Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[C:1]([O:5][C:6](=[O:15])[NH2:7])([CH3:4])([CH3:3])[CH3:2].[N:16]1([CH:11]2[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(N)=O
Product: NC1CCC(N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.3 %

Procedure:
To a solution of (4-oxo-cyclohexyl)-carbamic acid tert-butyl ester (426 mg, 2.00 mmol) and morpholine (175 μL, 2.00 mmol) in CH2Cl2 (25 mL) and acetic acid (120 μL) was added sodium triacetoxyborohydride (636 mg, 3.00 mmol) and the mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and diluted with saturated aqueous sodium carbonate (30 mL). The aqueous layer was washed with CH2Cl2 (4×20 mL), and the combined organic extracts were dried (MgSO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography on silica gel (MeOH/CH2Cl2, 1:9) afforded the title compound as a white solid (76.2 mg, 13%). 1H NMR (CDCl3) δ 1.04-1.17 (m, 6H), 1.25-1.38 (m, 4H), 1.44 (s, 9H), 1.93 (d, 2H, J=12.0 Hz), 2.07 (d, 2H, J=12.0 Hz), 2.12-2.17 (m, 2H), 3.25-3.36 (br m, 1H), 4.35 (br m, 1H), 4.81 (br d, 1H).
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[N:22][CH:21]=[C:20]([C:24]#[N:25])[N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-:28].Cl>C1COCC1.O>[C:24]([C:20]1[N:19]=[C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:26])=[O:3])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)[CH:23]=[N:22][CH:21]=1)#[N:25].[C:24]([C:20]1[N:19]=[C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:3])=[O:26])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)[CH:23]=[N:22][CH:21]=1)(=[O:28])[NH2:25]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cncc(C#N)n3)cc(C)c21
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Oc2cncc(C#N)n2)cc2c1C(CC(=O)O)OB2O
Product: Cc1cc(Oc2cncc(C(N)=O)n2)cc2c1C(CC(=O)O)OB2O
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution [6-(6-cyano-pyrazin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (0.2 g, 0.556 mmol) in THF (3 mL) was added a solution of LiOH (0.041 g, 1.69 mmol) in water (3 mL) at 0° C. The resulting mixture was stirred at 0° C. for 5 hours, acidified to pH 2 using 6M hydrochloric acid and extracted with EtOAc. The organic extracts were washed with water, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by preparative HPLC to give [6-(6-cyano-pyrazin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid as a white solid (0.067 g) and [6-(6-carbamoyl-pyrazin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid as a white solid (0.025 g).
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=O)[CH:14]=1>C(O)(=O)C>[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[CH:1][C:2]2[NH:11][C:10](=[O:12])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:14]=1
Reactant: Cc1nc2ccccc2c(=O)[nH]1
Reactant: O=Cc1cccnc1
Solvent: CC(=O)O
Product: O=c1[nH]c(C=Cc2cccnc2)nc2ccccc12
Temperature: 25 °C

Procedure:
A mixture of 2-methylquinazolin-4-one (6.1 g) and 3-pyridinecarbaldehyde (4.1 g) in acetic acid (80 mL) was heated to reflux for 20 hours. After cooling to room temperature, the precipitate was collected by filtration, washed with methanol and dried to obtain the title compound as an acetic acid salt (10.5 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([OH:14])=O)=[CH:4][N:3]=1.C(Cl)(=O)C([Cl:18])=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([Cl:18])=[O:14])=[CH:4][N:3]=1
Reactant: O=C(O)c1cnc(Cl)nc1C(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(Cl)c1cnc(Cl)nc1C(F)(F)F
Yield: 70 %

Procedure:
The title compound was prepared as described in Example 25, but employing a solution of 2-chloro-4-trifluoromethylpyrimidine-5-carboxylic acid (1.5 g, 7.1 mmol) and oxalyl chloride (1.0 g, 8 mmol) in CH2Cl2 (30 mL) resulted in a 70% yield (1.1 g); 1H NMR (CDCl3) δ 9.31 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(C(C)C)[CH:20]([CH3:22])[CH3:21])C.ICCC>COCCOC>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:21][CH2:20][CH3:22])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1ccc(C2CCNCC2)cc1
Solvent: CCCI
Solvent: COCCOC
Product: CCCN1CCC(c2ccc(C(=O)OC)cc2)CC1
Temperature: 70 °C

Procedure:
4-Piperidin-4-yl-benzoic acid methyl ester (28 mmol), ethyldiisopropylamine (31 mol) and 1-iodopropane (42 mmol) are dissolved in 1,2-dimethoxyethane (100 ml) and the mixture is heated at 70° C. overnight. After evaporation of the solvent, the residue is dissolved in a mixture of water and sodium carbonate (to ensure basic conditions) and extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is purified by flash chromatography on silica gel with CH2Cl2/MeOH=9:1 as mobile phase. The product containing fractions are combined and evaporated. The residue is suspended in diethylether and the solid filtered of and dried (vacuum). A pale brown powder with Rf=0.35 (CH2Cl2/MeOH=9:1) is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.Cl.[Cl:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].C(OCCCCC)(=O)C>CC(C)=O.O>[ClH:13].[N:16]1([CH2:15][CH2:14][O:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: ClCCN1CCCCC1
Reactant: COC(=O)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCCOC(C)=O
Solvent: CC(C)=O
Product: O=C(O)c1ccc(OCCN2CCCCC2)cc1
Temperature: 95 °C

Procedure:
To two 125 mL 3 neck flasks with mechanical stirring, condensers, and a heating apparatus consisting of an RTD probe in the flask hooked via a temperature controller to a heating mantle the following were added: 7.61 g of methyl 4-hydroxybenzoate, 11.05 g of β-chloroethylpiperidine hydrochloride, 16.59 g of powdered potassium carbonate, and 60 mL of amyl acetate. The flasks were placed in an ambient oil bath and heated under nitrogen to 95° C.-100° C. The reaction was allowed to proceed until HPLC indicated 8% unreacted methyl 4-hydroxybenzoate in A, 12% unreacted in B. The flasks were then cooled to less than 50° C. 40 mL deionized water was added with stirring to dissolve solids. The aqueous layer was separated and discarded. The water wash was repeated and the aqueous layer was separated and discarded. HPLC of organic layers showed 6% 4-hydroxybenzoate remains in A, 3% in B. 25 mL of 8N hydrochloric acid was added with stirring to extract the intermediate. The layers were separated and the acid layers returned to reaction flasks. The acid solutions were heated at about 95° C. for about 4 hours. The flasks were then cooled to less than 40° C. and 25 mL of acetone was added. The mixture was then cooled to 0° C.-5° C. for 1 hour. The mixture was filtered and the cakes rinsed with approximately 25 mL of acetone and dried. A=11.50 g (80.5%), B=10.5 g (73.8%)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Br[CH:11]([CH2:17][CH2:18][CH3:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[C:5]([C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][CH:11]([CH2:17][CH2:18][CH3:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:6]
Reactant: N#Cc1cccc(O)c1
Reactant: CCCC(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCCC(Oc1cccc(C#N)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5.0 g (42 mmol) of 3-hydroxybenzonitrile and 8.78 g (42.0 mmol) of ethyl 2-bromovalerate in 80 ml of acetonitrile is treated with 13.7 g (42.0 mmol) of caesium carbonate and stirred at room temperature for 18 hours. The reaction mixture is filtered off and the filtrate evaporated. A colourless oil is obtained; FAB 248
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[OH:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)[C:18]([N:26]1[CH2:27][CH2:28][CH:23]([OH:22])[CH2:24][CH2:25]1)=[O:20])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)O
Reactant: OC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1
Reaction time: 0.08 h

Procedure:
To a stirred solution of Boc-3-(4-fluorophenyl)-(S)-alanine (10.0 g, 35.3 mmol), 4-hydroxypiperidine hydrochloride (5.1 g, 37.1 mmol) and HOBt (7.2 g, 52.9 mmol) in DMF (100 mL), was added DIPEA (12.3 mL, 70.6 mmol) and after 5 min, EDCI (7.4 g, 38.8 mmol) and the reaction stirred at rt for 16 h. The solvent was removed in vacuo and the residue partitioned between water (150 mL) and ethyl acetate (2×150 mL). The combined organic fractions were washed with sodium hydroxide solution (2M, 50 mL), hydrochloric acid (2N, 50 mL), dried (MgSO4) and concentrated in vacuo. The product was chromatographed on silica gel eluting with ethyl acetate to give the title compound as a white solid. m/z (ES+)=367 [M+H]+; RT=3.28 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)C[Mg]Br.[Cl:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][N:18]2[C:23](=[O:24])[CH:22]=[CH:21][C:20]([CH:25]=[O:26])=[CH:19]2)=[CH:15][CH:14]=1>C1COCC1>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][N:18]2[CH:19]=[C:20]([CH:25]([OH:26])[C:10]3[CH:9]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=3)[CH:21]=[CH:22][C:23]2=[O:24])=[CH:27][CH:28]=1
Reactant: COc1cccc(C[Mg]Br)c1
Reactant: O=Cc1ccc(=O)n(Cc2ccc(Cl)cc2)c1
Solvent: C1CCOC1
Product: COc1cccc(C(O)c2ccc(=O)n(Cc3ccc(Cl)cc3)c2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 64 %

Procedure:
According to Scheme 7 Method B: A solution of 3-methoxybenzylmagnesium bromide (1.2 eq, 1.00 mmol, 1.00 mL) was added dropwise to a solution of 1-(4-chlorobenzyl)-1,6-dihydro-6-oxopyridine-3-carbaldehyde (1 eq, 1.21 mmol, 0.30 g, Example 10 Step 1) in THF (15 mL) at −78° C. under a nitrogen atmosphere. The reaction mixture was stirred for 14 hours at room temperature. The resulting mixture was poured onto ice and extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered and evaporated. Purification by flash chromatography (AIT Flashsmart prepacked column 25 g SiO2, CH2Cl2/AcOEt 80/20 to 70/30) afford 1-(4-chlorobenzyl)-5-(hydroxy(3-methoxyphenyl)methyl)pyridin-2(1H)-one (0.64 mmol, 0.28 g, 64%) as a yellow semi-solid.
Reaction SMILES: [C:1]([CH2:5][C:6]1([CH2:13][CH3:14])[C:11](=[O:12])[CH:10]=[CH:9][CH2:8][CH2:7]1)([O:3][CH3:4])=[O:2].S(C)C.[C:18]1([Mg]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[C:1]([CH2:5][C:6]1([CH2:13][CH3:14])[CH2:7][CH2:8][CH:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][C:11]1=[O:12])([O:3][CH3:4])=[O:2]
Reactant: Br[Mg]c1ccccc1
Reactant: CCC1(CC(=O)OC)CCC=CC1=O
Solvent: CSC
Solvent: C1CCOC1
Product: CCC1(CC(=O)OC)CCC(c2ccccc2)CC1=O
Yield: 71 %

Procedure:
The enone, 6-carbomethoxymethyl-6-ethyl-2-cyclohexen-1-one (X) prepared by the process of Example 1, Step (c) (61.1 mmol, 12.0 g), CuBr.Me2S (6.11 mmol, 1.256 g) and Me2S (12.3 ml) were stirred in 85 ml of dry THF at -40° C. under nitrogen and treated with 61.1 mmol (20.4 ml of 3M in THF), of PhMgBr added dropwise over 30 minutes. The reaction was then quenched with 250 ml of 1M HCl (aq.) and extracted with 4×100 ml of petroleum ether. Drying (Na2SO4) and flash chromatography afforded 11.87 g (43.3 mmol, 71%) of product. The two diastereomers were separated by preparative HPLC on a Prep 500A using a brand of silica gel available from Waters Associates, Milford, Ma., affording 4.8 g of each isomer, designated "less polar isomer" and "more polar isomer."
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]3[C:12](=[CH:13][C:4]=2[N:3]=1)[C:11]([CH3:15])([CH3:14])[C:10](=[O:16])[C:9]3([CH3:18])[CH3:17].Cl.Cl[CH2:21][C:22]1[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[C:25]([CH3:31])=[CH:24][N:23]=1.[OH-].[Na+]>O>[CH2:29]([O:28][C:26]1[C:25]([CH3:31])=[CH:24][N:23]=[C:22]([CH2:21][S:1][C:2]2[NH:3][C:4]3[CH:13]=[C:12]4[C:8](=[CH:7][C:5]=3[N:6]=2)[C:9]([CH3:18])([CH3:17])[C:10](=[O:16])[C:11]4([CH3:14])[CH3:15])[CH:27]=1)[CH3:30]
Reactant: CC1(C)C(=O)C(C)(C)c2cc3[nH]c(S)nc3cc21
Reactant: CCOc1cc(CCl)ncc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1cc(CSc2nc3cc4c(cc3[nH]2)C(C)(C)C(=O)C4(C)C)ncc1C

Procedure:
6.1 g of 5,7-dihydro-2-mercapto-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(1H)-one were suspended in 100 ml of alcohol and treated while cooling with ice with 5.2 g of 2-chloromethyl-4-ethoxy-5-methylpyridine hydrochloride. Thereafter, a solution of 1.9 g of sodium hydroxide in 50 ml of water was added dropwise thereto, the mixture was left to boil at reflux overnight and subsequently evaporated to dryness in vacuo. The residue was dissolved in 300 ml of methylene chloride. The solution was washed firstly with 200 ml of 1.5N sodium hydroxide solution and then with 3×200 ml of water, dried over sodium sulfate and evaporated in vacuo. The product was purified on 120 g of silica gel with ethyl acetate/methylene chloride (1:1) as the elution agent. Crystallization from methylene chloride/petroleum ether gave 2-[[(4-ethoxy-5-methyl-2pyridyl)methyl]thio]-5,7-dihydro-5,5,7,7-tetramethylindeno [5,6-d]imidazol-6(1H)- one of melting point 187°-189° .
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[CH:9]=[N:8][CH:7]=[C:6]([N:11]3[CH2:19][C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Cl:20])[CH:17]=4)[C:12]3=[O:21])[C:5]=2[CH2:4][CH2:3]1.CCN(CC)CC.[C:29](Cl)(=[O:31])[CH3:30]>C(Cl)Cl>[Cl:20][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:21])[N:11]([C:6]1[C:5]3[CH2:4][CH2:3][CH:2]([NH:1][C:29](=[O:31])[CH3:30])[C:10]=3[CH:9]=[N:8][CH:7]=1)[CH2:19]2
Reactant: CC(=O)Cl
Reactant: NC1CCc2c1cncc2N1Cc2cc(Cl)ccc2C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC1CCc2c1cncc2N1Cc2cc(Cl)ccc2C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
To a stirred solution of 2-(7-amino-6,7-dihydro-5H-[2]pyrindin-4-yl)-5-chloro-2,3-dihydro-isoindol-1-one (126 mg, 0.42 mmol) and Et3N (1.0 mL) in DCM (10 mL) was added acetyl chloride (0.032 mL, 0.44 mmol) at 0° C. and stirred at 0° C. for 1 hour. The resulting mixture was extracted with EtOAc (2×100 mL) and the combined organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with a 0 to 50% EtOAc-heptane gradient to give a racemic mixture of title compound (121 mg, 85%) as light yellow solid. MS: 342.1 (M+H+). This racemic mixture was then separated by chiral HPLC to afford (−)-N-[(S or R)-4-(5-chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-6,7-dihydro-5H-[2]pyrindin-7-yl]-acetamide (33 mg, example 318), MS: 342.1 (M+H+) and (+)-N—[(R or S)-4-(5-chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-6,7-dihydro-5H-[2]pyrindin-7-yl]-acetamide (27 mg, example 319). MS: 342.1 (M+H)+.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Br:8][C:9]1[CH:10]=[C:11]([CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1)[NH2:12]>>[Br:8][C:9]1[CH:10]=[C:11]([NH:12][C:5](=[O:7])[CH3:6])[CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1
Reactant: Nc1cc(Br)cc([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(Br)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
Acetic anhydride (14 ml) was added dropwise at 0° C. to 3-bromo-5-nitroaniline (14 g, 64.5 mmol). The mixture was stirred for 30 min at RT and then quenched by the addition of crushed ice. The precipitate formed was filtered and washed with cold water to obtain off-white solid. The solid was dried under vacuum to give the product in 78% yield (13 g). 1H NMR (300 MHz, DMSO-d6): δ 10.54 (br s, 1H), 8.45 (s, 1H), 8.2 (s, 1H), 8.03 (s, 1H), 2.11 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=O)(C)(C)C.[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.[NH2:35][CH2:36][CH:37]([OH:48])[CH2:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=1>>[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([S:25]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:35][CH2:36][CH:37]([OH:48])[CH2:38][O:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)=[O:18])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: COc1ccc(OCC(O)CN)cc1
Product: CON=C1C[C@@H](C(=O)NCC(O)COc2ccc(OC)cc2)N(S(=O)(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-sulfonyl chloride, and (2RS)-1-amino-3-(4-methoxyphenoxy)-2-propanol, the title compound was obtained in 69% purity by HPLC. MS(ESI+): m/z=554.
Reaction SMILES: [N:1]1([C:7]2[CH:28]=[CH:27][C:10]([NH:11][C:12]3[N:17]=[C:16]([C:18]4[N:22]([CH:23]([CH3:25])[CH3:24])[C:21]([CH3:26])=[N:20][CH:19]=4)[CH:15]=[CH:14][N:13]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[CH2:37][CH2:38][S:39](Cl)(=[O:41])=[O:40].CO.C(Cl)Cl>C(Cl)Cl>[CH:38]([S:39]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:28]=[CH:27][C:10]([NH:11][C:12]3[N:17]=[C:16]([C:18]4[N:22]([CH:23]([CH3:25])[CH3:24])[C:21]([CH3:26])=[N:20][CH:19]=4)[CH:15]=[CH:14][N:13]=3)=[CH:9][CH:8]=2)[CH2:2][CH2:3]1)(=[O:41])=[O:40])=[CH2:37]
Reactant: O=S(=O)(Cl)CCCl
Reactant: Cc1ncc(-c2ccnc(Nc3ccc(N4CCNCC4)cc3)n2)n1C(C)C
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: C=CS(=O)(=O)N1CCN(c2ccc(Nc3nccc(-c4cnc(C)n4C(C)C)n3)cc2)CC1
Reaction time: 1.25 h

Procedure:
2-[4-(Piperazin-1-yl)anilino]-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidine (Example 20; 370 mg 0.98 mmol) was stirred in DCM (10 ml) at room temperature. Triethylamine (150 mg 1.49 mmol) was added followed by dropwise addition of 2-chloro-1-ethanesulphonyl chloride (196 mg 1.2 mmol) in DCM (1 ml). After stirring for 1.25 hours, the reaction was evaporated under reduced pressure and triturated with ether. The resulting solid was treated with water (15 ml), the basified with saturated sodium hydrogen carbonate solution and extracted into DCM (2×20 ml). The organics were washed with brine (10 ml), dried and evaporated to give a gum. After chromatography on silica gel using MeOH:DCM (3:97 to 5:95), the title compound was obtained as a yellow solid (140 mg 30.4%). NMR 1.39 (d, 6H), 2.46 (s, 3H), 3.16 (s, 8H), 5.68 (septuplet, 1H), 6.20 (d, 1H), 6.85 (dd, 1H), 6.91 (d, 2H), 6.95 (d, 1H), 7.38 (s, 1H), 7.47 (d, 2H), 8.30 (d, 1H), 9.16 (s, 1H); m/z 468.
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH2:17]Cl)[C:11]=2[OH:19])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH3:20][C:21]1([CH3:29])[CH2:26][CH:25]([CH3:27])[CH2:24][CH:23]([OH:28])[CH2:22]1.[H-].[Na+]>O1CCOCC1>[N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH2:17][O:28][CH:23]3[CH2:24][CH:25]([CH3:27])[CH2:26][C:21]([CH3:29])([CH3:20])[CH2:22]3)[C:11]=2[OH:19])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC1CC(O)CC(C)(C)C1
Reactant: Cc1cc(CCl)c(O)c(-n2nc3ccccc3n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(COC2CC(C)CC(C)(C)C2)c(O)c(-n2nc3ccccc3n2)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
2-(2H-Benzotriazol-2-yl)-6-chloromethyl-4-methyl-phenol (0.8 g, 2.9 mmol) is partly solved in dioxane (23 mL) at 80° C. 3,3,5-Trimethyl-cyclohexanol (12.3 g, 86 mmol) and sodium hydride (200 mg, 5 mmol, 60% in mineral oil) are added subsequently. The orange reaction mixture is stirred at 70° C. for one hour and evaporated to dryness. The residue is dissolved in ethyl acetate and extracted with water. The organic layer is dried over sodium sulphate, filtered and evaporated to dryness. The crude product is purified by column chromatography (ethyl acetate/heptane 1:4) to yield 0.8 g of 2-(2H-Benzotriazol-2-yl)-6-(3,3,5-trimethyl-cyclohexyloxymethyl)-4-methyl-phenol.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=[C:4]([N:12]([CH2:16][CH:17]=[CH2:18])[CH2:13][CH:14]=[CH2:15])[N:3]=1.C(N(CC)CC)C.[ClH:26].[C:27]([Cl:35])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1.Cl>C(Cl)Cl.O1CCOCC1>[ClH:35].[ClH:26].[CH2:13]([N:12]([CH2:16][CH:17]=[CH2:18])[C:4]1[N:3]=[C:2]([NH:1][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=2)[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=1)[CH:14]=[CH2:15]
Reactant: O=C(Cl)c1cccnc1
Reactant: C=CCN(CC=C)c1nc(N)n2oc(=O)nc2n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C=CCN(CC=C)c1nc(NC(=O)c2cccnc2)n2oc(=O)nc2n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
4.5 g. of 7-amino-5-diallylamino-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-2-one are suspended in 100 ml. of methylene chloride and 15 ml. of triethylamine. A suspension of 4.5 g. of nicotinoyl chloride hydrochloride in 50 ml. of methylene chloride is slowly added dropwise at 0° C. The dark solution is stirred at 0° C. for 2 hours, then washed twice with water and dried over sodium sulfate. The solvent is distilled off under reduced pressure and the residue is chromatographed over silica gel. The thus-obtained crude product is treated in methylene chloride with hydrochloric acid in dioxan, there being obtained pure N-{5-diallylamino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-7-yl}nicotinamide dihydrochloride having a melting point of 135°-140° C.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[N:9]([C:16](=O)[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[F:26])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:3])[NH2:2].[H-].[Na+].Cl>CN(C=O)C.CCOCC>[F:26][C:20]1[C:21]([F:25])=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][CH2:17][C:16]1[N:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:8]2[CH:7]=[CH:6][S:5][C:4]=2[C:1](=[O:3])[N:2]=1
Reactant: CCOC(=O)CN(C(=O)CCc1cccc(F)c1F)c1ccsc1C(N)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(CCc2cccc(F)c2F)nc(=O)c2sccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
Ethyl 2-((2-carbamoylthiophen-3-yl)-(3-(2,3-difluorophenyl)propanoyl)amino)acetate (Int. B56) (500 mg) in dry DMF (3 ml) was cooled in an ice bath and treated portion wise with sodium hydride (50 mg, 60% dispersion in oil). The reaction mixture was stirred at room temperature for 30 min to give an orange homogeneous solution. Excess 1 M hydrogen chloride in ether was added giving a pale yellow solution and a precipitate. The mixture was heated in an oil bath at 120° C. for 30 min. The solution was concentrated and re-dissolved in ethyl acetate. The solution was washed with saturated sodium bicarbonate, brine, dried and concentrated in vacuo to give a solid. Trituration with ether afforded the title compound as a white solid (375 mgs, 78%); 1H-NMR (CDCl3) δ 1.29 (3H, t), 3.01 (2H, t), 3.30 (2H, t), 4.29 (2H, q), 4.84 (2H, s), 6.96 (1H, d), 7.03, (3H, m) and 7.77 (1H, d). (APCI+) Found (M+1)=379, C18H16F2N2O3S requires 378.