Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][NH:6][C:7](=[O:11])[CH2:8][CH2:9][CH3:10])C.Cl.CCOCC.O>C1COCC1>[O:3]=[CH:4][CH2:5][NH:6][C:7](=[O:11])[CH2:8][CH2:9][CH3:10]
Reactant: CCCC(=O)NCC(OCC)OCC
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCCC(=O)NCC=O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 55 %

Procedure:
A solution of N-(2,2-diethoxyethyl)butyramide (2.0 g, 0.0098 mol.)) in 10 mL of THF at 0° C. was added HCl(2N) in ether (4.9 mL, 1.0 eq) and water (0.34 mL, 2 eq). The solution was then stirred for 2 to 3 h at 0° C. the solvent was evaporated at room temperature and solid NaHCO3 was added, filtration and concentration to give after silica gel chromatography N-(2-oxoethyl)butyramide as a colorless oil (0.55 g g, 55% yield). 1HNMR (400 MHz, CDCl3): δ 0.89 (t, J=7.2 Hz, 3H); 1.58-1.63 (m, 2H); 2.12 (t, J=7.2 Hz, 2H); 4.17 (d, J=5.2 Hz, 2H); 6.31 (sbroad, 1H); 9.63 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([F:18])([F:17])[F:16])[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:24][CH2:25][CH2:26][F:27])[N:3]=1.[NH3:28]>C1COCC1>[F:27][CH2:26][CH2:25][O:24][C:4]1[N:3]=[C:2]([NH2:28])[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:5]=1[C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([F:18])([F:17])[F:16])[CH2:11][CH2:10]1)=[O:7]
Reactant: O=C(N[C@H]1CC[C@H](C(F)(F)F)CC1)c1cc([N+](=O)[O-])c(Cl)nc1OCCF
Reactant: N
Solvent: C1CCOC1
Product: Nc1nc(OCCF)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]

Procedure:
The sub-title compound is prepared from 6-chloro-2-(2-fluoro-ethoxy)-5-nitro-N-(trans-4-trifluoromethyl-cyclohexyl)-nicotinamide (1.30 g, 2.98 mmol) and conc. ammonia (0.90 mL, 14.92 mmol) in THF (30 mL) in analogy with method described in example 3c.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[OH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[OH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:23][CH:22]=1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Reactant: OCc1ccc(B(O)O)cc1
Product: N#Cc1cc(-c2ccc(CO)cc2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, light yellow solid (75 mg, 91%), MS (ISP) m/z=332.5 [(M+H)+], mp 256.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 4-hydroxymethyl-phenylboronic acid (49.4 mg, 0.325 mmol).
Reaction SMILES: [C:1]1([N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)[CH:22]=[O:23].P(Cl)(Cl)(Cl)=O>O>[C:14]1([N:7]([C:1]2[CH:2]=[CH:3][C:4]([CH:22]=[O:23])=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 95 °C

Procedure:
101.4 g of triphenylamine and 35.5 mL of dimethyl formamide (DMF) were placed in a three-neck flask, and while stirring with cooling in ice water, 84.4 mL of phosphorus oxychloride was dropped into the flask. The temperature was raised to 95° C., and the mixture was reacted for 5 hours. The reaction solution was poured into 4 L of warm water and stirred for 1 hour. The precipitate was then collected and washed in a 1:1 mixture solution of ethanol/water, and 4-(N,N-diphenylamino) benzaldehyde was obtained. The yield was 91.5 g (yield rate of 81.0%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][SH:6].[OH-].[Na+].Cl[C:10](Cl)=[CH:11][N+:12]([O-:14])=[O:13].Cl>CO.C(Cl)Cl.O>[CH3:1][N:2]1[CH2:3][CH2:4][CH2:5][S:6][C:10]1=[CH:11][N+:12]([O-:14])=[O:13]
Reactant: CNCCCS
Reactant: O=[N+]([O-])C=C(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CN1CCCSC1=C[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
Into 40 ml of methanol were added 5.0 g of 1-methylamino-3-propanethiol and 0.8 g of caustic soda, followed by stirring, to be completely dissolved therein. Then, the mixture was cooled to 0° C. While stirring the solution, a solution of 1.6 g of caustic soda dissolved in 25 ml of methanol and a solution of 2.8 g of 2,2-dichloronitroethylene diluted in 20 ml of methanol were added at the same time dropwise slowly over 50 minutes, and the reaction was carried out for one hour at about 8° C. After the reaction, the reaction mixture was neutralized to pH 7 with 3 N aqueous hydrochloric acid, and then with addition of 60 ml of water, extraction with 50 ml of methylene chloride was repeated four times. The extracts were concentrated to give 3.38 g of tetrahydro-3-methyl-2-(nitromethylene)-1,3-thiazine (yield: 97%).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.C[Si](C=[N+]=[N-])(C)C.[NH2:20][C:21]1[C:26]([CH:27]=O)=[CH:25][CH:24]=[C:23]([CH3:29])[N:22]=1.C(O)(=O)C>O.O1CCCC1>[C:27]([C:26]1[C:21]([NH2:20])=[N:22][C:23]([CH3:29])=[CH:24][CH:25]=1)#[CH:1]
Reactant: CC(C)NC(C)C
Reactant: Cc1ccc(C=O)c(N)n1
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc(C)nc1N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76.3 %

Procedure:
To a tetrahydrofuran (5 mL) solution of diisopropylamine (439 μL, 3.13 mmol) was added n-butyl lithium (1.81 mL, 1.6 M hexane solution, 2.89 mmol) under nitrogen atmosphere at −78° C., which was stirred for 15 minutes at 0° C. Then, trimethylsilyldiazomethane (1.81 mL, 2 M tetrahydrofuran solution, 3.62 mmol) was added to the reaction mixture at −78° C., which was stirred for 30 minutes at −78° C. To the reaction mixture was added a tetrahydrofuran (2 mL) solution of 2-amino-6-methyl-pyridine-3-carbaldehyde (328 mg, 2.41 mmol) described in Manufacturing Example 170-1-4 at −78° C., which was stirred for 25 minutes while the temperature was slowly raised to −30° C. Acetic acid (414 mL, 7.23 mmol) was added to the reaction mixture at −78° C., and the temperature was slowly raised, after which water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (243 mg, 76%).
Reaction SMILES: [NH:1]1[C@@H:10]2[C@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[NH:4][CH2:3][C:2]1=[O:11].[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:15]=1[CH:16]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>CC(O)=O.C(Cl)Cl>[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:15]=1[CH2:16][N:4]1[C@@H:5]2[C@H:10]([CH2:9][CH2:8][CH2:7][CH2:6]2)[NH:1][C:2](=[O:11])[CH2:3]1
Reactant: O=C1CN[C@H]2CCCC[C@@H]2N1
Reactant: COc1ccc(C=O)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(CN2CC(=O)N[C@H]3CCCC[C@@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 6.3 %

Procedure:
A mixture of (4aS,8aS)-octahydroquinoxalin-2(1H)-one (8.82 g, 57.19 mmol), 2,4-dimethoxybenzaldehyde (9.50 g, 57.19 mmol), and sodium triacetoxyborohydride (36.31 g, 171.57 mmol) in 1% HOAc in CH2Cl2 (250 mL) was stirred at room temperature for 16 h. The mixture was neutralized with saturated aqueous NaHCO3 solution (200 mL). The organic layer was separated and washed with H2O (100 mL), brine (100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0% to 100% 90:9:1 CH2Cl2/CH3OH/NH4OH in CH2Cl2) afforded (4aS,8aS)-4-(2,4-dimethoxybenzyl)octahydroquinoxalin-2(1H)-one (1.10 g, 11.1% over two steps). 1H NMR and MS consistent.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[C:12](OCC)(OCC)(OCC)[CH3:13]>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[O:7][C:12]([CH3:13])=[N:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccc(Br)cc1
Reactant: CCOC(C)(OCC)OCC
Product: Cc1nnc(-c2ccc(Br)cc2)o1

Procedure:
The title compound was prepared from 4-bromobenzoic hydrazide and triethyl orthoacetate following a similar procedure to that of Description 35, to afford fine white crystals (77%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7](Br)[CH:6]=1.C[C:14]([N:16](C)C)=O>CCOC(C)=O.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:14]#[N:16])[CH:6]=1
Reactant: COC(=O)Cc1cccc(Br)c1
Reactant: CC(=O)N(C)C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cccc(C#N)c1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of (3-bromophenyl)-acetic acid methyl ester 46 (1.20 g, 5.28 mmol) in dry dimethyl-acetamide (5 mL) is added under argon zinc cyanide (0.78 g, 6.64 mmol) and tetrakis(triphenylphosphine) palladium (0.63 g, 0.55 mmol). The mixture is stirred for 24 hours at 80° C. After cooling to room temperature, the mixture is diluted with EtOAc (15 mL) and water (20 mL). The resulting precipitate is removed by vacuum filtration. The organic layer of the filtrate is separated and washed with H2O, then dried over MgSO4, filtered and concentrated. Purification by silica gel chromatography (0 to 20% EtOAc/hexane) to give (3-cyano-phenyl)acetic acid methyl ester 47 as an oil: 1H-NMR (400 MHz, CDCl3) δ=7.63 (d, J=8.0 Hz, 1H), 7.47 (d, J=1.2 Hz, 1H), 7.30 (dd, J=1.2 Hz, J=8.0 Hz, 1H), 3.72 (s, 3H), 3.69 (s, 2H). MS calculated for C10H9O2ClN (M+H+) 210.0, found 210.0.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:12])=[N:8][NH:9]2)=[CH:5][CH:4]=1.[Cl:13][C:14]1[N:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:22]=2)[N:15]=1>C(O)(C)C>[ClH:13].[CH3:1][N:2]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:12])=[N:8][NH:9]2)=[CH:5][CH:4]=1)[C:18]1[N:17]=[C:16]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][S:28]([CH3:31])(=[O:29])=[O:30])[CH:22]=2)[N:15]=[CH:14][N:19]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: CNc1ccc2c(C)n[nH]c2c1
Solvent: CC(C)O
Product: Cc1n[nH]c2cc(N(C)c3ncnc(Nc4cccc(CS(C)(=O)=O)c4)n3)ccc12
Product: Cl
Yield: 38.4 %

Procedure:
To a flask containing a magnetic stir bar was added 0.027 g (0.17 mmol) of N,3-dimethyl-1H-indazol-6-amine and 0.058 g (0.19 mmol) of 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and 2 mL of isopropanol and the resultant mixture heated at reflux for ca. 16 hours. Upon cooling the reaction mixture a solid precipitated. The solid was filtered and washed with ethyl acetate (2×4 mL), acetonitrile (4 mL), and ethyl ether (4 mL) and dried under vacuum to give 0.03 g (42%) of N2-methyl-N2-(3-methyl-1H-indazol-6-yl)-N4-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazine-2,4-diamine hydrochloride as a light pink solid. Some of the peaks in the NMR spectrum are broad at room temperature. Heating to 90° C. produces peaks that are well resolved. HNMR: δ 12.5 (br s, 1H), 9.9 (br s, 1H), 8.24 (m, 1H) 7.72 (d, 1H) 7.5 (m), 7.38 (s, 1H), 7.01 (d, 1H) 6.9 (br s, 1H) 3.47 (s, 3H), 2.75 (br s, 3H), 2.47 (S, 3H). HNMR (at 90° C.): δ 9.62 (s, 1H), 8.29 (s, 1H), 7.76 (d, 1H), 7.66 (s, 1H), 7.54 (d, 1H), 7.43 (s, 1H) 7.1 (m, 3H), 4.13 (s, 2H), 3.56 (s, 3H), 2.93 (s, 3H), 2.55 (s, 3H); MS (ES+, m/z)=424 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][C:10](=[O:20])[C:11]=2[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])[N:7]=1.C(N(CC)CC)C.[F:28][C:29]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32]>ClC(Cl)C>[F:18][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([F:19])[C:12]=1[C:11]1[C:10](=[O:20])[CH:9]=[CH:8][N:6]2[C:5]=1[CH:4]=[CH:3][C:2]([NH:1][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:29]=1[F:28])=[N:7]2
Reactant: Nc1ccc2c(-c3c(F)cccc3F)c(=O)ccn2n1
Reactant: O=C(Cl)c1ccc(F)cc1F
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2c(-c3c(F)cccc3F)c(=O)ccn2n1)c1ccc(F)cc1F
Temperature: 80 °C

Procedure:
To a solution of 2-amino-5-(2,6-difluorophenyl)-6H-pyrido[1,2-b]pyridazin-6-one (50 mg, 0.18 mmol) dissolved in dichloroethane (2 mL) was added triethyl amine (0.079 mL, 0.55 mmol) and 2,4-difluorobenzoyl chloride (49 mg, 0.28 mmol). The mixture was heated to 80° C. for 2 hrs until no further progress was observed. Concentrated reaction to an oil and the crude residue was purified via silica gel chromatography (CH2Cl2/MeOH) to yield the title compound.
Reaction SMILES: [H-].[Na+].[C:3]([O:8][CH3:9])(=[O:7])[CH2:4][CH2:5][CH3:6].[CH:10](OC)=[O:11]>COCCOC>[OH:11]/[CH:10]=[C:4](/[CH2:5][CH3:6])\[C:3]([O:8][CH3:9])=[O:7]
Reactant: COC=O
Reactant: CCCC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC/C(=C/O)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
To a suspension of NaH (7.99 g, 200 mmol) in DME (100 mL) was added a mixture of methyl butyrate (5.1 g, 49.9 mmol) and methyl formate (17.99 g, 300 mmol) in DME (100 mL) dropwise at 0° C. under nitrogen. The mixture was stirred at room temperature overnight, and then filtered through a pad of celite. To the filtrate was added ether (200 mL), and let the suspension stand for 4 h. The solid was collected by filtration, washed with diethyl ether and dried in vacuo to afford the title compound (3 g, 23.05 mmol). LCMS: rt=1.108 min, [M+H+]=130
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(#N)C.[OH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=1.Cl.Cl[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CN(C)C=O>[N:24]1([CH2:23][CH2:22][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: NC(=O)c1ccc(O)cc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(OCCN2CCOCC2)cc1
Reaction time: 0.5 h
Yield: 23.8 %

Procedure:
Potassium carbonate (15.1 g, 109 mmol, 3 eq.), acetonitrile (73 mL) and then 4-hydroxybenzamide (5 g, 36.5 mmol, 1 eq.) are placed in a 250 mL round-bottomed flask. The suspension is stirred for 30 minutes, followed by addition of 4-(2-chloroethyl)morpholine hydrochloride (8.82 g, 47 mmol, 1.3 eq.). 10 mL of dimethylformamide are added to this suspension, and the mixture is then stirred at a temperature in the region of 40° C. for 16 hours. The solvent is then evaporated off and the residue is diluted with water and extracted with dichloromethane. The aqueous phase is acidified with 5 N hydrochloric acid and reextracted with dichloromethane. The organic phases are combined, dried over magnesium sulfate and then concentrated to dryness under vacuum. 4-(2-Morpholin-4-ylethoxy)benzamide 2.17 g (23%) is thus obtained in the form of a white solid, which is used directly in the following step.
Reaction SMILES: C(O[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)C.[F:12][C:13]1[CH:14]=[C:15]([CH2:20][C:21]#[N:22])[CH:16]=[CH:17][C:18]=1[F:19]>>[F:12][C:13]1[CH:14]=[C:15]([CH2:20][C:4]([C:5]2[CH:6]=[CH:7][N:8]=[CH:9][CH:10]=2)=[O:11])[CH:16]=[CH:17][C:18]=1[F:19].[F:12][C:13]1[CH:14]=[C:15]([CH2:20][CH:21]([NH2:22])[C:5]2[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: N#CCc1ccc(F)c(F)c1
Reactant: CCOC(=O)c1ccncc1
Product: NC(Cc1ccc(F)c(F)c1)c1ccncc1
Product: O=C(Cc1ccc(F)c(F)c1)c1ccncc1

Procedure:
The title compound was generated from commercially available isonicotinic acid ethyl ester and (3,4-difluoro-phenyl)-acetonitrile according to the general procedure D described above. The intermediates 2-(3,4-difluoro-phenyl)-1-pyridin-4-yl-ethanone and 2-(3,4-difluoro-phenyl)-1-pyridin-4-yl-ethylamine were isolated and characterized.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:10]=[C:11]1[N:16]2[CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH:15]2[CH2:14][NH:13][CH2:12]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:1]1([C:7]([N:13]2[CH2:12][C:11](=[O:10])[N:16]3[CH2:17][CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH:15]3[CH2:14]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CNCC2c3ccccc3CCCN12
Reactant: O=C(Cl)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(C1CCCCC1)N1CC(=O)N2CCCc3ccccc3C2C1
Temperature: 0 °C
Reaction time: 5 h
Yield: 63.6 %

Procedure:
Cyclohexanoyl chloride (0.34 g) was added to a solution of 4-oxo-1,2,3,4,6,7,8,12b-octahydropyrazino[2,1-a][2]benzazepine (0.5 g) in chloroform (20 ml, ethanol-free) maintained at 0° C. and triethylamine (0.26 g) added. The mixture was maintained at 0° C. for 30 min then at room temperature for 5 h. The solution was washed with, first, dilute hydrochloric acid and secondly with sodium bicarbonate solution. The chloroform solution was dried (MgSO4) and evaporated. The residue was recrystallised from chloroform/40°-60° C. petroleum ether to give white crystals of the title compound (0.48 g, 64%) m.p. 187°-90° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:4][CH:3]=1.C([Li])CCC.[B:24](OC)([O:27]C)[O:25]C.C(OC1C=CC(B(O)O)=CC=1)CCCCCCC>C1COCC1>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([B:24]([OH:27])[OH:25])=[CH:3][CH:4]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: COB(OC)OC
Reactant: CCCCCCCCCCOc1ccc(Br)cc1
Agent: CCCCCCCCOc1ccc(B(O)O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1ccc(B(O)O)cc1

Procedure:
Quantities: compound 28 (9.39 g, 0.03 mol) in anhydrous THF (100 ml), n-butyllithium (12.1 ml, 2.5M in hexane, 0.03 mol), trimethyl borate (6.24 g, 0.066 mol) in anhydrous THF (20 ml). The experimental procedure was as described for the preparation of compound 33.
Reaction SMILES: [F:1][C:2]1[C:12]([F:13])=[C:11]([F:14])[C:10]([F:15])=[CH:9][C:3]=1[C:4]([CH2:6][C:7]#[N:8])=[O:5].[CH:16]([O-])([O-])[O:17][CH2:18][CH3:19].C(OC(=O)C)(=O)C>>[CH2:18]([O:17][CH:16]=[C:6]([C:4](=[O:5])[C:3]1[CH:9]=[C:10]([F:15])[C:11]([F:14])=[C:12]([F:13])[C:2]=1[F:1])[C:7]#[N:8])[CH3:19]
Reactant: N#CCC(=O)c1cc(F)c(F)c(F)c1F
Reactant: CCOC([O-])[O-]
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C#N)C(=O)c1cc(F)c(F)c(F)c1F
Temperature: 100 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
A mixture of 2-(2,3,4,5-tetrafluorobenzoyl)acetonitrile (13.1 g), ethyl orthoformate (13.4 g) and acetic anhydride (15.4 g) is heated at 100° C. with stirring for 3 hours. The reaction mixture is concentrated under vacuum to yield an orange brownish oily residue. When the oily residue is allowed to stand at room temperature, it crystallizes slowly. The resulting crystals are collected and washed successively with a 2:1 mixture of hexane and ethyl acetate, and a 5:1 mixture of hexane and ethyl acetate to give 3-ethoxy-2-(2,3,4,5-tetrafluorobenzoyl)acrylonitrile (14.5 g) as light orange crystals, m.p. 99°-101° C.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][NH2:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:12][N:13]1[CH:17]=[C:16]([S:18](Cl)(=[O:20])=[O:19])[N:15]=[CH:14]1.S(Cl)(Cl)(=O)=O.CCN(C(C)C)C(C)C>CC#N>[C:4]([O:3][C:1]([NH:8][CH2:9][CH2:10][NH:11][S:18]([C:16]1[N:15]=[CH:14][N:13]([CH3:12])[CH:17]=1)(=[O:20])=[O:19])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(=O)(Cl)Cl
Product: Cn1cnc(S(=O)(=O)NCCNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.8 %

Procedure:
Mono-N-Boc-ethylenediamine (5; 5 g, 31.2 mmol, 1 eq) was sulfonylated with 1-methyl-1H-imidazole-4-sulfonyl chloride (6.76 g, 37.4 mmol, 1.2 eq). The appropriate sulfonyl chloride (1.2 equiv) was added to a solution of the amine (1 equiv) and DIPEA (2 equiv) in anhydrous CH3CN (0.1 M) at 0° C. The reaction was warmed to room temperature and stirred for 16 h, at which time the solvent was evaporated. The residue was re-dissolved in CH2Cl2, washed with 5% NaHCO3, water, brine, dried (Na2SO4), filtered and concentrated. After 16 h, the solvent was reduced and then the reaction mixture was dry-loaded onto silica gel and purified by flash column chromatography (eluent CH2Cl2/MeOH/NH4OH, 1092:7:1) to give the title compound as a white powder (9 g, 95%): δH (500 MHz, CD2Cl2) 1.37 (s, 9H, C(CH3)3), 2.99 (t, J=5.8 Hz, 2H, CH2NHSO2), 3.11 (q, J=5.8 Hz, 2H, CH2NHBoc), 3.71 (s, 3H, CH3), 5.53 (s, 1H, NHSO2), 5.68 (s, 1H, NHBoc), 7.48 (s, 1H, Im), 7.56 (s, 1H, Im); δC (125 MHz, CD2Cl2) 27.6, 33.5, 39.8, 42.6, 78.9, 124.0, 127.2, 139.2, 156.1; HRMS (ES+) calcd for [C11H20N4O4S+H] 305.1284. found 305.1294.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:7][C:6](=[O:8])[C:5](=[C:9]([NH:11][C@@H:12]2[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[C@@H:16]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[O:15][C@@H:13]2[OH:14])[CH3:10])[C:4](=[O:32])[CH2:3]1.[Cl:34][C:35]([Cl:39])([Cl:38])[C:36]#[N:37].N12CCCN=C1CCCCC2>C(Cl)Cl>[Cl:34][C:35]([Cl:39])([Cl:38])[C:36](=[NH:37])[O:14][CH:13]1[O:15][C@H:16]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:17]([O:23][C:24](=[O:26])[CH3:25])[C@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:12]1[NH:11][C:9](=[C:5]1[C:4](=[O:32])[CH2:3][C:2]([CH3:33])([CH3:1])[CH2:7][C:6]1=[O:8])[CH3:10]
Reactant: CC(=O)OC[C@H]1O[C@H](O)[C@H](NC(C)=C2C(=O)CC(C)(C)CC2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: N#CC(Cl)(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(=O)OC[C@H]1OC(OC(=N)C(Cl)(Cl)Cl)[C@H](NC(C)=C2C(=O)CC(C)(C)CC2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
A mixture of 2-Deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-3,4,6-tri-O-acetyl-α-D-glucopyranose (100 mg, 0.21 mmol) and trichloroacetonitrile in CH2Cl2 was cooled to 0° C. and 1,8-diazabicyclo(5.4.0)undec-7-en (2 mg) added. The reaction mixture was stirred at 0° C. for 1.5 h and at room temperature for 2 h. The solution was evaporated, and the residue chromatographed using CHCl3/EtOAc 1:1 as the mobile phase to give 2-deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-3,4,6-tri-O-acetyl-α,β-D-glucopyranosyl trichloroacetimidate (13) (71 mg, 55%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][N:28]=1)[C:5]([NH:7][C:8]1[O:9][C:10]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[CH:15][CH:14]=[C:13]([O:24][CH3:25])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>CN1C(=O)CCC1>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]2[C:10]3[O:9][C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:26]=[CH:27][N:28]=[C:2]([N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)[CH:3]=4)=[N:12][C:11]=3[C:13]([O:24][CH3:25])=[CH:14][CH:15]=2)=[CH:18][CH:19]=1
Reactant: C1COCCN1
Reactant: COc1ccc(-c2ccc(F)cc2)c2oc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COc1ccc(-c2ccc(F)cc2)c2oc(NC(=O)c3ccnc(N4CCOCC4)c3)nc12

Procedure:
From 2-bromo-N-[7-(4-fluoro-phenyl)-4-methoxy-benzooxazol-2-yl]-isonicotinamide with cesium carbonate and morpholine in NMP. ES-MS m/e (%): 449 (M+H+, 100).