Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([O:21][CH2:22]/[CH:23]=[C:24](/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])\[CH3:25])[CH:20]=1)[C:15]([OH:17])=O)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[NH2:32][CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][N:35]1[CH2:39][CH3:40]>>[CH2:39]([N:35]1[CH2:36][CH2:37][CH2:38][CH:34]1[CH2:33][NH:32][C:15](=[O:17])[C:14]1[CH:18]=[C:19]([O:21][CH2:22]/[CH:23]=[C:24](/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])\[CH3:25])[CH:20]=[C:12]([O:11][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4])[CH:13]=1)[CH3:40]
Reactant: CCN1CCCC1CN
Reactant: CC(C)=CCC/C(C)=C/COc1cc(OC/C=C(\C)CCC=C(C)C)cc(C(=O)O)c1
Product: CCN1CCCC1CNC(=O)c1cc(OC/C=C(\C)CCC=C(C)C)cc(OC/C=C(\C)CCC=C(C)C)c1
Yield: 82 %

Procedure:
In a manner identical to Example 15, 3,5-digeranyloxybenzoic acid (2.13 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.7 ml), thereby yielding 2.14 g (82%) of the aimed compound
Reaction SMILES: C([N:5]1[C:18](=[O:19])[N:8]2[CH:9]=[C:10]([C:14]([CH3:17])([CH3:16])[CH3:15])[N:11]=[C:12]([Cl:13])[C:7]2=[N:6]1)(C)(C)C.[Cl-].[Cl-].[Cl-].[Al+3]>ClCCCl>[C:14]([C:10]1[N:11]=[C:12]([Cl:13])[C:7]2[N:8]([C:18](=[O:19])[NH:5][N:6]=2)[CH:9]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1cn2c(=O)n(C(C)(C)C)nc2c(Cl)n1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(C)(C)c1cn2c(=O)[nH]nc2c(Cl)n1
Temperature: 80 °C

Procedure:
A solution of 4.10 g of the product of Step E in 1,2-dichloroethane (142 mL) was treated with 5.60 g of aluminum trichloride and the suspension was heated to 80° C. After two h, the reaction mixture was cooled to ambient temperature and poured into ice water (500 g). After the ice had dissolved, the mixture was extracted with EtOAc and the organic layer was washed with sat. sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to afford 6-tert-butyl-8-chloro-2H-[1,2,4]triazolo[4,3-a]pyrazin-3-one as a yellow solid. MS (M+H+)=227.3.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[CH2:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1>>[N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[CH2:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[C:6]([C:10]([O:12][CH3:13])=[O:11])[CH:5]=3)[NH:1][CH:2]=2)=[CH:32][CH:33]=1
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Reactant: ClCc1ccc(OCc2ccc3ccccc3n2)cc1
Product: COC(=O)c1ccc2[nH]cc(Cc3ccc(OCc4ccc5ccccc5n4)cc3)c2c1

Procedure:
This compound was prepared from methyl indole-5-carboxylate and 4-(quinolin-2-ylmethoxy)benzyl chloride (Example 1a) by the method described in Example 12, part i, m.p. 179°-180° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:13]=[C:14]([CH3:15])[C:3]=12.[CH3:22][NH:23][CH3:24].O1CCCC1>O>[CH3:22][N:23]([CH3:24])[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:13]=[C:14]([CH3:15])[C:3]=12
Reactant: Cc1nn(-c2ccccn2)c2nc3ccccc3c(Cl)c12
Reactant: CNC
Solvent: O
Solvent: C1CCOC1
Product: Cc1nn(-c2ccccn2)c2nc3ccccc3c(N(C)C)c12
Temperature: 100 °C
Yield: 97 %

Procedure:
4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (1.00 g, 3.39 mmol) was added to a 2M dimethylamine in tetrahydrofuran solution (5.00 mL, 10.0 mmol), and the solution was heated under reflux overnight at 100° C. in a sealed tube. The solution was cooled to room temperature and poured into water, and the organic matter was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (ethyl acetate to ethyl acetate:methanol=9:1) to give the title compound (1.00 g, 97% yield).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[NH:33][C:20]3[C:21](=[O:32])[N:22]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:23]=[CH:24][C:19]=3[N:18]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:41]([C:43]1[CH:50]=[CH:49][CH:48]=[CH:47][C:44]=1[CH2:45]Br)#[N:42]>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:34])[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[N:33]([CH2:45][C:44]3[CH:47]=[CH:48][CH:49]=[CH:50][C:43]=3[C:41]#[N:42])[C:20]3[C:21](=[O:32])[N:22]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:23]=[CH:24][C:19]=3[N:18]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1CBr
Reactant: O=C(NC1CCCC(c2nc3ccn(Cc4ccccc4)c(=O)c3[nH]2)C1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccccc1Cn1c(C2CCCC(NC(=O)OCc3ccccc3)C2)nc2ccn(Cc3ccccc3)c(=O)c21
Temperature: 25 °C
Reaction time: 17 h
Yield: 66 %

Procedure:
To a solution of [3-(5-benzyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-yl)-cyclohexyl]-carbamic acid benzyl ester (0.1 g, 0.22 mmol) in DMF (3 mL) were added Cs2CO3 (0.14 g, 0.44 mmol) and a solution of 2-cyanobenzyl bromide (52 mg, 0.26 mmol) in 3 mL DMF. After stirring for 17 h at room temperature, the reaction mixture was diluted with water (10 mL) and extracted with CH2Cl2. The combined extracts were dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash chromatography, eluting with 1% MeOH in CH2Cl2 to give {3-[5-benzyl-3-(2-cyano-benzyl)-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-yl]-cyclohexyl}-carbamic acid benzyl ester (83 mg, 66% yield). 1H-NMR (CDCl3): δ 7.73 (m, 1H), 7.48 (m, 1H), 7.32 (m, 1H), 7.15 (d, 1H, J=7.2 Hz), 6.90 (d, 1H, J=8.0 Hz), 6.68 (d, 1H, J=7.6 Hz), 6.21 (m, 1H), 5.92 (m, 1H), 5.05 (s, 2H), 4.70 (m, 1H), 3.58 (m, 1H), 2.80 (m, 1H), 2.01 (m, 2H), 1.85 (m, 1H), 1.70 (m, 2H), 1.51 (m, 2H), 1.17 (m, 1H). MS: calculated for C35H33N5O3+H 572.3; found: 572.5.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2Br)[O:9][N:8]=1.O.[CH3:22][N:23](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[C:22]#[N:23])[O:9][N:8]=1
Reactant: COc1ccc(Br)c(-c2nc(-c3ccccn3)no2)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: COc1ccc(C#N)c(-c2nc(-c3ccccn3)no2)c1
Temperature: 80 °C
Yield: 4 %

Procedure:
In a similar fashion, a mixture of 3-(2-pyridyl)-5-(2-bromo-5-methoxyphenyl)-1,2,4-oxadiazole (33.2 mg, 0.1 mmol), zinc cyanide (17.6 mg, 0.15 mmol) and Pd(PPh3)4 (11.5 mg, 0.01 mmol) in N,N-dimethylformamide (1 mL) was heated under an argon atmosphere at 80° C. for 16 hours. After cooling, the reaction mixture was poured into water and the crude product extracted with dichloromethane. Silica gel chromatography using 50% ethyl acetate in hexane afforded 1.1 mg (4%) of 3-(2-pyridyl)-5-(2-cyano-5-methoxyphenyl)-1,2,4-oxadiazole.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[CH2:22]([O:29][C:30](Cl)=[O:31])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C1C=CC=CC=1>[C:30](=[O:31])([O:29][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1
Reactant: CCCCCCCOC(=O)Cl
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCOC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
0.976 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 10 ml. of absolute pyridine and reacted with 1.07 g. of chloroformic acid n-heptyl ester as in Example 1. The 1.8 g. of yellow oil obtained according to the procedure described in Example 1 is dissolved in benzene and chromatographed on 90 g. of silica gel. Benzene elutes 1.782 g. of colorless crystals which are recrystallized from ether-hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl n-heptyl carbonate obtained melts at 50.2°-50.5° and has a clearing point of 65.2°. UV (EtOH): ε 270 = 25900.
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:36])[CH2:7][CH:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:14][CH:13]=1)[C:9]#[C:10][CH3:11])C.Cl>C(O)C.O>[CH3:25][C:24]1[O:23][C:22]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:34])([F:33])[F:35])=[CH:28][CH:27]=2)=[N:21][C:20]=1[CH2:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH:8]([C:9]#[C:10][CH3:11])[CH2:7][C:6]([OH:36])=[O:5])=[CH:17][CH:16]=1
Reactant: CC#CC(CC(=O)OCC)c1ccc(OCc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC#CC(CC(=O)O)c1ccc(OCc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
2N KOH(aq) was added to a solution of 18.3 (304 mg, 0.65 mmol) in ethanol (5 mL). The reaction was stirred at room temperature overnight and then taken up in copious water. The aqueous solution was adjusted to pH=2.0 with 1N HCl(aq) and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water, followed by brine. The solvent was removed under reduced pressure and the resulting residue was purified via radial chromatography (40% ethyl acetate in Hexanes+0.1% AcOH) to yield 150 mg (52%) of compound 18 as a glass. LC/MSD m/e: 444.0 (M+H); 1H NMR (400 MHz) (acetone) δ 8.21 (2H, m), 7.89 (2H, d, J=8.0 Hz), 7.38 (2H, m), 7.03 (2H, m), 5.06 (2H, s), 4.06 (1H, m), 2.70 (2H, m), 2.52 (3H, s), 1.81 (3H, s).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C@H:6]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[S:21][C:22]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)=[CH:23][C:24]=3[CH3:25])=[CH:14][CH:13]=2)[CH2:7][C:8]([O:10]C)=[O:9])=[N:2]1.[Li+].[OH-]>C1COCC1.CO>[O:1]1[CH:5]=[CH:4][C:3]([C@H:6]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]3[S:21][C:22]([C:26]4[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=4)=[CH:23][C:24]=3[CH3:25])=[CH:16][CH:17]=2)[CH2:7][C:8]([OH:10])=[O:9])=[N:2]1
Reactant: COC(=O)C[C@@H](c1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)cc2C)cc1)c1ccon1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc([C@H](CC(=O)O)c2ccon2)cc1
Temperature: 25 °C
Yield: 71 %

Procedure:
To a solution of 62.9 (64 mg, 0.13 mmol) in 3:1 THF/MeOH (2.8 mL) was added 1N LiOH (0.7 mL). The mixture was stirred for 1 Hour at room temperature, quenched with 1N HCl (0.8 mL), and extracted with EtOAc. The combined organics were washed with water and brine, dried (Na2SO4), and concentrated to afford 62 (45 mg, 70%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.29 (d, 1H), 7.65 (d, 2H), 7.60 (d, 2H), 7.20 (d, 2H), 7.15 (s, 1H), 6.95 (d, 2H), 6.07 (d, 1H), 5.10 (s, 2H), 4.55 (t, 1H) 3.35 (dd, 1H), 2.98 (dd, 1H), 2.28 (s, 3H).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].CC(C)([O-])C.[K+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:30])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)=[CH:17][C:16]=1[F:31]>O1CCCC1>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:30])[CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[CH2:3][CH:2]([CH3:4])[C:1]([O:6][CH3:7])=[O:5])=[CH:17][C:16]=1[F:31]
Reactant: O=C(Cc1cccc(Cl)c1)c1ccc(Cl)c(F)c1
Reactant: C=C(C)C(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(C)CC(C(=O)c1ccc(Cl)c(F)c1)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyl methacrylate (125.0 g, 1097 mmol) and potassium tert-butoxide (1 M in tetrahydrofuran, 115 mL, 115 mmol) were sequentially added to a solution of 1-(4-chloro-3-fluorophenyl)-2-(3-chlorophenyl)ethanone (327.0 g, 1160 mmol, Example 4, Step B) in anhydrous tetrahydrofuran (2.61 L), at 0° C. The reaction mixture was stirred for 1 hour at 0° C. and then warmed to ambient temperature and stirred for 12 hours. On completion, the reaction was quenched with water (1.0 L) and extracted with ethyl acetate (2×2.5 L). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to get the crude material which was purified by flash column chromatography (silica gel: 60 to 120 mesh, product eluted in 4% ethyl acetate in hexane) affording the title compound (mixture of diastereomers) as light yellow liquid.
Reaction SMILES: OS(O)(=O)=O.N([O-])=O.[Na+].N[C:11]1[C:12]([Cl:20])=[C:13]([C:16]([Cl:19])=[CH:17][CH:18]=1)[C:14]#[N:15].[BrH:21]>C(O)(=O)C>[Br:21][C:11]1[C:12]([Cl:20])=[C:13]([C:16]([Cl:19])=[CH:17][CH:18]=1)[C:14]#[N:15]
Reactant: Br
Reactant: N#Cc1c(Cl)ccc(N)c1Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1c(Cl)ccc(Br)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 1 mL of conc. H2SO4 was portionwise added sodium nitrite (1.38 mmol). After complete dissolution, a solution of 3-amino-2,6-dichlorobenzonitrile (1.24 mmol) in 2.5 mL glacial acetic acid was added at 0° C. After 30 min at 0° C., a precooled solution of CuBr (2.76 mmol) in 0.5 mL HBr (48% in H2O) was slowly added. The reaction was stirred at 0° C. for 45 min and then at RT for 45 min. The mixture was quenched with water and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo to give the desired product as brown solid.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].C(=O)([O-])[O-].[K+].[K+].Cl.[C:18]([C:22]1[CH:26]=[C:25]([NH2:27])[N:24]([CH:28]([CH3:30])[CH3:29])[N:23]=1)([CH3:21])([CH3:20])[CH3:19].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:18]([C:22]1[CH:26]=[C:25]([NH:27][C:2](=[O:3])[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:24]([CH:28]([CH3:30])[CH3:29])[N:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)n1nc(C(C)(C)C)cc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)n1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
To a mixture of phenyl chloroformate (170 mg, 1.1 mmol) and potassium carbonate (210 mg, 1.5 mmol) in DCM (3 mL) at 0° C., was added dropwise a solution of 3-tert-butyl-1-isopropyl-1H-pyrazol-5-amine hydrochloride (220 mg, 1 mmol) in N,N-diisopropylethylamine (130 mg, 1 mmol) and the reaction mixture was stirred at 0° C. for 3 h. The mixture was filtrated, concentrated under reduced pressure, and the residue dissolved in dichloromethane. The organic phase was washed water, brine and concentrated under reduced pressure to give the crude product which was purified via recrystallization from diethyl ether to afford phenyl 3-tert-butyl-1-isopropyl-1H-pyrazol-5-ylcarbamate (300 mg, 100%) as a colorless solid. LC-MS (ESI) m/z 302 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:22])[C:5]2=[C:6]([CH2:8][C@H:9]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[Br:21])[NH:10]/[C:11]/2=[N:12]\[OH:13])[N:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:30][CH2:31][C@H:32]1[CH2:36][O:35][C:34]([CH3:38])([CH3:37])[O:33]1>CN(C=O)C>[CH3:37][C:34]1([CH3:38])[O:33][C@@H:32]([CH2:31][CH2:30][O:13]/[N:12]=[C:11]2\[NH:10][C@@H:9]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[Br:21])[CH2:8][C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([CH3:22])[C:5]\2=3)[CH2:36][O:35]1
Reactant: Cc1nc(N)nc2c1/C(=N/O)N[C@@H](c1ccc(F)cc1Br)C2
Reactant: CC1(C)OC[C@H](CCI)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nc(N)nc2c1/C(=N/OCC[C@H]1COC(C)(C)O1)N[C@@H](c1ccc(F)cc1Br)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
To a solution of (R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one oxime (85c, 9.2 mg, 0.025 mmol) in dry DMF (1 mL) was added Cs2CO3 (12.2 mg, 0.0375 mmol) and the reaction mixture stirred at ambient temperature for 30 minutes. Then, (S)-4-(2-iodoethyl)-2,2-dimethyl-1,3-dioxolane (85d, 7.68 mg, 0.03 mmol) was added and the reaction mixture stirred overnight. LCMS showed complete consumption of the starting material. The reaction mixture was poured onto crushed ice and the resulting solid was filtered and rinsed with cold water. Drying afforded (R,Z)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one O-2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)ethyl oxime (7.8 mg, 63%) as a light brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.35 (s, 3H) 1.41 (s, 3H) 2.02 (qd, J=6.32, 3.03 Hz, 2H) 2.75 (s, 3H) 2.94 (dd, J=16.42, 8.84 Hz, 1H) 3.17 (dd, J=16.42, 4.55 Hz, 1H) 3.59 (dd, J=8.08, 7.07 Hz, 1H) 4.09 (dd, J=8.08, 6.06 Hz, 1H) 4.17-4.28 (m, 3H) 4.98 (ddd, J=8.72, 4.55, 1.64 Hz, 1H) 7.07 (td, J=8.27, 2.65 Hz, 1H) 7.34 (dd, J=8.08, 2.78 Hz, 1H) 7.43 (dd, J=8.72, 5.94 Hz, 1H). MS (ES) [M+H] calculated for C21H27BrFN5O3, 495.11. found 495.30.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9]=2[OH:17])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[NH3:26]>>[NH2:26]/[C:6](/[C:5]1[CH:18]=[CH:19][C:2]([CH3:1])=[CH:3][CH:4]=1)=[C:8]1\[C:9](=[O:17])[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[S:12]\1
Reactant: N
Reactant: Cc1ccc(C(=O)c2sc3ccccc3c2O)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: Cc1ccc(/C(N)=C2\Sc3ccccc3C2=O)cc1
Yield: 62 %

Procedure:
Prepared as in Example 1 from 2-(4-methylbenzoyl)-benzo[b]thiophen-3-ol, phosphorus(V) chloride and concentrated ammonia with a yield of 62% theory.
Reaction SMILES: COS(OC)(=O)=O.[CH3:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][N+:10]=1[O-].[C-:19]#[N:20].[K+]>O>[CH3:8][C:9]1[N:10]=[C:11]([C:19]#[N:20])[CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1
Reactant: [C-]#N
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Agent: [K+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: Cc1cc([N+](=O)[O-])cc(C#N)n1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 72.1 %

Procedure:
To 10.2 ml (13.5 g, 104 mmol, 1.1 equiv.) of dimethylsulfate were added 15.0 g (94.4 mmol) of 2-Methyl-4-nitropyridine-N-oxide at 60° C. The reaction mixture was then stirred for 90 min at 70° C., and allowed to cool to room temperature. The solidified residue was triturated with 30 ml of ether. The product was filtered, washed with 20 ml of ether, and dried. The product was then dissolved in 100 ml of water and added dropwise over a period of 30 min. to a at −8° C. cooled solution of 24.6 g (377 mmol, 4.0 equiv.) of potassium cyanide in 100 ml of water. The reaction mixture was stirred for a further 15 min. at −8° C. The product was filtered off, washed twice with 15 ml of water and dried in vaccuo to yield the title compound (11.1 g, 72%) as a light brown solid.
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]1[CH2:19][CH2:18][CH2:17][CH:16]([NH:20][C:21](=[O:39])[C@@H:22]([NH:27][C:28]([C:30]2[O:31][C:32]3[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=3[CH:34]=2)=[O:29])[CH2:23][CH:24]([CH3:26])[CH3:25])[CH:15]([OH:40])[CH2:14]1)(=[O:12])=[O:11].CO.O>>[O:31]1[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[CH:34]=[C:30]1[C:28]([NH:27][C@@H:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:21]([NH:20][CH:16]1[CH2:17][CH2:18][CH2:19][N:13]([S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:41])=[O:2])(=[O:11])=[O:12])[CH2:14][CH:15]1[OH:40])=[O:39])=[O:29]
Reactant: COC(=O)c1ccccc1S(=O)(=O)N1CCCC(NC(=O)[C@H](CC(C)C)NC(=O)c2cc3ccccc3o2)C(O)C1
Solvent: CO
Solvent: O
Product: CC(C)C[C@H](NC(=O)c1cc2ccccc2o1)C(=O)NC1CCCN(S(=O)(=O)c2ccccc2C(=O)O)CC1O
Yield: 27.2 %

Procedure:
2-(4-{(S)-2-[(benzofuran-2-carbonyl)-amino]-4-methyl-pentanoylamino}-3-hydroxy-azepane-1-sulfonyl)-benzoic acid methyl ester (compound 83a, 180 mg, 0.309 mmol) was dissolved in 5:1 MeOH/water (6 ml) LiOH (14 mg, 0.34 mmol) was added and the reaction mixture was stirred and refluxed for 6 h. The reaction mixture was then quenched with water and 6 N HCl (adjusted to pH=2), extracted with EtOAc (3×10 ml), dried with MgSO4, filtered, concentrated, and chromatographed (silica gel, 1% acetic acid/4% MeOH/CH2Cl2) to yield the title compound as a white solid (48 mg, 27%): M+H+=572.2
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.[N:21]([C@H:24]1[C@H:31]2[C@H:27]([CH2:28][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:30]2)[CH2:26][CH2:25]1)=[N+]=[N-]>O1CCCC1>[CH2:32]([N:29]1[CH2:30][C@H:31]2[C@H:24]([NH2:21])[CH2:25][CH2:26][C@H:27]2[CH2:28]1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: [N-]=[N+]=N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Temperature: 80 °C

Procedure:
Triphenylphosphine (4.49 g, 17.13 mmol) and water (1.234 mL, 68.5 mmol) were added successively to a mixture of (3aS,4R,6aR)-4-azido-2-benzyloctahydrocyclopenta[c]pyrrole (1.384 g, 5.71 mmol) in tetrahydrofuran (30 mL). The reaction was refluxed at 80° C. for 2 hours. The crude material was adsorbed onto silica gel and applied to a silica gel cartridge (Analogix®, Burlington, Wis., RS-40) and eluted with 1-10% methanol (2 N ammonia)/chloroform to give (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.45 (d, J=7.4, 2H), 7.38 (t, J=7.5, 2H), 7.29 (t, J=7.3, 1H), 3.52 (s, 2H), 3.14 (dd, J=5.7, 10.7, 1H), 2.62-2.55 (m, 1H), 2.52 (dd, J=3.2, 9.0, 1H), 2.38-2.29 (m, 3H), 2.20-2.13 (m, 1H), 2.01-1.84 (m, 2H), 1.40-1.29 (m, 2H).
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9](Cl)=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([C:9]([C:8]3[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:7]=3[N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:10])[CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Reactant: Clc1ccc(N2CCNCC2)cc1
Product: O=C(c1cc([N+](=O)[O-])ccc1N1CCOCC1)N1CCN(c2ccc(Cl)cc2)CC1

Procedure:
The title compound was prepared according to the procedure described for example 46 from 2-morpholin-4-yl-5-nitro-benzoyl chloride and 4-chloro-phenyl-piperazine (orange solid), MS (m/e): 449.2 (M+H, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:21]([F:24])([F:23])[F:22])=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=2)[CH:7]=1.[C:25]1([CH3:37])[CH:30]=[CH:29][C:28]([S:31]([N:34]=[C:35]=[O:36])(=[O:33])=[O:32])=[CH:27][CH:26]=1>ClCCl>[CH3:37][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:34][C:35](=[O:36])[O:17][CH2:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[CH:7]=[C:2]([Cl:1])[C:3]([C:21]([F:22])([F:23])[F:24])=[CH:4][C:5]=3[N+:18]([O-:20])=[O:19])=[CH:10][CH:11]=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)cc1Nc1ccc(CCO)cc1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(Nc3cc(Cl)c(C(F)(F)F)cc3[N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
To a stirred solution of 2-(4-{[5-chloro-2-nitro-4-(trifluoromethyl)phenyl]amino}phenyl)ethanol (step 2 of Example 104, 1.0 g, 2.77 mmol) in dichloromethane (45 ml) was added p-toluenesulfonyl isocyanate (574 mg, 2.91 mmol), and the mixture was stirred at room temperature for 2 h. The mixture was quenched with water (100 ml). The organic layer was separated. The aqueous layer was extracted with dichloromethane (100 ml×3). The combined organic layer was washed with brine (50 ml), dried (MgSO4), and concentrated. Purification by flash column chromatography eluting with hexane/ethyl acetate (gradient elution from 2:1 to 1:1) to afford 1.51 g (98%) of the title compound as an orange solid.