Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1SC=CC=1)(=O)C.[CH3:9][CH2:10][CH2:11][CH2:12][C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17].CCCCCCCCCCCCCCCCCC(CCCCCCCCCCCCCCCCC)=O.Cl[Si](CC)(CC)CC.[F:63]OC(F)(F)F>>[F:63][CH:12]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10][CH3:9]
Reactant: FOC(F)(F)F
Reactant: CCCCC(=O)CCCC
Agent: CC(=O)c1cccs1
Agent: CCCCCCCCCCCCCCCCCC(=O)CCCCCCCCCCCCCCCCC
Agent: CC[Si](Cl)(CC)CC
Product: CCCCC(=O)C(F)CCC

Procedure:
Similarly, 2-acetylthiophene, 5-nonanone and stearone give, for example, by treatment with chlorotriethylsilane, the corresponding siloxy compounds which, upon reaction with trifluoromethyl hypofluorite, give 2-β-fluoroacetylthiophene, 4-fluorononane-5-one and α-fluorostearone, respectively.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][C:11](=O)[CH2:12]2)=[CH:7][CH:6]=1>CCOCC.CCCCC.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][NH:2][C:11]1[CH2:10][CH2:9][C:8]2[C:13](=[CH:14][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[CH:12]=1
Reactant: COc1ccc2c(c1)CC(=O)CC2
Reactant: CN
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCCCC
Solvent: CCOCC
Product: CNC1=Cc2cc(OC)ccc2CC1
Reaction time: 0.5 h

Procedure:
This compound was prepared according to the procedure described by Evans, et al., J. Org. Chem. 35, 4122 (1970) as follows. Into a dry, nitrogen purged, 500 ml, 3-neck flask fitted with mechanical stirrer, dropping funnel and nitrogen inlet tube was added a solution of 14.3 g (460 mmole) methylamine in anhydrous ether (100 ml) and a solution of 20.0 g (113.5 mmole) 7-methoxy-2-tetralone in same solvent (100 ml) and the solution was placed under a slow stream of nitrogen and cooled to -18° (ice-methanol). A solution of 11.56 g (61 mmole) titanium tetrachloride in pentane (50 ml) was added dropwise with stirring over 30 min period. After the addition, the reaction mixture was stirred at room temperature for 1 hr and then fast filtered. The solid residue was washed with ether (50 ml) and the filtrate and washings were combined. Removal of the solvent in vacuo gave 20.6 g (96%) of XIId as an oxygen-sensitive oil which crystallized on standing; IR (neat), 3430 (NH), 1630 cm-1 (C=C--N); NMR δ, 2.15 (m, 2, benzylic), 2.55 (m, 2, allylic), 2.70 (s, 3, NCH3), 3.15 (broad, NH), 3.70 (s, 3, OCH3), 5.13 (s, 1, C-1H), 6.25-6.90 (m, 3, ArH).
Reaction SMILES: [CH3:1][CH:2]1CC[N:6]2[C:9](=[O:21])[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][C:19](=[O:20])[C:14]=4[S:13][C:11]=3[N:12]=[C:5]2[CH2:4][CH2:3]1.[CH2:22]([O:24][C:25](C1C2=NC3SC4CCCCC=4C=3C(=O)N2CCC1)=[O:26])[CH3:23]>>[CH2:22]([O:24][C:25]([CH:4]1[C:5]2=[N:12][C:11]3[S:13][C:14]4[C:19](=[O:20])[CH2:18][CH2:17][CH2:16][C:15]=4[C:10]=3[C:9](=[O:21])[N:6]2[CH2:1][CH2:2][CH2:3]1)=[O:26])[CH3:23]
Reactant: CCOC(=O)C1CCCn2c1nc1sc3c(c1c2=O)CCCC3
Reactant: CC1CCc2nc3sc4c(c3c(=O)n2CC1)CCCC4=O
Product: CCOC(=O)C1CCCn2c1nc1sc3c(c1c2=O)CCCC3=O

Procedure:
Compound 18 was synthesized by the method described for compound 17 using compound 15 as a starting material.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:11][C:12](=[O:16])[C:13]([OH:15])=O)[CH:8]=2)[NH:3]1.[CH3:17][C:18]1[CH:30]=[CH:29][CH:28]=[CH:27][C:19]=1[CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(OCC)C>[CH3:17][C:18]1[CH:30]=[CH:29][CH:28]=[CH:27][C:19]=1[CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:13](=[O:15])[C:12]([NH:11][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2](=[O:1])[CH2:10]3)=[O:16])[CH2:23][CH2:22]1
Reactant: O=C1Cc2cc(NC(=O)C(=O)O)ccc2N1
Reactant: Cc1ccccc1CC1CCNCC1
Solvent: CCOCC
Product: Cc1ccccc1CC1CCN(C(=O)C(=O)Nc2ccc3c(c2)CC(=O)N3)CC1

Procedure:
The title compound is prepared from N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-oxalamic acid (Example 101b) and 4-(2-methyl-benzyl)-piperidine [J. Org. Chem., 64, 3763. (1999)] according to the method described in Example 1c. Melting Point: 211-213° C. (diethylether)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14](F)[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1
Reactant: C1CCNC1
Reactant: Fc1cccc(Nc2cc(Cl)nn3ccnc23)n1
Solvent: O
Product: Clc1cc(Nc2cccc(N3CCCC3)n2)c2nccn2n1
Temperature: 205 °C
Yield: 18.4 %

Procedure:
A suspension of 6-chloro-N-(6-fluoropyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (132 mg, 0.5 mmol) and pyrrolidine (54 mg, 0.75 mmol) in water (0.3 mL) was heated to 205° C. in a microwave oven for 30 minutes. The reaction mixture was purified by chromatography (silica gel, 200-300 mesh, CH2Cl2:MeOH=200:1) to give 6-chloro-N-(6-(pyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (29 mg, 18%) as a light yellow solid. LC-MS: [M+H]+, 315.0, tR=1.837 min.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.Br[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:1]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:23]1[C:24]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Nc1ccccc1-c1ccccc1
Reactant: Brc1cccc2ccccc12
Agent: CC(C)(C)O[Na]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccccc2Nc2cccc3ccccc23)cc1
Temperature: 110 °C
Yield: 65 %

Procedure:
Trisdibenzylideneacetonedipalladium (0.276 g, 0.3 mmol) and tri-tert-butylphosphine (0.121 g, 0.6 mmol) were put into a flask, and then dissolved in 40 mL of toluene. Subsequently, 2-biphenylamine (2.53 g, 15 mmol), 1-bromonaphthalene (3.11 g, 15 mol) and tert-butoxy sodium (2.16 g, 22.5 mmol) were added into the flask, and then refluxed at a temperature of 110° C. for 12 hours. After the flask including the reactant mixture was cooled to room temperature, the reactant mixture was washed using an ammonium chloride aqueous solution (150 mL) to separate an organic layer. The separated organic layer was washed with distilled water three times, and was then dried with magnesium sulfate. Thereafter, residues from which volatile components were removed at reduced pressure were purified using a silica gel chromatography tube in a mixed solvent of hexane and ethylacetate (1:10), and were then recrystallized in normal hexane to produce 2.88 g of N-(biphenyl-2-yl)naphthalene-1-amine.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[CH:9]=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[C:12]([CH:14]=1)[NH2:13].[C:18]([O:22][CH3:23])(=[O:21])[CH2:19][SH:20].O>CN(C=O)C>[NH2:13][C:12]1[CH:14]=[C:8]([S:20][CH2:19][C:18]([O:22][CH3:23])=[O:21])[CH:9]=[CH:10][C:11]=1[N+:15]([O-:17])=[O:16]
Reactant: COC(=O)CS
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CSc1ccc([N+](=O)[O-])c(N)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
14.1 4.25 g (30.7 mmol) of potassium-carbonate are added to a solution of 2.65 g (15.4 mmol) of 5-chloro-2-nitroaniline and 1.66 g (1 5.4 mmol) of methyl thioglycolate in 14 ml of DMF, and the mixture is stirred at room temperature for 18 hours. The reaction mixture is introduced into water, and the resultant precipitate is filtered off, giving methyl (3-amino-4-nitrophenylsulfanyl)acetate as a yellow solid; ESI 243.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([S:37][CH2:38][C:39]5[N:43]([CH2:44][CH3:45])[CH:42]=[N:41][N:40]=5)=[CH:33][CH:32]=4)=[O:29])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:55])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([S:37]([CH2:38][C:39]5[N:43]([CH2:44][CH3:45])[CH:42]=[N:41][N:40]=5)=[O:55])=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:46]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nncn4CC)cc2)CCN3CCC)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nncn4CC)cc2)CCN3CCC)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-ethyl-4H-1, 2, 4-triazol-3-ylmethylthio) phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxamide (0.93 g) in dichloromethane (20 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.54 g) in dichloromethane (10 ml) at −78° C., and the mixture was stirred at −78° C. for 1 hour. To the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:5→1:3→1:2), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-ethyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 137) (694.7 mg) as yellow amorphous.
Reaction SMILES: [C:1]([Mg]Cl)([CH3:4])([CH3:3])[CH3:2].[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12].[Cl-].[NH4+]>O1CCCC1>[Br:7][C:8]1[CH:9]=[C:10]([CH:11]([OH:12])[C:1]([CH3:4])([CH3:3])[CH3:2])[CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)[Mg]Cl
Reactant: O=Cc1cccc(Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)C(O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
t-Butylmagnesium chloride (0.93 mol/l solution in tetrahydrofuran, 75.5 mL, 70.26 mmol) was added to a solution of 3-bromobenzaldehyde (10 g, 54.05 mmol) in tetrahydrofuran (100 mL) in a nitrogen atmosphere at −78° C. The mixture was stirred at the same temperature for one hour and then heated to room temperature. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure to give crude 1-(3-bromo-phenyl)-2,2-dimethyl-propan-1-ol.
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([OH:17])=O)=[CH:14][C:9]=2[N:8]=[CH:7]1)=[N+:2]=[N-:3].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH:37]1[CH:46]2[CH:41]([CH2:42][CH2:43][CH2:44][CH2:45]2)[CH2:40][CH2:39][CH2:38]1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[N:1]([CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([N:37]3[CH:46]4[CH:41]([CH2:42][CH2:43][CH2:44][CH2:45]4)[CH2:40][CH2:39][CH2:38]3)=[O:17])=[CH:14][C:9]=2[N:8]=[CH:7]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCn1cnc2cc(C(=O)O)ccc21
Reactant: C1CCC2NCCCC2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: [N-]=[N+]=NCCn1cnc2cc(C(=O)N3CCCC4CCCCC43)ccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.3 %

Procedure:
To a solution of 1-(2-azidoethyl)-1H-benzimidazole-5-carboxylic acid (1 g, 0.00433 mol) in dry DMF (7.0 mL) was added with stirring HOBt (0.876 g, 0.00649 mol), DIPEA (2.25 mL, 0.0129 mol), decahydroquinoline (0.902 g, 0.00649 mol) at 0° C. To the resulting mixture was added EDCl (1.24 g, 0.00649 mol) and stirred for 15 h at an ambient temperature. The reaction mixture was diluted with ice water (100 mL) and extracted with EtOAc (3×50 mL). The combined organic phases were washed with water, dried (Na2SO4) and the solvent evaporated to give [1-(2-azidoethyl)-1H-benzimidazol-5-yl]-(octahydroquinolin-1-yl)methanone (1.5 g, 98%).
Reaction SMILES: C([O:5]O)(C)(C)C.[Cl:7][C:8]1[C:13]([Cl:14])=[C:12]([S:15][CH2:16][CH3:17])[CH:11]=[CH:10][C:9]=1[NH:18][C:19](=[O:27])[C@:20]([OH:26])([CH3:25])[C:21]([F:24])([F:23])[F:22]>CCCCCCCCCC.C(Cl)(Cl)Cl>[Cl:7][C:8]1[C:13]([Cl:14])=[C:12]([S:15]([CH2:16][CH3:17])=[O:5])[CH:11]=[CH:10][C:9]=1[NH:18][C:19](=[O:27])[C@:20]([OH:26])([CH3:25])[C:21]([F:22])([F:23])[F:24]
Reactant: CCSc1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1Cl
Reactant: CC(C)(C)OO
Solvent: CCCCCCCCCC
Solvent: ClC(Cl)Cl
Product: CCS(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1Cl
Reaction time: 18 h

Procedure:
t-Butyl hydrogen peroxide (2.4 ml of a 5.5M solution in decane) was added to a solution of (R)-N-[2,3-dichloro-4-ethylsulphanylphenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide Method 1) (0.23 g) and d-10-camphorsulphonic acid (0.018 g) in chloroform (10 ml) and the mixture was stirred for 18 hours. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-50% EtOAc/isohexane to give the title compound (0.22 g) as a white solid. NMR (CDCl3+1 drop DMSO): 1.21-1.28 (m, 3H), 1.71 (s, 3H), 2.77-2.89 (m, 1H), 3.04-3.16 (m, 1H), 7.14 (s, 1H), 7.78 (d, 1H), 8.66 (d, 1H), 9.73 (s, 1H); m/z: 376.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.C([Li])CCC.[B:27](OCC)([O:31]CC)[O:28]CC.Cl>C1COCC1.CCCCCC>[C:16]1([C:9]2[C:8]3[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:2]([B:27]([OH:31])[OH:28])=[C:15]3[C:10]=2[CH:11]=[CH:12][CH:13]=[CH:14]3)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOB(OCC)OCC
Reactant: Brc1c2ccccc2c(-c2ccccc2)c2ccccc12
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1c2ccccc2c(-c2ccccc2)c2ccccc12
Temperature: -80 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
An amount of 14 g (42 mmol) of 9-bromo-10-phenylanthracene was dissolved in dehydrated THF and cooled to −80° C. Then, 31.2 ml (49 mmol) of a solution of n-butyllithium in n-hexane was added dropwise. Forty minutes later, 13 g (89 mmol) of triethyl borate was added. After two-hour reaction, a diluted hydrochloric acid solution was added and allowed to stand for 12 hours. Then, the separated organic layer was recrystallized to obtain 10 g (33.6 mmol) of 10-phenylanthracene-9-boronic acid. The yield was 75.2%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:12][CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH2:16][N:17]([CH:24]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]1=[O:31])[C:18]2=[O:23].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:12][CH2:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH2:16][N:17]([CH:24]2[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]2=[O:31])[C:18]3=[O:23])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CCC(N2Cc3c(CNC(=O)Nc4cccc(Cl)c4)cccc3C2=O)C(=O)N1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 89.2 %

Procedure:
3-Chlorophenyl isocyanate (0.4 g, 2.7 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and triethylamine (0.3 g, 2.9 mmol) in THF (30 mL) at 5-10° C. After stirring at 5° C. for 10 minutes, the mixture was stirred at room temperature overnight. The reaction was quenched with methanol (1 mL) and then concentrated. The residue was stirred with 1N HCl (30 mL) for 1 hour and filtered. The solid was slurried with hot methanol (15 mL) to give 1-(3-chloro-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-urea (0.8 g, 91%): mp 250-252° C.; 1H NMR (DMSO-d6) δ 2.00-2.05 (m, 1H), 2.37-2.65 (m, 2H), 2.86-2.98 (m, 1H), 4.37 (d, J=5.3 Hz, 2H, CH2), 4.44 (d, J=17.2 Hz, 1H), 4.51 (d, J=17.3 Hz, 1H), 5.11-5.18 (dd, J=4.9 and 13.1 Hz, 1H, CH), 6.82 (t, J=5.4 Hz, 1H, NH), 6.92-6.95 (m, 1H, Ar), 7.18-7.27 (m, 2H, Ar), 7.48-7.65 (m, 4H, Ar), 8.84 (s, 1H, NH), 11.01 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.57, 31.18, 39.68, 46.20, 51.59, 116.15, 117.13, 120.78, 121.57, 128.30, 130.21, 130.35, 131.64, 133.06, 135.37, 139.90, 141.86, 154.99, 168.07, 171.00, 172.82; Anal. calcd. for C21H19N4O4Cl: C, 59.09; H, 4.49; N, 13.13; Cl, 8.31. Found: C, 59.06; H, 4.39; N, 13.24; Cl, 7.95.
Reaction SMILES: [CH3:1][O:2][C@H:3]([CH3:7])[C:4]([OH:6])=O.[Cl:8][C:9]1[CH:10]=[C:11]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[O:34][C@H:35]([CH3:39])[CH2:36][NH:37][CH3:38])[N:27]=[CH:26][N:25]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[Cl:8][C:9]1[CH:10]=[C:11]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[O:34][C@H:35]([CH3:39])[CH2:36][N:37]([CH3:38])[C:4](=[O:6])[C@H:3]([O:2][CH3:1])[CH3:7])[N:27]=[CH:26][N:25]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: CO[C@H](C)C(=O)O
Reactant: CNC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: CO[C@H](C)C(=O)N(C)C[C@@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 44 %

Procedure:
The procedure described in Example 1 was repeated using (R)-(+)-2-methoxypropionic acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(1R)-1-methyl-2-(methylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 2.3, preparation of starting materials) to give the title compound as a brown gum in 44% yield; NMR spectrum (DMSO-d6 373K) 1.11 (d, 3H), 1.37 (d, 3H), 2.97 (s, 3H), 3.09 (s, 3H), 3.38 (m, 1H), 4.17 (q, 1H), 4.26 (dd, 1H), 5.16 (m, 1H), 5.28 (s, 2H), 7.24 (m, 2H), 7.33 (d, 1H), 7.37 (dd, 1H), 7.56 (d, 1H), 7.64 (dd, 1H), 7.69 (t, 1H), 7.86 (dt, 1H), 8.13 (d, 1H), 8.44 (s, 1H), 8.59 (d, 1H), 9.89 (s, 1H); Mass spectrum MH+ 536.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.Cl.[C:11]([OH:15])(=[O:14])[CH:12]=O>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[N:9]=[CH:12]/[C:11]([OH:15])=[O:14])=[CH:4][CH:3]=1
Reactant: O=CC(=O)O
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: O
Product: O=C(O)/C=N/Nc1ccc(F)cc1

Procedure:
To a solution of 4-fluorophenyl hydrazine 1.32 g (0.011 mol) in water (30 mL) at room temperature was added HCl (1.32 g, 0.014 mol) followed by the drop-wise addition of glyoxylic acid (50%, 1.71 g, 0.012 mol) over 20 minutes. The thick suspension was stirred for 30 m. The product was isolated by filtration, washed with water and then dissolved in ethyl acetate (40 mL), dried over magnesium sulfate, filtered and the product isolated as a solid.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:29]=[CH:28][C:7]([O:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:16]=3)[N:11]([CH2:22][C:23]([O:25]C)=[O:24])[C:10]=2[CH3:27])=[CH:6][CH:5]=1.O>C1COCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([S:18]([CH3:21])(=[O:19])=[O:20])[CH:16]=3)[N:11]([CH2:22][C:23]([OH:25])=[O:24])[C:10]=2[CH3:27])=[CH:28][CH:29]=1
Reactant: COC(=O)Cn1c(C)c(Oc2ccc(Cl)cc2)c2cc(S(C)(=O)=O)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Oc2ccc(Cl)cc2)c2cc(S(C)(=O)=O)ccc2n1CC(=O)O
Reaction time: 2 h

Procedure:
A solution of 1M sodium hydroxide (1 ml) was added to a stirred mixture of the product from step (iii) (235 mg) in THF (1 ml). After 2 h, water (10 ml) was added and the solution extracted with DCM. The solution was acidified with 2 M hydrochloric acid and extracted with ethylacetate. These later organics were dried and evaporated under reduced pressure. Yield 135 mg
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>CN(C=O)C.CCCCC>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:1]=[N+:2]=[N-:3])[CH3:16]
Reactant: CCOC(=O)CCCCCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: CCOC(=O)CCCCCCN=[N+]=[N-]
Reaction time: 16 h
Yield: 95.1 %

Procedure:
Sodium azide (1.7 g, 0.026 mol) was added to ethyl 7-bromoheptanoate 1 (4.1 g, 0.017 mol) in DMF (40 mL) at 23° C. The reaction was stirred for 16 h, diluted with pentane and washed with water. The organic portion was washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give 3.22 g (95%) of the azide 2 as a clear, colorless liquid.
Reaction SMILES: [CH2:1]([C@H:8]([C@H:12]([OH:16])[C:13]([OH:15])=[O:14])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:19](OC)([CH3:21])[CH3:20]>CC(C)=O.[Cu](Cl)Cl>[CH3:20][C:19]1([CH3:21])[O:16][C@H:12]([C@H:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]([OH:11])=[O:10])[C:13](=[O:15])[O:14]1
Reactant: COC(C)(C)OC
Reactant: O=C(O)[C@@H](O)[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl[Cu]Cl
Solvent: CC(C)=O
Product: CC1(C)OC(=O)[C@@H]([C@H](Cc2ccccc2)C(=O)O)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.8 %

Procedure:
To a solution of (2R,3S)-2-benzyl-3-hydroxysuccinic acid (2.08 g; 9.28 mmol; 1.00 eq.) in acetone (50.0 mL) was added 2,2-dimethoxypropane (2.3 mL; 18.55 mmol; 2.0 eq.) and copper(II) chloride (124.73 mg; 0.93 mmol; 0.10 eq.). The resulting reaction mixture was stirred for 4 h at RT. The reaction mixture was evaporated and the residue taken up in CHCl3. Activated charcoal is added and the resulting mixture stirred for one hour. Filtration on a pad of celite gave the title product (single diastereoisomer) as a greenish oil (1.81 g, 74%) used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:13][C:14](SC)=[C:15]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:32][C@@H:33]([NH2:37])[CH:34]([CH3:36])[CH3:35]>>[F:31][C:2]([F:30])([F:1])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([NH:37][C@H:33]([CH3:32])[CH:34]([CH3:36])[CH3:35])=[C:15]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:19])=[O:20])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CSC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CC(C)[C@@H](C)N
Product: CC(C)[C@@H](C)NC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Yield: 13 %

Procedure:
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-(4-chlorophenylsulfonyl)-3-methylsulfanyl-2-propenenitrile (0.200 g, 0.4 mmol) was stirred in (R)-1,2-dimethylpropylamine (0.2 ml) at 80° C. in a sealed flask for 20 h. Work up as described in Example 1, 2) gave 30 mg (13%) of the title compound as white crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:13]([O:16][C@@H:17]([CH2:19][CH2:20][CH:21]=[CH2:22])[CH3:18])[CH2:14][CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[OH:24][C@H:25]1[CH2:29][NH:28][C@H:27]([C:30]([O:32][CH3:33])=[O:31])[CH2:26]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:13]([O:16][C@@H:17]([CH2:19][CH2:20][CH:21]=[CH2:22])[CH3:18])[CH2:14][CH3:15])[C:10]([N:28]1[CH2:29][C@H:25]([OH:24])[CH2:26][C@H:27]1[C:30]([O:32][CH3:33])=[O:31])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Reactant: C=CCC[C@@H](C)O[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCC[C@@H](C)O[C@@H](CC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a round-bottom flask equipped with a stir bar was added (2S,3S)-2-((tert-butoxycarbonyl)amino)-3-(pent-4-en-1-yloxy)pentanoic acid (all material from step 1, 438 mg, 1.39 mmol), (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate-HCl salt (277 mg, 1.53 mmol), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (“HATU”, 528 mg, 1.39 mmol), and CH2Cl2 (10 mL). To the mixture was added N,N-diisopropylethylamine (0.728 mL, 4.17 mmol). The mixture was stirred at room temperature for 16 h. The reaction mixture was transferred to a separatory funnel and was thrice washed with aq. 1N HCl; then brine. The organic phase was dried over MgSO4; filtered; then concentrated in vacuo to afford (2S,4R)-methyl 1-((2S,3S)-2-((tert-butoxycarbonyl)amino)-3-((R)-hex-5-en-2-yloxy)pentanoyl)-4-hydroxypyrrolidine-2-carboxylate as a yellow oil.