Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH2:6]([C:8](CC)(P(O)(O)=O)[C:9]([OH:11])=[O:10])C.[CH2:18]([O:25][C:26]1[CH:33]=[C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:31]=[CH:30][C:27]=1C=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>O1CCCC1>[CH2:18]([O:25][C:26]1[CH:33]=[C:32]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=[CH:30][C:27]=1/[CH:6]=[CH:8]/[C:9]([OH:11])=[O:10])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CCC(CC)(C(=O)O)P(=O)(O)O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)/C=C/c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: -70 °C
Reaction time: 3 h
Yield: 36.7 %

Procedure:
To a solution of 2.5 M n-butyl lithium (3.64 mL) in dry tetrahydrofuran (THF) (20 mL) that is cooled to −70° C. under nitrogen is added a solution of diethyl phosphonoacetic acid (0.89 g) in THF (5 mL). After 30 minutes a solution of 2,4-dibenzyloxybenzaldehyde (1.46 g) in THF (5 mL) is slowly added to the cooled solution so as to maintain the temperature. The resulting mixture is stirred at −70° C. for 3 hours and then at 25° C. for 18 hours. The resulting suspension is treated with water, the THF is removed in vacuo,the residue is extracted with ethyl acetate, the extract is dried and evaporated. The residual solid is recrystallized from isopropanol to yield (E)-3-(2,4-dibenzyloxyphenyl)prop-2-enoic acid as colourless crystals (0.6 g), m.p. 153-155° C. H NMR (DMSO) 5.15 (2H,s), 5.21(2H,s), 6.4(1H,d,J=16 Hz), 6.7(1H,d), 6.85(1H,s), 7.3-7.5(10H,m), 7.6(1H,d), 7.8(1H,d,J=16 Hz).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[CH:6]=[N:7][NH:8][CH:9]=1.Br[CH2:11][C:12]#[N:13].[Cl-].[NH4+]>O1CCCC1>[CH3:3][S:4][C:5]1[CH:6]=[N:7][N:8]([CH2:11][C:12]#[N:13])[CH:9]=1
Reactant: CSc1cn[nH]c1
Reactant: N#CCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CSc1cnn(CC#N)c1
Temperature: 0 °C
Yield: 72.5 %

Procedure:
Sodium hydride (631 mg, 16 mmol) was added to a solution of 4-(methylthio)-1H-pyrazole (1500 mg, 13.14 mmol) in anhydrous tetrahydrofuran (30 mL) under nitrogen at 0° C. The reaction mixture was stirred at 0° C. until gas evolution was no longer observed. Bromoacetonitrile (1.005 mL, 14.43 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 18 h. The mixture was poured into a solution of aqueous ammonium chloride (30 mL) and was extracted with ethyl acetate (60 mL×3). The combined organics were dried over sodium sulfate. The residue was filtered through a plug of silica gel which was eluted with ethyl acetate and the filtrate was concentrated under reduced pressure. The crude material was purified via flash chromatography (0-50% ethyl acetate in heptanes) to afford 2-(4-(methylthio)-1H-pyrazol-1-yl)acetonitrile (1460 mg, 72.54%). MS (ES+) (M+H) 154.1; LCMS retention time 0.40 min (Method N).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=2)=[CH:22][CH:21]=1
Reactant: Oc1ccc(-c2ccc(F)cc2F)cc1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cccc(COc2ccc(-c3ccc(F)cc3F)cc2)c1
Yield: 63.4 %

Procedure:
1-Bromomethyl-3-nitro-benzene (110 mg, 0.508 mmol), 2′,4′-difluoro-biphenyl-4-ol (110 mg, 0.533 mmol), and dried, finely ground potassium carbonate (74 mg, 0.533 mmol) in 10 mL acetone were refluxed under argon for 20 hrs. The reaction mixture was cooled, filtered, concentrated and re-dissolved in ethyl acetate. The ethyl acetate solution was washed with saturated NaHCO3, dried over MgSO4, filtered and evaporated in vacuo. The crude product was purified by flash chromatography with a gradient of 0-20% ethyl acetate in hexanes to yield 0.11 g (63%) of 2,4-difluoro-4′-(3-nitro-benzyloxy)-biphenyl. LC-MS (ES) calculated for C19H13F2NO3, 341.32; found m/z 340.3 [M−H]−.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[N:17][C:18]=3[NH:28][NH2:29])[N:13]=2)=[CH:8][CH:7]=1.O.[C:31]1(C)C(S(O)(=O)=O)=CC=C[CH:36]=1.C1(C)C=CC=CC=1.C(OC)(OC)(OC)C>CO>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][C:19]3[C:18]4=[N:28][N:29]=[C:31]([CH3:36])[N:17]4[CH:16]=[CH:15][C:14]=3[N:13]=2)=[CH:8][CH:7]=1
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: NNc1nccc2nc(-c3ccc(C4OCCO4)cc3)c(-c3ccccc3)cc12
Agent: COC(C)(OC)OC
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1nnc2c3cc(-c4ccccc4)c(-c4ccc(C5OCCO5)cc4)nc3ccn12
Temperature: 100 °C

Procedure:
To a solution of [2-(4-[1,3]dioxolan-2-yl-phenyl)-3-phenyl-[1,6]naphthyridin-5-yl]-hydrazine (3-4, 0.35 g, 0.91 mmol) and toluenesulfonic acid monohydrate (17 mg, 0.09 mmol) in 3:1 toluene:MeOH (4 mL) was added trimethyl orthoacetate (0.157 mL, 1.23 mmol). The mixture was heated to 100° C. in a microwave reactor for 75 min. The reaction mixture was then concentrated in vacuo. The solid was collected and dried with toluene azeotropically to give the title compound which was used for next step without further purification. LRMS m/z (M+1) Calcd: 409.2. Found 409.2.
Reaction SMILES: Br[C:2]([C:5](=[O:7])[CH3:6])=[CH:3]O.[C:8]([CH2:11][NH:12][C:13](=[O:15])[CH3:14])(=[S:10])[NH2:9]>CC(C)=O>[C:5]([C:2]1[S:10][C:8]([CH2:11][NH:12][C:13](=[O:15])[CH3:14])=[N:9][CH:3]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)NCC(N)=S
Reactant: CC(=O)C(Br)=CO
Solvent: CC(C)=O
Product: CC(=O)NCc1ncc(C(C)=O)s1
Yield: 30.1 %

Procedure:
A mixture of 2-bromo-1-hydroxy-3-oxo-1-butene (9.61 g) and N-[(thiocarbamoyl)methyl]acetamide (7.70 g) in acetone (100 ml) was refluxed for one hour with stirring. The resulting precipitate was collected by filtration and chromatographed on silica gel eluting with a mixture of chloroform and methanol (20:1, V/V) to give 5-acetyl-2-(acetylaminomethyl)thiazole (3.48 g).
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1C)(C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:31][C:32]1([CH3:39])[NH:36][C:35](=[O:37])[CH2:34][C:33]1=[O:38].[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:48]=[C:49](Br)[C:50]([CH3:53])=[CH:51][CH:52]=2)=[CH:43][CH:42]=1>O1CCOCC1.CO.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:40][C:41]1[CH:42]=[CH:43][C:44]([C:47]2[CH:52]=[C:51]([CH:34]3[C:33](=[O:38])[C:32]([CH3:39])([CH3:31])[NH:36][C:35]3=[O:37])[C:50]([CH3:53])=[CH:49][CH:48]=2)=[CH:45][CH:46]=1
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1Br
Reactant: CC1(C)NC(=O)CC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)NC(C)(C)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Under argon, in a heat-dried apparatus, 7.4 mg of Pd(OAc)2, 22 mg of di-tert-butyl(2′-methylbiphenyl-2-yl)phosphine and 0.78 g of K3PO4 in 4.8 ml of air-free dioxane are introduced as initial charge. 203 mg of 5,5-dimethylpyrrolidine-2,4-dione and 659 mg of 3-(4-chlorophenyl)-6-methylbromobenzene are added and the mixture is stirred for 16 hours under reflux. The mixture is then left to cool to room temperature, diluted with ca. 6 ml of methanol and filtered, and the filter residue is after-washed with ca. 3 ml of MeOH. The combined filtrates are concentrated by evaporation on a rotary evaporator. The residue is taken up in ca. 6 ml of water and rendered weakly acidic using 1 N hydrochloric acid. The precipitated solid is filtered off with suction and washed with ca. 3 ml of water. It is then washed from the filter with acetone and the filtrate is concentrated by evaporation. This gives 0.597 g of solid. Reversed-phase separation with water/acetonitrile (gradient) gives 93 mg (14% of theory) with a purity of 98.6% according to HPLC/MS.
Reaction SMILES: Cl.[CH3:2][NH2:3].[Cl:4][C:5]1[N:6]=[C:7]([C:12]([NH:14][C@H:15]2[CH2:20][CH2:19][N:18]([C:21]3[S:22][C:23]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:24]([CH:26]=O)[N:25]=3)[CH2:17][C@H:16]2[O:33][CH2:34][CH3:35])=[O:13])[NH:8][C:9]=1[CH2:10][CH3:11].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.ClC(Cl)C.C(OCC)(=O)C>[Cl:4][C:5]1[N:6]=[C:7]([C:12]([NH:14][C@H:15]2[CH2:20][CH2:19][N:18]([C:21]3[S:22][C:23]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:24]([CH2:26][NH:3][CH3:2])[N:25]=3)[CH2:17][C@H:16]2[O:33][CH2:34][CH3:35])=[O:13])[NH:8][C:9]=1[CH2:10][CH3:11]
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C=O
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1CNC
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.2 %

Procedure:
3 Å molecular sieves (500 mg) and methylamine hydrochloride (105 mg, 1.55 mmol) were added to a solution of ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl)-4-formyl-1,3-thiazole-5-carboxylate obtained in Example (28a) (500 mg, 1.03 mmol) in methanol (5 mL), and the mixture was stirred at room temperature for two hours. The reaction solution was filtered, and then the filtrate was concentrated under reduced pressure. Sodium triacetoxyborohydride (437 mg, 2.06 mmol) was added to a solution of the resulting residue in dichloroethane (10 mL), and the mixture was stirred at room temperature for 20.5 hours. The reaction solution was diluted with ethyl acetate, and then the mixture was extracted with a 1 N aqueous hydrochloric acid solution. A 1 N aqueous sodium hydroxide solution was added to the aqueous layer, followed by extraction with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate. Following filtration, the filtrate was concentrated under reduced pressure to obtain 145 mg of the title compound as a yellow oily substance (28%).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[N:15]=[N:14][C:13]([NH2:16])=[CH:12][CH:11]=1.[Cl-].[CH3:18][NH+:19]1[CH2:24][CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH2:21][CH2:20]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C(O)CCC.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:18][N:19]1[CH2:20][CH:21]=[C:22]([C:10]2[N:15]=[N:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:23][CH2:24]1
Reactant: Nc1ccc(Br)nn1
Reactant: C[NH+]1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCCCO
Product: CN1CC=C(c2ccc(N)nn2)CC1
Temperature: 115 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
In a 15 mL microwave reaction vial was added potassium phosphate tribasic (1.43 g, 6.74 mmol), 6-bromopyridazin-3-amine (335 mg, 1.93 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridinium chloride (500 mg, 1.93 mmol), X-PHOS (138 mg, 289 μmol) and bis(dibenzylideneacetone)palladium (83 mg, 144 μmol) in 7 mL n-butanol and 1.4 mL H2O. The tube was sealed under argon and heated at 115° C. in oil bath for 3 hrs then stirred at room temperature overnight. The phases were separated and the aqueous was extracted with EtOAc. (10 ml). Water (20 mL) was added to the residual aqueous phase and was extracted with DCM (3×10 mL). The extracts were combined with the EtOAc organic phase. The resultant solution was absorbed onto silica gel and purified by LC chromatography eluting with 0-10% (10% NH4OH in MeOH) in 1/1 EtOAc/hexane to afford 300 mg (82%) of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][C:16]2[N:15]=[CH:14][N:13]=[C:12](O)[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:21]>>[CH2:1]([N:8]1[CH2:17][C:16]2[N:15]=[CH:14][N:13]=[C:12]([Cl:21])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2c1CCN(Cc1ccccc1)C2
Product: Clc1ncnc2c1CCN(Cc1ccccc1)C2
Temperature: 100 °C
Yield: 81 %

Procedure:
7-Benzyl-4-hydroxy-5,6,7,8-tetrahydro-1,3,7-triazanaphthalene [Ozdowska et al Rocz. Chem. Ann. Soc. Chim. Pol. 50,1771 (1976)] 95.0 g, 15.9 mmol) was added to POCl3 and the mixture heated to 100° C. for 1 h. The reaction was cooled, concentrated under reduced pressure and the residue quenched with ice. After neutralising with K2CO3 the product was extracted with CH2C2, the organic layer washed with H2O, dried over MgSO4 and evaporated to give the subtitle compound as a brown oil (3.33 g, 81%). Rf 0.45 (CH2Cl2 /MeOH/0.88NH3 92/7/1, v/v).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([S:20]([NH:23][CH3:24])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=2)[N:8]=1)=O.[NH:26]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=1)N>>[CH3:24][NH:23][S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:26]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:15]=1)(=[O:22])=[O:21]
Reactant: CNS(=O)(=O)c1cccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)c1
Reactant: Cc1cc(NN)ccn1
Product: CNS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccnc(C)c3)n2)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-N-methyl-benzenesulfonamide (A-31) and 4-hydrazino-2-methylpyridine according to the method described for example 91. MS: M=423.1 (M+H)+
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:31][CH2:30][C@:21]3([NH:25][C@@H:24]([C:26](OC)=[O:27])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[BH4-].[Li+]>O1CCCC1>[F:42][C:2]([F:1])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:31][CH2:30][C@:21]3([NH:25][C@@H:24]([CH2:26][OH:27])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: COC(=O)[C@H]1CC[C@@]2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1[C@H]1C[C@]2(CC[C@H](CO)N2)CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
To a solution of methyl (2R,5S,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-1,8-diazaspiro[4.5]decane-2-carboxylate (Intermediate 12, 350 mg, 0.580 mmol) in Tetrahydrofuran (THF) (6 ml) at 0° C. lithium borohydride (0.568 ml, 1.160 mmol) was added and the reaction mixture was stirred at room temperature and under nitrogen atmosphere overnight. Volatiles were evaporated in vacuo and the residue was dissolved in Methanol (2 ml)/HCl 1 N in water (4 ml). After 1 h stirring combined solvents were evaporated in vacuo. The residue was dissolved in Ethyl acetate (4 ml) and washed with NaHCO3 sat. sol. (2×3 ml). Organic phase was dried and evaporated and the residue was purified by flash chromatography on silica gel using a Biotage 12+M as column and Dichloromethane/Methanol 95:5 as eluent affording the title compound (160 mg, 0.278 mmol, y=47.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=2)[CH:7]=1.Cl.C(=O)(O)[O-].[Na+]>CO.[Fe]>[NH2:16][C:12]1[CH:11]=[C:10](/[CH:9]=[CH:8]/[C:6]2[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[CH:7]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cccc(/C=C/c2cncc(Cl)c2)c1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Product: Nc1cccc(/C=C/c2cncc(Cl)c2)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 50.3 %

Procedure:
A mixture of 3-chloro-5-[(E)-2-(3-nitrophenyl)vinyl]pyridine (2.99 g), iron powder (2.6 g) and hydrochloric acid (35%, 8 ml) in methanol (50 ml) was stirred at 60° C. for 3 hours. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 3-[(E)-2-(3-aminophenyl)vinyl]-5-chloropyridine (1.33 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:19]([O-:21])=[O:20])[C:5]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])=[N:6][C:7]=1F.[CH:22]1([C:25]2[NH:29][N:28]=[C:27]([NH2:30])[CH:26]=2)[CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>C1COCC1>[CH:22]1([C:25]2[NH:29][N:28]=[C:27]([NH:30][C:7]3[C:2]([F:1])=[CH:3][C:4]([N+:19]([O-:21])=[O:20])=[C:5]([NH:9][C@H:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[CH3:11])[N:6]=3)[CH:26]=2)[CH2:24][CH2:23]1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: C[C@H](Nc1nc(F)c(F)cc1[N+](=O)[O-])c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1[N+](=O)[O-])c1ccc(F)cc1
Temperature: 55 °C
Yield: 66.2 %

Procedure:
To a solution of (S)-5,6-difluoro-N-(1-(4-fluorophenyl)ethyl)-3-nitropyridin-2-amine (Method 23, 0.60 g, 2.0 mmol) in THF (10 ml) at room temperature was added 5-cyclopropyl-1H-pyrazol-3-amine (0.50 g, 4.0 mmol), and DIEA (0.26 g, 2.0 mmol). The reaction was then heated to 55° C. for 24 hours, cooled to room temperature, and quenched with water. The reaction was then extracted with DCM (2×75 ml), and the combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by column chromatography (DCM-MeOH=100:1) to give the title compound (0.53 g, 66%). 1H NMR (400 MHz, CD3OD) δ 8.00 (d, J=11.1 Hz, 1H), 7.38-7.35 (m, 2H), 7.07-7.02 (m, 2H), 6.17 (s, 1H), 5.41-5.39 (m, 1H), 1.93-1.87 (m, 1H), 1.61 (d, J=7.0 Hz, 3), 1.02-1.00 (m, 2H), 0.69-0.66 (m, 2H). MS: Calcd.: 400. Found: [M+H]+ 401.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([S:11][CH3:12])=[N:9][CH:10]=[C:5]2[C:4](=O)[NH:3]1.P(Br)(Br)([Br:16])=O.O>C(#N)C>[Br:16][C:4]1[C:5]2[C:6](=[N:7][C:8]([S:11][CH3:12])=[N:9][CH:10]=2)[N:2]([CH3:1])[N:3]=1
Reactant: CSc1ncc2c(=O)[nH]n(C)c2n1
Reactant: O=P(Br)(Br)Br
Solvent: CC#N
Solvent: O
Product: CSc1ncc2c(Br)nn(C)c2n1
Temperature: 5 °C
Reaction time: 1 h
Yield: 61.7 %

Procedure:
1-Methyl-6-methylsulfanyl-1,2-dihydro-pyrazolo[3,4-d]pyrimidin-3-one (2.0 g, 0.01 mol) was refluxed with phosphorus oxybromide (6 g) in acetonitrile (60 mL). Water (100 mL) was then added and the reaction mixture cooled to 5° C., hold for 1 hour and filtered to give 1.6 g (61%) of pure 3-bromo-1-methyl-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine; 1H-NMR (DMSO): δ 2.61 (s, 3H), 3.96 (s, 3H), 9.00 (s, 1H), LC/MS (m/e)=260.8 (MH+), Rt=1.89 min.
Reaction SMILES: [Br:1][CH2:2][C:3](OCC)([O:38]CC)[C:4](=[N:35][O:36][CH3:37])[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:12]([CH:15]=[CH2:16])[CH2:13][S:14][C@H:9]12)=[O:6].Cl>C(Cl)Cl>[Br:1][CH2:2][C:3](=[O:38])[C:4](=[N:35][O:36][CH3:37])[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])=[C:12]([CH:15]=[CH2:16])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)C(CBr)(OCC)OCC)[C@H]2SC1
Agent: Cl
Solvent: ClCCl
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)C(=O)CBr)[C@H]2SC1
Temperature: 25 °C
Yield: 60.5 %

Procedure:
To a solution of benzhydryl 7-(4-bromo-3,3-diethoxy-2-methoxyiminobutyramido)-3-vinyl-3-cephem-4-carboxylate (syn isomer) (6.5 g) in methylene chloride (60 ml) was added conc. hydrochloric acid (6ml) at 3° to 5° C., and the mixture was stirred from under ice-cooling to at ambient temperature for 8 hours. After methylene chloride (100 ml) was added to the reaction mixture, it was washed with water and then dried over anhydrous magnesium sulfate. Removal of the solvent gave a residue, which was washed with diethyl ether to obtain benzhydryl 7-(4-bromo-2-methoxyiminoacetoacetamido)-3-vinyl-3-cephem-4-carboxylate (syn isomer) (3.5 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[CH:19]=[CH2:20].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH:20]=[CH:19][C:18]([O:22][CH2:23][CH3:24])=[O:21])=[CH:6][CH:7]=1
Reactant: C=CC(=O)OCC
Reactant: Nc1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc(N)nc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
2-Amino-5-bromopyridine (15 g) was dissolved in a mixed solvent of N,N-dimethylformamide (hereinafter referred to as “DMF”; 60 ml) and N,N-diisopropylethylamine (60 ml). Ethyl acrylate (12 ml), palladium acetate (980 mg), and tris(2-methylphenyl)phosphine (10.5 g) were added thereto in a nitrogen atmosphere, and the mixture was stirred at 100° C. for 12 hours. The reaction mixture was filtered through Celite and separated with ethyl acetate and water. The organic layer was washed with a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was crystallized with N-hexane to obtain Compound 1a (15.5 g, 89%) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>O1CCCC1.CO.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([N:10]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccc([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCN(c2cccc(N)c2)CC1
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To 10% palladium-carbon (10 mg), a solution of tert-butyl 4-(3-nitrophenyl)-1,4-diazepane-1-carboxylate (C27, 15 mg) in tetrahydrofuran (2 mL) and methanol (2 mL) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour under a hydrogen atmosphere. The insoluble matter was removed by filtration through Cerite, and then the solvent was evaporated under reduced pressure to obtain tert-butyl 4-(3-aminophenyl)-1,4-diazepane-1-carboxylate (C28, 12 mg).