Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([O:17][CH3:18])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:19]([O:22][CH2:23][C:24]1[C:29]([N:30]2[CH2:42][CH2:41][N:33]3[C:34]4[CH2:35][CH2:36][CH2:37][CH2:38][C:39]=4[CH:40]=[C:32]3[C:31]2=[O:43])=[CH:28][C:27]([F:44])=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1)(=[O:21])[CH3:20].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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(Cl)Cl.C(OCC)C.CO>[C:19]([O:22][CH2:23][C:24]1[C:29]([N:30]2[CH2:42][CH2:41][N:33]3[C:34]4[CH2:35][CH2:36][CH2:37][CH2:38][C:39]=4[CH:40]=[C:32]3[C:31]2=[O:43])=[CH:28][C:27]([F:44])=[CH:26][C:25]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([O:17][CH3:18])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:21])[CH3:20]
Reactant: COc1nccc(Nc2cc(Br)cn(C)c2=O)n1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: COc1nccc(Nc2cc(-c3cc(F)cc(N4CCn5c(cc6c5CCCC6)C4=O)c3COC(C)=O)cn(C)c2=O)n1
Temperature: 130 °C
Yield: 98.9 %

Procedure:
Following Example 121b, 263a (158 mg, 0.5 mmol), 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 210d (242 mg, 0.5 mmol), 1M sodium carbonate solution (2 mL, 2 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol) and 1,2-dimethoxyethane (5 mL) were heated at 130° C. for 15 minutes in the microwave reactor. Work-up and flash column chromatography (silica, 60:35:5 methylene chloride/diethyl ether/methanol) gave a 98% yield (290 mg) of 263b as yellow oil: MS (ESI+) m/z 587.6 (M+H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:8]([F:11])([F:10])[F:9])([OH:7])[C:4](O)=[O:5].C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[NH2:29][C:30]1[CH:43]=[CH:42][C:33]([C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:35])=[CH:32][CH:31]=1>O1CCCC1>[C:36]1([C:34]([C:33]2[CH:32]=[CH:31][C:30]([NH:29][C:4](=[O:5])[C:3]([OH:7])([C:8]([F:11])([F:10])[F:9])[C:2]([F:13])([F:12])[F:1])=[CH:43][CH:42]=2)=[O:35])[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C(O)C(O)(C(F)(F)F)C(F)(F)F
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1ccc(NC(=O)C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 23 °C
Reaction time: 1.5 h

Procedure:
Tetrahydrofuran (35 ml,dry) was added to a mixture of 2,2-bis-trifluoromethyl 2-hydroxyacetic acid (1.08 g,5.1 mmol) and 1,1'-carbonyldiimidazole (0.83 g,5.1 mmol), while under a nitrogen atmosphere. There was an immediate evolution of carbon dioxide. The reaction was refluxed for 0.5 hrs and cooled to 23° C. The reaction was treated with 4-aminobenzophenone (1.01 g,5.1 mmol), stirred at 23° C. for 1.5 hrs, and then at reflux 18 hrs. The reaction was evaporated to a yellow oil-solid mixture. The mixture was dissolved in ethyl ether, treated with hydrogen chloride in ethyl ether, and filtered. The filtrate was evaporated to a yellow oil-solid mixture. Chromatography of this mixture on silica gel, eluting with 5% ethylether in methylenechloride provided the title compound as an off-white solid; mp 143°-146° C. 1H-NMR (250 MHz,d6 -DMSO): 7.67(m, 2H, ArH), 7.83(m, 5H, ArH),7.96(d, J=8.8, 2H, ArH), 9.82(s, 1H, OH), 10.82(s, 1H, NH). MS(CI,CH4): 392 (M+1).
Reaction SMILES: Cl.[C:2]1([CH:12]([NH:14][CH2:15][CH2:16][C@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)O)[CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].S(Cl)([Cl:33])=O>CC(OC)(C)C.O.C1(C)C=CC=CC=1>[ClH:33].[C:2]1([C@H:12]([NH:14][CH2:15]/[CH:16]=[CH:17]/[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=2)[CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(NCC[C@@H](O)c1cccc(C(F)(F)F)c1)c1cccc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: COC(C)(C)C
Product: C[C@@H](NC/C=C/c1cccc(C(F)(F)F)c1)c1cccc2ccccc12
Temperature: 60 °C

Procedure:
(R)-3-(1-(naphthalen-1-yl)ethylamino)-1-(3-(trifluoromethyl)phenyl)propan-1-ol hydrochloride (IX) (50.0 g, 121.990 mmol) is suspended in MTBE (200 ml) and water (80 ml) at room temperature. Sodium hydroxide (30% w/w aqueous solution) is added drop-wise (17.1 g, 128.250 mmol) in order to control the exothermic reaction and the mixture is stirred until the starting solid dissolves completely. The organic layer is then separated and washed repeatedly with water up to neutral pH. Thus MTBE is flushed with toluene and thionyl chloride (16.7 g, 140.372 mmol) is added slowly to the resulting toluenic solution, while maintaining 10°-20° C. The reaction mixture is heated up to 60° C. and maintained for 4 hrs, or until positive IPC (via HPLC). At reaction completion MTBE is charged (170 ml) and the mixture is heated up to 80°-85° C. and trace water is removed azeotropically. The mixture is cooled down to 60° C., MTBE is restored, then cooled down to 10° C. and aged two hours. 46.1 g of a 96.2:3.8 (HPLC % area) mixture of (R)-3-chloro-N-(1-(naphthalen-1-yl)ethyl)-3-(3-(trifluoromethyl)phenyl)propan-1-amine hydrochloride (X) and (R,E)-N-(1-(naphthalen-1-yl)ethyl)-3-(3-(trifluoromethyl)phenyl)prop-2-en-1-amine hydrochloride (XI) is obtained as a white powder after filtration, washing with a 1:1 vol/vol toluene/MTBE mixture (3×40 ml) end exsiccation at 55° C. under vacuum.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][CH:12]=C)[C:9](=[O:14])[S:8][C:5]2=[N:6][CH:7]=1.CO.[O:17]=[O+][O-].CSC>C(Cl)Cl.O=O>[F:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][CH:12]=[O:17])[C:9](=[O:14])[S:8][C:5]2=[N:6][CH:7]=1
Reactant: O=[O+][O-]
Reactant: C=CCn1c(=O)sc2ncc(F)cc21
Agent: O=O
Solvent: ClCCl
Solvent: CO
Solvent: CSC
Product: O=CCn1c(=O)sc2ncc(F)cc21
Temperature: 25 °C

Procedure:
6-Fluoro-1-(2-propen-1-yl)[1,3]thiazolo[5,4-b]pyridin-2(1H)-one (0.046 g, 0.22 mmole) was dissolved in DCM (8 ml) and MeOH (1 ml) and the solution cooled to −70° C. A gas mixture containing ozone in oxygen was bubbled through the solution for 20 mins to give a pale green solution. Argon was then bubbled through the solution for 5 mins then dimethyl sulphide (0.064 ml, 0.87 mmole) added. The mixture was allowed to warm to rt then evaporated to dryness to give a crude product which was used without further purification.
Reaction SMILES: CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH3:23][C:24]([CH3:53])([CH3:52])[C@H:25]([NH:37][C:38]([C@H:40]([CH2:49][CH:50]=[CH2:51])[C@H:41]([O:46][CH2:47][CH3:48])[C:42]([O:44][CH3:45])=[O:43])=[O:39])[C:26]([NH:28][C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30])=[O:27].[F:54][C:55]1[CH:56]=[C:57](Br)[CH:58]=[CH:59][C:60]=1[O:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:53][C:24]([CH3:23])([CH3:52])[C@H:25]([NH:37][C:38]([C@H:40]([CH2:49]/[CH:50]=[CH:51]/[C:57]1[CH:58]=[CH:59][C:60]([O:61][C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)=[C:55]([F:54])[CH:56]=1)[C@H:41]([O:46][CH2:47][CH3:48])[C:42]([O:44][CH3:45])=[O:43])=[O:39])[C:26]([NH:28][C@@H:29]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH3:30])=[O:27]
Reactant: Fc1cc(Br)ccc1Oc1ccccc1
Reactant: C=CC[C@@H](C(=O)N[C@H](C(=O)N[C@H](C)c1ccccc1)C(C)(C)C)[C@H](OCC)C(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCO[C@H](C(=O)OC)[C@@H](C/C=C/c1ccc(Oc2ccccc2)c(F)c1)C(=O)N[C@H](C(=O)N[C@H](C)c1ccccc1)C(C)(C)C
Yield: 60.4 %

Procedure:
A mixture of palladium acetate (12 mg, 0.05 mmol) and tri-(2-methylphenyl)phosphine (30 mg, 0.10 mmol) in anhydrous acetonitrile (1 mL) was sonicated at room temperature for 1 min until a creamy-coloured suspension formed. This suspension was added via Pasteur pipette to a stirred solution of methyl (2S,3R)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-2-ethoxy-hex-5-enoate (415 mg, 0.96 mmol), 3-fluoro-4-phenoxy-bromobenzene (Preparation 10)(400 mg, 1.50 mmol), and triethylamine (280 μL, 2.0 mmol) in anhydrous acetonitrile (1 mL) under nitrogen. The mixture was purged with nitrogen, then heated at reflux for 16 h. After being cooled, the mixture was poured into ethyl acetate (70 mL) and washed with 5% aqueous citric acid (20 mL), saturated aqueous sodium chloride (50 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with dichloromethane:ethyl acetate) to give mainly methyl (2S,3R,5E)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-2-ethoxy-6-(3-fluoro-4-phenoxyphenyl)hex-5-enoate as a pale yellow foam (359 mg, 69%). 1H nmr suggested that two alkene isomers, the (5Z) and (4E) were also present. The mixture of alkenes was taken onto the next step (see c, below).
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:10]=[C:11]2[C:34](=[CH:35][CH:36]=1)[C:15]1=[N:16][O:17][C:18]([C:19]3[C:23]([C:24]([F:27])([F:26])[F:25])=[C:22]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:21][N:20]=3)=[C:14]1[CH2:13][CH2:12]2)[CH2:3][CH2:4][C:5]([O:7]C)=[O:6].C1COCC1.CO.[OH-].[Na+]>O>[O:1]=[C:2]([C:9]1[CH:10]=[C:11]2[C:34](=[CH:35][CH:36]=1)[C:15]1=[N:16][O:17][C:18]([C:19]3[C:23]([C:24]([F:27])([F:26])[F:25])=[C:22]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[O:21][N:20]=3)=[C:14]1[CH2:13][CH2:12]2)[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: COC(=O)CCC(=O)c1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)CCC(=O)c1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 70 h
Yield: 93.2 %

Procedure:
A mixture of methyl 4-oxo-4-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butanoate (Preparation 109A, 22 mg, 0.044 mmol), THF (2 mL), MeOH (0.5 mL), water (0.5 mL) and 2N aqueous sodium hydroxide (0.2 mL, 0.400 mmol) was stirred at room temperature under nitrogen for 70 h. The reaction mixture was concentrated and the residue was acidified with 10% citric acid (1.5 mL) and extracted with dichloromethane (4×2 mL). The combined dichloromethane extracts were dried (sodium sulfate) and concentrated under reduced pressure to give 4-oxo-4-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butanoic acid (20 mg, 0.041 mmol, 94% yield) as a yellow solid.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Br[CH2:9][C:10]1[CH:23]=[CH:22][CH:21]=[CH:20][C:11]=1[O:12][CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CN(C)C=O>[NH:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH2:9][C:10]1[CH:23]=[CH:22][CH:21]=[CH:20][C:11]=1[O:12][CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(C)Oc1ccccc1CBr
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccccc1Cc1ncc[nH]1
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
To a suspension of 5.7 g of 50% sodium hydride in 200 ml of dry dimethylformamide was added slowly 8.0 g of imidazole at room temperature, and then the mixture was stirred for 30 minutes. A solution of 34.1 g of ethyl 2-(o-bromomethylphenoxy)propionate in 50 ml of dry dimethylformamide was added to the mixture at room temperature over a period of 1 hour, and then the reaction mixture was stirred at the same temperature for 1 hour. After removal of the solvent under vacuum, 150 ml of dichloromethane was added to the residual oil and the solution was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residual oil was chromatographed on silica gel using dichloromethane-ethanol (20:1 by volume) to give 15 g of ethyl 2-[o-(1-imidazolylmethyl)phenoxy]propionate as colorless needles. M.P.: 84°-85° C.
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[CH:15]=[C:14]2[C:21]#[N:22])=[O:5].[H-].[Na+].IC.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[CH:15]=[C:14]2[C:21]#[N:22])=[O:5]
Reactant: CON(C)C(=O)[C@@H]1CCC[C@H]1c1ccc2c(c1)c(C#N)cn2C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1cc(C#N)c2cc([C@@H]3CCC[C@H]3C=O)ccc21
Temperature: -45 °C
Reaction time: 0.25 h
Yield: 93.9 %

Procedure:
A solution of trans-2-(3-Cyano-1-methyl-1H-indol-5-yl)-cyclopentanecarboxylic acid methoxy-methyl-amide (0.080 g, 0.27 mMol) in anhydrous tetrahydrofuran (5 mL) was treated with sodium hydride (0.013 g, 1.68 mMol). The mixture was stirred for 15 minutes and then treated with iodomethane (0.077 g, 0.54 mMol). After stirring 1.5 hours, the mixture was quenched with water and evaporated. The residue was dissolved in ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give a hazy oil. This residue was dissolved in anhydrous tetrahydrofuran (5 mL), cooled to −45° C., and treated with lithium aluminum hydride (0.021 g, 0.54 mMol). The suspension was stirred for 2 hours and then quenched in the usual manner. The resulting mixture was filtered over sand and concentrated in vacuo. Silica gel flash column chromatography (50% hexanes, ethyl acetate) gave the product as a clear oil (0.064 g, 76%). LC-MS: 1.39 min (2 min gradient); 312.21 (MH)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.C([Li])CCC.CCCCCC.C(OCC)C.I[C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:25]=1[O:33][CH3:34]>C1COCC1.[Cl-].[Zn+2].[Cl-].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>[CH3:34][O:33][C:25]1[CH:26]=[CH:27][C:28]([N+:30]([O-:32])=[O:31])=[CH:29][C:24]=1[C:6]1[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=1
Reactant: COc1ccc([N+](=O)[O-])cc1I
Reactant: Cn1cccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 59.1 %

Procedure:
A solution of N-methylpyrazole (5.12 g, 62.4 mmol) in THF (100 mL) was cooled to −78° C. and 2.5 M n-butyllithium in hexane (27.5 mL, 68.8 mmol) was added. After stirring for 30 minutes at the same temperature, 0.5 M zinc chloride in THF (107 mL, 53.5 mmol) and 1 M zinc chloride in diethyl ether (15.3 mL, 15.2 mmol) were added. The mixture was allowed to warm to room temperature and 2-iodo-4-nitroanisole (17.4 g, 62.4 mmol) followed by tetrakis(triphenylphosphine)palladium (3.6 g, 3.1 mmol) were added. After stirring at 60° C. for 20 hours, the black solution was concentrated on a rotary evaporator, and extracted with ethyl acetate and brine. Combined organic layers were dried over magnesium sulfate, filtered, and partly concentrated until a solid started to precipitate. Hexane was added, precipitate was filtered off, and washed with a cold 3:1 mixture of hexane/ethyl acetate to give 5-(2-methoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole (8.6 g, 36.9 mmol, 59%) as a tan solid. LCMS m/z (%/o)=234 (M+H, 100). 1H NMR (400 MHz, CDCl3) δ: 8.34 (dd, J=2.8, 9.2 Hz, 1H), 8.19 (d, J=2.8 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.08 (d, J=9.2 Hz, 1H), 6.31 (d, J=1.6 Hz, 1H), 3.96 (s, 3H), 3.74 (s, 3H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl:5][C:6]1[C:11]([O:12][CH2:13][C@@H:14]2[CH2:16][O:15]2)=[CH:10][CH:9]=[CH:8][N:7]=1.O.[N-]=[N+]=[N-].[Na+]>O.O1CCOCC1>[N:1]([CH2:16][C@H:14]([OH:15])[CH2:13][O:12][C:11]1[C:6]([Cl:5])=[N:7][CH:8]=[CH:9][CH:10]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Clc1ncccc1OC[C@@H]1CO1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: [N-]=[N+]=NC[C@H](O)COc1cccnc1Cl
Temperature: 90 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
Dissolve sodium azide (22.84 g, 351.3 mmol) in water (195 mL). Separately, dissolve 2-chloro-3-[[(2S)-oxiran-2-yl]methoxy]pyridine (32.6 g, 175.6 mmol) in 1,4-dioxane (800 mL). Slowly add the water/sodium azide solution to the dioxane solution; heat to 90° C.; and stir for 1 hour. Cool the mixture and concentrate it under reduced pressure. Add water; extract with EtOAc (2×); combine the extracts; dry the combined extracts over Na2SO4; filter; and collect the filtrate. Remove the solvents under reduced pressure to provide the title compound (40.28 g, 92.8%) as a reddish white solid. MS (m/z): 229 (M+1).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=O)[CH2:4][C:5]#[N:6].Cl.[NH2:11][OH:12].C(O)C.Cl>O>[F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[C:5]([NH2:6])[O:12][N:11]=1
Reactant: NO
Reactant: N#CCC(=O)C(F)(F)F
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(C(F)(F)F)no1
Yield: 13.8 %

Procedure:
Trifluoroacetoacetonitrile (1.37 g, 0.010 mole), hydroxylamine hydrochloride (0.69 g, 0.010 mole), ethanol and water were heated under reflux for 3 hours. After the addition of hydrochloric acid (1.21 g, 0.012 mole), the mixture was further heated under reflux to give the title compound (0.21 g, 13.7%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[F:20][C:21]1([F:35])[C:25](=[CH2:26])[CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:22]1=[O:34].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[F:35][C:21]1([F:20])[C:25](=[CH2:26])[CH2:24][N:23]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:22]1([C:19]1[C:14]([F:13])=[N:15][CH:16]=[CH:17][CH:18]=1)[OH:34]
Reactant: Fc1ccccn1
Reactant: C=C1CN(C(=O)OC(C)(C)C)C(=O)C1(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=C1CN(C(=O)OC(C)(C)C)C(O)(c2cccnc2F)C1(F)F
Reaction time: 0.25 h
Yield: 66.9 %

Procedure:
Under a nitrogen atmosphere, to a solution of diisopropylamine (23.9 g) in anhydrous tetrahydrofuran (175 mL) was added dropwise a 1.61 mol/L hexane solution (136 mL) of n-butyllithium at −78° C., and the mixture was stirred at the same temperature for 15 min. To the obtained solution was added dropwise a solution of 2-fluoropyridine (21.9 g) in anhydrous tetrahydrofuran (25 mL) at the same temperature over 30 min, and the mixture was stirred for 2 hr. To the obtained suspension was added dropwise a solution of tert-butyl 3,3-difluoro-4-methylene-2-oxopyrrolidine-1-carboxylate (25.0 g) in anhydrous tetrahydrofuran (50 mL) at the same temperature, and the mixture was stirred for 3 hr. Saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=2:1). The obtained crystals were washed with diisopropyl ether to give the title compound as colorless crystals (yield 23.7 g, 67%).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:11]([CH3:13])[CH3:12])[CH2:6]2.[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Mg]Br>CCOCC.Cl[Ni](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>[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:11]([CH3:13])[CH3:12])[CH2:6]2
Reactant: CC(C)C1=Cc2c(Cl)cccc2C1
Reactant: Cc1ccccc1[Mg]Br
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: Cc1ccccc1-c1cccc2c1C=C(C(C)C)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chloro-2-isopropylindene (9.8 g, 51 mmol) and NiCl2(PPh3)2 (1.8 g, 2.8 mmol) are dissolved in 150 mL of Et2O. 2-Methylphenylmagnesium bromide (51 mmol) as an Et2O solution was added to the solution and the reaction was stirred overnight at room temperature. After overnight stirring, the reaction was slowly quenched with H2O to neutralize unreacted Grignard. The solution was subsequently treated with 100 mL of 10% HCl(aq) and neutralized with saturated sodium bicarbonate aqueous solution. The organic layer was dried with magnesium sulfate and the solvent was removed by rotary evaporation. The remaining residue was loaded onto a silica gel column and eluted with hexane. Yield was 6.6 g (52%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[NH:11][C:10](=[O:20])[C:9]=2[C:21]#[N:22])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[Br-].[Li+].CS(O[CH2:32][C:33]1[N:37]([CH3:38])[N:36]=[CH:35][N:34]=1)(=O)=O>COCCOC.CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[N:11]([CH2:32][C:33]3[N:37]([CH3:38])[N:36]=[CH:35][N:34]=3)[C:10](=[O:20])[C:9]=2[C:21]#[N:22])[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ncnc1COS(C)(=O)=O
Reactant: COc1ccc2[nH]c(=O)c(C#N)c(-c3cccc(F)c3)c2c1
Agent: [Br-]
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: COCCOC
Product: COc1ccc2c(c1)c(-c1cccc(F)c1)c(C#N)c(=O)n2Cc1ncnn1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-(3-fluorophenyl)-6-methoxy-2-oxo-1,2-dihydroquinoline-3-carbonitrile (46.0 mg, 0.156 mmol) in 2 mL of 1,2-dimethoxyethane and 0.5 mL of N,N-dimethylformamide at 0° C. was added sodium hydride (8.0 mg of 60% dispersion in mineral oil, 0.23 mmol). After 10 minutes, lithium bromide was added (27 mg, 0.31 mmol), and the reaction was stirred for one hour. A solution of (1-Methyl-1H-1,2,4-triazol-5-yl)methyl methanesulfonate (33 mg, 0.17 mmol) in 0.5 mL of N,N-dimethylformamide was added, and the reaction was allowed to warm to room temperature. After one hour, the reaction was quenched with water and partitioned between EtOAc and water, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was crystallized from EtOAc/hexane to provide the titled product. 1H NMR, difference nOe, and HMQC NMR spectral data for the product were consistent with the titled compound. HRMS (ES) exact mass calculated for C21H16FN5O2 (M+H+): 390.1361. Found 390.1409.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[C:13]([CH3:14])=[CH:12][N:11]=[C:10]([NH:15][C:16]2[S:17][C:18]([C:21]#[N:22])=[CH:19][N:20]=2)[CH:9]=1)(C)(C)C.C1C=CN=CC=1.F.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[OH:6][CH2:7][C:8]1[C:13]([CH3:14])=[CH:12][N:11]=[C:10]([NH:15][C:16]2[S:17][C:18]([C:21]#[N:22])=[CH:19][N:20]=2)[CH:9]=1
Reactant: Cc1cnc(Nc2ncc(C#N)s2)cc1C(C)(C)O[SiH2]C(C)(C)C
Agent: F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc(Nc2ncc(C#N)s2)cc1CO
Temperature: 25 °C

Procedure:
2-[4-(tert-Butyl-dimethyl-silanyloxymethyl)-5-methyl-pyridin-2-ylamino]-thiazole-5-carbonitrile (9-7, 0.650 g, 1.80 mmol) was dissolved in 5 mL THF. HF-pyridine (Aldrich), 0.5 mL, was added and the reaction was stirred at room temperature. After 4 hours the reaction was diluted with water and the pH was adjuted to 7 with K2CO3 (s). The resulting precipitate was filtered and washed with water to afford 9-8 as an orange solid which was used in the next step without further purification. 1H NMR (DMSO-d6) δ 12.15 (s, 1H), 8.24 (s, 1H), 8.10 (s, 1H), 7.26 (s, 1H), 5.48 (bs, 1H), 4.52 (s, 2H), 2.13 (s, 3H).