Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:12]([C:14]1[N:18]([CH3:19])[C:17](B(O)O)=[CH:16][CH:15]=1)#[N:13].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:12]([C:14]1[N:18]([CH3:19])[C:17]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=2)=[CH:16][CH:15]=1)#[N:13]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cn1c(C#N)ccc1-c1ccc(S(N)(=O)=O)cc1
Reaction time: 16 h
Yield: 36.4 %

Procedure:
According to general procedure B, 4-bromobenzenesulfonamide (472 mg, 2.0 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (360 mg, 2.4 mmol), potassium fluoride (350 mg, 6.0 mmol), and tris(dibenzylideneacetone)-dipalladium (48 mg, 0.05 mmol) were placed in an oven dried flask under nitrogen and dry THF (5 mL) was added. Tri-t-butylphosphine (0.30 mL, 0.1 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. Purification afforded 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)benzenesulfonamide (190 mg). MS (ES) m/z 261.8; HPLC purity 99.6% at 210-370 nm, 7.1 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:25][CH3:26])=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH2:8][CH2:9][C:10]2([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[O:15][C:14](=[O:16])[CH2:13][C:12](=[O:17])[CH2:11]2)[CH:7]=1.O.Cl.Cl.[CH3:30][N:31]1[C:35]([CH:36]=O)=[N:34][C:33]([C:38]2[CH:43]=[N:42][CH:41]=[CH:40][N:39]=2)=[N:32]1.C(N(CC)CC)C.Cl>C(O)(C)C.O>[Cl:1][C:2]1[C:3]([O:25][CH3:26])=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH2:8][CH2:9][C:10]2([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[O:15][C:14](=[O:16])[C:13]([CH2:36][C:35]3[N:31]([CH3:30])[N:32]=[C:33]([C:38]4[CH:43]=[N:42][CH:41]=[CH:40][N:39]=4)[N:34]=3)=[C:12]([OH:17])[CH2:11]2)[CH:7]=1
Reactant: COc1cc(OC)c(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: Cn1nc(-c2cnccn2)nc1C=O
Agent: Cl
Solvent: O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: COc1cc(OC)c(CCC2(C3CCCC3)CC(O)=C(Cc3nc(-c4cnccn4)nn3C)C(=O)O2)cc1Cl
Temperature: 25 °C
Yield: 24.8 %

Procedure:
A solution of 6-[2-(5-chloro-2,4-dimethoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione (0.300 g, 0.78 mmol, from step 6 below) in hot isopropanol (5 mL) was treated with (CH3)2NHBH3 (48 mg, 0.815 mmol, 1.04 equiv), then with a solution of 2-methyl-5-pyrazin-2-yl-2H-[1,2,4]triazole-3-carbaldehyde dihydrochloride monohydrate (229 mg, 0.819 mmol, 1.05 equiv, from step 3 below) in isopropanol (3 mL) containing triethylamine (0.230 mL, 2 equiv). The reaction mixture was stirred at room temperature, resulting in complete conversion after 1 h. The mixture was acidified with 1 M aqueous HCl to a pH of 2, stirred for 10 min, and concentrated in vacuo to afford a resin. This was diluted with water and extracted with dichloromethane containing 10% methanol (3×15 mL). The extract was dried over Na2SO4, filtered, and concentrated, affording the crude product (410 mg). This material was recrystallized from hot methylene chloride/ether, then the resulting solid triturated with acetone containing petroleum ether, filtered, and dried, affording the title product (107 mg, 24%). 1H NMR (300 MHz, DMSO-d6): δ 1.26–1.75 (m, 8H), 1.78–2.13 (m, 2H), 2.37 (m, 1H), 2.45–2.50 (m, 2H, overlap with DMSO-d5), 2.65 (d, J=17.9 Hz, 1 H), 2.73 (d, J=17.9 Hz, 1 H), 3.73 (s, m overlap, 5H), 3.80 (s, 3H), 3.95 (s, 3H), 6.63 (s, 1H), 7.05 (s, 1 H), 8.6 (m, overlap, 2H), 8.93 (s, 1H), 11.07 (br s, 1H). LC-MS (APCI) calcd for C28H32ClN5O5: 553.21, found (M+H+): 554.4 m/z.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]1.[ClH:37].CCOCC>O1CCOCC1>[ClH:37].[NH:27]1[CH2:28][CH2:29][CH:24]([CH2:23][CH2:22][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]3([C:14]4=[CH:15][C:16]5[O:20][CH2:19][O:18][C:17]=5[CH:21]=[C:13]4[O:12][CH2:11]3)[C:2]2=[O:1])[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C1N(CCC2CCNCC2)c2ccccc2C12COc1cc3c(cc12)OCO3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of tert-butyl 4-[2-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)ethyl]piperidine-1-carboxylate (0.94 g, 1.91 mmol) in dioxane (5.00 mL) was added 4.0 M HCl in dioxane (2.00 mL, 8.00 mmol). The mixture was stirred at ambient temperature for 30 min followed by the addition of anhydrous ether (40.0 mL). The precipitated white solid was filtered, washed with ether and dried to give the title compound (0.75 g, 91%): 1H NMR (300 MHz, CD3OD) δ 7.37 (t, 1H), 7.20-7.07 (m, 3H), 6.52 (s, 1H), 6.10 (s, 1H), 5.86 (s, 2H), 4.83 (d, 1H), 4.67 (d, 1H), 3.97-3.75 (m, 2H), 3.45-3.33 (m, 2H), 3.01-2.85 (m, 2H), 2.15-2.01 (m, 2H), 1.82-1.37 (m, 5H); 13C NMR(75 MHz, CD3OD) δ 179.8, 157.6, 150.4, 143.7, 143.4, 133.6, 130.3, 124.9, 124.8, 120.8, 110.3, 103.7, 102.9, 94.3, 81.4, 59.8, 45.2, 38.5, 34.4, 32.6, 29.8, 29.7; MS (ES+) m/z 393 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][C:20]2[N:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:30])[NH:27]3)=[CH:22][CH:21]=2)[CH2:11][CH2:10]1>[Ni].CCO.C1COCC1>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[N:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:30])[NH:27]3)=[CH:22][CH:21]=2)[CH2:13][CH2:14]1
Reactant: Cc1cccc(N2CCN(CCCC=Cc3ccc4c(n3)NC(=O)CC4)CC2)c1Cl
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cccc(N2CCN(CCCCCc3ccc4c(n3)NC(=O)CC4)CC2)c1Cl
Yield: 87.1 %

Procedure:
7-{5-[4-(2-Chloro-3-methyl-phenyl)-piperazin-1-yl]-pent-1-enyl}-3,4-dihydro-1H-[1,8]naphthyridin-2-one (0.322 g, 0.758 mmol) was hydrogenated using Ra—Ni (0.5 g) in 1:1 EtOH/THF (50 mL) for 21 h. The reaction was filtered and concentrated. Purification by liquid chromatography (SiO2, 5% MeOH/CH2Cl2 to 7% MeOH/CH2Cl2) gave the title compound as a light yellow foam (282 mg, 0.660 mmol, 87%). MS: APCI: M+1: 427.3 (Exact Mass: 426.22).
Reaction SMILES: C([NH:4][N:5]([CH2:12][CH2:13][OH:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=O)C.[OH-].[Na+]>Cl>[C:6]1([N:5]([CH2:12][CH2:13][OH:14])[NH2:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)NN(CCO)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NN(CCO)c1ccccc1

Procedure:
A solution of acetyl-2-(2-hydroxyethyl)-2-phenylhydrazine (i) (0.5 g, 2.57 mmol) in 6N hydrogen chloride 5 ml was refluxed for 2 hours. The reaction was cooled to room temperature and basified with 6N sodium hydroxide to PH 8. The solution was extracted with DCM 2×50 ml, washed with brine 2×30 ml. The organic was dried (MgSO4) and removed in vacuo. The residue was used to next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:35]=[C:34]([C:36]2[C:41]([I:42])=[CH:40][C:39]([I:43])=[C:38]([CH2:44][CH3:45])[C:37]=2[I:46])[CH:33]=[CH:32][C:5]=1[C:6]([C:8]1([O:26][C@H:25]([CH2:27][O:28]C(=O)C)[C@@H:20]([O:21]C(=O)C)[C@H:15]([O:16]C(=O)C)[C@H:13]1[NH2:14])[O:9]C(=O)C)=[O:7])([O-])=O.Cl>>[NH2:1][C:4]1[CH:35]=[C:34]([C:36]2[C:41]([I:42])=[CH:40][C:39]([I:43])=[C:38]([CH2:44][CH3:45])[C:37]=2[I:46])[CH:33]=[CH:32][C:5]=1[C:6]([C:8]1([O:26][C@H:25]([CH2:27][OH:28])[C@@H:20]([OH:21])[C@H:15]([OH:16])[C@H:13]1[NH2:14])[OH:9])=[O:7]
Reactant: CCc1c(I)cc(I)c(-c2ccc(C(=O)C3(OC(C)=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3N)c([N+](=O)[O-])c2)c1I
Agent: Cl
Product: CCc1c(I)cc(I)c(-c2ccc(C(=O)C3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3N)c(N)c2)c1I

Procedure:
2-nitro-4-(3′-ethyl-2′,4′,6′-triiodophenyl)-benzoyl-1,3,4,6-tetra-O-acetyl-D-glucosamine (15) is treated with stannous chloride and hydrochloric acid to yield 2-amino-4-(3′-ethyl-2′,4′,6′-triiodophenyl)-benzoyl-D-glucosamine (16).
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[CH:14][C:6]2[C:7](=[O:13])[CH:8]=[C:9]([C:11]#[N:12])[O:10][C:5]=2[CH:4]=1.[Na].[OH:17][C:18]1[CH:19]=[C:20]([CH:33]=[CH:34][CH:35]=1)[O:21][CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.O>CS(C)=O>[C:11]([C:9]1[O:10][C:5]2[CH:4]=[C:3]([CH2:2][O:17][C:18]3[CH:35]=[CH:34][CH:33]=[C:20]([O:21][CH2:22][C:23]4[CH:32]=[CH:31][C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]=4)[CH:19]=3)[CH:15]=[CH:14][C:6]=2[C:7](=[O:13])[CH:8]=1)#[N:12]
Reactant: Oc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: N#Cc1cc(=O)c2ccc(CBr)cc2o1
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc(=O)c2ccc(COc3cccc(OCc4ccc5ccccc5n4)c3)cc2o1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1.5 g of 7-bromomethyl-2-cyano-4-oxo-4H-1-benzopyran and 1.5 g of the sodium salt of 2-(3-hydroxyphenoxy)methylquinoline are combined in 10 ml of dimethylsulfoxide and stirred at room temperature for 5 hours. The mixture is poured into water and extracted with methylene chloride. The organic solution is dried and evaporated. The residue is recrystallized from ethyl acetate/dimethylformamide to give 0.72 g of 2-cyano-7-(3-(quinolin-2-ylmethoxy)phenoxymethyl)-4-oxo-4H-1-benzopyran.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=O)=[CH:13][CH:14]=3)[C:9]([C:18]#[N:19])=[N:8]2)=[C:4]([C:22]([F:25])([F:24])[F:23])[CH:3]=1.[O:26]=[C:27]1[N:31]([CH2:32][C:33]([OH:35])=[O:34])[C:30](=[O:36])[CH2:29][S:28]1>>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:29]4/[C:30](=[O:36])[N:31]([CH2:32][C:33]([OH:35])=[O:34])[C:27](=[O:26])[S:28]/4)=[CH:13][CH:14]=3)[C:9]([C:18]#[N:19])=[N:8]2)=[C:4]([C:22]([F:24])([F:25])[F:23])[CH:3]=1
Reactant: N#Cc1nn(Cc2ccc(Cl)cc2C(F)(F)F)c2ccc(C=O)cc12
Reactant: O=C(O)CN1C(=O)CSC1=O
Product: N#Cc1nn(Cc2ccc(Cl)cc2C(F)(F)F)c2ccc(/C=C3\SC(=O)N(CC(=O)O)C3=O)cc12

Procedure:
[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-3-cyano-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]acetic acid was prepared from 1-(4-chloro-2-trifluoromethyl-benzyl)-5-formyl-1H-indazole-3-carbonitrile and (2,4-dioxothiazolidin-3-yl)-acetic acid following General Procedure F.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:26][CH2:25][C:20]3(OCC[O:21]3)[CH2:19][C@H:18]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:13]1=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CC(C)=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:26][CH2:25][C:20](=[O:21])[CH2:19][C@H:18]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:13]1=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CC[C@@H]1N1CC[C@H](NC(=O)OCc3ccccc3)C1=O)OCCO2
Agent: Cl
Solvent: CC(C)=O
Product: CCOC(=O)[C@@H]1CC(=O)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 65 °C

Procedure:
Example 1, Alternative Step 9d: Pyrrolidinone 4 (50.0 g, 0.11M) was dissolved in acetone (500 mL) and 1N HCl (500 mL) was added. The reaction mass was then heated to 65° C. After 20 mins HPLC indicated complete reaction. The reaction mass was allowed to cool to RT and the acetone was removed on a rotary evaporator. During this distillation the product precipitated from solution as a white solid. This was isolated by filtration and the cake washed with water. The cake was then dried azeotropically with toluene (3×300 mL) to give ethyl (1R,2S)-2-((3S)-3-Benzyloxycarbonylamino-2-oxo-pyrrolidin-1-yl)-5-oxo-cyclohexanecarboxylate 5 as a white solid (39.8 g, 88%, 97 area-% purity). 1H-NMR: (300 MHz, CDCl3) δ 7.37-7.32 (m, 5H), 6.65 (br d, J 4.0 Hz, 1H), 5.12 (s, 2H), 4.54-4.47 (m, 1H), 4.34-4.26 (m, 1H), 4.18 (dq, J 11.0 Hz, 7.0 Hz, 1H), 4.09 (dq, J 11.0 Hz, 7.0 Hz, 1H), 3.36-3.20 (m, 3H), 2.70-2.35 (m, 6H), 2.05-1.96 (m, 1H), 1.81 (quin., J 11.0 Hz, 1H), 1.24 (t, J 7.0 Hz, 3H). HPLC: YMC-Pack Pro C18 5 μm 4.6×150 mm, 0.05% TFA (20% MeOH, 80% H2O), to 0.05% TFA (20% MeOH, 80% MeCN), 0-100% 10 min gradient. 8.95 min (Compound 5). HRMS: m/z 403.1864 [Calc: C21H27N2O6 403.1869].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[CH:17]=[CH:18][CH3:19]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][CH:17]=[CH:18][CH3:19])=[C:4]([I:9])[CH:3]=1
Reactant: Oc1ccc(Cl)cc1I
Reactant: CC=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC=CCOc1ccc(Cl)cc1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a mixture of 4-chloro-2-iodo phenol (5.11 mmol, 1.3 g) in DMF (40 mL) and potassium carbonate (10 mmol, 1.4 g) was added crotyl bromide (10.2 mmol, 1.6 g) and the reaction mixture was stirred at room temperature for one hour. The reaction was quenched with H2O (100 mL) and extracted with EtOAc (2×50 mL). The EtOAc layer was collected, dried, filtered and the filtrate was evaporated to obtain 4-chloro-2-iodo O-crotyl phenol (94%, 1.5 g).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([S:12](Cl)(=[O:14])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1.[CH2:27]([NH:29][CH2:30][CH2:31][O:32][CH3:33])[CH3:28]>>[CH2:27]([N:29]([CH2:30][CH2:31][O:32][CH3:33])[S:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:2](=[O:1])[N:3]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:4][CH2:5]2)[CH2:7][CH2:8]1)(=[O:14])=[O:13])[CH3:28]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)Cl)CC2
Reactant: CCNCCOC
Product: CCN(CCOC)S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
This material was prepared in analogy to example 285 step B) from 1-Oxo-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-8-sulfonyl chloride and ethyl-(2-methoxy-ethyl)-amine. The reaction was subjected to work-up and purification after stirring for 2 h at room temperature. MS (ESI): 480.4 (MH+).
Reaction SMILES: CS(O[C:6]1([CH2:23][CH3:24])[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.[CH3:25][NH:26][CH3:27]>C(O)(C)C>[C:11]1([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:9][C:6]([CH2:23][CH3:24])([N:26]([CH3:27])[CH3:25])[CH2:7]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCC1(OS(C)(=O)=O)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CNC
Solvent: CC(C)O
Product: CCC1(N(C)C)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 70 °C
Yield: 25.3 %

Procedure:
A mixture of 1-(diphenylmethyl)-3-ethyl-3-azetidinyl methanesulfonate (1.00 g, 2.89 mmol) (Ellsworth, Edmund Lee; Hoyer, Denton Wade; Hutchings, Kim Marie; Kendall, Jackie Diane; Murphy, Sean Timothy; Starr, Jeremy Tyson; Tran, Tuan Phong. WO 2005049605), dimethylamine (2 M in THF, 14.45 ml, 28.9 mmol) and TEA (0.80 ml, 5.78 mmol) in isopropanol was heated to 70° C. overnight. Standard work-up followed by RP-HPLC provided 1-(diphenylmethyl)-3-ethyl-N,N-dimethyl-3-azetidinamine (0.215 g, 25.3%). LCMS: (M+H)+ 295.2.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.CC1C=C(O)C=CC=1C.[O:20]1[CH2:24][CH2:23][CH2:22][C@@H:21]1[CH2:25][N:26]1[C:34]2[CH:33]=[C:32]3[O:35][CH2:36][CH2:37][O:38][C:31]3=[CH:30][C:29]=2[C:28](=[O:39])[C:27]1=[O:40].C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(=O)C2=O)C=CC=CC=1>>[OH:39][C:28]1([C:8]2[C:7]([OH:10])=[CH:6][C:5]3[O:1][CH2:2][CH2:3][C:4]=3[CH:9]=2)[C:29]2[CH:30]=[C:31]3[O:38][CH2:37][CH2:36][O:35][C:32]3=[CH:33][C:34]=2[N:26]([CH2:25][C@H:21]2[CH2:22][CH2:23][CH2:24][O:20]2)[C:27]1=[O:40]
Reactant: Oc1ccc2c(c1)OCC2
Reactant: O=C1C(=O)N(C[C@H]2CCCO2)c2cc3c(cc21)OCCO3
Agent: Cc1ccc(O)cc1C
Agent: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: O=C1N(C[C@H]2CCCO2)c2cc3c(cc2C1(O)c1cc2c(cc1O)OCC2)OCCO3

Procedure:
Following the procedure as described in PREPARATION 6A, and making non-critical variations using 2,3-dihydrobenzofuran-6-ol to replace 3,4-dimethylphenol, and 6-[(2R)-tetrahydrofuran-2-ylmethyl]-2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione to replace 1-(diphenylmethyl)-1H-indole-2,3-dione, 8-hydroxy-8-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-6-[(2R)-tetrahydrofuran-2-ylmethyl]-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one was obtained: Rf 0.45 (ethyl acetate/hexanes, 1/1); MS (ES+) m/z 408.1 (M−17).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:20][C:21](OC(C)=O)=[O:22].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O.O>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[C:21](=[O:22])[CH3:20])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1ccc2cn[nH]c2c1
Agent: C1COCCOCCOCCOCCOCCO1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)n1ncc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.6 %

Procedure:
6-nitroindazole (1 g, 6.13 mmol) was dissolved in dimethylformamide (15 mL), and added with triethylamine (1.7 mL, 12.2 mmol), Ac2O (0.69 mL, 7.4 mmol) and 18-Crown-6 (0.38 g, 1.23 mmol). The reaction solution was stirred for about 4 hours at room temperature. The reaction mixture was added with distilled water, and further stirred for about 1 hour. The resulting solid was filtered under reduced pressure, and washed with distilled water. The filtered solid was dried with warm wind in an oven (40° C.) for 3 hours or more to obtain the title compound (0.9 g, 75%).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH:7]=[O:8].[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>COCCOC.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:9]1([C:2]2[CH:6]=[CH:5][O:4][C:3]=2[CH:7]=[O:8])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1occc1Br
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: O=Cc1occc1-c1ccccc1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 107.4 %

Procedure:
Prepare a mixture of 3-bromofuran-2-carbaldehyde (381 mg, 2.19 mmol), phenylboronic acid (534 mg, 4.38 mmol), and 2M potassium carbonate (3.28 mL, 6.57 mmol) in 1,2-dimethoxyethane (20 mL). Bubble nitrogen into this mixture for 20 minutes. Add Pd2(dba)3 (68 mg, 0.06 mmol) and PPh3 (68 mg, 0.26 mmol) and purge the mixture with nitrogen for an additional 10 minutes. Then heat the mixture to 80° C. After 24 hours, evaporate the solvent and redissolve the residue in ethyl acetate. Extract the aqueous phase with ethyl acetate (2×10 mL), wash the combined organic phases with brine (40 mL), dry (magnesium sulfate), filter and concentrate. Perform flash chromatography on silica gel eluting with 5:1 hex/ethyl acetate to afford 405 mg of the title compound as a white solid. MS: m/e=173 [MH+]
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@@H:10]([OH:23])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CN=C1.[C:36]([Si:40]([CH3:43])([CH3:42])Cl)([CH3:39])([CH3:38])[CH3:37]>CN(C=O)C>[C:1]([NH:8][C@@H:9]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@@H:10]([O:23][Si:40]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:43])[CH3:42])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccccc1)C(=O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@@H](Cc1ccccc1)C(=O)O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 6.35 g of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-phenylmethylhexanoic acid in 90 ml of DMF is treated, while being stirred, with 8 g of imidazole and 10 g of t-butyldimethylchlorosilane. After having been stirred at RT for 18 h, the yellow, clear solution is poured onto ice-water, and this mixture is extracted three times with 250 ml of ethyl acetate on each occasion. The combined extracts are washed, in succession, three times with 10% citric acid, once with water, three times with aqueous, saturated sodium bicarbonate solution, once with water and, finally, with saline. After drying over sodium sulfate, the solvent is evaporated and the resulting tert-butyl dimethylsilyl ether (13.5 g) is dissolved in 53 ml of THF and treated with 53 ml of acetic acid and 20 ml of water. After having been stirred at RT for 3 h, the mixture is poured onto water, and this mixture is extracted three times with ether. The collected ether extracts are washed twice with water and once with saline and dried over sodium sulfate. After concentrating, the crude product is purified by column chromatography (SiO2, hexane/ethyl acetate: 3.5/1.5), and the title compound is obtained. TLC Rf (D)=0.37; FAB-MS (M+H)+ =528.
Reaction SMILES: C(O[C:4](=[O:17])[C:5](=[N:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Br:16])[C:6]#[N:7])C.[CH2:18]([NH2:20])[CH3:19].O.C(N(CC)CC)C>CO>[Br:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][N:8]=[C:5]([C:6]#[N:7])[C:4]([NH:20][CH2:18][CH3:19])=[O:17]
Reactant: CCN
Reactant: CCOC(=O)C(C#N)=NNc1ccccc1Br
Solvent: O
Solvent: CO
Solvent: CCN(CC)CC
Product: CCNC(=O)C(C#N)=NNc1ccccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [(2-bromophenyl)-hydrazono]-cyanoacetic acid ethyl ester (1.0 g, 3.4 mmol) in methanol (14 mL) was added 70% ethyl amine in water (16 mL, 20.2 mmol) followed by triethyl amine (468 uL, 3.6 mmol). The reaction was stirred at room temperature overnight, concentrated and dried under high vacuum. The material was routinely used crude. Purification on silica gel using a gradient of 10to 50% ethyl acetate in hexanes afforded the title compound as a yellow solid. 1H NMR (300.132 MHz, CDCl3) δ 14.33 (s, 1H), 7.67 (dd, J=8.3, 1.4 Hz, 1H), 7.53 (dd, J=8.1, 1.3 Hz, 1H), 7.34 (tq, J=7.8, 0.6 Hz, 1H), 7.01 (td, J=7.7, 1.6 Hz, 1H), 3.45 (dq, J=5.9, 7.2 Hz, 2H), 1.26 (t, J=7.3 Hz, 3H). HPLC 4.66 min.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][S:41](=[O:45])(=[O:44])[CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:38]3[CH2:43][CH2:42][S:41](=[O:45])(=[O:44])[CH2:40][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=S1(=O)CCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCS(=O)(=O)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with thiomorpholine 1,1-dioxide (Syntech) to give the title compound. HR-MS (ES, m/z) calculated for C33H39Cl2N4O4S [(M+H)+] 657.2064, observed 657.2067.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>O>[N:16]1([S:2]([C:5]2[CH:6]=[CH:7][C:8]([O:14][CH3:15])=[C:9]([CH:13]=2)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1C(=O)O
Reactant: C1CCNC1
Solvent: O
Product: COc1ccc(S(=O)(=O)N2CCCC2)cc1C(=O)O
Reaction time: 6 h

Procedure:
5-Chlorosulphonyl-2-methoxybenzoic acid (4.9 g) was added to a solution of pyrrolidine (10 g) in water (150 ml). The solution was stirred for 6 hours, filtered and acidified with dilute hydrochloric acid to yield the title compound as colourless microcrystals (5.27 g; 84%).