Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]=O)=[C:17]([F:23])[CH:16]=3)=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4].ClC(Cl)C.[C:28]([NH2:32])([CH3:31])([CH3:30])[CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]3[CH:22]=[CH:21][C:18]([CH2:19][NH:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:17]([F:23])[CH:16]=3)=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)N
Reactant: CCCCNc1ccc2ncc(-c3ccc(C=O)c(F)c3)n2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCCNc1ccc2ncc(-c3ccc(CNC(C)(C)C)c(F)c3)n2n1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
A mixture of 4-(6-butylamino-imidazo[1,2-b]pyridazin-3-yl)-2-fluoro-benzaldehyde (30 mg, 0.10 mmol) and dichloroethane (DCE, 1 mL) was treated with tert-butyl amine (0.011 mL, 0.11 mmol) and the resulting reaction mixture was maintained at RT for 20 min. The reaction was then treated with sodium triacetoxyborohydride (23 mg, 0.11 mmol) and the resulting mixture was maintained until LCMS indicated complete consumption of the aldehyde. The reaction was quenched with saturated aqueous sodium bicarbonate, the layers were separated, and the aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), then dried (MgSO4), filtered and concentrated to afford a residue that was purified by reverse phase HPLC to afford butyl-{3-[4-(tert-butylamino-methyl)-3-fluoro-phenyl]-imidazo[1,2-b]pyridazin-6-yl}-amine (32 mg, 86%) as a white solid: 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.21 (dd, J=12.3, 1.5 Hz, 1H), 7.93 (dd, J=8.0, 1.7 Hz, 1H), 7.82 (s, 1H), 7.58 (d, J=9.7 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 6.68 (d, J=9.7 Hz, 1H), 4.02 (s, 2H), 3.34 (t, J=7.2 Hz, 2H), 1.60-1.73 (m, 2H), 1.39-1.51 (m, 2H), 1.24-1.35 (m, 10H), 0.91-1.00 (m, 3H); LCMS (ESI) m/e 370.2 [(M+H)+, calcd for C21H29FN5 370.2].
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([Cl:15])=[N:12][O:13][CH3:14])(=[O:4])=[O:3].C1([O:22][C:23](=O)[NH:24][C:25]2[N:30]=[C:29]([O:31][CH3:32])[N:28]=[C:27]([CH3:33])[N:26]=2)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>>[CH3:14][O:13][N:12]=[C:11]([Cl:15])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[S:2]([NH:1][C:23]([NH:24][C:25]1[N:30]=[C:29]([O:31][CH3:32])[N:28]=[C:27]([CH3:33])[N:26]=1)=[O:22])(=[O:3])=[O:4]
Reactant: COc1nc(C)nc(NC(=O)Oc2ccccc2)n1
Reactant: CON=C(Cl)c1ccccc1S(N)(=O)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CON=C(Cl)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)nc(OC)n1
Yield: 67.4 %

Procedure:
By the procedure of Example 5, 0.4 g of the product of Example 4 was reacted with 0.46 g of phenyl(4-methoxy-6-methyl-1,3,5-triazin-2-yl)carbamate and 0.25 g of DBU. The resulting suspension was acidified, without prior filtration, with concentrated hydrochloric acid and filtered. The residue was washed with excess water and suction-dried to yield 0.45 g of the subject compound, m.p. 182° to 184° C.
Reaction SMILES: [CH2:1]([O:3][C:4](Cl)=[O:5])[CH3:2].[C:7]1([N:13]2[CH2:17][CH2:16][C:15]([NH:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[N:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>O1CCCC1>[C:7]1([N:13]2[CH2:17][CH2:16][C:15]([N:18]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[C:4](=[O:5])[O:3][CH2:1][CH3:2])=[N:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)Cl
Reactant: c1ccc(N2CCC(Nc3cccnc3)=N2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)N(C1=NN(c2ccccc2)CC1)c1cccnc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Ethylchloroformate (0.75 ml) was added dropwise to a solution of 4,5-dihydro-1-phenyl-N-(3-pyridinyl)-1H-pyrazol-3-amine (1.66 g) and triethylamine (2.85 ml) in tetrahydrofuran (150 ml) at -45° under N2. The solution was allowed to warm to room temperature and stirred for 24 hours. The solution was filtered, evaporated to dryness, and the residue chromatographed on silica gel eluting with ethyl acetate in dichloromethane to give an oil which crystallised on triturating with ether. The solid was recrystallised from ether and petrol to give the title compound (0.66 g) mp 110°-12° (dec).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[C:4](F)[CH:3]=1.[C-:15]#[N:16].[Na+]>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[C:4]([CH:3]=1)[C:15]#[N:16]
Reactant: [C-]#N
Reactant: Fc1cc(Br)ccc1-c1ccccn1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1cc(Br)ccc1-c1ccccn1
Temperature: 180 °C
Yield: 79.2 %

Procedure:
2-(4-Bromo-2-fluorophenyl)pyridine (1.0 g, 3.9 mmol) and sodium cyanide (214 mg, 4.3 mmol) were combined in DMSO (20 mL) under argon. The reaction mixture was heated at 180° C. overnight. TLC analysis showed no starting material present. The reaction mixture was diluted with EtOAc (100 mL), and washed with H2O (3×100 mL), brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford a dark oil. The crude product was purified by column chromatography eluting with 1:9 EtOAc:Hexane. to afford 5-bromo-2-pyridin-2-ylbenzonitrile (800 mg, 80%). MS 262.1 (M++H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:15])[CH:7]([S:12]([CH3:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:16](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(=O)CC>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:15])[C:7]([S:12]([CH3:14])=[O:13])=[CH:8][N:9]2[CH3:16])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CS(=O)C1C=Nc2cc(F)ccc2C1=O
Agent: [K+]
Solvent: CCC(C)=O
Solvent: COS(=O)(=O)OC
Product: Cn1cc(S(C)=O)c(=O)c2ccc(F)cc21

Procedure:
7-Fluoro-3-methylsulphinyl-4-quinolone (5.0 g.) was dissolved in hot butanone (250 ml.) containing anhydrous potassium carbonate (3.06 g.). The resulting suspension was stirred and treated dropwise with dimethyl sulphate (2.09 ml.). The mixture was stirred and boiled under reflux for 1 hour and filtered while hot. The filtrate was allowed to cool, giving a crystalline product. The product was collected and dried to give 7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone, m.p. 226°-8°.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10]([C:12]1[CH:13]=[C:14]([CH:18]2[C:27]([CH3:29])([CH3:28])[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:30]([O:32]C)=[O:31])[CH:24]=3)[NH:19]2)[CH:15]=[CH:16][CH:17]=1)=[O:11])[CH3:2].[OH-].[Na+]>CO>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10]([C:12]1[CH:13]=[C:14]([CH:18]2[C:27]([CH3:29])([CH3:28])[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:30]([OH:32])=[O:31])[CH:24]=3)[NH:19]2)[CH:15]=[CH:16][CH:17]=1)=[O:11])[CH3:2]
Reactant: CCN1CCCC1CNC(=O)c1cccc(C2Nc3ccc(C(=O)OC)cc3CC2(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCN1CCCC1CNC(=O)c1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1

Procedure:
A mixture of methyl 2-(3-((1-ethylpyrrolidin-2-yl)methylcarbamoyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (44 mg, 0.1 mmol) in methanol (1.6 mL) and 1 M sodium hydroxide aqueous solution (1.27 mL, 1.27 mmol) was heated to reflux for 30 min, LC-MS showed the reaction was complete and only the desired product formed. The solvent was concentrate in vacuo and the residue was dissolved in water and acidified with 1 M hydrochloric acid solution. The off-white precipitated solid was collected by filtration to afford 25 mg of 2-(3-((1-ethylpyrrolidin-2-yl)methylcarbamoyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid was a white solid. Yield: 58.7%. MS (ESI+APCI) M+1=436.3.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][C:5](Br)=[CH:4][N:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>CN(C)C=O>[NH2:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][C:5]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:4][N:3]=1
Reactant: Nc1ncc(Br)nc1N1CCOCC1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: Nc1ncc(N2CCOCC2)nc1N1CCOCC1

Procedure:
A mixture of the above-obtained 2-amino-3-morpholino-5-bromopyrazine (0.04 mmole), morpholine (0.07 mmole) and 50 ml. of dimethylformamide are heated at 100°-140° C. for about 3 to 5 days in an atmosphere of nitrogen. The reaction mixture is cooled and evaporated to dryness at a water bath temperature of 55° C. A chloroform solution of the residue is extracted twice with 0.1 M sodium hydroxide, dried over magnesium sulfate and evaporated to leave 2-amino-3,5-dimorpholinopyrazine.
Reaction SMILES: [CH2:1]([N:8]([CH3:16])[C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][OH:33])=[CH:28][CH:27]=1>CN(C=O)C>[CH2:1]([N:8]([CH3:16])[C:9]1[CH:14]=[CH:13][N:12]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][OH:33])=[CH:28][CH:27]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccc(CCI)cc1
Reactant: CN(Cc1ccccc1)c1cc[nH]c(=O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)c1ccn(CCc2ccc(CO)cc2)c(=O)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 500 mg (2.33 mmol) 4-(benzyl-methyl-amino)-1H-pyridin-2-one (preparation 14b) and 1.52 g (4.67 mmol) cesium carbonate in 2.3 mL of DMF is stirred 15 min at RT and then 1.22 g (4.67 mmol) [4-(2-iodo-ethyl)-phenyl]-methanol (preparation 1b) is added. The mixture is stirred overnight at RT and the solvent is evaporated. The residue is dissolved in MeOH and is purified by reverse HPLC (Waters symmetry, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][C:3]=1[NH2:4].[C:15](Cl)(Cl)=[S:16]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][C:3]=1[N:4]=[C:15]=[S:16]
Reactant: S=C(Cl)Cl
Reactant: CCOC(=O)c1cc(N)c(Cl)cc1Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(N=C=S)c(Cl)cc1Cl
Temperature: 10 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
23.4 g (0.1 mol) of 2,4-dichloro-5-ethoxycarbonylaniline were dissolved in 80 ml of chloroform. The resulting solution was cooled to 10° C. or lower and 14.9 g (0.13 mol) of thiophosgene were added dropwise thereto. The mixture was stirred at room temperature for two hours, and then refluxed for three hours. The reaction mixture was concentrated to give 27 g (yield 97.7%) of the desired product as pale brown crystals with a melting point of 45°-46° C.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:32])[CH:10]([N:14]1[C:18]2[CH:19]=[C:20]([F:24])[C:21]([F:23])=[CH:22][C:17]=2[N:16]=[C:15]1[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[CH:11]1[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C(OC(=O)C)(=O)C.[N:44]([O-])=[O:45].[Na+]>>[CH2:1]([N:8]([N:44]=[O:45])[C:9](=[O:32])[CH:10]([N:14]1[C:18]2[CH:19]=[C:20]([F:24])[C:21]([F:23])=[CH:22][C:17]=2[N:16]=[C:15]1[C:25]1[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=1)[CH:11]1[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCc1ccccc1)C(C1CC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=NN(Cc1ccccc1)C(=O)C(C1CC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a ice-cold solution of 13.15 g (29.1 mmol) N-benzyl-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclopropyl-acetamide in 95 ml (1.659 mol) acetic acid and 199.7 ml (3.52 Mol) acetic anhydride were added in portions over 60 min. 10.04 g (145 mmol) sodium nitrite. The reaction mixture was stirred for 1 h at 0° C., then at room temperature overnight. The mixture was evaporated and the residue was taken up in saturated aqueous sodium bicarbonate solution and ethyl acetate and the pH was adjusted to 7 with solid sodium bicarbonate. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified by silica gel column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 50:50) to give the desired compound as a light yellow solid (53%). MS (Turbo Spray): m/z=481.1 [M+H].
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:12]([O:11][C:9]([N:16]1[CH2:21][CH2:20][CH:19]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[I:1])[CH2:18][CH2:17]1)=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: Nc1ccccc1I
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2I)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.6 %

Procedure:
A mixture of 2-iodoaniline (1.100 g, 5.00 mmol), 1-Boc-4-piperidone (1.500 g, 7.50 mmol)), acetic acid (1.0 mL, 17.5 mmol) and sodium triacetoxy borohydride (2.420 g, 11 mmol) in 1,2-dichloroethane (30 mL) was stirred at ambient temperature for 2 days. The reaction was quenched with water, and the organic phase was separated. The aqueous phase was extracted with dichloromethane. The combined organic phase was washed with water, brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography to afford 4-(2-Iodophenylamino)piperidine-1-carboxylic acid tert-butyl ester (1.560 g, 50%). 1H NMR (300 MHz, CDCl3) δ 7.63 (dd, J=1.5 and 7.8 Hz, 1H), 7.20-7.14 (m, 1H), 6.56 (d, J=8.4 Hz, 1H), 6.41 (dt, J=1.5 and 7.8 Hz, 1H), 3.99-3.95 (m, 2H), 3.48-3.43 (m, 1H), 3.03-2.94 (m, 2H), 2.02-1.97 (m, 2H), 1.52-1.36 (m, 11H).
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[O:24][CH:25]=[C:26]([C:28](=[O:48])[NH:29][C@@H:30]3[CH2:34][CH2:33][N:32]([C:35]([O:37][CH2:38][C:39]4[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=4)=[O:36])[CH2:31]3)[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:18][CH:19]1[CH2:20][N:21]([C:23]2[O:24][CH:25]=[C:26]([C:28](=[O:48])[NH:29][C@@H:30]3[CH2:34][CH2:33][N:32]([C:35]([O:37][CH2:38][C:39]4[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=4)=[O:36])[CH2:31]3)[N:27]=2)[CH2:22]1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(C(=O)N[C@@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)co2)C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(N[C@@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1coc(N2CC(O)C2)n1
Reaction time: 8 h
Yield: 97.1 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-[(3R)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-oxazol-2-yl}azetidine (810 mg, 1.21 mmol) (obtained as described in Reference Example 77(1)) in anhydrous tetrahydrofuran (40 ml) was added a solution of acetic acid (83 μl, 1.45 mmol) and 1.0 M tetra-n-butylammonium fluoride in tetrahydrofuran (1.45 ml, 1.45 mmol) in an ice bath and the mixture was stirred in an ice bath overnight. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate→ethyl acetate:methanol (95:5) as the eluant to afford 3-hydroxy-1-{4-[(3R)-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-ylcarbamoyl]-1,3-oxazol-2-yl}azetidine (507 mg, yield 97%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([F:13])[C:3]=1[CH:14]([O:16][Si](C(C)(C)C)(C)C)[CH3:15].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([F:13])[C:3]=1[CH:14]([OH:16])[CH3:15]
Reactant: CCOC(=O)c1ccc(Cl)c(C(C)O[Si](C)(C)C(C)(C)C)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)c1ccc(Cl)c(C(C)O)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.3 %

Procedure:
Ethyl 4-chloro-2-fluoro-3-(1-t-butyldimethylsilyloxyethyl)benzoate (25 g) and tetrabutylammonium fluoride (210 ml of 1.0M solution in THF) were dissolved in THF and stirred for 4 hours at room temperature. The mixture was diluted with ether and washed with water. The organic extract was dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness yielding ethyl 4-chloro-2-fluoro-3-(1-hydroxyethyl)benzoate (16.8 g) as a clear oil, NMR (CDCl3) 1.3(t,3H), 1.5(d,3H), 2.5(bs,1H), 4.3(q,2H), 5.3(q,1H), 7.1(d,1H), 7.7(t, 1H).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:31]1[CH2:30][CH2:29][CH:28]([NH:27][C:25]([C:21]2[C:17]3=[N:18][CH:19]=[CH:20][C:15]([C:8]4[CH:9]=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)=[C:16]3[NH:23][C:22]=2[CH3:24])=[O:26])[CH2:33][CH2:32]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: COc1ccc(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)c1
Agent: Cl
Product: COc1ccc(-c2ccnc3c(C(=O)NC4CCN(C(C)=O)CC4)c(C)[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f11) and commercially acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].[F:5][C:6]1[C:7]([NH:20][C:21]2[CH:26]=[CH:25][C:24](I)=[CH:23][C:22]=2[F:28])=[C:8]([CH:16]=[CH:17][C:18]=1[F:19])[C:9]([NH:11][O:12][CH2:13][CH2:14][OH:15])=[O:10]>>[NH2:4][CH2:1][C:2]#[C:3][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:7]2[C:6]([F:5])=[C:18]([F:19])[CH:17]=[CH:16][C:8]=2[C:9]([NH:11][O:12][CH2:13][CH2:14][OH:15])=[O:10])=[C:22]([F:28])[CH:23]=1
Reactant: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: C#CCN
Product: NCC#Cc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Yield: 100 %

Procedure:
The title compound was prepared by Sonogashira reaction of propargyl amine and 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide by the general procedure of Example 1, Step A. The orange oil resulting from workup was purified by chromatography on silica gel (10% MeOH/CH2Cl2 as eluant), to give 2-[4-(3-amino-1-propynyl)-2-fluoroanilino]-3,4-difluoro-N-(2-hydroxyethoxy)benzamide as a pale orange solid (100%); m.p. (Et2O) 72-76° C. 1H NMR [400 MHz, (CD3)2SO] δ 9.14 (v br s, 1 H), 7.49-7.44 (m, 1 H), 7.21 (dd, J=12.3, 1.7 Hz, 1 H), 7.24-7.14 (m, 1 H), 7.08 (dd, J=8.4, 1.6 Hz, 1 H), 6.77 (ddd, J=8.8, 8.8, 5.1 Hz, 1 H), 5.45 (br s, 2 H), 3.83 (t, J=4.8 Hz, 2 H), 3.55 (t, J=5.0 Hz, 2 H), 3.41-3.32 (m, 2H, obscured by H2O). Not all exchangeable protons observed. CRL10671. Await HRMS. Anal. calcd. for C28H16F3N3O3: C, 57.0; H, 4.3; N, 1.1. Await Found. HRMS (EI) calcd for C18H16F3N3O3 379.1144 (M+), found 379.1140.
Reaction SMILES: [CH:1]([C:3]1[C:12]([CH3:13])=[CH:11][C:6]([O:7][CH2:8][C:9]#[N:10])=[CH:5][C:4]=1[CH3:14])=[O:2].[N-:15]=[N+:16]=[N-:17].[Na+].[Cl-].[NH4+].O>CN(C=O)C>[CH3:14][C:4]1[CH:5]=[C:6]([O:7][CH2:8][C:9]2[NH:17][N:16]=[N:15][N:10]=2)[CH:11]=[C:12]([CH3:13])[C:3]=1[CH:1]=[O:2]
Reactant: Cc1cc(OCC#N)cc(C)c1C=O
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2nnn[nH]2)cc(C)c1C=O
Temperature: 100 °C

Procedure:
To a solution of (4-formyl-3,5-dimethyl-phenoxy)-acetonitrile (120 mg) in DMF (3 mL) were added sodium azide (62 mg) and ammonium chloride (51 mg). The reaction mixture was heated at 100° C. for 1 h. The mixture was then diluted by water and the whole was loaded onto a cartridge that contained C18 silica gel (reverse phase). Wash-to-waste (10 mL water) was followed by elute-to-collect (10 mL, acetonitrile) and, after evaporation of volatiles, 2,6-dimethyl-4-(1H-tetrazol-5-yl-methoxy)-benzaldehyde was obtained.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:16]3[C:15]4[CH2:17][NH:18][CH2:19][CH2:20][C:14]=4[NH:13][C:12]=3[N:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].C(N(CC)CC)C>ClCCCl>[C:1]1([NH:7][C:8]2[C:16]3[C:15]4[CH2:17][N:18]([C:21](=[O:23])[CH3:22])[CH2:19][CH2:20][C:14]=4[NH:13][C:12]=3[N:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(Nc2ccnc3[nH]c4c(c23)CNCC4)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2[nH]c3nccc(Nc4ccccc4)c3c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.9 %

Procedure:
Phenyl-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (40 mg, 0.15 mmol), acetic anhydride (18 mg, 0.18 mmol), and triethylamine (0.06 mL, 0.45 mmol) were dissolved in 1,2-dichloroethane (2.0 mL), and stirred overnight at room temperature. The reaction mixture was added directly to a Biotage column. The crude product was purified via Biotage eluting with CH2Cl2/MeOH (9/1, v/v) to provide 8 (5 mg, 11% yield) as a tan solid. LC-MS (M+H=307, obsd.=307).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:12]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-]>ClCCl>[CH2:20]([N:19]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH2:20]([N:19]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(CN(Cc2ccccc2)C2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1,4-dioxaspiro[4.5]decan-8-one (25 g, 0.16 mol) in 1,2-dichloroetrane (396 mL) was added dibenzylamine (32.3 mL, 0.16 mol) under nitrogen atmosphere and the resulting solution was stirred for 2 hours at room temperature. Then sodium triacetoxyborohydride (55.4 g, 0.25 mol) was added portionwise and the reaction mixture was stirred at room temperature overnight. A mixture of bicarbonate and dichloromethane (1:1) was added to the reaction mixture and it was stirred for half an hour, then the organic phase was extracted and washed with bicarbonate and brine, dried, filtered and the organic solvent was evaporated under reduced pressure. The resulting oil was precipitated with hexane obtaining a white solid as a title compound (80%), which was used in the next step without further manipulation.