Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:14][C:15]([N:17]([CH2:29][C:30]([NH:32][NH2:33])=[O:31])[CH:18]1[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:19]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[CH2:34]([O:41][N:42]1[C:48](=[O:49])[N:47]2[CH2:50][C@H:43]1[CH2:44][CH2:45][CH:46]2[C:51](O)=[O:52])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:34]([O:41][N:42]1[C:48](=[O:49])[N:47]2[CH2:50][C@H:43]1[CH2:44][CH2:45][C@H:46]2[C:51]([NH:33][NH:32][C:30](=[O:31])[CH2:29][N:17]([C:15]([O:14][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:16])[CH:18]1[CH2:21][N:20]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:19]1)=[O:52])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CC(N(CC(=O)NN)C(=O)OC(C)(C)C)C1
Reactant: O=C(O)C1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(N(CC(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
DIPEA (14 g, 0.11 mol) was added to a 0° C. solution of tert-butyl 3-(tert-butoxycarbonyl(2-hydrazinyl-2-oxoethyl)amino)azetidine-1-carboxylate (15 g, 0.044 mol), (5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (10 g, 0.036 mol) and HATU (15 g, 0.04 mol) in CH2Cl2 (250 mL). The mixture was allowed to warm to rt then was stirred at rt for 2 hrs. The mixture was quenched with saturated sodium chloride (50 mL) and the organic layer was separated. The water layer was extracted with EtOAc (3×). The combined organic layer was washed with saturated sodium chloride (2×), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (gradient elution 0-50% EtOAc/petroleum ether) to afford tert-butyl 3-((2-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-2-oxoethyl)(tert-butoxycarbonyl)amino)azetidine-1-carboxylate (18.5 g, 86%). ESI-MS (EI+, m/z): 603.3 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]2[N:8]=[C:9]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[C:10]([C:11]#[N:12])=[C:4]2[NH:3]1.[H-].[Na+].[CH3:21]I.O>CN(C=O)C>[CH3:21][N:3]1[C:2](=[O:1])[CH2:7][CH2:6][N:5]2[N:8]=[C:9]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[C:10]([C:11]#[N:12])=[C:4]12
Reactant: N#Cc1c(-c2cccnc2)nn2c1NC(=O)CC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)CCn2nc(-c3cccnc3)c(C#N)c21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-oxo-2-(pyridin-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile (50 mg, 0.21 mmol) in DMF (2 mL) was added NaH (17 mg, 0.42 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 30 mins, then methyl iodide (30 mg, 0.21 mmol) was added. The mixture was stirred at 0° C. for an additional 30 mins. 1 mL of water was added to quench the reaction which was extracted with ethyl acetate. The combined organic extracts were dried, filtered and concentrated in vacuo. The residue was purified by HPLC to afford 4-methyl-5-oxo-2-(pyridine-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile: MS (m/z): 254.1 [M+H]+, 1H NMR (CD3OD, 400 MHz): δ8.06 (s, 1 H), 8.60 (d, 1 H, J=1.6 Hz), 8.36 (d, 1H, J=8.0 Hz), 7.59 (dd, 1 H, J=8.0 Hz, J=56 Hz), 4.44 (t, 2 H, J=7.6 Hz), 3.04 (t, 2H, J=7.6 Hz).
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10][N:11]([CH2:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[CH:21]3)[CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[C:8]([Cl:27])[N:7]=[C:6]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])[CH2:2][CH2:3][CH3:4].ClS([N:39]=[C:40]=O)(=O)=O.CN(C=O)C.[OH-].[NH4+]>C(#N)C>[CH2:1]([N:5]1[C:9]([CH2:10][N:11]([CH2:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[C:21]3[C:40]#[N:39])[CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])=[C:8]([Cl:27])[N:7]=[C:6]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH3:34])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(-c2ccccc2C)nc(Cl)c1CN(CCC(C)C)Cc1ccc2[nH]ccc2c1
Reactant: O=C=NS(=O)(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCCCn1c(-c2ccccc2C)nc(Cl)c1CN(CCC(C)C)Cc1ccc2[nH]cc(C#N)c2c1
Temperature: 0 °C
Yield: 6 %

Procedure:
To an ice-cooled solution of 5-{[(3-butyl-5-chloro-2-o-tolyl-3H-imidazol-4-ylmethyl)-(3-methyl-butyl)-amino]-methyl}-1H-indole (173 mg, 0.363 mmol) in 5 ml of anhydrous acetonitrile under nitrogen is added a solution of chlorosulfonyl isocyanate (69.5 mg, 0.491 mmol, 1.35 eq.) in 1 ml of acetonitrile, after stirring for 20 mim, a solution of DMF (30.1 mg) in 2 ml of acetonitrile is added dropwise, stirred for additional 1 h. The reaction mixture is poured into ice water and basified with diluted ammonium hydroxide solution; the mixture is extracted with dichloromethane, dried over sodium sulfate. The solvent is evaporated; the residue is purified through flash chromatography to give 11 mg of 5-{[(3-butyl-5-chloro-2-o-tolyl-3H-imidazol-4-ylmethyl)-(3-methyl-butyl)-amino]-methyl}-1H-indole-3-carbonitrile as white solid. 1H NMR (400 MHz, CDCl3) δ 7.63 (1H, s), 7.38 (1H, d, J=3Hz), 7.15˜7-36 (4H, m), 7.07 (4H, dd, J=1.2, 8.4 Hz), 6.89-6.93 (2H, m), 3.73 (2H, t, J=7.5 Hz), 3.65 (2H, s), 3.57 (2H, s), 2.55 (2H, d, f=6.9 Hz), 2.02 (3H, s), 1.62 (1H, m), 1.46 (2H, q, J=6.6 Hz), 1.14 (2H, m), 0.85 (6H, d, J=6.6 Hz), 0.75 (2H, m), 0.51 (3H, t, J=7.2 Hz); MS (+VE) m/z 502 (M+1).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([O:19][C:20]([N:22]1[CH2:28][CH:27]=[CH:26][CH2:25][CH2:24][CH:23]1[CH3:29])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[CH2:12]([O:19][C:20]([N:22]1[C@H:23]([CH3:29])[CH2:24][CH2:25][C@H:26]2[C@@H:27]([O:9]2)[CH2:28]1)=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1CCC=CCN1C(=O)OCc1ccccc1
Solvent: ClCCl
Product: C[C@@H]1CC[C@@H]2O[C@H]2CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 58.6 %

Procedure:
m-Chloro-perbenzoic acid (1.10 g, 57–86% pure) was added to a solution of 2-methyl-2,3,4,7-tetrahydro-azepine-1-carboxylic acid benzyl ester (0.72 g, 2.94 mmol) in CH2Cl2 at 0 degrees C. The reaction mixture was stirred for half an hour, then was warmed to RT. Additional m-chloro-perbenzoic acid (0.660 g, 57–86% pure) was added and the reaction was stirred 2 h. The reaction mixture was concentrated in vacuo by rotary evaporation, then 80 ml of 9:1 hexanes/EtOAc was added and the reaction mixture was filtered. The filtrate was concentrated in vacuo by rotary evaporation, then was chromatographed (silica gel, 20% EtOAc:hexanes) to give (1S,4R,7S)-4-methyl-8-oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acid benzyl ester (0.450 g, 75%) and the title compound (0.15 g, 25% yield): 1H NMR: 7.42–7.22 (m, 5H), 5.13 (2H, s), 4.50–4.15 (m, 2H), 3.27 (1H, d), 3.12–2.95 (1H, m), 2.15–1.70 (m, 2H), 1.47 (m, 2H), 1.12 (3H, d); Liquid Chromatgraphy/Electrospray mass spec: M+H+=262.0.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[CH:18][CH:17]=1)=[O:15])[CH2:7][CH2:6]2)#[N:2].[H-].[Na+].[CH3:31]I.O>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([N:13]([CH3:31])[C:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)=[CH:18][CH:17]=1)=[O:15])[CH2:7][CH2:6]2)#[N:2]
Reactant: CI
Reactant: N#Cc1ccc2c(c1)CCC(NC(=O)c1ccc(-c3ccc(F)cc3)cc1)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)c1ccc(-c2ccc(F)cc2)cc1)C1CCc2cc(C#N)ccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4′-Fluoro-biphenyl-4-carboxylic acid (6-cyano-1,2,3,4-tetrahydro-naphthalen-2-yl)-amide, 3, (0.200 g, 0.541 mmol) in anhydrous DMF (4 mL) is added 60% NaH dispersed in mineral oil (32 mg, 1.5 eq.) and the resulting solution is stirred at room temperature for 30 min. Methyl iodide (0.101 mL, 3 eq.) is added to the solution and the reaction solution is stirred for another 30 min. A minimal amount of water is added to quench the reaction and the mixture is dried over anhydrous MgSO4 then concentrated in vacuo to afford 0.201 g of the desired product which is used without further purification. LRMS: 385.22 (M+H).
Reaction SMILES: CC([N:5]([C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=1)=[S:27])[C@H:6]([C:23]([OH:25])=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][CH:9]=1)(C)C.BrC1C=CC2N=C(N[C@H](C(O)=O)[CH2:46][C:47]3[CH:52]=CC(OCCCC(=O)NC4NCCCN=4)=C[CH:48]=3)SC=2C=1>ClC1C=CC=CC=1.C(OCC)(=O)C>[Br:35][C:32]1[CH:31]=[CH:30][C:29]2[N:28]=[C:26]([NH:5][C@H:6]([C:23]([O:25][C:47]([CH3:52])([CH3:48])[CH3:46])=[O:24])[CH2:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][CH:9]=3)[S:27][C:34]=2[CH:33]=1
Reactant: CCOC(=O)CCCOc1ccc(C[C@@H](C(=O)O)N(C(=S)Nc2ccc(Br)cc2)C(C)(C)C)cc1
Reactant: O=C(CCCOc1ccc(C[C@H](Nc2nc3ccc(Br)cc3s2)C(=O)O)cc1)NC1=NCCCN1
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1ccc(C[C@H](Nc2nc3ccc(Br)cc3s2)C(=O)OC(C)(C)C)cc1
Reaction time: 2 h
Yield: 19.9 %

Procedure:
0.6 ml of SO2Cl2 in 5 ml of chlorobenzene is added to a solution of amino thiourea 8-1 (3 g, 5.3 mmol) in 60 ml of chlorobenzene at 0° C., agitation is carried out for 2 hours at ambient temperature, followed by diluting in ethyl acetate, washing, drying and evaporating the organic phase under reduced pressure, in order to obtain the crude product which is purified by chromatography eluting with a heptane/ethyl acetate mixture 80/20. 593 mg of expected product is obtained 8-2.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[C:9]=1[OH:15].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC#N>[CH2:16]([O:15][C:9]1[C:8]([Br:7])=[CH:13][CH:12]=[CH:11][C:10]=1[Br:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Oc1c(Br)cccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1cccc(Br)c1OCc1ccccc1
Temperature: 23 °C
Reaction time: 48 h

Procedure:
Powdered K2CO3 (27.6 g, 200 mmol, 2.0 equiv) was added to a solution of 2,6-dibromophenol (14) (25.0 g, 100 mmol, 1.0 equiv) in MeCN (300 mL). Benzyl bromide (18.0 g, 12.5 mL, 105 mmol, 1.05 equiv) was added slowly to the light blue suspension. The reaction temperature increased only from 22 to 24° C. over 5 min. The reaction suspension was heated at reflux for 6 hr, allowed to cool to room temperature and stand for 48 hr. The mixture was filtered, solids were washed with EtOAc (300 mL) and the filtrate was concentrated under reduced pressure. The residual oil was dissolved in 1:1 MTBE/heptanes (500 mL), the solution washed with 10% NaOH (100 mL), H2O (100 mL), brine (100 mL), dried over Na2SO4, filtered and the solution concentrated under reduced pressure giving 36.9 g (108%) of crude 15 as a yellow oil that crystallized after pumping on high vacuum for 1.5 hr. Crude 15 was used without further purification.
Reaction SMILES: C(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]([N+:13]([O-:15])=[O:14])[C:9](O)=[N:10][CH:11]=1>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:3][C:9]1[C:8]([N+:13]([O-:15])=[O:14])=[CH:7][C:6]([Cl:5])=[CH:11][N:10]=1
Reactant: O=C(Cl)Cl
Reactant: O=[N+]([O-])c1cc(Cl)cnc1O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(Cl)cnc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
75 g of phosgene are introduced at a temperature of 85°-95° C. over 1 hour into a mixture of 87.5 g of 5-chloro-2-hydroxy-3-nitropyridine in 500 ml of toluene and 3 ml of N,N-dimethylformamide. The reaction mixture is kept for 2 hours under reflux at 85°-95° C. and then allowed to cool to room temperature over a period of 18 hours. The reaction mixture is washed 3 times with water and the organic phase is dried over sodium sulfate and thereafter concentrated by evaporation. The crude product, obtained in the form of a brown oil, is crystallised from 200 ml of n-hexane, giving 67.5 g of 2,5-dichloro-3-nitropyridine (70% of theory) with a melting point of 38°-39° C.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:6]=1[O:7][CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH2:4][C:5]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:6]=1[O:7][CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(COc2cc(Cl)ccc2CN=[N+]=[N-])cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(COc2cc(Cl)ccc2CN)cc1
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To a solution of methyl 4-(2-azidomethyl-5-chlorophenoxymethyl)-benzoate (389 mg; prepared in Reference Example 49) in THF (4.0 ml), triphenylphosphine (462 mg) was added at room temperature. The mixture was stirred for 3 hours. After stirring, water was added thereto. The mixture was stirred for 15 hours. The reaction mixture was concentrated under the reduced pressure. the residue was purified on silica gel column chromatography (CHCL3:MeOH=50:1→10:1) to give the title compound (339 mg) having the following physical data.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.[CH2:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH3:19].C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH2:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:27][CH2:28][N:29]([C:2]2[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=2)[CH2:30][CH2:31]1)[CH3:19]
Reactant: CCc1ccccc1N1CCNCC1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCc1ccccc1N1CCN(c2nc(NCCO)nc(NCCO)c2C#N)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 1-(2-ethyl-phenyl)-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at 60° C. to yield 4-[4-(2-ethyl-phenyl)-piperazin-1-yl]-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, light brown solid; MS: [M+H]+=412.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:27]#[N:28])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]3[CH2:23][C:22]3([F:25])[F:24])[C:17]([OH:19])=O)[C:10](=[O:26])[CH:9]=2)[CH:7]=1.[NH2:29][C:30]1[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:32][CH:31]=1.CC(C)N=C=NC(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:27]#[N:28])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]3[CH2:23][C:22]3([F:25])[F:24])[C:17]([NH:29][C:30]3[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])=[CH:32][CH:31]=3)=[O:19])[C:10](=[O:26])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2CC2(F)F)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: COc1cn(C(CC2CC2(F)F)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
88.0 mg (215 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[2,2-difluorocyclopropyl]propanoic acid (mixture of two racemic diastereomers), 41.6 mg (215 μmol) of tert-butyl 4-aminobenzoate, 30.6 mg (215 μmol) of Oxima and 34.0 μl (215 μmol) of DIC in 2.1 ml of dimethylformamide were reacted according to General Method 5B. Yield: 101 mg (66% of theory)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1.[OH:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:5]([C:11]#[N:12])=[C:6]([O:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:7]=1
Reactant: OCCc1ccccn1
Reactant: CS(=O)c1nc(N)nc(-c2ccccn2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(OCCc2ccccn2)nc(N)nc1-c1ccccn1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyridin-2-yl-pyrimidine-5-carbonitrile, 2-(2-hydroxyethyl)pyridine and DBU in DME. ES-MS m/e (%): 319 (M+H+, 100).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH3:11])[CH3:10].[OH-].[K+]>C(O)C>[CH3:10][C:9]([CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH3:11])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(C(=O)OCC)=C(C)C
Reactant: Br[Mg]c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)C(C)(C)c1ccccc1
Temperature: 50 °C

Procedure:
Diethyl (α, α -dimethylbenzyl)malonate was prepared by the conjugate addition of phenyl magnesium bromide to diethyl isopropylidenemalonate as described by C. Holmberg [Liebigs Ann. Chem., 748 (1981)]. A solution of this diester (42.1 g, 0.15 mol) in ethanol (100 ml) was treated by dropwise addition with a solution of potassium hydroxide (8.48 g, 0.13 mol) in 100 ml of ethanol. After heating at 90° C. for 1 h and at 50° C. for 20 h, the reaction mixture was evaporated on the rotary evaporator to a residue. The residue was diluted with water and extracted with ether to remove unreacted starting material. The aqueous phase was cooled to 5° C., acidified to pH 3 with 6N HCl, and extracted with methylene chloride. The organic layer was washed with brine solution and dried over magnesium sulfate. Evaporation of the solvent gave 27.3 g (84%) of liquid product. NMR (CDCl3): 1.05 (3H,t), 1.6 (6H,s), 3.78 (1H,s), 3.96 (2H,m), 7.2-7.4 (5H,m).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([CH2:7][N:8]=[N+:9]=[N-:10])=[CH:5][CH:4]=1)#[N:2].Cl[C:14](=[CH2:17])[C:15]#[N:16]>O>[C:15]([C:14]1[N:10]=[N:9][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:12][CH:11]=2)[CH:17]=1)#[N:16]
Reactant: N#Cc1ccc(CN=[N+]=[N-])cc1
Reactant: C=C(Cl)C#N
Solvent: O
Product: N#Cc1ccc(Cn2cc(C#N)nn2)cc1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A mixture of 4-cyanobenzyl azide (0.8 g) and 2-chloroacrylonitrile (0.88 9) in water (5 ml) is stirred at about 80° C. for 20 hours. Excess 2-chloroacrylonitrile is distilled off in vacuo, the mixture is cooled to room temperature and the precipitated product is isolated by filtration and washed with water. The product (yield 0.92 g; 88% of theory) of m.p. 93.5-94° C. (recrystallization from ethyl acetate/toluene) is obtained after drying.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[N:22]1([C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[NH:32][CH:31]=[CH:30]3)[CH:26]=[N:25][CH:24]=[N:23]1>>[N:22]1([C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[N:32]([C:2]2[N:7]=[CH:6][C:5]([O:8][CH:9]4[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]4)=[CH:4][CH:3]=2)[CH:31]=[CH:30]3)[CH:26]=[N:25][CH:24]=[N:23]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Reactant: c1ncn(-c2ccc3[nH]ccc3c2)n1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-n3ccc4cc(-n5cncn5)ccc43)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-6) and 5-(1H-1,2,4-triazol-1-yl)-1H-indole (intermediate 58) (0.440 g, 29%).
Reaction SMILES: C(Cl)(Cl)Cl.[C:5]([O:9][C:10](=[O:43])[N:11]([CH2:32][C:33]1[CH:42]=[CH:41][C:36]2[O:37][CH2:38][CH2:39][O:40][C:35]=2[CH:34]=1)[CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][N:20]2[C:29]3[C:24](=[C:25]([NH2:30])[CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][C:21]2=[O:31])[CH2:14][CH2:13]1)([CH3:8])([CH3:7])[CH3:6].[C:44](Cl)(=[O:46])[CH3:45].C(=O)([O-])O.[Na+]>C(N(CC)CC)C>[C:5]([O:9][C:10](=[O:43])[N:11]([CH2:32][C:33]1[CH:42]=[CH:41][C:36]2[O:37][CH2:38][CH2:39][O:40][C:35]=2[CH:34]=1)[CH:12]1[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][N:20]2[C:29]3[C:24](=[C:25]([NH:30][C:44]([CH3:45])=[O:46])[CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][C:21]2=[O:31])[CH2:16][CH2:17]1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3c(N)cccc32)CC1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To 2 mL of a chloroform solution containing 60 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-amino-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 14 mg of triethylamine and 11 mg of acetyl chloride were added, and stirred at room temperature for 2 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 60 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-acetamino-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=[O:11].[NH2:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1)=[O:11]
Reactant: COc1cc2ncnc(N)c2cc1OC
Reactant: O=C=Nc1c(Cl)cccc1Cl
Product: COc1cc2ncnc(NC(=O)Nc3c(Cl)cccc3Cl)c2cc1OC

Procedure:
Using an analogous procedure to that described in Example 3, 2,6-dichlorophenyl isocyanate was reacted with 4-amino-6,7-dimethoxyquinazoline (European Patent Application No. 30156, Chemical Abstract volume 95, abstract 187290) to give the title compound; NMR Spectrum: (DMSOd6) 3.96 (s, 3H), 7.31 (m, 2H), 7.38 (t, 1H), 7.5 (d, 2H), 7.6 (d, 2H), 8.43 (s, 1H), 8.7 (s, 1H), 10.61 (s, 1H), 12.09 (s, 1H); Mass Spectrum: M+H+ 393 & 395.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])=[CH:4][CH:3]=1.[Cl:14]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])=[CH:4][C:3]=1[Cl:14]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1ccc(N2CCCC2=O)cc1
Solvent: CC#N
Product: Nc1ccc(N2CCCC2=O)cc1Cl
Yield: 44.7 %

Procedure:
1-(4-Aminophenyl)pyrrolidin-2-one (0.3 g, 1.7 mmol) and N-chlorosuccinimide (0.227 g, 1.7 mmol) were dissolved in acetonitrile (10 ml). The reaction was stirred and heated at reflux for 2 hours. The solvent was removed in vacuum and the residue purified by silica gel column chromatography eluting with 50% ethyl acetate in dichloromethane to afford the title compound as a white powder (0.16 g, 44.6%). 1H-NMR (500 MHz, CDCl3): δ 2.14 (m, 2H), 2.57 (t, J=8.3 Hz, 2H), 3.77 (t, J=7.1 Hz, 2H), 6.75 (d, J=8.7 Hz, 1H), 7.31 (dd, J=2.5 Hz, 8.7 Hz, 1H), 7.48 (d, J=2.5 Hz, 1H), 8.8 (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:7]2[CH2:8][NH:9][CH2:10][CH2:11][N:6]2[N:5]=1)([O-:3])=[O:2].[C:13](Cl)(=[O:15])[CH3:14].C([O-])([O-])=O.[K+].[K+]>ClCCl>[N+:1]([C:4]1[CH:12]=[C:7]2[CH2:8][N:9]([C:13](=[O:15])[CH3:14])[CH2:10][CH2:11][N:6]2[N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc2n(n1)CCNC2
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(=O)N1CCn2nc([N+](=O)[O-])cc2C1
Reaction time: 8 h
Yield: 59.5 %

Procedure:
To a solution of 2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 205a (672 mg, 4.0 mmol) in dichloromethane (20 mL) was added acetyl chloride (936 mg, 12.0 mmol) and K2CO3 (1104 mg, 8.0 mmol). The mixture was stirred overnight. It was then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica-gel column chromatography eluting with 100:1 dichloromethane/methanol to afford 209a as white solid (500 mg, 60%). MS: [M+H]+ 211.2