Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](I)=[CH:4][C:3]=1[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:14].[K].[C:38]1([N:44]2[C:48]([SH:49])=[N:47][N:46]=[N:45]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CN(C)C=O>C(O)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:49][C:48]2[N:44]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:45]=[N:46][N:47]=2)=[CH:4][C:3]=1[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:14]
Reactant: CCCCCCCCCCCCCCOc1ccccc1NC(=O)c1cc(I)c2ccccc2c1O
Reactant: Sc1nnnn1-c1ccccc1
Agent: [K]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1ccccc1NC(=O)c1cc(Sc2nnnn2-c2ccccc2)c2ccccc2c1O
Temperature: 90 °C
Yield: 90 %

Procedure:
1-hydroxy-4-iodo-2'-tetradecyloxy-2-naphthanilide (9 g) and 1-phenyl-5-mercapto-tetrazole potassium salt (3 g) were solubilized im dimethylformamide (25 ml). The solution was heated at 90° C. for 1 hour under stirring. After adding ethanol (25 ml), a white solid precipitated. The solid collected by filtration was crystallized from ethanol. The yield was 90% of 1-hydroxy-4-(1-phenyl-5-tetrazolylthio)-2'-tetradecyloxy-2-naphthanilide of formula ##STR11##
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[CH2:11][CH2:12][CH:13]=[O:14]>ClCCl>[Br:1][CH:12]([CH2:11][C:5]1[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:4]=1[Cl:3])[CH:13]=[O:14]
Reactant: O=CCCc1c(F)cccc1Cl
Reactant: BrBr
Solvent: ClCCl
Product: O=CC(Br)Cc1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of bromine (11 g, 0.081 mol) in dichloromethane (50 mL) was slowly added to a solution of 3-(2-chloro-6-fluoro-phenyl)-propionaldehyde (15 g, 0.081 mol) in dichloromethane (250 mL) at 0° C. The mixture was stirred overnight at room temperature and then the solvent was removed to give the crude product which was used directly in the next step.
Reaction SMILES: I[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[S:8][CH:9]=[CH:10][C:11]=1I.[CH3:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[C:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(N(CCCC)CCCC)CCC>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[CH2:23]([C:22]1[C:11]2[CH:10]=[CH:9][S:8][C:7]=2[C:3]2[S:4][CH:5]=[CH:6][C:2]=2[C:21]=1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: Ic1ccsc1-c1sccc1I
Reactant: CCCCCCCCC#CCCCCCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Product: CCCCCCCCc1c(CCCCCCCC)c2ccsc2c2sccc12
Temperature: 130 °C
Yield: 84.8 %

Procedure:
To a two-necked RB flask under nitrogen was added 1.39 g (3.3 mmol) of 3,3′-diiodo-2,2′-bithiophene, 222 mg (0.33 mmol) of Pd(OAc)2, 2.5 g (10 mmol) of 9-octadecyne, tributyl amine 1.85 g (10 mmol), and 10 mL of anhydrous DMF. The mixture was heated at 130° C. for 4 hours. After cooling down to room temperature, 50 mL of ether ethyl was. The organic phase was washed with water several times, dried by MgSO4, concentrated under reduced pressure. The residue was further purified by flash chromatography on silica gel (hexane as eluent) to afford the pure product as a colorless liquid (1.16 g, yield: 85%). 1H NMR (300 MHz, CDCl3) δ 7.46 (d, 2H, J=5.43 Hz), 7.37 (d, 2H, J=5.42 Hz), 3.01 (t, 4H, J=7.89 Hz), 1.68 (m, 4H), 1.51 (m, 4H), 1.30 (m, 16H), 0.89 (t, 6H, J=6.7 Hz). 13C NMR (400 MHz, CDCl3) δ 137.47, 131.58, 131.32, 123.55, 123.38, 31.87, 31.52, 30.43, 30.16, 29.48, 29.27, 22.63, 14.04. MS: m/z=414.7 [M]+ (Calcd.: 414.7).
Reaction SMILES: Br[CH:2]([C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:7])[CH2:3][CH2:4][Cl:5].[F-:15].[K+].C1OCCOCCOCCOCCOCCOC1.C1C=CC=CC=1>O>[F:15][CH:2]([C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:7])[CH2:3][CH2:4][Cl:5]
Reactant: O=C(c1ccc(Cl)cc1)C(Br)CCCl
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: O=C(c1ccc(Cl)cc1)C(F)CCCl
Yield: 52.8 %

Procedure:
A mixture of 68 g of 4-chlorophenyl 1-bromo-3-chloropropyl ketone, 27.5 g of dry potassium fluoride, 11 g of 18-crown-6 and 200 ml of dry benzene is heated under reflux for 8 hours. Thereafter, 200 ml of water are added, and the organic phase is separated off, washed several times with water, dried over sodium sulphate and evaporated down in vacuo. The residue is stirred with light benzine, with the addition of a small amount of toluene. After the resulting solid has been filtered off under suction and drying has been carried out, 28.5 g (53% of theory) of 4-chlorophenyl 1-fluoro-3-chloropropyl ketone of melting point 53° C. are obtained. ##STR216##
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:18]2[CH:22]=[N:21][N:20]=[C:19]2[CH2:23][N:24]2[C:28](=[O:29])[C:27]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]3[C:25]2=[O:34])=[C:8]([CH:17]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])([O-:3])=[O:2].[Br:35]N1C(=O)CCC1=O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:18]2[C:19]([CH2:23][N:24]3[C:25](=[O:34])[C:26]4=[CH:33][CH:32]=[CH:31][CH:30]=[C:27]4[C:28]3=[O:29])=[N:20][N:21]=[C:22]2[Br:35])=[C:8]([CH:17]=1)[C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:10])([O-:3])=[O:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1-n1cnnc1CN1C(=O)c2ccccc2C1=O
Product: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1-n1c(Br)nnc1CN1C(=O)c2ccccc2C1=O

Procedure:
Following the procedure of Example 2, 5-nitro-2-[3-phthalimidomethyl-4H-1,2,4-triazol-4-yl]benzophenone is reacted with N-bromosuccinimide to form 5-nitro-2-[3-bromo-5-phthalimidomethyl-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:8]([C@@H:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)([O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH:23]1([CH2:29][C@H:30]([NH:43][C:44](=O)[O:45]C2C=CC([N+]([O-])=O)=CC=2)[CH2:31][N:32]([CH3:42])[C:33]([O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])=[O:34])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:8]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:44](=[O:45])[NH:43][C@H:30]([CH2:31][N:32]([CH3:42])[C:33]([O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])=[O:34])[CH2:29][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:18]2)([O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C[C@H](CC1CCCCC1)NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)OCC[Si](C)(C)C
Reactant: CCOC(=O)CO[C@@](C)(c1cccc(Cl)c1)[C@@H]1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CO[C@@](C)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 47 %

Procedure:
A mixture of ethyl 2-((R)-1-(3-chlorophenyl)-1-((R)-piperidin-3-yl)ethoxy)acetate, (S)-4-nitrophenyl 1-cyclohexyl-3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)propan-2-ylcarbamate (0.096 g, 0.20 mmol), and DIPEA (1 mL) in CH2Cl2 was stirred at rt for 24 h. After the reaction mixture was evaporated under reduced pressure, the crude product was purified by reversed-phase HPLC to afford 0.0425 g (47% in two steps) of ethyl 2-((R)-1-(3-chlorophenyl)-1-((R)-1-((S)-1-cyclohexyl-3-(methyl((2-(trimethylsilyl)ethoxy)carbonyl)amino)propan-2-ylcarbamoyl)piperidin-3-yl)ethoxy)acetate. MS ESI +ve m/z 668 (M+H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[NH:12]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH:14]=[CH:13]1>C(OCC)(=O)C>[NH:12]1[C:16]2=[N+:17]([O-:9])[CH:18]=[CH:19][CH:20]=[C:15]2[CH:14]=[CH:13]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1cnc2[nH]ccc2c1
Solvent: CCOC(C)=O
Product: [O-][n+]1cccc2cc[nH]c21
Temperature: 0 °C
Reaction time: 24 h
Yield: 84.8 %

Procedure:
m-Chloroperbenzoic acid (25 wt % water content, 12.7 g, 55.2 mmol) in ethyl acetate (30 mL) was gradually added dropwise to 1H-pyrrolo[2,3-b]pyridine (5.14 g, 43.5 mmol) in ethyl acetate (45 mL) cooled to 0° C., and the reaction mixture was stirred at room temperature for one day and then stirred with m-chloroperbenzoic acid (25 wt % water content, 3.93 g, 17.1 mmol) in ethyl acetate (4 mL) at room temperature for 4 hours. The reaction mixture was cooled with ice and filtered, and the resulting solid was purified by silica gel column chromatography (silica gel NH type manufactured by Fuji Silysia Chemical Ltd.: chloroform/methanol=10/1 (v/v)) to give the title compound as a yellow solid (4.95 g, yield 85%).
Reaction SMILES: [CH3:1][C:2]1([CH2:5]Cl)[CH2:4][O:3]1.[C-:7]#[N:8].[Na+].[C-:10]#[N:11].[K+]>Cl.O>[C:7]([CH2:4][C:2]([CH3:1])([OH:3])[CH2:5][C:10]#[N:11])#[N:8]
Reactant: [C-]#N
Reactant: CC1(CCl)CO1
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: CC(O)(CC#N)CC#N
Temperature: 40 °C
Reaction time: 10 h
Yield: 96.8 %

Procedure:
To a solution of 50 g 2-methyl-2-chloromethyloxirane in 23 ml concentrated hydrochloric acid at ice-bath temperature a solution of 27.4 g sodium cyanide in 23 ml hydrochloric acid was added. After stirring for 10 hours at that temperature the reaction mixture was warmed to 40° C. and a solution of 33.8 g potassium cyanide in 50 ml water was added. The resulting mixture was warmed to 50° C. and stirred for 4 hours. After cooling the solution was neutralized and extracted three times with 150 ml ethyl acetate each. The combined organic layers were dried with anhydrous magnesium sulphate. Removal of the solvent afforded 56.4 g (96%) of 1,3-dicyano-2-methyl-2-hydroxypropane. This crude material was sufficiently pure to be submitted directly to the following ring closure.
Reaction SMILES: [CH:1]1([CH2:4][CH:5]([C:8]2[CH:9]=[N:10][CH:11]=[N:12][CH:13]=2)[C:6]#[N:7])[CH2:3][CH2:2]1.CI.[CH3:16]C([O-])(C)C.[K+]>O1CCOCC1>[CH:1]1([CH2:4][C:5]([CH3:16])([C:8]2[CH:9]=[N:10][CH:11]=[N:12][CH:13]=2)[C:6]#[N:7])[CH2:3][CH2:2]1
Reactant: CC(C)(C)[O-]
Reactant: N#CC(CC1CC1)c1cncnc1
Agent: [K+]
Solvent: CI
Solvent: C1COCCO1
Product: CC(C#N)(CC1CC1)c1cncnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
To a solution of 3-cyclopropyl-2-(pyrimidin-5-yl)propanenitrile (1.5 g, 8.67 mmol) and MeI (1.45 g, 13.0 mmol) in 1,4-dioxane (20 ml) was added t-BuOK (9.57 ml, 9.57 mmol) dropwise at room temperature under N2. The mixture was stirred for 1 h at room temperature then quenched by sat.aq NH4Cl (20 ml) and extracted with EtOAc (3×30 ml). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give 3-cyclopropyl-2-methyl-2-(pyrimidin-5-yl)propanenitrile (1.5 g), which was used directly for next step.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[C:5]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3([C:29]4[C:20](=[CH:21][C:22]5[O:27][CH2:26][CH2:25][O:24][C:23]=5[CH:28]=4)[O:19][CH2:18]3)[C:10]2=[O:30])[CH:4]=[CH:3]1.[H-].[Na+].I[CH3:34]>CN(C)C=O.O>[CH3:34][N:7]1[C:2](=[O:1])[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3([C:29]4[C:20](=[CH:21][C:22]5[O:27][CH2:26][CH2:25][O:24][C:23]=5[CH:28]=4)[O:19][CH2:18]3)[C:10]2=[O:30])=[CH:6]1
Reactant: CI
Reactant: O=C1N(Cc2ccc(=O)[nH]c2)c2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)ccc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.4 %

Procedure:
To a cooled (0° C.) solution of 1′-[(6-oxo-1,6-dihydropyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.07 g, 0.17 mmol) in anhydrous N,N-dimethylformamide (3 mL) was added sodium hydride (60% in mineral oil, 0.01 g, 0.25 mmol). The mixture was stirred at ambient temperature for 1 h, and iodomethane (0.02 mL, 0.27 mmol) was added. The mixture was stirred at ambient temperature for 16 h, diluted with water (15 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers was washed with brine (35 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with a 10% to 30% gradient of acetone in dichloromethane to afford 1′-[(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.03 g, 42%) as a colorless solid: mp 205-207° C.; 1H NMR (300 MHz, CDCl3) δ7.40-7.34 (m, 2H), 7.33-7.26 (m, 1H), 7.21-7.16 (m, 1H), 7.11-7.04 (m, 1H), 6.91-6.85 (m, 1H), 6.60-6.54 (m, 1H), 6.50 (s, 1H), 6.12 (s, 1H), 4.77 (ABq, J=75.6, 9.0 Hz, 2H), 4.66 (ABq, J=58.2, 15.3 Hz, 2H), 4.22-4.08 (m, 4H), 3.53 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 177.7, 162.5, 155.2, 144.7, 141.5, 139.6, 138.3, 137.4, 132.2, 128.9, 124.3, 123.8, 121.3, 120.7, 114.0, 111.2, 108.5, 99.5, 79.8, 64.5, 63.9, 57.9, 40.8, 37.9; MS (ES+) m/z 416.9 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])(=[O:3])[CH3:2].ClCCl.[CH3:15][C:16]([CH3:21])=[CH:17][C:18](Cl)=[O:19]>C(N(CC)CC)C>[C:1]([NH:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:7]([NH:8][C:18](=[O:19])[CH:17]=[C:16]([CH3:21])[CH3:15])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: CC(C)=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(NC(=O)C=C(C)C)c1

Procedure:
56.7 g. ( 0.42 mole ) 3-acetamidoaniline in 400 ml. dichloromethane and 65 ml. ( 0.46 tool ) triethylamine are mixed, while cooling with ice, with 59.0 g. (0.46 mole) 3,3-dimethylacryloyl chloride and stirred for 2 hours at ambient temperature. The solution is thereafter extracted with water and the separated organic phase is dried over anhydrous sodium sulphate, evaporated and the residue mixed with ethyl acetate. Upon standing in a refrigerator, crystals separate out. Yield 45.7 g. (47% of theory); m.p. 144°-148° C.
Reaction SMILES: C([N:14]1[CH2:17][C:16]2([C:21](=[O:22])[N:20]=[CH:19][N:18]2[CH3:23])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:24]>CO.C(OCC)C.[OH-].[OH-].[Pd+2]>[ClH:24].[CH3:23][N:18]1[CH2:19][NH:20][C:21](=[O:22])[C:16]21[CH2:17][NH:14][CH2:15]2
Reactant: CN1C=NC(=O)C12CN(C(c1ccccc1)c1ccccc1)C2
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: CN1CNC(=O)C12CNC2

Procedure:
To a solution of 2-benzhydryl-5-methyl-2,5,7-triazaspiro[3.4]oct-6-en-8-one (I-5A-10a; 189 mg, 0.619 mmol) in methanol (30 ml) was added 1 M HCl in diethyl ether (1.3 ml). After the addition of 20% Pd(OH)2 on carbon (50% water; 95 mg), the mixture was placed on a Parr® shaker and then reduced (50 psi H2) at room temperature for 5 hours. The reaction was filtered through a 0.45 μM disk, and then concentrated, in vacuo, to give a solid. Trituration from diethyl ether afforded I-5A-10b (124 mg, 94%) as an off-white solid: +APcI MS (M+1) 142.0; 1H NMR (400 MHz, CD3OD) δ 4.38 (d, J=12.0 Hz, 2H), 4.17 (s, 2H), 4.13 (d, J=12.5 Hz, 2H), 2.71 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:13](O)=[O:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:25]1C=CN=C1)=O.C(N(CC)CC)C.[NH4+].[OH-]>O1CCCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:13]([NH2:25])=[O:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1(Cc2ccccc2)CCN(Cc2ccccc2)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)C1(Cc2ccccc2)CCN(Cc2ccccc2)C1
Reaction time: 18 h
Yield: 103.9 %

Procedure:
A mixture of 1,3-dibenzylpyrrolidine-3-carboxylic acid (Example A28, 4.0 g, 13.5 mmol), 1,1′-carbonyldiimidazole (2.42 g, 14.9 mmol), and triethylamine (2.08 mL, 14.9 mmol) in tetrahydrofuran (100 mL) is heated at reflux for 1.5 hours. The solution is cooled, poured into NH4OH (300 mL), and stirred for 18 hours. The mixture is extracted with chloroform, the organic layer is washed with water, dried, and concentrated to afford 4.13 g of the title compound as an oil; MS EI+: m/z 295 (MH+).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][N:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:4][C:3]1=O.P(Cl)(Cl)([Cl:16])=O>C(#N)C>[Cl:16][C:3]1[CH:2]([CH3:1])[CH2:6][N:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC1CN(c2cccnc2)NC1=O
Solvent: CC#N
Product: CC1CN(c2cccnc2)N=C1Cl
Temperature: 75 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
Crude 4-methyl-1-(pyridin-3-yl)pyrazolidin-3-one (35.2 g, ˜82.4 mmol) was introduced into a 250 mL three-neck round bottom flask equipped with a reflux condenser. Acetonitrile (100 mL) was then added. To this yellow mixture was added phosphoryl chloride (11.56 mL, 124 mmol) slowly. The yellow slurry was stirred at 75° C. for 1 hour. The mixture was cooled down and concentrated to remove volatiles. The brown residue was carefully quenched with water (120 mL), and basified with NaOH (50 wt % in water) to pH 10 while keeping the temperature below 60° C. The mixture was then extracted with ethyl acetate (3×150 mL). The combined organic extracts were washed with water (80 mL) and concentrated under reduced pressure to afford the crude product as dark purple oil. The crude product was purified by flash column chromatography using 0-70% ethyl acetate/hexanes as eluent to provide the title compound as a brown oil (12.3 g, 76% over two steps): 1H NMR (400 MHz, CDCl3) δ 8.27 (dd, J=2.8, 0.7 Hz, 1H), 8.15 (dd, J=4.6, 1.4 Hz, 1H), 7.38 (ddd, J=8.4, 2.9, 1.4 Hz, 1H), 7.18 (ddd, J=8.4, 4.7, 0.7 Hz, 1H), 4.17-4.06 (m, 1H), 3.47 (t, J=8.9 Hz, 1H), 3.44-3.34 (m, 1H), 1.37 (d, J=6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 148.17, 142.07, 141.10, 134.74, 123.39, 119.92, 56.62, 43.62, 16.16; EIMS m/z 195 ([M]+).
Reaction SMILES: [F:1][C:2]1[C:21](F)=[CH:20][C:5]2=[N:6][C:7]3[N:8]([O:18][CH3:19])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.CS(O)(=O)=O.CS(O)(=O)=O.[NH2:33][C:34]1([CH3:38])[CH2:37][NH:36][CH2:35]1>>[NH2:33][C:34]1([CH3:38])[CH2:37][N:36]([C:21]2[C:2]([F:1])=[CH:3][C:4]3[C:5]([CH:20]=2)=[N:6][C:7]2[N:8]([O:18][CH3:19])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=2[CH:13]=3)[CH2:35]1
Reactant: CC1(N)CNC1
Reactant: COn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Agent: CS(=O)(=O)O
Product: COn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CC(C)(N)C4)cc3nc21
Yield: 68.3 %

Procedure:
8-(3-Amino-3-methyl-1-azetidinyl)-7-fluoro-1-methoxy-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3carboxylic acid was prepared under the conditions of Example 15, but starting with 1.53 g of 7,8-difluoro-1-methoxy-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3carboxylic acid and 2.22 g of 3-amino-3-methylazetidine dimethane-sulphonate. 1.27 g of 8-(3-amino-3-methyl-1-azetidinyl)-7-fluoro-1-methoxy-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at 346° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH2:15]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][C:24]=1[O:31][CH2:32][O:33][CH3:34])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[K+].Cl>CCO.CCOCC>[CH2:15]([O:22][C:23]1[CH:30]=[CH:29][C:26](/[CH:27]=[CH:13]/[C:12]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:9][O:10][CH3:11])=[CH:7][C:2]=2[OH:1])=[O:14])=[CH:25][C:24]=1[O:31][CH2:32][O:33][CH3:34])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COCOc1cc(C=O)ccc1OCc1ccccc1
Reactant: COCOc1ccc(C(C)=O)c(O)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: COCOc1ccc(C(=O)/C=C/c2ccc(OCc3ccccc3)c(OCOC)c2)c(O)c1
Temperature: 25 °C
Reaction time: 144 h
Yield: 57.7 %

Procedure:
To 1-(2-hydroxy-4-(methoxymethoxy)phenyl)ethanone (618 mg, 3.15 mmol) and 4-(benzyloxy)-3-(methoxymethoxy)benzaldehyde (816 mg, 3 mmol) in a 25-mL round-bottom flask under Ar atmosphere was added 2.5 mL of a freshly made 5% KOH in EtOH solution. The mixture was vigorously stirred at rt until it solidified and kept at rt for 6 days. It was taken up in ether (100 mL) and added 0.5 M HCl to pH=5, and stirred for 3 min. The mixture was washed with water (2×100 mL) and dried over MgSO4 and concentrated. The residue was chromatographed (hexane/EtOAc) to afford (E)-3-(4-(benzyloxy)-3-(methoxymethoxy)phenyl)-1-(2-hydroxy-4-(methoxymethoxy)phenyl)prop-2-en-1-one as a clear oil (780 mg, 58%). MS (ESI) m/z 451 (M+H+).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:5][OH:6])[CH3:4].N1C=CN=C1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>CN(C)C=O>[C:15]([Si:12]([CH3:14])([CH3:13])[O:6][CH2:5][C@H:3]([NH2:2])[CH3:4])([CH3:18])([CH3:17])[CH3:16]
Reactant: C[C@@H](N)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@@H](N)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
D-Alaninol hydrochloride (500 mg, 6.66 mmol) (Aldrich) was dissolved in anhydrous dimethylformamide (10 mL) (Aldrich). Imidazole (544 mg, 8 mmol) (Aldrich) and tert-butyldimethylsilyl chloride (1.05 g, 7 mmol) (Aldrich) were successively added at room temperature. This mixture was stirred at room temperature for 2 hours, quenched with a solution of water-saturated aqueous sodium bicarbonate solution (5:1, 15 mL) and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated under reduce pressure to yield (R)-2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethylamine as a colorless oil. (Yield 852 mg, 68%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:22][C:23]1[C:27]([CH3:29])([CH3:28])[O:26][C:25](=O)[CH:24]=1.Cl>C1COCC1.O>[Br:22][C:23]1[C:27]([CH3:29])([CH3:28])[O:26]/[C:25](=[C:6]2/[C:7](=[O:11])[NH:8][C:9]3[C:5]/2=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=3)/[CH:24]=1
Reactant: O=C1Cc2ccc(F)cc2N1
Reactant: CC1(C)OC(=O)C=C1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1Br
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6-fluorooxindole (3 g, 20 mmol) in THF (50 mL) at 0° C., was added 40 mL of 1M LHMDS in THF. The reaction mixture was stirred at 0° C. for 15 minutes. A solution of 4-bromo-5,5-dimethyl-5H-furan-2-one (5) (1.91 g, 10 mmol) in 5 mL of THF was added to the above reaction mixture. The reaction was stirred at 0° C. for further 30 minutes and then at room temperature for 2.5 hrs. To the reaction, 80 mL of 2M HCl was added. The resulting mixture was stirred at 50-55° C. for one hour, cooled down to room temperature, poured to 1000 mL of water and was stirred at room temperature for one hour. The precipitates formed were collected and washed with water, dried in vacuum to give the title compound as a yellow solid product (2.4 g, yield: 74%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH3:13])(=[O:12])=[O:11].[C:14]([Zn]C#N)#[N:15]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:14]([C:6]1[CH:5]=[CH:4][C:3]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:2]([F:1])[CH:7]=1)#[N:15]
Reactant: N#C[Zn]C#N
Reactant: CS(=O)(=O)Nc1ccc(I)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc(C#N)cc1F
Yield: 167.1 %

Procedure:
A mixture of Example 10A (5.0 g, 16 mmol), dicyanozinc (1.12 g, 9.5 mmol), and Pd(PPh3)4 (0.92 g, 0.79 mmol) in DMF (15 mL) was heated at 80° C. overnight. The mixture was concentrated in vacuo then diluted with EtOAc (400 mL) and washed with brine (3×100 mL). The organic extract was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography (SiO2, 25-50% Hexanes/EtOAc gradient) to afford the title compound (3.4 g, 99% yield). 1H NMR (300 MHz, DMSO-d6) δ 10.28 (s, 1H), 7.92 (dd, J=10.7, 1.8 Hz, 1H), 7.73-7.56 (m, 2H), 3.31 (s, 3H). MS (ESI; M−H) m/z 213.