Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(N(CC)CC)C.ClC(OCC1C=CC=CC=1)=O.CC(C(OC(=O)C[N:37]([C:57]([O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:58])[C@H:38]([C:40]([N:42]1[CH2:56][CH2:55][CH2:54][C@H:43]1[C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])=[O:41])[CH3:39])C)(C)C>O1CCCC1>[CH3:7][C:6]([CH3:9])([O:5][C:3](=[O:4])[CH2:2][N:37]([C:57]([O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:58])[C@H:38]([C:40]([N:42]1[CH2:56][CH2:55][CH2:54][C@H:43]1[C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])=[O:41])[CH3:39])[CH3:8]
Reactant: CC(OC(=O)CN(C(=O)OCc1ccccc1)[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)C(C)(C)C
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)N(CC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of L-alanyl-L-proline, phenylmethyl ester, p-toluenesulfonic acid salt (32.16 g., 72 mmole), tert-butyl bromoacetate (14.2 g., 72 mmole), triethylamine (20.1 ml., 144 mmole), and tetrahydrofuran (290 ml.) are stirred at room temperature for 72 hours. Benzyl chloroformate (12.4 ml., 87.8 mmole) and triethylamine (12.5 ml., 87.8 mmole) are added and the mixture stirred overnight. The reaction product is evaporated, and partitioned between water and ethyl acetate. The ethyl acetate solubles are washed with dilute hydrochloric acid and then water. The ethyl acetate solution is then evaporated and chromatographed over silica gel (mesh 230-400) using the solvent system ethyl acetate/hexane (1:1) (10 psi pressure) to give 19.5 g. of 1-[N-[2-(1,1-dimethylethylethoxy)-2-oxoethyl]-N-[(phenylmethoxy)carbonyl]-L-alanyl]-L-proline, phenylmethyl ester.
Reaction SMILES: [C:1]([C:4]([C@@H:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].Br[CH2:23][CH2:24][C:25]1[CH:33]=[CH:32][C:28]2[O:29][CH:30]=[CH:31][C:27]=2[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:4]([C@@H:17]1[CH2:21][CH2:20][N:19]([CH2:23][CH2:24][C:25]2[CH:33]=[CH:32][C:28]3[O:29][CH:30]=[CH:31][C:27]=3[CH:26]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: BrCCc1ccc2occc2c1
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)[C@@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)C(c1ccccc1)(c1ccccc1)[C@@H]1CCN(CCc2ccc3occc3c2)C1

Procedure:
A mixture containing 3-(S)-(-)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (1.79 g--see Preparation 10(B)), 5-(2-bromoethyl)benzo[2,3-b]furan (1.2 g--see Preparation 17), anhydrous potassium carbonate (3 g) and acetonitrile (30 ml) was heated under reflux for 30 minutes. The mixture was partitioned between ethyl acetate (30 ml) and 10% aqueous potassium carbonate (30 ml), the layers were separated, and the aqueous layer extracted with ethyl acetate (3×50 ml). The combined ethyl acetate extracts were dried (MgSO4) and concentrated in vacuo to give a brown gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (2%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a foam, yield 1.4 g.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.NS(O)(=O)=O.[C:24]([O:30][C:31](C)(C)[CH3:32])(=[O:29])[CH2:25][C:26]([CH3:28])=O>C(OCC)(=O)C>[CH3:28][C:26]1[C:25]([C:24]([O:30][CH2:31][CH3:32])=[O:29])=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]2[C:2](=[CH:15][CH:14]=[C:13]([N+:16]([O-:18])=[O:17])[CH:12]=2)[N:1]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: NS(=O)(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)nc2ccc([N+](=O)[O-])cc2c1-c1ccccc1
Temperature: 120 °C
Reaction time: 12 h
Yield: 76.1 %

Procedure:
A mixture of 2-amino-5-nitrobenzophenone (1 g, 4.1 mmol), H2NSO3H (40 mg) and tert-butyl acetoacetate (1.3 ml, 10.3 mmol) was stirred for 12 h at 120° C. under N2. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (MgSO4) and concentrated in vacuo to give a solid, which was recrystallised from EtOH to give a pale orange solid (1.05 g, 76%). 1H NMR (300 MHz, CDCl3) δ 8.41-8.5(m, 2H, 8.15 (d, J=9 Hz, 1H), 7.52-7.55(m, 3H), 7.3-7.4 (m, 2H), 2.82(s, 3H), 1.24(s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:30][CH2:31][C:32]([CH3:35])([OH:34])[CH3:33]>ClCCl>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:30][CH2:31][C:32]([CH3:35])([OH:34])[CH3:33])=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Reactant: CC(C)(O)CN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(O)CNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.8 %

Procedure:
7-Benzyloxy-4-chloro-3-nitroquinoline (66.4 g, 0.21 mol) was dissolved in a mixture of dichloromethane (1.5 L) and triethylamine (59 mL, 0.422 mol). A solution of 1-amino-2-methyl-2-propanol (22.5 g, 0.25 mol) in dichloromethane (100 mL) was added dropwise. The reaction was stirred at ambient temperature for 3 hours and then quenched with 1% aqueous sodium carbonate solution. A precipitate formed which was filtered to provide 60 g of crude 1-(7-benzyloxy-3-nitroquinolin-4-ylamino)-2-methylpropan-2-ol as a yellow-brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([F:23])[C:17]=1[NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11](Cl)[O:12][CH:13]=1)=[O:8].[CH:24]([C:27]1[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=1)([CH3:26])[CH3:25]>>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([F:23])[C:17]=1[NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11]([O:33][C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([CH:24]([CH3:26])[CH3:25])[CH:28]=2)[O:12][CH:13]=1)=[O:8]
Reactant: CC(C)c1cccc(O)c1
Reactant: CS(=O)(=O)Nc1c(F)cc(CNC(=O)c2coc(Cl)n2)cc1F
Product: CC(C)c1cccc(Oc2nc(C(=O)NCc3cc(F)c(NS(C)(=O)=O)c(F)c3)co2)c1
Yield: 72.3 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid 3,5-difluoro-4-methanesulfonylamino-benzylamide (38 mg, 0.11 mmol) was reacted with 3-isopropyl phenol (18 mg, 0.12 mmol) to give the title compound (37 mg, 70%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]([Mg]Cl)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1.C(OCC)C>[CH2:8]([C:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: O=C1CCCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC1(Cc2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 66 %

Procedure:
To 3.00 g (30.57 mmol) of cyclohexanone in 102 mL of tetrahydrofuran at 0° C. was added 36.68 mL (36.68 mmol) of a 1 M solution of benzyl magnesium chloride in diethyl ether and the mixture was allowed to warm to RT and stirred for 17 h. The reaction was quenched with methanol, followed by water. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 3.84 g (66%) of 1-benzylcyclohexanol. Then, 2.23 g (11.69 mmol) of the compound was dissolved in 5.8 mL of toluene and 2.00 g (11.69 mmol) of methyl(2S)-2-isocyanatohexanoate was added. The mixture was heated at 85° C. for 12 d. The solution was concentrated and the residue was purified by silica gel column chromatography eluting with an ethyl acetate:hexanes solution (1:6) to give 1.90 g (45%) of methyl(2S)-2-({[(1-benzylcyclohexyl)oxy]carbonyl}amino)hexanoate. Rf=0.39 (1:4 ethyl acetate:hexanes); 1H NMR (300 MHz, DMSO-d6) δ 7.36 (d, J=8 Hz, 1H), 7.25-7.10 (m, 5H), 4.02-3.97 (m, 1H), 3.65 (s, 3H), 3.12 (s, 2H), 1.72-1.06 (m, 16H), 0.87 (t, J=7 Hz, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=1.[NH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]1>O.C(#N)C>[OH:27][CH:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[CH2:22][CH2:23]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc(NC2CCC(O)CC2)cc1C(F)(F)F
Temperature: 80 °C

Procedure:
Potassium carbonate (304 mg, 2.2 mmol) is dissolved in a minimum amount of water and 4-fluoro-2-trifluoromethylbenzonitrile (378 mg, 2.0 mmol) and trans-4-aminocyclohexanol (460 mg, 4.0 mmol) dissolved in acetonitrile (10 mL) are added. The reaction is then heated at 80° C. for 3 days. After cooling to room temperature, the mixture is concentrated under reduced pressure, is taken up in ethyl acetate (15 mL) and washed with saturated aqueous ammonium chloride (2×10 mL) followed by water (10 mL). The organic phase is collected and dried over sodium sulphate, filtered and concentrated under reduced pressure. The desired product is isolated as a colourless solid (80% yield).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.C(N(CC)[C:16]([C:18]1[C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH:33]([CH3:35])[CH3:34])=[CH:20][CH:21]=[C:22]([O:24][CH3:25])[CH:23]=1)=[O:17])C.[Cl-].[NH4+]>O1CCCC1>[CH:33]([O:32][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:26]=1[C:19]1[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:18]=1[C:16]2=[O:17])([CH3:35])[CH3:34]
Reactant: CCN(CC)C(=O)c1cc(OC)ccc1-c1ccccc1OC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(=O)c1cccc(OC(C)C)c1-2
Temperature: 65 °C
Reaction time: 0.08 h
Yield: 54.2 %

Procedure:
Combine n-butyl lithium (22.00 mL of 2.5 M, 0.055 mole) and diisopropylamine (6.07 g, 0.060 mole), while stirring, in 150 mL tetrahydrofuran (THF) at -50° C. Wait approximately 5 minutes, then dropwise add N,N-diethyl-2'-isopropoxy-4-methoxy-biphenyl-2-carboxamide (3.80 g, 0.011 mole) dissolved in 50 mL THF. Remove the cooling source and allow the reaction to obtain ambient temperature, then stir while heating at 65° C. for 5 hours. The reaction changes color to orange, then to dark brown. Continue stirring the reaction overnight at ambient temperature overnight, then cool in an ice bath and neutralize with about 100 mL of a saturated solution of ammonium chloride. The reaction changes color to orange. Wash the THF solvent separately with brine (saturated sodium chloride) and dry over magnesium sulfate. Filter and concentrate to give a red liquid. Chromatography purification of this; material (20% ethyl acetate: 80% hexane) results in an orange liquid which solidifies when dried under high vacuum to give an orange solid (1.60 g, 50%). m.p. 89°-90° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:7][CH:6]([C:8]([OH:10])=O)[CH2:5][C:4]([CH3:12])([CH3:11])[O:3]1.[NH:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[N:15]1.S(Cl)(Cl)=O>C(Cl)Cl>[N:14]1([C:8]([CH:6]2[CH2:5][C:4]([CH3:12])([CH3:11])[O:3][C:2]([CH3:1])([CH3:13])[CH2:7]2)=[O:10])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[N:15]1
Reactant: CC1(C)CC(C(=O)O)CC(C)(C)O1
Reactant: c1ccc2[nH]nnc2c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC1(C)CC(C(=O)n2nnc3ccccc32)CC(C)(C)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2,2,6,6-tetramethyl-tetrahydro-pyran-4-carboxylic acid (1.4 g, 6.8 mmol) and benzotriazole (2.4 g, 20.3 mmol) in 34 mL of DCM was added thionyl chloride (0.55 mL, 7.4 mmol) dropwise and the mixture was allowed to stir for 8 hrs at RT. The mixture was filtered to remove the ppt and the filtrate washed with saturated NaHCO3 (2×40 mL) and then brine (50 mL). The organic layer was dried over Na2SO4 and concentrated to give 1.9 g (97%) of a white ppt.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]([CH3:24])[CH:18]2[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(N(CC)CC)C>COCCOC>[Cl:1][C:2]1[N:11]=[C:10]([N:20]2[C:21]3[C:17](=[CH:16][C:15]([O:14][CH3:13])=[CH:23][CH:22]=3)[CH:18]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:19]2[CH3:24])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CCOC(=O)CC1c2cc(OC)ccc2NC1C
Reactant: Clc1nc(Cl)c2ccccc2n1
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1c2cc(OC)ccc2N(c2nc(Cl)nc3ccccc23)C1C

Procedure:
A mixture of 2,4-dichloroquinazoline (3.2g.), ethyl 5-methoxy-2-methylindolin-3-ylacetate (4.0g.) and triethylamine (2.23ml; dried over potassium hydroxide pellets) in dry 1,2-dimethoxyethane (50ml.) was heated under reflux for 30 mins. The mixture was evaporated in vacuo, and to the residue was added water (100ml.) and ethyl acetate (50ml.). The aqueous layer was separated and extracted with ethyl acetate (2 × 30ml.), and the extracts were washed with water (30ml.), dried(MgSQ 4) and evaporated. The residual syrup slowly crystallised to give ethyl 1-(2-chloroquinazolin-4-yl)-5-methoxy-2-methylindolin-3-ylacetate, m.p. 111°-112° C. This indoline ester (3.6g.) was added to a solution of sodium (0.5g.) in methanol (50ml.; dried over magnesium methoxide), and the resulting solution was heated under reflux for 18 hrs. After removal of methanol in vacuo, the mixture was added to water (50ml.) and acidified with acetic acid to give 1-(2-methoxyquinazolin-4-yl)-5-methoxy-2-methylindolin-3-ylacetic acid hemihydrate, m.p. 115°-120° C. This acid (3.0g.) was dissolved in dry methanol (40ml.) containing concentrated sulphuric acid (0.1ml.), and the mixture was heated under reflux for 5 hrs. Saturated sodium acetate solution (2ml.) was added, and the mixture was evaporated in vacuo. The residue was partitioned between water (50ml.) and ether (40ml.). After separation, the aqueous layer was extracted with ether (2 × 20ml.). The ether extracts were washed successively with saturated sodium hydrogen carbonate solution (20ml.) and water (20ml.), dried (Na2SO4), and evaporated to give methyl 1-(2-methoxyquinazolin-4-yl)-5-methoxy-2-methhylindolin-3-ylacetate as a dark yellow syrup [pure by TLC (system A); NMR: 5--OCH3 at 6.3τ; 2-- OCH3 at 6.15τ ].
Reaction SMILES: [O:1]([C:8]1[C:9]([NH:21][C:22]2[S:26][N:25]=[C:24]([CH:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]3)[N:23]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)[Cl:41].CO>Cl.O1CCOCC1>[ClH:41].[ClH:41].[ClH:41].[O:1]([C:8]1[C:9]([NH:21][C:22]2[S:26][N:25]=[C:24]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[N:23]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCC(c2nsc(Nc3ncc(Sc4ccccn4)cc3Oc3ccccc3)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: c1ccc(Oc2cc(Sc3ccccn3)cnc2Nc2nc(C3CCNCC3)ns2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
Tert-butyl 4-(5-(3-phenoxy-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylate (0.587 g, 1.04 mmol) was dissolved in 1:1 CH2Cl2/methanol and 4N HCl in dioxane added. The reaction was stirred at ambient temperature for 1 hour. The reaction was concentrated and dried in a vacuum oven to provide the title compound (0.473 g, 98.0% yield). 1H NMR (d6-DMSO) δ 12.39 (s, 1H), 8.95 (bs, 1H), 8.80 (bs, 1H), 8.39 (d, 1H), 8.37 (m, 1H), 7.67 (dt, 1H), 7.47 (d, 1H), 7.43 (t, 2H), 7.22-7.12 (m, 5H), 3.30 (d, 2H), 3.16-2.99 (m, 3H), 2.17 (d, 2H), 1.98 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([N:17]([CH3:27])[C@H:18]([CH3:26])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.O.[NH2:29][NH2:30]>C(O)C>[NH2:13][C:12]1[C:11]2[C:10](=[CH:9][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([N:17]([CH3:27])[C@H:18]([CH3:26])[CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:5]=3)=[CH:15][CH:14]=2)[NH:30][N:29]=1
Reactant: C[C@H](Cc1ccccc1)N(C)c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: C[C@H](Cc1ccccc1)N(C)c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-(2-amino-6-{methyl[(1R)-1-methyl-2-phenylethyl]amino}-4-pyrimidinyl)-2-fluorobenzonitrile (200 mg, 0.55 mmol) in ethanol (2 mL) was added hydrazine hydrate (2.0 mL, 99%), and the reaction mixture was heated at 120° C. under microwave conditions with stirring for 1 hour. The mixture was cooled to room temperature and concentrated. The resulting residue was washed with Et2O (30 mL) and dried in vacuo to afford the title compound (156 mg) as a yellow solid. LC-MS (ES) m/z=374 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.12 (d, J=6.0 Hz, 3H), 2.77-2.89 (m, 6H), 5.36 (s, 2H), 5.99 (s, 2H), 6.35 (s, 1H), 7.12-7.16 (m, 1H), 7.23-7.27 (m, 4H), 7.49-7.52 (m, 1H), 7.68-7.70 (m, 1H), 7.88 (s, 1H), 11.50 (s, 1H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:18]([OH:20])=O)=[N:8][C:9]=2[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:3][CH2:2]1.[NH2:21][C@@H:22]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:23]([NH2:25])=[O:24]>>[NH2:25][C:23](=[O:24])[C@@H:22]([NH:21][C:18](=[O:20])[C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:8]=1)[CH2:26][CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)C[C@H](N)C(N)=O
Reactant: O=C(O)c1ccc(C2CC2)c(OCc2ccccn2)n1
Product: CC(C)C[C@H](NC(=O)c1ccc(C2CC2)c(OCc2ccccn2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(pyridin-2-ylmethoxy)-pyridine-2-carboxylic acid (Example 189 b) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=383.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:20][CH2:19][CH2:18][N:17]([CH3:21])[CH2:16][CH2:15]1)[CH:5]=O.[Cl:22][C:23]1[CH:24]=[C:25]([NH2:31])[C:26]([NH2:30])=[CH:27][C:28]=1[CH3:29]>>[Cl:22][C:23]1[C:28]([CH3:29])=[CH:27][C:26]2[NH:30][C:5]([C:4]3[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][CH2:13][N:14]4[CH2:20][CH2:19][CH2:18][N:17]([CH3:21])[CH2:16][CH2:15]4)=[C:2]([Cl:1])[CH:3]=3)=[N:31][C:25]=2[CH:24]=1
Reactant: CN1CCCN(CCCOc2ccc(C=O)cc2Cl)CC1
Reactant: Cc1cc(N)c(N)cc1Cl
Product: Cc1cc2[nH]c(-c3ccc(OCCCN4CCCN(C)CC4)c(Cl)c3)nc2cc1Cl
Yield: 7.9 %

Procedure:
This compound was prepared by the method described in Example 1, using 3-chloro-4-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-benzaldehyde (61 mg, 0.20 mmol, 1.0 equiv), 4-chloro-5-methyl-benzene-1,2-diamine (31 mg, 0.20 mmol, 1.0 equiv), and Na2S2O5 (48 mg, 0.25 mmol, 1.3 equiv) in General Procedure 3. Purification by Method 2 afforded 7.1 mg (8%) of the title compound. MS (electrospray): mass calculated for C23H28Cl2N4O, 446.16. m/z found, 447.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.96 (d, J=2.2 Hz, 1H), 7.83 (dd, J=8.6, 2.2 Hz, 1H), 7.45 (s, 1H), 7.34 (s, 1H), 7.10 (d, J=8.7 Hz, 1H), 4.08 (t, J=6.0 Hz, 2H), 2.76-2.64 (m, 10H), 2.36 (s, 3H), 2.30 (s, 3H), 1.96-1.88 (m, 2H), 1.80-1.73 (m, 2H).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[NH2:20][CH2:21][CH2:22][CH:23]1[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24]1>CN(C=O)C.CCOC(C)=O>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:20][CH2:21][CH2:22][CH:23]2[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24]2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: CC(C)(C)OC(=O)N1CC(CCN)C1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(CCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)C1
Temperature: 120 °C
Yield: 28.6 %

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (74 mg, 0.249 mmol) was dissolved in dry DMF (1 mL) nitrogen atmosphere. tert-Butyl 3-(2-aminoethyl)azetidine-1-carboxylate (50 mg, 0.249 mmol) was added followed by TEA (25 mg, 0.247 mmol) and the reaction mixture was heated in a microwave reactor for at 120° C. for 20 mins. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3-solution, dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC affording the title compound (33 mg, 28.8%). 1H NMR (500 MHz, CDCl3): δ 1.43 (s, 9H), 1.62 (q, 2H), 1.73 (s, 9H), 2.19-2.27 (m, 1H), 2.83 (q, 2H), 3.23-3.26 (m, 2H), 3.84 (t, 2H), 5.25 (t, 1H), 7.42-7.51 (m, 5H); 13C NMR (125 MHz, CDCl3): δ 26.24, 27.82, 28.61, 34.35, 41.72, 54.06, 61.82, 79.63, 107.55, 125.15, 128.93, 130.09, 131.79, 135.04, 156.38, 159.81; Mass Spectrum: M−H+ 462.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][C:25]([OH:28])([CH3:27])[CH3:26])=[C:18]([O:29][CH3:30])[CH:17]=3)=[O:14])[NH:11][CH:12]=2)=[CH:4][CH:3]=1.Br[CH2:32][CH2:33]Br>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]3[C:13](=[O:14])[N:15]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][C:25]([OH:28])([CH3:27])[CH3:26])=[C:18]([O:29][CH3:30])[CH:17]=4)[CH2:33][CH2:32][N:11]3[CH:12]=2)=[CH:6][CH:7]=1
Reactant: BrCCBr
Reactant: COc1cc(NC(=O)c2cc(-c3ccc(Cl)cc3)c[nH]2)ccc1OCCC(C)(C)O
Product: COc1cc(N2CCn3cc(-c4ccc(Cl)cc4)cc3C2=O)ccc1OCCC(C)(C)O

Procedure:
Following the procedure described in Example 1 step D, the product of step B (120 mg) was alkylated with 1,2-dibromoethane to yield 15 mg of the title compound. MS (ESI) 455 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH3:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Ca+2]>C(O)C>[CH3:19][CH:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:3]=2[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:5])[CH2:22][CH2:21]1
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCO
Product: CC1CCN(c2ccc([N+](=O)[O-])cc2C(=O)c2ccccc2)CC1
Yield: 88.4 %

Procedure:
Proceeding as indicated in example 2, with 0.03 mole (7.8 g) of 2-chloro-5-nitro-benzophenone, 0.05 mole (5.7 cm3) of 4-methylpiperidine and 0.03 mole (4.1 g) of calcium carbonate in 80 cm3 of ethanol, 8.6 g (Yield: 88%) of the expected product are obtained. M.P. 81° C.
Reaction SMILES: N1CCCCC1.[OH:7][C:8]1[CH:17]=[CH:16][C:11]([CH:12]=[CH:13][CH:14]=O)=[CH:10][C:9]=1[O:18][CH3:19].[C:20]([CH2:22][C:23]([N-:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])#[N:21]>C(O)C>[CH2:26]([NH:25][C:23](/[C:22](=[CH:14]/[CH:13]=[CH:12]/[C:11]1[CH:16]=[CH:17][C:8]([OH:7])=[C:9]([O:18][CH3:19])[CH:10]=1)/[C:20]#[N:21])=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1cc(C=CC=O)ccc1O
Reactant: N#CCC(=O)[N-]Cc1ccccc1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cc(/C=C/C=C(\C#N)C(=O)NCc2ccccc2)ccc1O

Procedure:
The compound was prepared as described in Example 37 by adding piperidine to a solution of 4-hydroxy-3-methoxycinnamaldehyde (35 mg, 0.2 mmol) and N-(cyanoacetyl)benzylamide (34 mg, 0.2 mmol) in ethanol. After recrystallization from ethanol-water a yellow solid was obtained (50 mg, 75%). The product gave the following analytical data: