Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:25]>O1CCCC1>[F:21][C:16]1[CH:15]=[C:14]([C:10]2([O:13][CH3:25])[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]2)[CH:19]=[CH:18][C:17]=1[F:20]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(F)c(F)c2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(c2ccc(F)c(F)c2)CCN(C(=O)OC(C)(C)C)C1
Yield: 76.9 %

Procedure:
Preparation according to Preparation 2. Tert-butyl-3-(3,4-difluorophenyl)-3-hydroxypyrrolidin-1-carboxylate (3.3 g, 11 mmol) in dry tetrahydrofuran (50 mL), sodium hydride (60% dispersion in mineral oil, 0.66 g, 16.5 mmol), iodomethane (1.37 mL, 22 mmol). Purification by flash column chromatography on silica gel (ethyl acetate/isooctane, 1:9 to 1:1) gave the title compound (2.65 g, 77%). MS m/z (rel. intensity, 70 eV) 257 (17), 240 (14), 171 (13), 127 (15), 57 (bp).
Reaction SMILES: [CH3:1][C:2]([NH:14]C(=O)C)([C:4]1[CH:5]=[N:6][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:9]=1)[CH3:3].Cl.O.[OH-].[Na+]>COC(C)(C)C>[CH3:3][C:2]([NH2:14])([C:4]1[CH:5]=[N:6][C:7]([C:10]([F:12])([F:13])[F:11])=[CH:8][CH:9]=1)[CH3:1]
Reactant: CC(=O)NC(C)(C)c1ccc(C(F)(F)F)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COC(C)(C)C
Product: CC(C)(N)c1ccc(C(F)(F)F)nc1
Temperature: 27.5 °C
Reaction time: 24 h
Yield: 74.3 %

Procedure:
Heat a mixture of N-[1-Methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-acetamide (93.5 moles, 19.1 kg), concentrated hydrochloric acid (805.9 moles; 66.2 L; 79.4 kg), and water (79.4 L; 79.4 kg) to 95-100° C. with stirring under nitrogen for 24 hours. Cool the reaction mixture to 20-35° C. and observe completion of the reaction by HPLC. Cool the reaction vessel to 10-20° C. and add tert-butyl methyl ether (105.4 L; 78.0 kg). Separate the phases, and discard the organic layer. Add 15% sodium hydroxide (910.9 moles; 205 L; 242.9 kg) to the aqueous phase and observe a pH of 9.5-10.5. Extract the aqueous layer with ethyl acetate (3×89 mL; 3×80.0 kg), combine the organic layers, and discard the aqueous phase. Concentrate the solution to approximately 2 volumes, add tert-butyl methyl ether (174 L; 129.1 kg), and concentrate the solution to approximately 2 volumes. Dilute the reaction vessel with n-heptane (168 L; 115.0 kg), concentrate the solution to approximately 2 volumes, and dilute with additional n-heptane (30 L, 20.7 kg). Cool the contents of the reaction mixture to 0-5° C. and stir the mixture for 2 hours at 0-5° C. Filter and dry the resultant solids under vacuum at 35-45° C. to afford the titled compound (14.19 kg; 74.3%, based on HPLC) as a 97.9% pure tan powder.
Reaction SMILES: CC(C)(C)[O-].[K+].CC1C=CC(S([CH2:17][N+:18]#[C-])(=O)=O)=CC=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[C:25]3[C:34]([CH:35]=O)=[N:33][N:32]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31](=[O:43])[C:26]=3[N:27]([CH3:30])[C:28]=2[CH:29]=1.CO>COCCOC>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[C:25]3[C:34]([CH2:35][C:17]#[N:18])=[N:33][N:32]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31](=[O:43])[C:26]=3[N:27]([CH3:30])[C:28]=2[CH:29]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: Cn1c2cc(Cl)ccc2c2c(C=O)nn(-c3ccccc3)c(=O)c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CO
Product: Cn1c2cc(Cl)ccc2c2c(CC#N)nn(-c3ccccc3)c(=O)c21
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 62.8 %

Procedure:
1.27 g (10.96 mmol) of potassium 1,1-dimethylethoxide are added, in small portions, to a solution of 2.14 g (10.96 mmol) of (4-methylbenzenesulphonyl)methyl isocyanide in 50 ml of 1,2-dimethoxyethane, the reaction mixture is stirred for 30 min at −60° C., 2.88 g (8.53 mmol) of 7-chloro-5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxaldehyde are added and the reaction mixture is stirred for 3 hours 30 min at −60° C. 9 ml of methanol are added and the reaction mixture is further stirred for 30 min at room temperature and for 1 hour at reflux. The mixture is cooled and concentrated under reduced pressure, water, 5 ml of acetic acid and 200 ml of dichloromethane are added to the residue, the organic phase is separated by settling and the aqueous phase is extracted with dichloromethane. The organic phases are combined, washed with water, dried over sodium sulphate, filtered and concentrated under reduced pressure and the residue is purified by chromatography on a column of silica gel. 1.87 g (5.36 mmol) of compound are isolated in the form of a white solid which is used as is in the following stage.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[C:4](=[O:21])[CH:5]2[CH2:20][C:8]3([CH2:19][C:18]4[C:14]5[N:15]=[N:16][NH:17][C:13]=5[CH:12]=[CH:11][C:10]=4[C:9]=13)[CH2:7][CH2:6]2>C(O)C.CO>[F:22][C:2]([F:1])([F:23])[C:3]1[C:4](=[O:21])[C@H:5]2[CH2:20][C@:8]3([CH2:19][C:18]4[C:14]5[N:15]=[N:16][NH:17][C:13]=5[CH:12]=[CH:11][C:10]=4[C:9]=13)[CH2:7][CH2:6]2
Reactant: O=C1C(C(F)(F)F)=C2c3ccc4[nH]nnc4c3CC23CCC1C3
Solvent: CO
Solvent: CCO
Product: O=C1C(C(F)(F)F)=C2c3ccc4[nH]nnc4c3C[C@@]23CC[C@@H]1C3

Procedure:
6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta-[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one [1.8 g, (8R,10aS): (8S,10aR) enantiomeric ratio ˜2:1] was dissolved in 1/1 ethanol/methanol (130 mL) and resolved by chiral HPLC on a 2.0×25 cm Daicel Chiralcel OJ column (4 mL injections, elution with 35% EtOH:Heptane at 7.5 mL/min, fractions monitored at 310 nm). The pure fractions containing the first enantiomer to elute (enantiomer A) were combined and concentrated to give (8R,10aS)-6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one as a white solid which had a negative rotation. The fractions containing the second enantiomer to elute (enantiomer B) were combined and concentrated to give(8S,10aR)-6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)- one as a solid which had a positive rotation.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1[F:27].[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[F:26][C:22]1[C:21]([F:27])=[CH:20][CH:25]=[CH:24][C:23]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2
Reactant: Fc1cccc(Br)c1F
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1cccc(-c2cccc3[nH]ccc23)c1F
Temperature: 75 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl) 1H-indole (3.78 g, 15.5 mmol), and 1-bromo-2,3-difluorobenzene (3 g, 15.5 mmol) in THF (55 mL) were added Palladium catalyst Pd(PPh3)4 (0.54 g, 0.47 mmol) and the freshly prepared sodium hydroxide solution (1.865 g, 47 mmol in 22 mL of water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 75° C. oil bath for overnight. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed with brine, and dried over Na2SO4. After filtration, the solvents were evaporated, and the crude product was purified by a silica gel column to give 2.92 g (82%) of 4-(2,3-difluoro-phenyl)-1H-indole.
Reaction SMILES: [F:1]/[C:2](=[CH:6]\[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)/[C:3]([OH:5])=O.[C:13]1([S:19]([C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1]/[C:2](=[CH:6]\[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)/[C:3]([NH:26][C:25]1[CH:24]=[CH:23][C:22]([S:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:21])=[O:20])=[CH:28][CH:27]=1)=[O:5]
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Reactant: O=C(O)/C(F)=C/c1cccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(S(=O)(=O)c2ccccc2)cc1)/C(F)=C/c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.3 %

Procedure:
The mixture of (Z)-2-fluoro-3-(pyridin-3-yl)acrylic acid (100 mg, 0.598 mmol),4-(phenylsulfonyl)aniline (140 mg, 0.598 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (341 mg, 0.897 mmol), DIEA (232 mg, 1.795 mmol) in DMF (Volume: 10 ml) was stirred at RT for overnight, removed DMF, extracted with EtOAc, washed with 1N NaOH, brine, dried and the biotage purification afforded the product (51 mg, 23%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6](=[O:7])[C:5]2=[CH:15][CH:16]=1.O>CO.[BH4-].[K+]>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:6]([OH:7])[N:8]([CH2:11][CH:12]([CH3:13])[CH3:14])[C:9]2=[O:10])=[CH:15][CH:16]=1.[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:15][CH:16]=1)[C:6](=[O:7])[N:8]([CH2:11][CH:12]([CH3:13])[CH3:14])[CH:9]2[OH:10]
Reactant: CC(C)CN1C(=O)c2ccc(Br)cc2C1=O
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)CN1C(=O)c2cc(Br)ccc2C1O
Product: CC(C)CN1C(=O)c2ccc(Br)cc2C1O
Temperature: 20 °C
Reaction time: 16 h
Yield: 199.4 %

Procedure:
5-Bromo-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one and 6-bromo-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one are prepared as described in Example 1, starting with 23.6 g of 4-bromo-N-isobutylphthalimide in 200 cm3 of methanol and 4.5 g of potassium borohydride. The reaction mixture is stirred at a temperature in the region of 20° C. for 16 hours and is then cooled to a temperature in the region of 0° C. and 175 cm3 of distilled water are added dropwise. The methanol is then partially evaporated off under reduced pressure (2 kPa) at a temperature in the region of 40° C. The aqueous phase is extracted 3 times with 200 cm3 of ethyl acetate. The organic extracts are combined, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 23.7 g of 5-bromo-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one and 6-bromo-3-hydroxy-2-isobutyl-2,3-dihydroisoindol-1-one are thus obtained in the form of a white powder (Rf=0.79, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (50/50 by volume)).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([CH2:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]([F:30])([F:29])[F:28])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:32])[C:18](=[O:31])[NH:19][N:20]=2)[CH2:9]1)=O)(C)(C)C.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[NH:8]1[CH2:11][CH:10]([CH2:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]([F:30])([F:28])[F:29])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:32])[C:18](=[O:31])[NH:19][N:20]=2)[CH2:9]1
Reactant: CC1C(=O)NN=C2COc3cc(C(F)(F)F)c(CC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1C(=O)NN=C2COc3cc(C(F)(F)F)c(CC4CNC4)cc3N21
Yield: 100 %

Procedure:
A solution of 3-(4-methyl-3-oxo-7-trifluoromethyl-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylmethyl)-azetidine-1-carboxylic acid tert-butyl ester (0.019 g, 0.042 mmol) in TFA (0.5 mL) and DCM (3 mL) was stirred at 25° C. for 2 h. The solvent was removed in vacuo to give 6-azetidin-3-ylmethyl-4-methyl-7-trifluoromethyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid (0.002 g, 100%). LC/MS (Table 1, Method 5) Rt=2.023 min; MS m/z: 355 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20](Cl)=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=[N:23]2)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:30][C:31]1([CH3:38])[O:35][CH:34]([CH2:36][NH2:37])[CH2:33][O:32]1>ClCCl>[CH2:8]([O:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([NH:37][CH2:36][CH:34]3[CH2:33][O:32][C:31]([CH3:38])([CH3:30])[O:35]3)=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=[N:23]2)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Reactant: CC1(C)OCC(CN)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)OCC(CNc2c([N+](=O)[O-])cnc3cc(OCc4ccccc4)ccc23)O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.2 %

Procedure:
Triethylamine (31.88 mL, 228.77 mmol, 1.5 eq) was added to a solution of 7-benzyloxy-4-chloro-3-nitroquinoline (48.00 g, 152.51 mmol, 1 eq) in dichloromethane (400 mL). Dropwise addition of 2,2-dimethyl-1,3-dioxolan-4-methanamine (20.0 g, 152.51 mmol, 1 eq) to the reaction mixture followed, which was then stirred at ambient temperature for 6 hours. The crude reaction mixture was concentrated under reduced pressure, and the resulting solid was triturated with water and then stirred for 1 hour. The precipitate was collected by filtration, washed with water, dried, suspended in diethyl ether (400 mL), sonicated, and the resulting precipitate material was collected by filtration. The product was dried under vacuum at 40° C. for 12 hours to afford 60.1 g of (7-benzyloxy-3-nitro-quinolin-4-yl)[(2,2-dimethyl[1,3]dioxolan-4-yl)methyl]amine as a yellow solid, mp 154-155° C. 1H-NMR (300 MHz, CDCl3) δ 9.74-9.62 (br m, 1H), 9.32 (s, 1H), 8.15 (d, J=9.4 Hz, 1H), 7.51-7.31 (m, 6H), 7.15 (dd, J=9.4, 2.7 Hz, 1H), 5.21 (s, 2H), 4.48-4.37 (m, 1H), 4.16-4.05 (m, 2H), 4.04-3.93 (m, 1H), 3.74 (dd, J=8.5, 5.9 Hz, 1H), 1.54 (s, 3H), 1.40 (s, 3H); MS (APCI) m/z 410.1 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33][C@@H:32]([NH2:35])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(C(C)C)CC)(C)C>CC(O)C>[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33][C@@H:32]([NH:35][C:18]2[C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=[C:14]3[N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH:11]=[CH:12][C:13]=23)[CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Temperature: 80 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
A suspension of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (8.16 g, 24.2 mmol), (R)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester (5.00 g, 26.8 mmol), and diisopropylethylamine (5.14 ml, 29.5 mmol) in propan-2-ol (150 ml) was heated at 80° C. for 13 h. The mixture was then cooled to 25° C. and stirred for 4 h. The resulting yellow solid was collected by vacuum filtration, washed with heptanes (1×20 ml), and was air-dried to afford (R)-3-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (9.90 g, 88%). LCMS (Method G, ESI): RT=1.19 min, m+H=488.3. This material was used in the next step below without additional purification or characterization.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])OC2=O.[NH2:13]CCCO.[O:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>>[OH:18][CH2:19][CH2:20][CH2:21][CH2:22][N:6]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[NH2:13])[CH:5]=[O:12]
Reactant: C1CCOC1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NCCCO
Product: Nc1ccccc1N(C=O)CCCCO
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
Isatoic anhydride (4.5 g), 3-aminopropanol (2.66 ml) were added to tetrahydrofuran (70 ml), and the mixture was stirred at room temperature for 4 hours. Tetrahydrofuran was removed and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain 4.7 g of N-(4-hydroxybutyl)(2-aminophenyl)formamide. Yield: 82%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([OH:20])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH2:21][C:22]([NH:24][CH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26]1)=[O:23].Br[CH2:40][CH:41]([F:43])[F:42]>>[F:42][CH:41]([F:43])[CH2:40][O:20][C:15]1[C:16]([O:18][CH3:19])=[CH:17][C:12]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:21][C:22]([NH:24][CH:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26]3)=[O:23])[CH:7]([CH2:6][C:5]3[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:13]=2[CH:14]=1
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CCC2
Reactant: FC(F)CBr
Product: COc1ccc(CC2c3cc(OCC(F)F)c(OC)cc3CCCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-7-methoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-N-indan-1-yl-acetamide with 2-bromo-1,1-difluoroethane.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:11][CH3:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:13]([O:15][C:16](=[O:26])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=1)[CH3:14].C(OC(=O)C=C(C1C=CC=C2C=1C(C#N)=CN2)C1C=CC=CC=1)C>>[CH2:13]([O:15][C:16](=[O:26])[CH:17]=[C:18]([C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:11][CH3:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=1)[CH3:14]
Reactant: CCOC(=O)C=Cc1cccc(C)n1
Reactant: COc1n[nH]c2cc(Br)ccc12
Agent: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Product: CCOC(=O)C=C(c1ccc2c(OC)n[nH]c2c1)c1cccc(C)n1

Procedure:
3-(3-Methoxy-1H-indazol-6-yl)-3-(6-methyl-pyridin-2-yl)-acrylic acid ethyl ester CCLIII was prepared from 6-bromo-3-methoxy-1H-indazole and 3-(6-methyl-pyridin-2-yl)-acrylic acid ethyl ester using the procedure described for preparation of 3-(3-Cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LVIII (Example 14).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH3:19])[CH2:14][CH2:13]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:20](=[O:23])([O-])[O-].[Cs+].[Cs+].CN(C)[CH:28]=[O:29]>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>[O:29]1[CH2:28][CH2:20][O:23][CH:4]1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH3:19])[CH2:14][CH2:13]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CCN1CCN(c2nc(Cl)cc3ccccc23)CC1
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Product: CCN1CCN(c2nc(-c3ccccc3C3OCCO3)cc3ccccc23)CC1

Procedure:
3-Chloro-1-(4-ethylpiperazin-1-yl)isoquinoline (3.5 g) and 4-(1,3,2-dioxaborynan-2-yl)-1-(1,3-dioxolan-2-yl) benzene (5.0 g) were reacted in dimethylformamide (50 ml), in the presence of cesium carbonate (7.3 g) and tetrakistriphenylphosphinepalladium (0.3 g) at 80° C. in a nitrogen stream for 12 hr. The reaction solution was evaporated, and then partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried and evaporated. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give 4.66 g of the title compound as a pale yellow oil.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([OH:11])[C:9]#[CH:10].Cl[C:13]1[N:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]2[OH:28].CN(C=O)C>CCOCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:28][C:16]1[C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:10]#[C:9][CH2:8][OH:11])[N:14]=2)[N:19]=[CH:18][C:17]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)c1cnc2ccc(Cl)nc2c1O
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2ccc(C#CCO)nc2c1O
Reaction time: 0.08 h

Procedure:
Triethylamine (10 mL) is added to dry cuprous iodide (52 mg) under nitrogen. The mixture is stirred for 5 minutes. Propargyl alcohol (50 μL) is added. After stirring another 5 minutes, dichlorobis(triphenylphosphine)palladium(II) (48 mg) is added. The mixture is again stirred for 5 minutes before the addition of ethyl 6-chloro-4-hydroxy[1,5]naphthyridine-3-carboxylate (Preparation 1, 348 mg) and DMF (10 mL). After stirring another 5 minutes, the remaining propargyl alcohol (660 μL) is added, and the reaction is tightly capped and stirred at 70° C. for 11 hours. After cooling, the mixture is diluted with ether (75 mL), sonicated to break up any solids, and filtered. The collected solid is washed with ether, dried under vacuum and recrystallized from ethanol.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=[NH:14])[NH2:13])=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH:15]([C:27](OCC)=[O:28])([C:22](OCC)=[O:23])[CH2:16][C:17]([O:19][CH2:20]C)=[O:18].C[O-].[Na+].Cl>O.CO>[OH:23][C:22]1[C:15]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:27]([OH:28])[N:13]=[C:12]([CH2:11][C:8]2[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=2)[N:14]=1
Reactant: N=C(N)Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CC(C(=O)OCC)C(=O)OCC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)Cc1c(O)nc(Cc2ccc([N+](=O)[O-])cc2)nc1O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A 250 mL round bottom flask was charged with 2-(4-nitrophenyl)ethanimidamide hydrochloride (approximately 6.47 g, 30.0 mmol, 48% purity), triethyl ethane-1,1,2-tricarboxylate (7.60 mL, 33.0 mmol) and methanol (43 mL). To this solution was added a 25% sodium methoxide solution in methanol (24.0 mL, 105.2 mmol) immediately resulting in a dark purple thick suspension. After stirring for three hours under reflux the dark purple mixture was cooled to 0° C. using an ice bath and carefully treated with 30 mL water. This mixture was slowly treated with 35 mL 6N hydrochloric acid giving a pale green suspension. The suspension was stirred for additional 30 minutes, filtered and the obtained fawn solid was washed with 100 mL water. The product was dried in a desiccator under vacuum for two days. The crude product was used without purification in the next step.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])=[O:2].[CH:14]1([Mg]Br)[CH2:16][CH2:15]1>C1COCC1>[CH:14]1([CH:1]([OH:2])[C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=2[OH:13])[C:6]([O:8][CH3:9])=[O:7])[CH2:16][CH2:15]1
Reactant: COC(=O)c1ccc(O)c(C=O)c1
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(O)c(C(O)C2CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
In an ice-bath, methyl 3-formyl-4-hydroxybenzoate 66.38A (900 mg, 5 mmol) (commercially available from Aldrich) was dissolved in 5 mL THF. Then cyclopropylmagnesium bromide, 0.5 m in THF (22000 μL, 11 mmol) (commercially available from Aldrich) was added slowly. The reaction was raised to room temperature immediately and stirred at room temperature for 2 hours. After quenching with 1N HCl 11 mL, the reaction was extracted with EtOAc and dried. Silica gel chromatography afforded 950 mg of the product 66.38B (85%).