Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[O:25][CH3:26].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:26][O:25][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][C:15]=1[CH2:14][N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH:8]=[CH:9]1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(Cn2ccc3ccc([N+](=O)[O-])cc32)c(OC)c1
Yield: 95.3 %

Procedure:
A solution of 6-nitroindole (4.0 g) and methyl 4-bromomethyl-3-methoxybenzoate (6.71 g) in dry acetone (125 ml) was treated with anhydrous potassium carbonate (4.0 g). The mixture was heated under reflux for 48 hours. The cloudy mixture was evaporated. The residue was suspended in ethyl acetate, and solid removed by filtration. The filtrate was evaporated and the residual oil was purified by flash chromatography on a 6×30 cm column of silica gel using 1:1 (v/v) methylene chloride:hexane as the eluent to give methyl 3-methoxy-4-(6-nitroindol-1-ylmethyl)benzoate as a bright yellow powder (8.0 g); NMR: 3.9(s, 3H, OCH3), 4.0(s, 3H, OCH3), 5.4(s, 2H, NCH2), 6.7(dd, 1H, H3 -indole), 6.8(d, 1H), 7.4(d, 1H, H2 -indole), 7.5-7.7(m, 3H), 8.0(dd, 1H, H5 -indole), 8.3(br s, 1H, H 7 -indole). A solution of a portion of the above nitroester (1.38 g) in ethyl acetate (15 ml), which contained 2 drops of 1:4 (v/v) acetic acid:ethyl acetate, was added to a suspension of pre-reduced 10% w/w palladium-on-charcoal (0.34 g) in ethyl acetate (5 ml). The mixture was shaken under 3.45 bar hydrogen for 24 hours and then filtered through diatomaceous earth. The residue was washed with hot chloroform and the combined filtrate and washings were evaporated to give methyl 4-(6-aminoindol-1-ylmethyl)-3-methoxybenzoate (B) (1.19 g) as a brown powder; NMR: 3.6(br, 2H, NH2), 3.9(s, 3H, OCH3), 4.0(s, 3H, OCH3), 5.3(s, 2H, NCH2), 6.4(d, 1H, H3 -indole), 6.5(s, 1H, H7 -indole), 6.6(m, 2H), 6.9(d, 2H, H2 -indole), 7.5(m, 3H).
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[CH2:13][CH:5]2[CH:4]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:3]1.CS(O)(=O)=O.[C:24](OC(=O)C)(=[O:26])[CH3:25].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:24]([C:10]1[CH:9]=[CH:8][C:7]2[N:6]3[C:2](=[O:1])[O:3][CH:4]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[CH:5]3[CH2:13][C:12]=2[CH:11]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)NCC1OC(=O)N2c3ccccc3CC12
Reactant: CC(=O)OC(C)=O
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NCC1OC(=O)N2c3ccc(C(C)=O)cc3CC12
Reaction time: 1 h

Procedure:
A mixture of (±) (1S,9aS/1R,9aR) N-[(9,9a-dihydro-3-oxo-1H,3H-oxazolo[3, 4-a]indol-1-yl)methyl]acetamide (X diastereomer B, EXAMPLE 11, 8 mg), methane sulfonic acid (0.5 ml), and acetic anhydride (10 μl) is stirred in methylene chloride (0.2 ml) from 0° to 20° for 19.5 hours. After this time the mixture is cooled in an ice bath and additional acetic anhydride (10 μl) is added. The mixture is stirred for one hour then added to a small amount of ice and saturated aqueous sodium bicarbonate (7 ml) is added, then solid sodium bicarbonate is added until alkaline. The mixture is then extracted with methylene chloride (5×, 20 ml total). The combined extract layers provide 8 mg of material. The 8 mg is then purified by chromatography (5 cm×0.5 cm disposable pipet, 40-63μ silica) eluting with 1% and 2.5% methanol/methylene chloride gradient while collecting 0.4 ml fractions. The appropriate fractions are pooled and concentrated to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1.Br[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:31]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:29][C:30](=[O:31])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1
Reactant: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(F)cnc2[nH]c1=O
Reactant: O=C(CBr)c1ccccc1
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(F)cnc2n(CC(=O)c2ccccc2)c1=O

Procedure:
This compound was prepared from 6-fluoro-2-oxo-4-[4-(thiophene-2-carbonyl)-piperazine-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (98) and 2-bromoacetophenone according to General Procedure B. Yield 293 mg (38%), MP 262° C.; 1H-NMR (DMSO-d6): δ 3.79 (m, 4H), 3.95 (m, 4H), 5.87 (s, 2H), 7.16 (dd, J=3.6, 5.2 Hz, 1H), 7.51 (d, J=3.6 Hz, 1H), 7.59 (m, 2H), 7.50 (m, 1H), 7.81 (dd, J=1.2, 4.8 Hz, 1H), 8.12 (m, 2H), 8.23 (dd, J=2.8, 9.2 Hz, 1H), 8.70 (d, J=2.8 Hz, 1H); EIMS: 502 (M+1). Anal. (C26H20FN5O3S) C, H, N.
Reaction SMILES: [Br:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=O)=[C:4]([F:11])[CH:3]=1.[CH3:12][C:13]1(C)[O:18]C(=O)CC(=O)[O:14]1.Cl>C(N(CC)CC)C>[Br:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH:6]=[CH:12][C:13]([OH:18])=[O:14])=[C:4]([F:11])[CH:3]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=Cc1cc(F)c(Br)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(O)C=Cc1cc(F)c(Br)cc1F
Temperature: 95 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-2,5-difluorobenzaldehyde (15.0 g) in triethylamine formiate (80 mL) at room temperature was added 2,2-dimethyl-1,3-dioxane-4,6-dione (9.77 g). After being stirred for 1 h, the mixture was heated at 95° C. with stirring for 15 hours. After cooling down, ice water was added. The mixture was adjusted to pH ˜1 with HCl (6 M) and then extracted with ethyl acetate (200 mL×3). The organic phase was washed with brine (50 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography eluting with DCM/petroleum ether (7:1) to give the subtitle compound as a white solid. MS ESI+: m/z=263 [M+H]+.
Reaction SMILES: [CH:1]1([C:4](=[O:26])[CH:5]([C:13](=[O:25])[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][C:15]=2[F:24])C(OC(C)(C)C)=O)[CH2:3][CH2:2]1>C1(C)C=CC=CC=1>[CH:1]1([C:4](=[O:26])[CH2:5][C:13]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:16][C:15]=2[F:24])=[O:25])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C(C(=O)c1ccc(S(C)(=O)=O)cc1F)C(=O)C1CC1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(C(=O)CC(=O)C2CC2)c(F)c1
Yield: 95.3 %

Procedure:
A mixture of t-butyl 3-cyclopropyl-2-(2-fluoro-4-methylsulphonylbenzoyl)-3-oxopropionate (10.5 g) and p-toluenesulphonic add (2.0 g) in toluene was stirred and heated at reflux for 4 hours. The mixture was washed with water, dried (anhydrous magnesium sulphate) and filtered. The flitrate was evaporated to dryness to give 3-cyclopropyl-1-(2-fluoro-4-methylsulphonylphenyl)-propan-1,3-dione (7.4 g) as a red gum, NMR (CDCl3); 0.9-1.3 (m,4H), 1.8-2.1 (m, 1H), 3.1 (s,3H), 6.3 (s, 1H), 7.5-8.0 (m,3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH2:12].[CH2:13]([O:16][CH2:17][CH:18]1[CH2:20][CH2:19]1)[C:14]#[CH:15].C(NC(C)C)(C)C>C(OCC)(=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:10]=[C:9]([C:15]#[C:14][CH2:13][O:16][CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH2:12]
Reactant: Nc1c(Cl)cc(I)c2c1OCO2
Reactant: C#CCOCC1CC1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: Nc1c(Cl)cc(C#CCOCC2CC2)c2c1OCO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.4 %

Procedure:
5-Chloro-7-iodo-1,3-benzodioxol-4-amine (1.0 g, 3.36 mmol) and [(prop-2-yn-1-yloxy)methyl]cyclopropane (739 mg, 6.72 mmol) in ethyl acetate (12 ml) were cooled in ice-methanol, under an atmosphere of nitrogen, then treated with bis(triphenylphosphine) palladium(II) dichloride (236 mg, 10 mol %) followed by copper(I) iodide (64 mg, 10 mol %) and diisopropylamine (681 mg, 6.74 mmol). The reaction was allowed to warm to room temperature and stirred for 4 hours and then filtered through Celite. The filtrate was purified by column chromatography on silica using 40% methyl tert-butyl ether in iso-hexane as eluent to give 5-chloro-7-[3-(cyclopropylmethoxy)prop-1-yn-1-yl]-1,3-benzodioxol-4-amine (850 mg, 90%) as a dark orange oil; NMR Spectrum: (CDCl3) 0.25 (m, 2H), 0.56 (m, 2H), 1.08 (m, 1H), 3.40 (d, 2H), 4.03 (s, 2H), 4.40 (s, 2H), 6.00 (s, 2H), 6.88 (s, 1H).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[CH3:17][S:18][CH2:19][C:20](O)=[O:21]>>[CH3:17][S:18][CH2:19][C:20]([NH:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16])=[O:21]
Reactant: CSCC(=O)O
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Product: CSCC(=O)Nn1nc(C(F)(F)F)c2ccccc2c1=O

Procedure:
The product from Example 11B and 2-(methylthio)acetic acid were treated using a method similar to that described in Example 57 to give the title compound 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.45 (ddd, J=8.0, 1.4, 0.7 Hz, 1H), 8.15 (td, J=7.7, 1.4 Hz, 1H), 8.04-8.11 (m, 2H), 3.37 (s, 2H), 2.24 (s, 3H); MS (ESI−) M/Z 316 (M−H)−.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:10])[CH2:4][CH:5]([O:8][CH3:9])[O:6][CH3:7].[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:18](O)=O)=[N:16][CH:17]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O>CN(C=O)C>[CH3:7][O:6][CH:5]([O:8][CH3:9])[CH2:4][C:3]1[N:10]=[C:18]([C:15]2[CH:14]=[CH:13][C:12]([F:11])=[CH:17][N:16]=2)[O:1][N:2]=1
Reactant: O=C(O)c1ccc(F)cn1
Reactant: COC(CC(=N)NO)OC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(Cc1noc(-c2ccc(F)cn2)n1)OC
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A solution of N-hydroxy-3,3-dimethoxypropanimidamide obtained in Reference Example 19 (1.0 g, 6.8 mmol) in DMF (3 mL) was added to a solution of 5-fluoropyridine-2-carboxylic acid (1.0 g, 7.1 mmol) and carbonyldiimidazole (1.3 g, 8.1 mmol) in DMF (4 mL), which was stirred for 1 hour at 40° C., and the mixture was stirred for 30 minutes. The reaction solution was heated to 90° C. and stirred for 15 hours. Water was added to the reaction mixture, followed by extraction with EtOAc. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over Na2SO4, then the drying agent was filtered off, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 25 g, hexane/EtOAc=75/25 to 0/100) to obtain the title compound (1.2 g) (colorless solid).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=2[O:11][C:12]([F:15])([F:14])[CH3:13])[CH2:3][CH2:2]1.[Cl:16][C:17]1[C:18](F)=[CH:19][C:20]([F:30])=[C:21]([CH:29]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[Cl:16][C:17]1[C:18]([O:10][C:7]2[CH:8]=[N:9][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:5]([O:11][C:12]([F:15])([F:14])[CH3:13])[CH:6]=2)=[CH:19][C:20]([F:30])=[C:21]([CH:29]=1)[C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Reactant: CC(F)(F)Oc1cc(O)cnc1C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(Oc2cnc(C3CC3)c(OC(C)(F)F)c2)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.4 %

Procedure:
A suspension of 6-cyclopropyl-5-(1,1-difluoroethoxy)pyridin-3-ol (Preparation 269, 155 mg, 0.72 mmol), tert-butyl 5-chloro-2,4-difluorobenzoate (179 mg, 0.72 mmol) and potassium carbonate (299 mg, 2.16 mmol) in dimethyl sulfoxide (3 mL) was stirred for 4 hours at room temperature. The reaction mixture was diluted with water (40 mL) then extracted with ethyl acetate (3×30 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography eluting with 5% diethyl ether in heptane to afford the title compound as a white solid (260 mg, 81%).
Reaction SMILES: CN(C)[C:3]1[S:4][C:5]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=2[C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:12][CH:11]=1)=[O:9].C1COCC1.[F:37][C:38]1[CH:39]=[C:40]([Mg]Br)[CH:41]=[CH:42][C:43]=1[O:44][CH3:45]>ClC1C=CC=CC=1>[F:37][C:38]1[CH:39]=[C:40]([C:3]2[S:4][C:5]3[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=3[C:7]=2[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:14][CH:15]=2)=[O:9])[CH:41]=[CH:42][C:43]=1[O:44][CH3:45]
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(N(C)C)sc2c1
Reactant: COc1ccc([Mg]Br)cc1F
Solvent: C1CCOC1
Solvent: Clc1ccccc1
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(OC)c(F)c3)sc2c1
Temperature: 25 °C
Yield: 42.2 %

Procedure:
A solution of [2-dimethylamino-6-methoxybenzothien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone (1.5 g, 3.6 mmol)(see U.S. Pat. No. 5,420,349) in chlorobenzene (15 mL) was cooled to 0° and treated with a 0.73 M THF solution of 3-fluoro-4-methoxyphenylmagnesium bromide (16.0 mL, 11.7 mmol)(prepared from 4-bromo-2-fluoroanisole, catalytic iodine, and magnesium turnings in THF). The mixture was allowed to warm to ambient temperature and when the starting material was consumed, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with water (2x), and brine (2x), dried (sodium sulfate), and concentrated. The residue was purified via chromatography (silica gel, 5-10% MeOH in CH2Cl2) to provide 0.79 g (44%) of the title compound as a brown oil: 1H NMR d 1.44 (m, 2H), 1.59 (m, 4H), 2.48 (m, 4H), 2.74 (t, J=6.0 Hz, 2H), 3.83 (s, 3H), 3.88 (s, 3H), 4.09 (t, J=6.0 Hz, 2H), 6.77-6.83 (m, 3H), 6.96 (dd, J=2.3 Hz, 8.9 Hz, 1H), 7.11-7.19 (m, 2H), 7.31 (d, J=2.3 Hz, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.75 (d, J=8.8 Hz, 2H); 13C NMR d 24.4, 26.1, 55.3, 55.9, 56.4, 57.9, 66.5, 104.7, 113.5, 114.6, 115.3, 116.7, 117.0, 124.4, 125.5, 126.7, 126.8, 130.5, 131.6, 132.6, 134.1, 140.4, 140.9, 148.0, 148.1, 153.8, 158.1, 163.5, 193.2; MS (FD) m/e 519 (M+); Anal. calc'd. for C30H30FNO4S: C, 69.34; H, 5.82; N, 2.69. Found: C, 69.63; H, 5.89; N, 2.64.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[N:8][C:7]=12)#[CH:2].[OH:26][CH2:27][C:28]([NH:31][S:32]([C:35]1[S:39][C:38](Cl)=[N:37][CH:36]=1)(=[O:34])=[O:33])([CH3:30])[CH3:29]>>[OH:26][CH2:27][C:28]([NH:31][S:32]([C:35]1[S:39][C:38]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=4)=[N:8][C:7]=23)=[N:37][CH:36]=1)(=[O:34])=[O:33])([CH3:30])[CH3:29]
Reactant: CC(C)(CO)NS(=O)(=O)c1cnc(Cl)s1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1cnc(C#Cc2cnn3c(C(F)(F)F)cc(-c4cccc(C(F)(F)F)c4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.10) (178 mg, 0.5 mmol) and 2-chloro-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.14) (135 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (163 mg, 55%). MS (ISN) 588.2 [(M+H)+]; mp 200° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@:5]1([NH:10]C(OC(C)(C)C)=O)[CH2:7][C@H:6]1[CH:8]=[CH2:9])=[O:4].C(Cl)Cl.[C:21]([OH:27])([C:23]([F:26])([F:25])[F:24])=[O:22]>>[F:24][C:23]([F:26])([F:25])[C:21]([OH:27])=[O:22].[CH3:1][O:2][C:3]([C@@:5]1([NH2:10])[CH2:7][C@H:6]1[CH:8]=[CH2:9])=[O:4]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C[C@@H]1C[C@]1(N)C(=O)OC

Procedure:
N-Boc-(1R,2S)-1-amino-2-vinylcyclopropane carboxylic acid methyl ester (125 mg, 0.52 mmol) stirred in CH2Cl2/TFA (1:1, 2 mL) at RT for 90 minutes. Solvents removed under vacuum to yield (1R,2S)-1-amino-2-vinylcyclopropane carboxylic acid methyl ester trifluoroacetic acid salt.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[CH:8]=[C:9]([CH2:14][S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:10]=1[N+:11]([O-])=O.C1COCC1>[Pd].CO>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([N:28]2[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]2)[CH:8]=[C:9]([CH2:14][S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:10]=1[NH2:11]
Reactant: CN1CCN(c2cc(CS(=O)(=O)c3cccc4ccccc34)c([N+](=O)[O-])c(OCCCl)c2)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCN(c2cc(CS(=O)(=O)c3cccc4ccccc34)c(N)c(OCCCl)c2)CC1
Reaction time: 20 h

Procedure:
A mixture of 1-[3-(2-chloroethoxy)-5-(naphthalene-1-sulfonylmethyl)-4-nitrophenyl]-4-methylpiperazine (0.45 g, 0.85 mmoles) and 10% Pd/C in a 1:1 mixture of THF and methanol was hydrogenated on a Parr hydrogenator at 40 lb/in2 for 20 hours. The reaction mixture was filtered through Celite. The filtrate was diluted with EtOAc, washed with water, dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (0.4 g, 0.82 mmoles), identified by HNMR and mass spectral analyses.
Reaction SMILES: [Li]CCCC.[CH2:6]([N:13]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:27][C:28]([CH3:33])([CH3:32])[C:29](Cl)=[O:30]>C1COCC1>[CH2:20]([N:13]([CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C@@H:14]([C:29](=[O:30])[C:28]([CH3:33])([CH3:32])[CH3:27])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCOC(=O)CN(Cc1ccccc1)Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C(=O)C(C)(C)C)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.6 %

Procedure:
In a round bottomed flask, at −78° C., under argon atmosphere, a solution of DIPA (0.29 mL, 2.12 mmol) in dry THF (10 ml) was treated with n-BuLi (2.5 M in n-hexane, 0.776 mL, 1.94 mmol). After 30 min a solution of ethyl 2-(dibenzylamino)-acetate [prepared as described in Example 47, step 1] (0.5 g, 1.77 mmol) in dry THF (10 mL) was added dropwise via cannula. After 15 min, trimethylacetyl chloride (0.53 mL, 3.53 mmol) was added dropwise at −78° C. and the mixture stirred for 10 min at rt. The reaction was then quenched with H2O, and Et2O was subsequently added. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give a crude product as an oil. Purification by column chromatography using a Teledyne ISCO apparatus, eluting with Cy:AcOEt (98:2) gave the title compound (0.492 g, 76%) as a colorless oil. MS (ESI) m/z: 368 [M−H]+; (ESI) m/z: 366 [M−H]−. 1H NMR (DMSO-d6) δ 0.93 (s, 9H), 1.16-1.25 (m, 3H), 3.79 (d, J=13.97 Hz, 2H), 3.98 (d, J=13.96 Hz, 2H), 4.07-4.25 (m, 2H), 4.60 (s, 1H), 7.20-7.41 (m, 10H).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[C:18]([Cl:19])=[C:17]([Cl:20])[C:10]2[S:11][C:12]([C:14](=[O:16])[CH3:15])=[CH:13][C:9]=2[CH:8]=1)C.[OH-].[Na+].Cl.C(OCC)C>C(O)C>[C:14]([C:12]1[S:11][C:10]2[C:17]([Cl:20])=[C:18]([Cl:19])[C:7]([O:6][CH2:5][C:4]([OH:21])=[O:3])=[CH:8][C:9]=2[CH:13]=1)(=[O:16])[CH3:15]
Reactant: CCOC(=O)COc1cc2cc(C(C)=O)sc2c(Cl)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: CC(=O)c1cc2cc(OCC(=O)O)c(Cl)c(Cl)c2s1
Reaction time: 2 h
Yield: 46.9 %

Procedure:
To 5.1 g of ethyl[(6,7-dichloro-2-acetylbenzo[b]thien-5-yl)oxy]acetate in 200 ml of 95% ethanol is added 150 ml of a 6N sodium hydroxide solution and the mixture is refluxed at 100° for 45 mins. The solvent is removed in vacuo to give a white slurry to which is added 250 ml of a 6N hydrochloric acid and 200 ml ethyl ether. The mixture is stirred for 2 hrs, filtered and the filter cake is distributed between 6N hydrochloric acid and ethyl ether. The organic layers are separated and the aqueous layers are extracted with ethyl ether. The combined organic extracts are washed, dried over anhydrous magnesium sulfate, filtered and the solvent is evaporated to give a solid. Recrystallization from acetone-hexane gives 2.2 g of [(2-acetyl-6,7-dichlorobenzo[b]thien-5-yl)oxy]acetic acid, mp 203°-205°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[Br:12].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:14]=1>N1C=CC=CC=1.[Cl-].[Na+].O>[Br:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[CH:3][C:2]([NH:1][S:19]([C:15]1[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=1)(=[O:21])=[O:20])=[CH:11]2
Reactant: Nc1cnc2c(Br)cccc2c1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: O=S(=O)(Nc1cnc2c(Br)cccc2c1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
3-Amino-8-bromoquinoline (300 mg, Production Example 5b) was dissolved in pyridine (5 ml), to which was then added 3-pyridinesulfonyl chloride (254 mg), followed by stirring at room temperature for 30 minutes. After the reaction was completed, the reaction solution was poured into brine and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated. The resulting crude crystals were washed with ethyl acetate and IPA, to give the title compound (270 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2].[I-].[Cl:22][C:23]1[CH:31]=[C:30]([Cl:32])[C:29]2[N:25]([C:26]([CH3:37])=[CH:27][C:28]=2[CH2:33]N(C)C)[CH:24]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:33][C:28]2[CH:27]=[C:26]([CH3:37])[N:25]3[C:29]=2[C:30]([Cl:32])=[CH:31][C:23]([Cl:22])=[CH:24]3)[C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCCC(CC(=O)OCC)n1c(=O)[nH]c2ccccc21
Reactant: Cc1cc(CN(C)C)c2c(Cl)cc(Cl)cn12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(CC(=O)OCC)n1c(=O)n(Cc2cc(C)n3cc(Cl)cc(Cl)c23)c2ccccc21
Yield: 38 %

Procedure:
To a solution of 3-(2-Oxo-2,3-dihydro-benzimidazol-1-yl)-hexanoic acid ethyl ester (30 mg, 0.11 mmol) in DMF (10 mL) were added (6,8-Dichloro-3-methyl-indolizin-1-ylmethyl)-dimethyl-amine iodide, CAS: (6,8-Dichloro-3-methyl-indolizin-1-ylmethyl)-dimethyl-amine iodide (65 mg, 0.16 mmol). and K2CO3 (45 mg, 0.33 mmol) at room temperature under nitrogen atmosphere. The solution was heated to 100 C for 2 hours. The solution was cooled down and water was added. The solution was extracted with EtOAc and the combined organic layer was dried with MgSO4. The solution was filtered and the filtrate was concentrated. The residue was purified by CombiFlash with 20% EtOAc in Hexane as the eluent to afford the desirable product 3-[3-(6,8-Dichloro-3-methyl-indolizin-1-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester (20 mg, 38%) as a yellow foam.
Reaction SMILES: [H-].[Na+].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[OH:13])[CH:6]=[CH:5][CH:4]=1.Br[CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C=O)C.O>[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:13][CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1cccc2cccnc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1cccc2cccnc12
Reaction time: 0.08 h
Yield: 59.1 %

Procedure:
To a solution of compound NaH (100 mg, 4.14 mmol) in DMF (3 mL) was added quinolin-8-ol (200 mg, 1.38 mmol) at 26° C. After stirred for 5 minutes, ethyl 2-bromopropanoate (300 mg, 1.65 mmol) was added and the reaction mixture stirred for 16 h at 26° C. The mixture was then diluted with water (20 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated to give ethyl 2-(quinolin-8-yloxy)propanoate (200 mg, 59.2%) as colorless oil which was used in next step without further purification. (304 mg, Yield 90%).