Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11]C(OC)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:16][C:17]1[CH:18]=[C:19]([CH2:23][CH2:24][NH2:25])[CH:20]=[CH:21][CH:22]=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[CH2:11][NH:25][CH2:24][CH2:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([CH3:16])[CH:18]=1
Reactant: Cc1cccc(CCN)c1
Reactant: COC(=O)Cc1ccc(OC)c(OC)c1
Solvent: CO
Product: COc1ccc(CNCCc2cccc(C)c2)cc1OC
Yield: 74 %

Procedure:
A solution of methyl 3,4-dimethoxyphenylacetate (18.5 g, 0.088 mole) and 2-(3-methylphenyl) ethylamine was heated at 180° for 1 h. The crude amide was dissolved in 50 ml of methanol and precipitated as fine needles with 150 ml of hexane to give the title compound (20.4 g, 74%). The mother liquor deposited more material which was recrystallized from toluene (charcoal) to give an additional 4.7 g (17%) of amide. The total yield of N-(3,4-dimethoxyphenylacetyl)-2-(3-methylphenyl) ethylamine, mp 101-102°, was 91%.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N+:8]=1[O-:13].[N+:14]([O-])([OH:16])=[O:15]>>[Cl:6][C:7]1[CH:12]=[C:11]([N+:14]([O-:16])=[O:15])[CH:10]=[CH:9][N+:8]=1[O-:13]
Reactant: [O-][n+]1ccccc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc[n+]([O-])c(Cl)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
With stirring, 1.5 liters of concentrated sulfuric acid was cooled to 0° C. and 1058 grams (6.06 moles) of 2-chloropyridine-N oxide was added portionwise during a 5 hour period. The reaction mixture temperature was maintained at 5°-10° C. and 590 ml of 90% nitric acid was added dropwise. Upon completion of addition the reaction mixture was heated to 80° C. and the source of heat was removed. The exothermic reaction caused the reaction mixture temperature to rise to 115° C. During a one hour period the reaction mixture temperature fell from 115° C. to 100° C., where it was maintained for four hours with an external heat source. The reaction mixture was cooled then poured into 12 liters of ice. The resultant solid was collected by filtration and washed three times by suspension in three one-liter portions of water. The solid was dried to yield 715 grams of 2-chloro-4-nitropyridine-N oxide. The mother liquor and washes were combined and extracted with four one-liter portions of chloroform. The combined extracts were dried with potassium carbonate and filtered. The filtrate was concentrated under under reduced pressure to a residual solid. The solid was triturated in 65 ml of 2-propanol to yield an additional 94.2 grams of 2-chloro-4-nitropyridine-N oxide.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([C:10]([N:12]2[CH2:17][CH2:16][C@H:15]([O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C@H:14]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:13]2)=O)[CH2:9][CH2:8]1.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH:39](/[C:44]([OH:46])=[O:45])=[CH:40]\[C:41]([OH:43])=[O:42]>O1CCCC1.CCOCC.C(O)C.CO.CC(C)=O>[C:44]([OH:46])(=[O:45])/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42].[CH:7]1([CH2:10][N:12]2[CH2:17][CH2:16][C@H:15]([O:18][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[C@H:14]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:13]2)[CH2:8][CH2:9]1
Reactant: O=C(C1CC1)N1CC[C@H](Oc2ccc(F)cc2)[C@H](c2ccccc2)C1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: CO
Solvent: CC(C)=O
Solvent: CCOCC
Product: Fc1ccc(O[C@H]2CCN(CC3CC3)C[C@H]2c2ccccc2)cc1

Procedure:
To a suspension of 0.66 g of lithium aluminum hydride in 50 ml of anhydrous tetrahydrofuran is added, dropwise at room temperature under nitrogen, a solution of 2.93 g of cis-1-cyclopropylcarbonyl-4-(4-fluorophenoxy)-3-phenylpiperidine in 50 ml of tetrahydrofuran. After the addition is complete the mixture is refluxed for 30 minutes, cooled, diluted with 50 ml of ether and cautiously treated with saturated sodium sulfate solution at 0°-10° C. until a flocculent white precipitate is obtained. The solid is filtered, washed with ether and the filtrate concentrated in vacuo. The residue is dissolved in ether (150 ml), washed with saturated sodium chloride solution (75 ml), dried overnight over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford a colorless gum. The gum is dissolved in ether (80 ml) and treated dropwise with a solution of 1.04 g of tumaric acid in a mixture of ethanol (15 ml) and ether (60 ml). After stirring for a few hours the colorless solid is filtered, washed with ether and dried to afford a salt. A second crop of solid is obtained from the filtrate. The solids are combined and recrystallized from 25 ml of boiling isopropanol to afford a crystalline solid. The solid and mother liquor are combined and the free base is regenerated. The nearly colorless gum is dissolved in 25% methanol/acetone solution and passed through a small silica gel column. The material thus obtained is dissolved in ether (50 ml) and treated dropwise with a solution of 0.91 g of fumaric acid in a mixture of ethanol (15 ml) and ether (60 ml). After stirring the mixture overnight, the solid is filtered, washed with ether and dried to yield product as a colorless solid, mp 167°-168.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:3]=1[CH2:4][NH:5][CH:6]1[CH2:8][CH2:7]1.[O:14]=[C:15]1[O:19][CH2:18][C@@H:17]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16]1>>[CH2:23]([O:22][C:21](=[O:30])[NH:20][C@@H:17]([CH2:16][C:15]([N:5]([CH:6]1[CH2:7][CH2:8]1)[CH2:4][C:3]1[CH:9]=[CH:10][CH:11]=[C:12]([Cl:13])[C:2]=1[Cl:1])=[O:14])[CH2:18][OH:19])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C1C[C@H](NC(=O)OCc2ccccc2)CO1
Reactant: Clc1cccc(CNC2CC2)c1Cl
Product: O=C(N[C@H](CO)CC(=O)N(Cc1cccc(Cl)c1Cl)C1CC1)OCc1ccccc1
Temperature: 100 °C
Yield: 52.1 %

Procedure:
Into a 100 mL round bottom flask fitted with a reflux condenser and a nitrogen inlet, N-(2,3-dichlorobenzyl)cyclopropanamine (30.3 g, 140.3 mmol) (Example 1A) and (S)-benzyl 5-oxotetrahydrofuran-3-ylcarbamate (22.0 g, 93.5 mmol) were added. The mixture was heated without solvent at 100° C. for 24 hours. Purification by column chromatography (5%->10% MeOH/dichloromethane) gave 22.0 g (52%) of 4A. ESI-MS:m/z 451.3 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:11](=O)([O-])[O-].[K+].[K+].C(Cl)Cl>[Cu]=O.CN(C)C=O>[CH2:11]1[O:10][C:9]2[C:2](=[C:3]([CH:6]=[CH:7][CH:8]=2)[CH:4]=[O:5])[O:1]1
Reactant: O=Cc1cccc(O)c1O
Reactant: O=C([O-])[O-]
Agent: O=[Cu]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=Cc1cccc2c1OCO2
Yield: 79.9 %

Procedure:
138.0 g (1.0 mol) of 2,3-dihydroxybenzaldehyde, 415.0 g (3.0 mol) of potassium carbonate, 4.7 g of copper oxide, 255.0 g (3.0 mol) of methylene chloride and 1500 ml of distilled dimethylformamide are boiled for 7 hours, while stirring intensively.. The reaction mixture is evaporated to dryness in vacuo and, after addition of 1000 ml of ice-water to the residue, the mixture is extracted four times by shaking with 300 ml of methyl tert-butyl ether each time. The combined ether extracts are washed with 5% strength sodium hydroxide solution and water and dried over sodium sulphate. The methyl tert-butyl ether is then stripped off (and can be reused) and the residue is distilled in vacuo at 92°-93° C./1 mbar. 120 g (80% of theory) of 2,3-methylenedioxybenzaldehyde having a melting point of 32°-33° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH3:17][C:18]([CH3:27])([CH3:26])[CH:19]([NH2:25])[C:20]1[S:21][CH:22]=[CH:23][N:24]=1>>[CH3:17][C:18]([CH3:27])([CH3:26])[CH:19]([NH:25][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])[C:20]1[S:21][CH:22]=[CH:23][N:24]=1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(Cl)cn1
Reactant: CC(C)(C)C(N)c1nccs1
Product: CC(C)(C)C(NC(=O)c1cc(OCC(F)(F)F)c(Cl)cn1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 24d, using 5-Chloro-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 24c) and 2,2-Dimethyl-1-thiazol-2-yl-propylamine (CAN 1247122-26-4) as starting materials and isolated (72 mg, 51%) as white solid; MS (ESI, m/z): 408.3 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[S:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][C:12]#[N:13].C1C(=O)N([Br:21])C(=O)C1>CN(C=O)C>[Br:21][C:7]1[S:6][C:5]([CH2:4][CH2:3][CH2:2][OH:1])=[C:9]([CH2:10][CH2:11][C:12]#[N:13])[CH:8]=1
Reactant: N#CCCc1ccsc1CCCO
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: N#CCCc1cc(Br)sc1CCCO
Temperature: 25 °C
Reaction time: 6 h
Yield: 32.4 %

Procedure:
To a solution of 3-[2-(3-hydroxy-propyl)-thiophen-3-yl]-propionitrile 83 (0.18 g, 0.9 mmol) in DMF (2 mL) was added NBS (0.18 g, 0.99 mmol). The mixture was then stirred at room temperature for 6 hours and then concentrated in vacuo. A solution of the residue in CH2Cl2 (80 mL) was washed with water, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel column chromatography (eluent: 50% EtOAc in hexane) afforded 84 (0.08 g). 1H NMR (400 MHz, d6-DMSO) δ: 7.06 (s, 1H), 4.53 (t, J=6.0 Hz, 1H), 3.41 (dd, J=6.0 and 11.5 Hz, 2H), 2.75 (m, 6H), 1.67 (m, 2H). MS (EI) m/z [(M+H+) (79Br)] 274, [(M+H+) (81Br)] 276, [(M−OH+) (79Br)] 256 and [(M−OH+) (881Br)] 258.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@H:5]([C:7]([OH:9])=[O:8])[NH2:6].[OH-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.S>O>[CH2:12]([O:8][C:7](=[O:9])[C@H:5]([CH2:4][CH2:3][CH2:2][OH:1])[NH2:6])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: N[C@@H](CCCO)C(=O)O
Agent: S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N[C@@H](CCCO)C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
Dissolve 5-hydroxynorvaline (13.3 g, 0.1 mol) in 1N sodium hydroxide (200 mL, 0.2 mol). Add a solution of CuSO4.5H2O (12.5 g, 0.05 mol) in water (50 mL). Stir the mixture until solution is complete. Treat with benzyl bromide (17.1 g, 0.1 mol) and stir at room temperature until reaction is complete. Suction filter, wash the residue with 1:3.5 methanol-water and dry at 60° C. to give the copper complex. Suspend the copper complex in water, treat with excess hydrogen sulfide, heat to boiling, then cool to room temperature. Mix with 1N sodium hydroxide and filter. Stir the filtrate with a slight excess of 1N hydrochloric acid and filter. Wash the residue with water and dry to give O-benzyl-5-hydroxynorvaline.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.C([O:23][C@@H:24]1[C@H:28]([O:29]C(=O)C2C=CC=CC=2)[C@@H:27]([CH2:38][O:39]C(=O)C2C=CC=CC=2)[O:26][C@H:25]1[N:48]1[CH:56]=[N:55][C:54]2[C:49]1=[N:50][C:51]([Cl:58])=[N:52][C:53]=2Cl)(=O)C1C=CC=CC=1.N>>[Cl:58][C:51]1[N:52]=[C:53]([NH:2][N:3]2[CH2:4][CH2:5][N:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:7][CH2:8]2)[C:54]2[N:55]=[CH:56][N:48]([C:49]=2[N:50]=1)[C@@H:25]1[O:26][C@H:27]([CH2:38][OH:39])[C@@H:28]([OH:29])[C@H:24]1[OH:23]
Reactant: NN1CCN(c2ccccc2)CC1
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: Cl
Agent: N
Product: OC[C@H]1O[C@@H](n2cnc3c(NN4CCN(c5ccccc5)CC4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Yield: 60 %

Procedure:
The title compound was prepared according to method A as described in Example 6 by reacting 1-amino-4-phenylpiperazine hydrochloride (also prepared using the method described by Overberger, C. G. and Herin, L. P., Journal of Organic Chemistry, 1962, 27, 417) (0.77 g, 3.0 mmol) with 9-(2',3',5'-tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.90 g, 3.0 mmol), followed by debenzoylation of the purified product using methanolic ammonia. This provided the title 2-chloro-N-(4-phenyl-1-piperazinyl)adenosine (0.81 g, 60%) (after column chromatography) as a foam, 1H NMR (DMSO-d6) δ3.53-3.60 (1H, m, H-5'a), 3.63-3.70 (1H, m, H-5'b), 3.95 (1H, q, H-4'), 4.13 (1H, q, H-3'), 4.51 (1H, q, H-2'), 5.07 (1H, t, 5'-OH), 5.22, 5.50 (2H, 2d, 2'- and 3'-OH), 5.85 (1H, d, H-1'), 6.77-7.26 (5H, 3m, Ar-H), 8.44 (1H, s, H-8), 9.50 (1H, s, N-H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)N.Cl.N([O-])=O.[Na+].[Cu](C#N)[C:19]#[N:20].[C-]#N.[Na+]>CC(C)=O.O.CCOC(C)=O>[Cl:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[C:19]#[N:20]
Reactant: N#C[Cu]C#N
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1N
Agent: Cl
Agent: O=N[O-]
Agent: [C-]#N
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(Cl)cc1C#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
To 5-chloro-2-methyl-4-nitroaniline (5 g, 26.8 mmol) in a mixture of acetone (17.5 mL) and water (19 mL) at 0° C. was added conc. HCl (5.6 mL). A solution of sodium nitrite (2.25 g, 32.6 mmol) in water (7.5 mL) was added dropwise and the mixture was allowed to stir at 0° C. for 30 min. The mixture was then added dropwise to a mixture of copper cyanide (3.75 g, 42 mmol) and sodium cyanide (5.5 g, 112 mmol) in water (25 mL) and EtOAc (12.5 mL). The mixture was allowed to stir at RT for 1 h and then water (50 mL) was added. The mixture was extracted with EtOAc (3×100 mL) and the combined organic fractions were washed with 2 M NaOH(aq) (50 mL) and brine (50 mL). The organic fraction was passed through a hydrophobic frit and the solvent was removed in vacuo. The residue was suspended in a 1:1 mixture of diethyl ether:iso-hexane. The solid formed was removed by filtration and washed with iso-hexane and dried. Further fractions were isolated from the filtrate and combined with the initial solid fraction to give 5-chloro-2-methyl-4-nitrobenzonitrile (3.22 g, 61%) as an off-white solid. LCMS (10 cm_ESCI_Formic_MeCN): [M+H]+=197 at 3.97 min. 1H NMR (400 MHz, CDCl3): δ 7.80 (s, 1H), 7.80 (s, 1H), 2.63 (s, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[CH:19]1[CH2:29][CH2:28][CH:27]([OH:30])[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH:20]1[F:31].C(N(CC)CC)C>ClCCl>[F:11][C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[CH:19]1[CH2:29][CH2:28][C:27](=[O:30])[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[CH:20]1[F:31]
Reactant: OC1CCC(c2cccc(F)c2F)C(F)c2cccnc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C1CCC(c2cccc(F)c2F)C(F)c2cccnc21
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
To a solution of oxalyl chloride (1.2 g, 9.5 mmol) in dichloromethane (15 mL) at −65° C. was added DMSO (0.85 mL, 12 mmol), and the mixture was stirred for 30 min. A solution of 5R,6S,9R and 5S,6R,9S)-6-(2,3-difluorophenyl)-5-fluoro-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol (0.35 g, 1.9 mmol) in dichloromethane (3 mL) was added dropwise and the resulting solution was stirred at −65° C. for 30 min. After triethylamine (2.3 mL, 17 mmol) was added, the reaction mixture was gradually warmed to 23° C. over a period of 4 h, and then partitioned between water and dichloromethane. The organic layer was washed with water (3×), brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 50% ethyl acetate in petroleum ether to give the title compound as a racemic mixture. MS: m/z=292.2 (M+1).
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[N:12]=[C:11]([CH:13]([OH:17])[CH2:14][CH2:15][CH3:16])[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[CH3:18].C([O-])(=O)C.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].C([O-])([O-])=O.[Na+].[Na+]>CO.C1COCC1>[NH2:3][C:4]1[N:12]=[C:11]([CH:13]([OH:17])[CH2:14][CH2:15][CH3:16])[N:10]=[C:9]2[C:5]=1[N:6]=[C:7]([Br:1])[N:8]2[CH3:18]
Reactant: CCCC(O)c1nc(N)c2ncn(C)c2n1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)(=O)[O-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCC(O)c1nc(N)c2nc(Br)n(C)c2n1
Reaction time: 0.25 h

Procedure:
Bromine (3.6 ml, 70.4 mmol) was added dropwise, at −14° C., to 1-(6-amino-9-methyl-9H-purin-2-yl)butan-1-ol (1700 mg, 7.69 mmol) dissolved in a mixture of MeOH (20 ml), THF (20 ml) and acetate buffer pH 4 (20 ml) (obtained by dissolving 4 g of sodium acetate in 100 ml of water and by adjusting pH 4 with glacial acetic acid). The reaction was stirred at this temperature for 15 minutes and then at RT for 10 minutes. Excess of bromine was eliminated with sodium metabisulphite and the reaction brought to pH 8 by addition of saturated solution of Na2CO3. The organic solvents were evaporated under reduced pressure, to give a solid that was filtered and used for the following reaction without further purification.
Reaction SMILES: Cl.[CH2:2]1[CH:10]2[N:5]([CH2:6][CH:7]=[C:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=4)[NH:13][CH:12]=3)[CH2:9]2)[CH2:4][CH2:3]1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:2]1[CH:10]2[N:5]([CH2:6][CH2:7][CH:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=4)[NH:13][CH:12]=3)[CH2:9]2)[CH2:4][CH2:3]1
Reactant: Fc1ccc2[nH]cc(C3=CCN4CCCC4C3)c2c1
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc2[nH]cc(C3CCN4CCCC4C3)c2c1
Reaction time: 0.08 h

Procedure:
The 3-(1,2,3,4,5,8-hexahydroindolizin-7-yl)-5-fluoro-1H-indole hydrochloride salt (450 mg, 1.54 mmol) was dissolved in trifluoroacetic acid (7.5 ml) forming an orange solution. The triethylsilane (197 mg, 1.7 mmol) was added and the reaction became colorless. TLC after 5 minutes showed no starting material present. The reaction was concentrated and the resulting oil poured into water and extracted with methylene chloride. The extract was washed with base, dried over sodium sulfate, and concentrated to give the product as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]#[N:16])=[CH:7][N:8]2[CH:11]2[CH2:14][CH2:13][CH2:12]2)=[CH:4][C:3]=1[F:17].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)[O:19]1.C([O-])(=O)C.[K+].OOS([O-])=O.[K+]>O1CCOCC1.O.C(OCC)(=O)C>[CH:11]1([N:8]2[C:9]3[C:5](=[CH:4][C:3]([F:17])=[C:2]([OH:19])[CH:10]=3)[C:6]([C:15]#[N:16])=[CH:7]2)[CH2:14][CH2:13][CH2:12]1
Reactant: N#Cc1cn(C2CCC2)c2cc(Br)c(F)cc12
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(=O)[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: N#Cc1cn(C2CCC2)c2cc(O)c(F)cc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
A mixture of 6-bromo-1-cyclobutyl-5-fluoro-1H-indole-3-carbonitrile (29.9 g, 102 mmol), bis(pinacolato)diboron (33.7 g, 133 mmol), PdCl2dppf-CH2Cl2 complex (4.16 g, 5.1 mmol) and potassium acetate (30 g, 306 mmol) in dioxane (300 mL) was stirred at 80° C. overnight. The mixture was then cooled to room temperature, treated with ethyl acetate (200 mL) and filtered through a silica-celite pad. The filtrate was concentrated, dissolved in acetone (300 mL) and cooled to 0° C. Into this solution was added a slurry of Oxone (125.5 g, 204 mmol) in water (300 mL). The mixture was stirred at room temperature for 15 min, diluted with ethyl acetate and separated. The aqueous layer was extracted with ethyl acetate. The organic extractions were combined and washed with sat. aq. NaHSO3, and brine, dried over Na2SO4 and concentrated. The residue was purified on silica gel to provide 1-cyclobutyl-5-fluoro-6-hydroxy-1H-indole-3-carbonitrile as a light grey solid (19.2 g, 82%).
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[NH2:5][C:6]1[CH:7]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:10][CH:11]=1.C([O-])([O-])=O.[K+].[K+].C>O.CS(C)=O>[F:15][C:12]([F:13])([F:14])[C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[NH:5][CH2:2][C:3]#[N:4]
Reactant: N#CCCl
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCNc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 73.7 %

Procedure:
Chloroacetonitrile (16 g), m-aminobenzotrifluoride (32.2 g), K2CO3 (39.2 g) and DMSO (40 ml) were heated with stirring in a round-bottomed three-necked flask at 70°-80° C. for 4.0 hours. Pouring the reaction mixture into approximately 1 liter of ice and water resulted in the formation of an oil. The mixture was extracted with CH2Cl2 and the extracts obtained treated with diatomaceous earth and activated charcoal, and then filtered. The filtrate was taken to dryness, which gave 29.5 g of m-trifluoromethylanilinoacetonitrile as a dark oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=C(N)[C:5]=1[Cl:11].[CH3:13][N:14]([CH:16]=O)[CH3:15].C(=O)([O-])[O-].[K+].[K+].CI>O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:16]([N:14]([CH3:13])[CH3:15])[C:5]=1[Cl:11]
Reactant: COC(=O)c1cccc(N)c1Cl
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COC(=O)c1cccc(N(C)C)c1Cl
Temperature: 60 °C
Yield: 75 %

Procedure:
2-Chloro-3-amino-benzoic acid methyl ester (1.20 g, 6.47 mmol) was placed in a round bottomed flask with DMF (5 mL), Potassium carbonate (1.97 g, 14.2 mmol) and methyl iodide (0.89 mL, 14.22 mmol) were added. A reflux condenser was fitted and the reaction was heated to 60° C. for 12 h. The reaction was cooled to rt, diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The organics were dried (MgSO4), concentrated, then purified by column chromatography using hexanes/ethyl acetate (1:1) to afford 2-chloro-3-dimethylamino-benzoic acid methyl ester (1.04 g, 75%)
Reaction SMILES: Br[C:2]1[CH:19]=[C:18]([Cl:20])[C:5]([CH2:6][N:7]2[CH2:11][CH2:10][C:9]3([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:8]2=[O:17])=[C:4]([Cl:21])[CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=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>[Cl:21][C:4]1[CH:3]=[C:2]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[CH:19]=[C:18]([Cl:20])[C:5]=1[CH2:6][N:7]1[CH2:11][CH2:10][C:9]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8]1=[O:17]
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C1N(Cc2c(Cl)cc(Br)cc2Cl)CCC12CCCCC2
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: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1N(Cc2c(Cl)cc(-c3ccc(F)cc3)cc2Cl)CCC12CCCCC2
Temperature: 90 °C
Yield: 102.7 %

Procedure:
Purged with N2 a mixture of 2-(4-bromo-2,6-dichloro-benzyl)-2-aza-spiro[4.5]decan-1-one (0.091 g, 0.23 mmol) and 4-fluorophenylboronic acid (0.097 g, 0.69 mmol) in toluene (6 mL) and 2M sodium carbonate (0.8 mL). Treat the reaction with Pd(PPh3)4 (0.013 g, 0.011 mmol) and heat to 90° C. for 2 hours under N2. Cool the reaction and dilute with ethyl acetate, and then wash with 1N HCl and water. Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford crude product. Purify with a 0 to 100% ethyl acetate in hexanes gradient on silica gel to afford 0.096 g (100%) of the titled product. Rf=0.25 (3/1 hexanes/ethyl acetate). MS (m/z): 406 (M+).