Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[Li]CCCC.C([O:17][C:18]([C:20]1[N:21]=[N:22][S:23][C:24]=1[NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=O)C>C1COCC1.C1CCCCC1>[N:4]1([CH2:3][CH2:2][NH:1][C:18]([C:20]2[N:21]=[N:22][S:23][C:24]=2[NH:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:17])[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1
Reactant: CCOC(=O)c1nnsc1Nc1ccccc1
Reactant: NCCN1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: O=C(NCCN1CCOCC1)c1nnsc1Nc1ccccc1
Yield: 60 %

Procedure:
To a solution of N-aminoethylmorpholine (228 mg, 10 mmole) in 2 mL anhydrous THF at −40° C. was added 0.8 mL of 2 M n-BuLi solution in cyclohexane. Some white solid was precipitated instantly. The suspension was stirred for about a half an hour. When the bath temperature reached −10° C., a solution of 5-phenylamino-[1,2,3]thiadiazole-4-carboxylic acid ethyl ester (60 mg, 0.24 mmole) in anhydrous THF was added to the mixture. After it was stirred at room temperature for an hour, the reaction was quenched with saturated NH4Cl solution. The solution was extracted with EtOAc and residue obtained after the removal of EtOAc was purified by preparative TLC (silica gel, CH2Cl2:MeOH=15:1). The title compound was isolated as a white powder in 60% yield (48 mg). 1H NMR (ppm, in CDCl3): 10.91 (br. s, 1H), 7.77 (br. s, 1H), 7.00-7.60 (m, 5H), 3.70 (m, 4H), 2.60 (m, 4H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=O)[CH3:2].[CH3:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[C:15]=1[NH2:16]>C(O)(=O)C.C(O)C>[CH3:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[C:15]=1[N:16]=[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[N:16][C:15]2[C:17]([CH:21]([CH3:22])[CH3:23])=[CH:18][CH:19]=[CH:20][C:14]=2[CH3:13])[CH3:11])[N:5]=1)[CH3:2]
Reactant: CC(=O)c1cccc(C(C)=O)n1
Reactant: Cc1cccc(C(C)C)c1N
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=Nc1c(C)cccc1C(C)C)c1cccc(C(C)=Nc2c(C)cccc2C(C)C)n1
Yield: 35 %

Procedure:
There were supplied 325 mg of 2,6-diacetylpyridine manufactured by Aldrich Chemical Company to a 25 mL-Schlenk tube. Thereto, 5 mL of anhydrous ethanol manufactured by Kanto Chemical Co., Inc., 0.62 mL of 2-methyl-6-isopropylaniline manufactured by Tokyo Chemical Industry Co., Ltd., and a few drops of acetic acid manufactured by Kanto Chemical Co., Inc. were added. The obtained mixture was refluxed for 24 hours. Then, the solvent contained in the mixture was distilled off, and the resultant mixture was subjected to recrystallization with methanol, thereby obtaining 298 mg (yield: 35%) of 2,6-bis[1-(2-methyl-6-isopropylphenylimino)ethyl]pyridine as a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][C:5]2([CH3:15])[CH3:14].[CH2:16]([O:18][C:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)=[O:20])[CH3:17]>N1C=CC=CC=1.O1CCCC1>[CH3:12][N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:25]([C:24]3[CH:28]=[CH:29][C:21]([C:19]([O:18][CH2:16][CH3:17])=[O:20])=[CH:22][CH:23]=3)=[O:26])=[CH:11][CH:10]=2)[C:5]([CH3:15])([CH3:14])[CH2:6][C:7]1=[O:13]
Reactant: CCOC(=O)c1ccc(C(=O)Cl)cc1
Reactant: CN1C(=O)CC(C)(C)c2cc(N)ccc21
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(C(=O)Nc2ccc3c(c2)C(C)(C)CC(=O)N3C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.7 %

Procedure:
37.2 g of 6-amino-3,4-dihydro-1,4,4-trimethyl-2(1H)-quinolinone were dissolved in 600 ml of pyridine and treated dropwise at room temperature with a solution of 43 g of 4-ethoxycarbonylbenzoyl chloride in 80 ml of tetrahydrofuran. After stirring at room temperature for 20 hours, the reaction mixture was poured on to ice-water, extracted several times with ethyl acetate, the organic phase was washed with cold 2N hydrochloric acid and water, dried and evaporated. Chromatography of the crude product (silica gel, eluent hexane/ethyl acetate 2:1, then ethyl acetate) and recrystallization from ethyl acetate/hexane, yielded 45.5 g of ethyl p-[(1,2,3,4-tetrahydro-1,4,4-trimethyl-2-oxo-6-quinolinyl)carbamoyl]-benzoate, m.p. 197°-199° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]Cl)=[CH:7][CH:6]=1)=[O:4].[C:13]([O:17][C:18]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C:21]1=[O:26])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][C:20]2([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH2:25][CH2:24][CH2:23][CH2:22][C:21]2=[O:26])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(SCl)cc1
Reactant: CC(C)(C)OC(=O)C1CCCCC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(SC2(C(=O)OC(C)(C)C)CCCCC2=O)cc1
Reaction time: 0.25 h
Yield: 56.7 %

Procedure:
A solution 10.8 g (53.2 mmol) of 4-methoxycarbonylphenylsulphenic acid chloride in 20 ml of methylene chloride (analytically pure) is added dropwise to a solution of 11.4 g (57 mmol) of 2-tert.butoxycarbonylcyclohexanone and 7.5 g (75 mmol) of triethylamine in 150 ml of methylene chloride. When the dropwise addition has ended the mixture is subsequently stirred for 15 mins. and is then diluted with methylene chloride and the organic phase is washed with 2N sulphuric acid and a saturated bicarbonate solution, dried with sodium sulphate and concentrated by evaporation. 20.5 g of a crude product are thus obtained, which is chromatographed on 2 kg of silica gel (Merck Si 60, 0.04-0.063 nm) using petroleum ether/ether 8:20 as the mobile solvent. A fraction is thus obtained which, after being concentrated by evaporation, yields 11 g of a solid product.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[NH2:19][CH:20]1[CH2:24][CH2:23][NH:22][CH2:21]1>>[NH2:19][CH:20]1[CH2:24][CH2:23][N:22]([C:2]2[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:21]1
Reactant: Clc1ccc(OCCOc2nccnc2Cl)cc1
Reactant: NC1CCNC1
Product: NC1CCN(c2nccnc2OCCOc2ccc(Cl)cc2)C1

Procedure:
The title compound was prepared according to the procedure described in Example 4, Step 2, starting from 2-chloro-3-[2-(4-chlorophenoxy)ethoxy]pyrazine*(150 mg, 0.53 mmol) and 3-aminopyrrolidine (247 mg, 2.87 mmol) with the exception that a final extraction step between EtOAc and 5% aqueous NaOH was carried out. This gave 123 mg (69%) of the title product. Anal. (C16H19CIN4O2) H, N; C: calcd. 57.40; found, 56.9.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:25](=[O:26])[N:24]([CH:27]([CH3:29])[CH3:28])[C:23]2[CH:30]=[CH:31][CH:32]=[CH:33][C:22]=2[N:21]([CH:34]([CH3:36])[CH3:35])[C:20]1=[O:37]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:25](=[O:26])[N:24]([CH:27]([CH3:29])[CH3:28])[C:23]3[CH:30]=[CH:31][CH:32]=[CH:33][C:22]=3[N:21]([CH:34]([CH3:36])[CH3:35])[C:20]2=[O:37])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CC(C)N1C(=O)C(N)C(=O)N(C(C)C)c2ccccc21
Product: CC(C)N1C(=O)C(NC(=O)[C@H](C)NC(=O)Cc2cc(F)cc(F)c2)C(=O)N(C(C)C)c2ccccc21

Procedure:
Following General Procedure I above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 3-amino-2,4-dioxo-1,5-bis-(1-methylethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (Example 8-P), the title compound was prepared as a white solid (melting point=232-233° C.). Purification was by flash chromatography eluting with EtOAc/hexanes (4:1 gradient to 6:1). Rf=0.31 (4:1 EtOAc/hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([OH:13])[CH3:12])[C:8]2[C:4](=[CH:5][N:6]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:7]=2)[CH:3]=1.N12CCCN=C1CCCCC2.[Cl:33][C:34]([Cl:38])([Cl:37])[C:35]#[N:36]>C(OCC)C>[Cl:33][C:34]([Cl:38])([Cl:37])[C:35](=[NH:36])[O:13][CH:11]([C:9]1[C:8]2[C:4](=[CH:5][N:6]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:19])[CH3:21])[N:7]=2)[CH:3]=[C:2]([Cl:1])[CH:10]=1)[CH3:12]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CC(O)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Product: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(±)-1-(5-Chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethanol (0.54 g, 1.65 mmol) was dissolved in diethyl ether (5 mL), cooled to 0° C. and treated with 1,8-diazabicyclo(5.4.0)undec-7-ene (50 μL, 0.33 mmol). The reaction was stirred for 10 min and treated with trichloroacetonitrile (250 μL, 2.48 mmol) dropwise over 10 min. The reaction was allowed to warm to room temperature overnight and concentrated. Flash chromatography on silica gel (5% ethyl acetate/hexanes) gave 600 mg (77%) as an oil. 1H-NMR (CDCl3, 300 MHz) δ 8.34 (s, 1H), 8.02 (s, 1H), 7.56 (d, J =1.5 Hz, 1H), 7.33 (m, 1H), 6.62 (q, J=6.2 Hz, 1H), 5.68 (s, 2H), 3.59-3.65 (m, 2H), 1.79 (m, 3H), 0.88-0.94 (m, 2H), 0.05 (s, 9H).
Reaction SMILES: [C:1]([N:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[C:19][C:20]1[S:24][CH:23]=[N:22][CH:21]=1)[C:6](=[O:12])[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl>O1CCOCC1.O>[C:1]([N:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[C:19][C:20]1[S:24][CH:23]=[N:22][CH:21]=1)[C:6](=[O:12])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)N(CCCCCC#Cc1cncs1)C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)N(CCCCCC#Cc1cncs1)C(=O)C(=O)O
Temperature: 50 °C
Reaction time: 1 h
Yield: 101.7 %

Procedure:
A solution of 310 mg of 16i in 9 ml of dioxane was mixed with a solution of 200 mg of KOH in 3 ml of water and was stirred at 50° C. for 1 hr. The mixture was diluted with water and acidified to pH3 with 0.5N HCl and the product was extracted into ethyl acetate. The organic extract was washed twice with water, dried and concentrated, to give 290 mg of 16j.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH3:37])[CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34]([OH:36])=O)[CH2:29]4)[CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.C(N(CC)C(C)C)(C)C.[C:53]([C:57]1[CH:58]=[C:59]([NH2:64])[C:60]([NH2:63])=[CH:61][CH:62]=1)([CH3:56])([CH3:55])[CH3:54].CN(C)C=O>>[NH2:64][C:59]1[CH:58]=[C:57]([C:53]([CH3:55])([CH3:54])[CH3:56])[CH:62]=[CH:61][C:60]=1[NH:63][C:34](=[O:36])[CH2:33][CH2:32][CH:30]1[CH2:29][CH:28]([N:27]([CH2:26][C@@H:18]2[C@@H:19]3[C@@H:20]([O:21][C:22]([CH3:25])([CH3:24])[O:23]3)[C@H:16]([N:13]3[C:9]4[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]5[CH:38]=[CH:39][C:40]([O:42][CH3:43])=[CH:41][C:3]=5[O:2][CH3:1])[C:8]=4[CH:15]=[CH:14]3)[CH2:17]2)[CH3:37])[CH2:31]1
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCC(=O)O)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCC(=O)Nc4ccc(C(C)(C)C)cc4N)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
N,N,N′,N′-Tetramethyl-0-(7-azabenzotriazol-1-yl}uronium Hexafluorophosphate (0.44 g, 1.2 mmol) added to a solution of 3-(3-((((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)propanoic acid (460 mg, 0.77 mmol) and N,N-Diisopropylethylamine (0.44 mL, 2.6 mmol) and 4-tert-butylbenzene-1,2-diamine (0.15 g, 0.93 mmol) in N,N-Dimethylformamide (5 mL, 60 mmol). The reaction was stirred overnight at RT, partially concentrated to ca. 2 mls and then NaHCO3 (saturated) was added. The mixture was extracted with EtOAc (3×) and the combined organics were dried with MgSO4 and concentrated. Purified by flash chromatography (DCM/7N NH3 in MeOH 95:5) to yield a solid (0.24 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].[N:9]([O-])=[O:10].[Na+].C(O)(=O)C>O>[OH:10][N:9]=[C:5]([C:6]#[N:7])[C:4]([O:3][CH2:1][CH3:2])=[O:8]
Reactant: CCOC(=O)CC#N
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(C#N)=NO

Procedure:
Ethylcyanoacetate (11.3 g, 100 mmol) is added to a solution of sodium nitrite (8.3 g, 120 mmol) in distilled water (50 ml) and acetic acid (8.0 ml=8.4 g, 140 mmol) is added to the stirred mixture. The ester disappears and soon yellow crystals of the sodium derivative start to separate. Next day the crystals are collected and then dissolved in 2N HCl (50 ml). The product is extracted with ether (four times, 50 ml each time) and the extracts dried over anhydrous Na2SO4. Removal of the solvent by evaporation in vacuo leaves a crystalline residue, ethyl 2-hydroxyimino-2-cyanoacetate, melting at 133° C. (12.4 g, 87%).
Reaction SMILES: Cl.CO[C:4](=[O:14])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH2:22]=[C:23]1[O:27][C:25](=[O:26])[CH2:24]1>C(O)C>[CH2:7]([N:6]1[CH2:5][C:4](=[O:14])[CH:24]([C:23](=[O:27])[CH3:22])[C:25]1=[O:26])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)CNCc1ccccc1
Reactant: C=C1CC(=O)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)C1C(=O)CN(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
N-Benzylglycine methyl ester hydrochloride (23.0 g) is dissolved in ethanol (180 ml) and thereto is added triethylamine (11.1 g) under ice-cooling and further added dropwise diketene (9.2 g). The mixture is stirred at room temperature for 1 hour and distilled to remove the solvent. The residue is dissolved in chloroform, washed with water, 10% hydrochloric acid, and water in this order, dried and then distilled to remove the solvent. The residue is dissolved in xylene (360 ml) and the solution is added dropwise to a solution of sodium methoxide [which is prepared from metal sodium (2.6 g) and methanol (180 ml)], and the mixture is stirred at 80° C. for 2.5 hours while distilling off methanol. After cooling, the reaction mixture is extracted with water. The extract is acidified with 10% hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract is washed with water, dried and distilled to remove the solvent. The residue is recrystallized from n-hexane-isopropyl ether-diethyl ether to give 1-benzyl-3-acetyl-2,4-dioxopyrrolidine (20.33 g, 87.7%). m.p. 74°-75° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][C@H:6]1[CH2:11][C@H:10]([C:12](=[O:19])[CH2:13][C:14](OCC)=[O:15])[CH2:9][CH2:8][N:7]1[C:20]([O:22][CH3:23])=[O:21].[OH-].[Na+].[NH2:30]O.Cl>CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][C@H:6]1[CH2:11][C@H:10]([C:12]2[O:19][NH:30][C:14](=[O:15])[CH:13]=2)[CH2:9][CH2:8][N:7]1[C:20]([O:22][CH3:23])=[O:21]
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(F)c(F)c2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(F)c(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 32.3 %

Procedure:
Trans-methyl 2-(3,4-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (0.278 g, 0.73 mmol) (from example 120, step 1) was dissolved in MeOH (3 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.029 g, 0.73 mmol) dissolved in water (0.300 mL) was added during 10 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.044 mL, 0.73 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h 15 min. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (4 mL, 24.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a yellow semi-solid. The compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-25% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Trans-methyl 2-(3,4-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (83 mg, 34%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.47-2.14 (m, 4H), 2.71-3.14 (m, 4H), 3.43-3.75 (m, 3H), 4.01-4.78 (m, 2H), 5.65 (s, 1H), 6.78-7.14 (m, 3H). MS m/z 353 (M+H)+
Reaction SMILES: B.[Br:2][C:3]1[CH:10]=[C:7]([C:8]#[N:9])[C:6]([NH2:11])=[CH:5][CH:4]=1.CCO>C1COCC1>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([NH2:11])=[C:7]([CH:10]=1)[CH2:8][NH2:9]
Reactant: N#Cc1cc(Br)ccc1N
Agent: B
Solvent: CCO
Solvent: C1CCOC1
Product: NCc1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 72 h
Yield: 125.3 %

Procedure:
A solution of borane in THF (1 M, 400 ml) was added at 0° C. to a suspension of 5-bromo-anthranilonitrile (60 g, 0.304 mol, prepared as described in S. M. Mackenzie et al, J. Chem. Soc. C, 1970, 17, 2298-2308) in THF (450 L), under N2. The mixture was stirred for 72 hours at r.t. After cooling at 0° C. absolute EtOH was added, then HCl was bubbled through the solution. The mixture was concentrated and the residue was suspended in isopropyl ether. The obtained solid was dried to give the di-hydrochloride of the title product (76.6 g, 91.4% yield). C7H9BrN2. 2HCl, MW 273.9; 1H-NMR (200 MHz, d6-DMSO) ppm: 4.13 (s, 2H); 5.82 (s, 4H), 7.24 (d, 1H), 7.55 (dd, 1H), 7.73 (s, 1H), 8.57 (s, 2H). Since the free base is used in the cyclization step, the hydrochloride was suspended in aqueous ammonia, stirred for some minutes after that the free base precipitates. The solid is filtered and dried (yield is quantitative).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[CH:4][N:3]=1.[N:10]12CCN(CC1)C[CH2:11]2.O>C(#N)C.[C-]#N.C([N+](CC)(CC)CC)C>[CH3:9][O:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([C:11]#[N:10])[CH:7]=1
Reactant: COc1cc(Cl)ncn1
Reactant: C1CN2CCN1CC2
Agent: CC[N+](CC)(CC)CC
Agent: [C-]#N
Solvent: O
Solvent: CC#N
Product: COc1cc(C#N)ncn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.9 %

Procedure:
To a solution of 4-chloro-6-methoxypyrimidine (10.6 g) in acetonitrile (150 mL) was added 1,4-diazabicyclo[2.2.2]octane (8.18 g), and the mixture was stirred at room temperature for 10 min. Tetraethylammonium cyanide (11.5 g) was added to the obtained reaction mixture, and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.00 g) as a pale-yellow oil.
Reaction SMILES: [C:1]([Si:5]([CH3:22])([CH3:21])[O:6][CH2:7][CH2:8][CH2:9][N:10]1C(=O)C2C(=CC=CC=2)C1=O)([CH3:4])([CH3:3])[CH3:2].CNN>C(O)C>[Si:5]([O:6][CH2:7][CH2:8][CH2:9][NH2:10])([C:1]([CH3:3])([CH3:4])[CH3:2])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)OCCCN1C(=O)c2ccccc2C1=O
Agent: CNN
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCCCN
Temperature: 75 °C
Yield: 36 %

Procedure:
To a solution of N-(3-hydroxypropyl)phthalimide (5.25 g, 24.36 mmol) in DMF (20 mL) was added imidazole (16.6 g, 240 mmol) and tert-butyldimethylsilyl chloride (19 g, 120 mmol). The reaction was stirred at room temperature for 18 hours before the volatiles were removed in vacuo and a portion of the crude product was subjected to column chromatography (SiO2, 1:1 DCM/hexanes) to give 2-[3-(tert-butyldimethyl-silanyloxy)propyl]isoindole-1,3-dione as a clear oil (5 g). 2-[3-(tert-Butyldimethyl-silanyloxy)propyl]isoindole-1,3-dione (5 g, 26.4 mmol) was dissolved in ethanol (50 ml) and methyl hydrazine (2.94 ml, 55.4 mmol) added. The reaction was heated to 75° C. for 8 hours before concentration in vacuo. The crude residue was triturated with a mixture of diethyl ether (150 mL) and hexanes (50 mL) and the resultant solid removed by filtration. The solvents were removed in vacuo to give the title compound as a pale yellow oil (1.8 g, 61%). δH (DMSO-d6) 4.58 (2H, br s), 3.63-3.58 (2H, m), 2.67-2.62 (2H, m), 1.60-1.55 (2H, m), 0.83 (9H, d, J 1.1 Hz), 0.00 (6H, d, J 1.2 Hz). LCMS (ES+) RT 1.77 minutes, 190 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[H-].[Na+].[C:12]([O:15][CH2:16]Br)(=[O:14])[CH3:13]>CN(C=O)C>[CH2:1]([N:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:13][C:12]([O:15][CH3:16])=[O:14])[CH3:2]
Reactant: CCNc1ccccc1
Reactant: CC(=O)OCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC(=O)OC)c1ccccc1
Reaction time: 0.75 h
Yield: 95.9 %

Procedure:
N-Ethylaniline 5 (2 g, 16.52 mmol) was added to a stirred suspension of sodium hydride (436 mg, 18.17 mmol) in DMF (20 ml) at ambient temperature under argon. After 45 minutes, bromomethyl acetate (3.02 g, 18.17 mmol) was added and the reaction mixture was stirred for 22 hr. DMF was removed under reduced pressure and the residue was treated with ethyl acetate (60 ml) and water (50 ml). The organic extract was washed with saturated brine (50 ml), dried (Na2SO4), filtered and evaporated to give crude Methyl 2-(ethylphenylamino) acetate 7 as liquid (3.06 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([NH2:29])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>O1CCCC1.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([NH:29][S:38]([CH3:37])(=[O:40])=[O:39])[C:25]([F:26])([F:27])[F:28])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl)C(F)(F)F
Yield: 90.3 %

Procedure:
To a mixture of 1-[9-chloro-1-(2,4,6-trichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanamine (80.0 mg, 0.165 mmol) and triethylamine (0.0460 mL, 0.330 mmol) in tetrahydrofuran (2 mL) was added methanesulfonyl chloride (0.0153 mL, 0.198 mmol) at 0° C. The resultant mixture was stirred at room temperature for 30 min and diluted with aqueous sodium bicarbonate. The resultant mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (83.7 mg, 0.149 mmol, 90%).
Reaction SMILES: [I-].[CH3:2][O:3][C:4]1[C:9]([CH3:10])=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][C:5]=1[C:15]1[O:16]CC(C)(C)[N+]=1C.C[OH:24]>[OH-].[Na+]>[CH3:2][O:3][C:4]1[C:9]([CH3:10])=[C:8]([C:11]([F:12])([F:13])[F:14])[CH:7]=[CH:6][C:5]=1[C:15]([OH:16])=[O:24]
Reactant: CO
Reactant: COc1c(C2=[N+](C)C(C)(C)CO2)ccc(C(F)(F)F)c1C
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Product: COc1c(C(=O)O)ccc(C(F)(F)F)c1C
Temperature: 25 °C

Procedure:
A solution of 515 mg (1.2 mmol) 2-(2-methoxy-3-methyl-4-trifluoromethyl-phenyl)-3,4,4-trimethyl-4,5-dihydro-oxazol-3-ium iodide in 5 ml methanol and 5 ml 20% NaOH was heated to 70° C. for 17 h. The yellow solution was cooled to rt, methanol was distilled off, the residue acidified with conc. HCl to pH 1 and extracted three times with tert-butyl methyl ether. The combined organic phases were washed twice with brine, dried over Na2SO4, filtered and evaporated: 2-Methoxy-3-methyl-4-trifluoromethyl-benzoic acid was obtained as yellow solid: MS (ISN): 233.04 ((M−H)−).