentrated hydrochloric acid, 10 g of ethyl acrylate, 175 mg of cuprous oxide, 40 ml of acetone and about 2.5 g of water were reacted, to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](=S)[NH2:5].[NH2:14][NH2:15].[OH2:16]>C(O)C>[CH3:1][C:2]1[C:10]([N+:11]([O-:12])=[O:16])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](=[NH:5])[NH:14][NH2:15]
Reactant: Cc1c(C(N)=S)cccc1[N+](=O)[O-]
Reactant: O
Reactant: NN
Solvent: CCO
Product: Cc1c(C(=N)NN)cccc1[N+](=O)[O-]
Temperature: 45 °C
Yield: 86 %

Procedure:
To a solution of 2-methyl-3-nitrobenzothioamide (2.50 g, 12.74 mmol) in ethanol (50 mL) at rt was added hydrazine, H2O (12.49 mL, 255 mmol). The mixture was heated at 45° C. for 4 hr and then concentrated under vacuum to a volume of approximately 20 mL. The residue was diluted with water (20 mL) and extracted with CH2Cl2 (5×50 mL). The combined extract was dried over anhydrous MgSO4. Removal of solvent under vacuum provide the desired product, 2-methyl-3-nitrobenzimidohydrazide (2.12 g, 10.92 mmol, 86% yield), as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[C:27]([Cl:28])=[C:26]([CH3:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[N:18]=1>>[N:20]1[CH:21]=[CH:22][N:23]=[CH:24][C:19]=1[C:17]1[N:18]=[C:13]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:14]2[C:27]([Cl:28])=[C:26]([CH3:29])[S:25][C:15]=2[N:16]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: Cc1sc2nc(-c3cnccn3)nc(Cl)c2c1Cl
Product: Cc1sc2nc(-c3cnccn3)nc(NCc3cccc([N+](=O)[O-])c3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyrazin-2-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3-nitrobenzylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([C:14]3[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27]C(=O)OC(C)(C)C)[CH2:22]1.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:52]>CN1C(=O)CCC1>[ClH:52].[NH2:27][C@@H:23]1[CH2:24][CH2:25][CH2:26][N:21]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12]([C:14]4[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=4)=[O:13])[C:4]=23)[CH2:22]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: Cn1ccc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)n1
Reactant: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Product: Cl
Product: Cn1ccc(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](N)C4)c23)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 3 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methyl-1H-pyrazole-3-carboxamide (0.190 g, 0.56 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (0.34 g, 1.69 mmol) and DIEA (0.2 mL, 1.12 mmol) in NMP (2 mL) were stirred at 156° C. (bath) for 24 hours. The solvent was removed, and the residue dissolved in ethyl acetate (20 mL), washed with water (10 mL), brine (10 mL) and dried over sodium sulfate. After removal of the solvent, the residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 30-70% CH3CN/water gradient; 30 CV) to give a solid. This solid was dissolved in DCM (3 mL), and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour. The solvent was removed. The residue was dissolved in DCM (1 mL), and 2N HCl in ether (3 mL) was added. The solid formed was collected by filtration to give (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methyl-1H-pyrazole-3-carboxamide hydrochloride (0.0096 g, 3% yield) as a solid. 1H NMR (400 MHz, D2O) δ 8.22 (s, 1H), 7.73 (s, 1H), 7.60 (d, 1H), 6.70 (d, 1H), 3.86 (s, 3H), 3.70 (m, 1H), 3.52 (m, 1H), 3.40 (m, 2H), 2.98 (m, 1H), 2.12 (m, 1H), 1.94 (m, 1H), 1.76 (m, 1H), 1.48-1.54 (m, 1H); LCMS (APCI+) m/z 418 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](O)=[N:8][C:9]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:10][CH:11]=1)=[O:5])[CH3:2].O=S(Cl)[Cl:21].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([Cl:21])=[N:8][C:9]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1cnc(-c2cccnc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of Compound 14c (5.05 g; 20.59 mmol) in DMF (70 mL) was added SOCl2 (3 mL; 41.23 mmol) dropwise at room temperature. The reaction was stirred at room temperature for 30 min, then poured into an ice water slurry of K2CO3 (3.41 g). The resultant solid (Compound 14d) was collected by filtration and dried. 1H NMR (300 MHz, CDCl3): δ 9.70 (s, 1H), 9.20 (s, 1H), 7.70-8.85 (m, 2H), 7.50 (dd, 1H), 4.50 (q, 2H), 1.45 (t, 3H); MS: m/z 264.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:40][C:41]([N:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][N:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: O=C(CCl)N1CCCCC1
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 9.8 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-1-piperidin-1-ylethanone (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.0 mg) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([C:20]#[N:21])[C:18]#[N:19].N1CCCCC1>C(O)(C)C>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[C:17]([C:20]#[N:21])[C:18]#[N:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: N#CCC#N
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: N#CC(C#N)=Cc1ccc(OCc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
14.22 g (67 mmol) of 4-benzyloxybenzaldehyde and 5.31 g (80.4 mmol) of malonodinitrile were suspended in 80 ml of isopropanol in the presence of 0.2 ml of piperidine. In so doing the mixture increased in temperature from 19° to 31° C. A solution resulted, from which a solid was finally obtained. This was filtered off after stirring for 30 min. There were obtained 10.3 g (59%) of 2-(4-benzyloxy-benzylidene)-malononitrile with m.p. 146°-148° C.