Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11]1[CH:16]=[CH:15][C:14]([NH:17]/[C:18](=[C:25]2\[C:26](=[O:37])[NH:27][C:28]3[C:33]\2=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.C(OCC)(=O)C.[ClH:44]>>[ClH:44].[NH2:8][C@H:9]([C:11]1[CH:12]=[CH:13][C:14]([NH:17]/[C:18](=[C:25]2\[C:26](=[O:37])[NH:27][C:28]3[C:33]\2=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=3)/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:16]=1)[CH3:10]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@H](N)c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 29a from (Z,S)-3-{1-[4-(1-tert.butoxycarbonylamino-ethyl)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone and ethyl acetate/hydrogen chloride.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:8]2[C:13]([C:14]=1[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=1)=[CH:12][CH:11]=[C:10]([Cl:23])[CH:9]=2)=[O:5])C.[Li+].[OH-]>CO>[CH2:24]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([Cl:23])[CH:9]=2)[C:14]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=2)=[C:6]1[C:4]([OH:5])=[O:3])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1c(Sc2cccc(Br)c2)c2ccc(Cl)cc2n1Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c(Sc2cccc(Br)c2)c2ccc(Cl)cc2n1Cc1ccccc1
Temperature: 50 °C

Procedure:
1-Benzyl-3-(3-bromo-phenylsulfanyl)-6-chloro-1H-indole-2-carboxylic acid ethyl ester (0.520 g, 1.04 mmol) was dissolved in MeOH:THE (1:1, 10 mL) and LiOH (5 mL, 1.0M aq., 5 mmol) was added. The reaction was heated to 50° C. for 1 hour then removed from heat and submitted to aqueous workup to give the title compound which was carried to the next step without further purification.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16](Br)[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.O.[CH3:23][N:24](C=O)C>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:23]#[N:24])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Brc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Temperature: 160 °C
Yield: 32 %

Procedure:
A mixture of (R)-indan-1-yl-(6-bromo-quinolin-2-yl)-amine (1.14 g, 3.36 mmol), zinc cyanide (434 mg, 3.7 mmol) and tetrakis-(triphenylphosphine)-palladium (388 mg, 0.34 mmol) in DMF (12 ml) was heated at 160° C. for 15 min in a microwave reactor. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with brine (2×50 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel and crystallization (diethyl ether/heptane) to yield 2-((R)-indan-1-ylamino)-quinoline-6-carbonitrile as light yellow solid (310 mg, 32%).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[C:6]([NH2:10])(=[O:9])[CH:7]=[CH2:8]>>[C:1]([O-:5])(=[O:4])[CH:2]=[CH2:3].[C:6]([NH2:10])(=[O:9])[CH:7]=[CH2:8]
Reactant: C=CC(=O)O
Agent: C=CC(N)=O
Product: C=CC(=O)[O-]

Procedure:
Example 1 is repeated in the same conditions except that the monomers consist of 204 parts of acrylic acid of 204 parts of acrylamide. A 50-50 acrylate-acrylamide copolymer is obtained which is defined by the exclusion chromatogram of FIG. 4.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([C:22](O)([CH3:24])[CH3:23])=[CH:17][C:16]=2[CH3:26])[C:8]=1[CH3:27])[CH2:4][CH3:5])[CH3:2]>C1C=CC=CC=1>[CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([C:22]([CH3:24])=[CH2:23])=[CH:17][C:16]=2[CH3:26])[C:8]=1[CH3:27])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C(C)(C)O)cc2C)c1C
Solvent: c1ccccc1
Product: C=C(C)c1cc(C)c(Oc2nc(C)cc(NC(CC)CC)c2C)c(C)c1

Procedure:
The title compound was prepared by reacting of 2-{4-[4-(1-Ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-phenyl}-propan-2-ol with Burgess Inner salt (Et3NS(O)2NCOOMe in benzene at reflux for 30 min. 1H NMR(CDCl3) d 7.17(s,2H), 6.08(s,1H), 5.34(s,1H), 5.02(s,1H), 3.72(d,1H), 3.32(m,1H), 2.12 and 2.15 (two sets of s, 12H), 1.4–1.6(m,4H), 0.97(t,6H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:13][CH2:12][C:11](=[CH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:9][CH2:10][CH:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[CH:19][CH:20]=3)[CH2:12][CH2:13]2)=[O:7])=[CH:23][CH:24]=1
Reactant: N#Cc1ccc(C=C2CCN(C(=O)c3ccc(Cl)cc3)CC2)cc1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: N#Cc1ccc(CC2CCN(C(=O)c3ccc(Cl)cc3)CC2)cc1
Reaction time: 2.5 h

Procedure:
8.4 g of 1-(4-chlorobenzoyl)-4-(4-cyanobenzylidene)piperidine are hydrogenated (5 bar) at ambient temperature for 15 minutes in 400 ml of toluene with the addition of 2 g of palladium black. After addition of 1 g of palladium black, the mixture is hydrogenated for an additional 2.5 hours, a further 1 g of catalyst is added and the mixture is hydrogenated for an additional hour. 7.9 g (93.3% of theory) of the title compound are obtained as a colourless powder of melting point 137°-139° C.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([OH:16])[C:7]2[N:8]([CH:15]=1)[C:9](=[O:14])[CH:10]=[C:11]([CH3:13])[N:12]=2.[CH2:17](Br)[CH:18]([CH3:20])[CH3:19]>CC(CC)=O.O.[Cu]>[Cl:3][C:4]1[CH:5]=[C:6]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])[C:7]2[N:8]([CH:15]=1)[C:9](=[O:14])[CH:10]=[C:11]([CH3:13])[N:12]=2
Reactant: Cc1cc(=O)n2cc(Cl)cc(O)c2n1
Reactant: CC(C)CBr
Agent: [Cu]
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(C)=O
Solvent: O
Product: Cc1cc(=O)n2cc(Cl)cc(OCC(C)C)c2n1
Reaction time: 1 h

Procedure:
To a stirred suspension of 1.6 g of powdered sodium hydroxide in 100 ml of pure ethyl methyl ketone is added 21. g of 7-chloro-9-hydroxy-2-methyl-4H-pyrido[1,2-a] pyrimidin-4-one. The mixture is stirred for about 1 hour and 1.5 g of isobutyl bromide dissolved in 10 ml of pure ethyl methyl ketone is added dropwise. Subsequently, 0.2 g of copper bronze is added and the mixture stirred and heated under reflux for 2 hours. The mixture is cooled, diluted with 20 ml of water, filtered, and the organic phase in the filtrate separated, washed with saturated aqueous sodium chloride, dried, and concentrated to give 7-chloro-9-(isobutoxy)-2-methyl-4H-pyrido[ 1,2-a] pyrimidin-4-one.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1>CN(C)C=O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: c1ccc2c(c1)CCN2
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)ccc1N1CCc2ccccc21

Procedure:
A stirred solution of 38.4 g (0.20 mole) of 1,4-dichloro-2-nitrobenzene and 59.6 g (0.50 mole) of indoline in 400 ml of dimethylformamide (DMF) was heated under nitrogen at 140°-145° C. overnight (23 hours). The DMF solvent was then removed in vacuo and the residue was dissolved in 500 ml of dichloromethane. This solution was extracted with H2O, with dilute hydrochloric acid, with brine, then dried over Na2SO4 and concentrated to an oil. This was adsorbed on a tall chromatography column containing 1.5 kg of silica gel packed in toluene. Elution with toluene brought forth 22.1 g (40% overall yield) of product, which crystallized. A small portion was recrystallized from hexane to afford 1-(4-chloro-2-nitrophenyl)indoline, m.p. 97°-99° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:5]([CH2:6][CH:7]=[CH2:8])[N:4]([C:9](=[C:14]([CH3:16])[CH3:15])[C:10]([O:12][CH3:13])=[O:11])[C:3]1=[O:17].N1C(C)=CC=CC=1C.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>C(Cl)Cl.C(OCC)(=O)C>[CH2:30]([O:29][C:27]([NH:1][C@@H:2]1[C@@H:5]([CH2:6][CH:7]=[CH2:8])[N:4]([C:9](=[C:14]([CH3:16])[CH3:15])[C:10]([O:12][CH3:13])=[O:11])[C:3]1=[O:17])=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=CC[C@@H]1[C@@H](N)C(=O)N1C(C(=O)OC)=C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Product: C=CC[C@@H]1[C@@H](NC(=O)OCc2ccccc2)C(=O)N1C(C(=O)OC)=C(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl [(3R,4R)-3-amino-4-allyl-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (7.0 g) in methylene chloride (110 ml) were added 2,6-lutidine (4.11 ml) and benzyl chloroformate (5.03 ml) at 0° C. and the mixture was stirred for 30 minutes at 0° C. The reaction mixture was diluted with ethyl acetate (800 ml) and the solution was washed with diluted hydrochloric acid, brine, aqueous saturated sodium bicarbonate, and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (200 g) eluting with a mixture of methylene chloride and ethyl acetate (20:1-4:1) to give methyl [(3R,4R)-3-benzyloxycarbonylamino-4-allyl-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (10.7 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1>[Pt].C(#N)C>[NH2:12][C:11]1[C:2]([Cl:1])=[N:3][C:4]2[C:9]([C:10]=1[NH:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1NCCCO
Agent: [Pt]
Solvent: CC#N
Product: Nc1c(Cl)nc2ccccc2c1NCCCO
Yield: 96.8 %

Procedure:
3-[(2-Chloro-3-nitroquinolin-4-yl)amino]propan-1-ol 11.53 g), acetonitrile (110 mL), and 5% platinum on carbon (1.3 g) were added sequentially to a Parr vessel. The vessel was placed under hydrogen pressure, 40 psi (2.8×105 Pa) for 4 hours. The reaction mixture was filtered through a layer of CELITE filter aid and the filtrate was concentrated under reduced pressure. The residue was dried under vacuum for 2 hours to provide 9.97 g of 3-[(3-amino-2-chloroquinolin-4-yl)amino]propan-1-ol as a brown sticky oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:29]C(=O)OC(C)(C)C)[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:19]4[C@H:26]([CH3:27])[S:25][CH2:24][C:20]=4[N:21]=[CH:22][N:23]=3)[C@@H:14]([CH3:28])[CH2:13]2)=[O:11])=[CH:4][CH:3]=1.[ClH:37]>C(Cl)Cl>[ClH:1].[ClH:37].[NH2:29][C@H:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:19]3[C@H:26]([CH3:27])[S:25][CH2:24][C:20]=3[N:21]=[CH:22][N:23]=2)[C@@H:14]([CH3:28])[CH2:13]1)=[O:11]
Reactant: C[C@@H]1SCc2ncnc(N3CCN(C(=O)[C@@H](Cc4ccc(Cl)cc4)NC(=O)OC(C)(C)C)C[C@@H]3C)c21
Agent: Cl
Solvent: ClCCl
Product: C[C@@H]1SCc2ncnc(N3CCN(C(=O)[C@H](N)Cc4ccc(Cl)cc4)C[C@@H]3C)c21

Procedure:
tert-Butyl (R)-3-(4-chlorophenyl)-1-((S)-3-methyl-4-((S)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate was treated with HCl (4M in dioxane, 4 mL) in DCM to afford (R)-2-amino-3-(4-chlorophenyl)-1-((S)-3-methyl-4-((S)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one dihydrochloride. MS (APCI+) [M+H]+ 432.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[CH:16][C:11]2[NH:12][C:13](=[S:15])[NH:14][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][C:19]([CH:21]=[CH2:22])=[O:20]>>[O:20]=[C:19]([CH3:18])[CH2:21][CH2:22][N:12]1[C:11]2[CH:16]=[CH:17][C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:9][C:10]=2[N:14]([CH2:22][CH2:21][C:19](=[O:20])[CH3:18])[C:13]1=[S:15]
Reactant: S=c1[nH]c2ccc(Cc3ccccc3)cc2[nH]1
Reactant: C=CC(C)=O
Product: CC(=O)CCn1c(=S)n(CCC(C)=O)c2cc(Cc3ccccc3)ccc21

Procedure:
14.4 g (60 mmoles) of 5-benzyl-benzimidazoline-2-thione amd 45 ml of methylvinylketone are boiled for 4 hours in the presence of 2 drops of 40%, methynolic Triton B solution. Then the reaction mixture is evaporated off. During storage the distillation residue crystallizes. This is recrystallized from 200 ml of ethanol and thus 19.86 g (87%) of title product melting at a temperature of 98°-100° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([SH:31])([C:27]([F:30])([F:29])[F:28])[CH2:10][C:11]([C:13]2[CH:25]=[CH:24][C:16]([C:17]([NH:19][CH:20]3[CH2:23][S:22][CH2:21]3)=[O:18])=[C:15]([CH3:26])[CH:14]=2)=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:32]OS(O)(=O)=O.[OH-].[K+]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:27]([F:30])([F:29])[F:28])[S:31][N:32]=[C:11]([C:13]3[CH:25]=[CH:24][C:16]([C:17]([NH:19][CH:20]4[CH2:23][S:22][CH2:21]4)=[O:18])=[C:15]([CH3:26])[CH:14]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NOS(=O)(=O)O
Reactant: Cc1cc(C(=O)CC(S)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NC1CSC1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C2=NSC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC1CSC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-[3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-3-mercapto-butyryl]-2-methyl-N-thietan-3-yl-benzamide (493 mg) dissolved in a minimum amount of tetrahydrofuran then was added Hydroxylamine-O-sulfonic acid (2 equiv.). Then a solution of potassium hydroxide (5.6 equiv.) in water (19 mL) was added dropwise. After stirring at room temperature for 30 minutes, the mixture was quenched with a solution of hydrochloric acid (1N), extracted with ethyl acetate and washed with brine. The collected organic phases were dried over magnesium sulfate, filtered and the filtrate was evaporated under vacuo. The crude mixture was then redissolved in a minimum amount of tetrahydrofuran then was added Hydroxylamine-O-sulfonic acid (2 equiv.) Then a solution of potassium hydroxide (5.6 equiv.) in water (19 mL) was added dropwise. After stirring at room temperature for 30 minutes, the mixture was quenched with a solution of hydrochloric acid (1N), extracted with ethyl acetate and washed with brine. The collected organic phases were dried over magnesium sulfate, filtered and the filtrate was evaporated under vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane/dichloromethane) to give 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isothiazol-3-yl]-2-methyl-N-thietan-3-yl-benzamide (128 mg)
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[C:19]([NH2:21])=O>C(Cl)(Cl)Cl>[Br:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[C:19]#[N:21]
Reactant: Cc1cc(Br)cc(C(N)=O)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClC(Cl)Cl
Product: Cc1cc(Br)cc(C#N)c1
Temperature: 25 °C

Procedure:
Phosphorous pentoxide (29.8 g, 210.2 mmol) was added to a suspension of 3-bromo-5-methylbenzamide (15.0 g, 70.1 mmol) in CHCl3 and the mixture was kept refluxing for 2 days (monitored by TLC). The reaction was allowed to cool to room temperature, and put into ice water under the condition of stirring. The organic layer was separated and the aqueous layer was extracted with dichloromethane (150 mL×2). The combined extracts were washed with brine, dried over NaSO4. The product, 3-bromo-5-methylbenzonitrile (7.20 g, 52%), was purified by flash column chomatography. 1H NMR (400 MHz, CDCl3) δ 7.60-7.56 (m, 2H), 7.40-7.39 (m, 1H), 2.39 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[N:12][C:13]([O:16][CH2:17][C@@H:18]3[CH2:22][O:21]C(C)(C)[O:19]3)=[CH:14][CH:15]=2)[C:5]([C:25]#[N:26])=[C:4]([S:27][CH2:28][C:29]2[N:30]=[C:31]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[O:32][CH:33]=2)[N:3]=1.O>C(O)(=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[N:12][C:13]([O:16][CH2:17][C@@H:18]([OH:19])[CH2:22][OH:21])=[CH:14][CH:15]=2)[C:5]([C:25]#[N:26])=[C:4]([S:27][CH2:28][C:29]2[N:30]=[C:31]([C:34]3[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=3)[O:32][CH:33]=2)[N:3]=1
Reactant: CC1(C)OC[C@@H](COc2ccc(-c3c(C#N)c(N)nc(SCc4coc(-c5ccc(Cl)cc5)n4)c3C#N)cn2)O1
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1c(N)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OC[C@@H](O)CO)nc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
95 mg (0.17 mmol) of the compound from example 32A are dissolved in 4 ml of acetic acid. 2 ml of water are then added. The reaction solution is stirred at RT for 12 h. The solvent is then removed on a rotary evaporator, and the residue is purified directly by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5). If required, the product may be purified further by HPLC chromatography on a chiral phase [column: Daicel Chiralpak AS 10 μm, 250 mm×20 mm; mobile phase: isohexane/ethanol 60:40 (v/v); flow rate: 15 ml/min; temperature: 40° C.; detection: 220 nm].
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][C:6](OS(C)(=O)=O)([C:8]1[C:17]2[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1)[CH3:7].CN(C=O)C>C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>[N:1]([C:6]([C:8]1[C:17]2[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1)([CH3:7])[CH3:5])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cccc2c(C(C)(C)OS(C)(=O)=O)ncnc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc2c(C(C)(C)N=[N+]=[N-])ncnc12
Reaction time: 96 h

Procedure:
Sodium azide (492 mg, 7.57 mmol) is added to methanesulfonic acid 1-methyl-1-(8-methyl-quinazolin-4-yl)-ethyl ester (680 mg, 78% content, 1.89 mmol) in DMF (1.5 mL, 19.56 mmol) and stirring is continued for 4 d. The reaction mixture is diluted with saturated Na2CO3 and EtOAc. The organic layer is washed with brine, dried and filtered to give 4-(1-azido-1-methyl-ethyl)-8-methyl-quinazoline (as a solution in EtOAc).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[NH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:21]([CH3:22])=[C:20]([CH3:23])[N:19]=[C:18]([CH3:24])[N:17]=1>>[O:5]([CH2:1][CH:2]([OH:4])[CH2:3][NH:12][CH2:13][CH2:14][NH:15][C:16]1[N:17]=[C:18]([CH3:24])[N:19]=[C:20]([CH3:23])[C:21]=1[CH3:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1nc(C)c(C)c(NCCN)n1
Reactant: c1ccc(OCC2CO2)cc1
Product: Cc1nc(C)c(C)c(NCCNCC(O)COc2ccccc2)n1

Procedure:
3.0 g. Phenyl glycidyl ether and 7.2 g. 4-(2-aminoethylamino)-2,5,6-trimethylpyrimidine are stirred for 20 hours at 60° to 70° C. in 5 ml. isopropyl alcohol, whereafter the mixture is separated with a column of silica gel, using methylene chloride-methanol-triethylamine (20:2:1 v/v/v) as elution agent. By recrystallizing from ethyl acetate, with the use of fullers' earth and active charcoal, there are obtained 2.9 g. (44% of theory) of the desired product in the form of colorless crystals; m.p. 119°-121° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[F:8].I[CH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[C:29]([C:37]#[N:38])[C:28]=1[O:39][CH3:40].[H-].[Na+].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([N:12]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]2)[CH2:10][O:11][CH2:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[C:29]([C:37]#[N:38])[C:28]=2[O:39][CH3:40])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1c(C#N)cc2ccccc2c1CI
Reactant: CC(C)(C)OC(=O)N1CCN(C(CO)c2ccc(F)c(Cl)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C#N)cc2ccccc2c1COCC(c1ccc(F)c(Cl)c1)N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
The requisite tert-butyl 4-{1-(3-chloro-4-fluorophenyl)-2-[(3-cyano-2-methoxy-1-naphthyl)methoxy]ethyl}piperazine-1-carboxylate was synthesized using the following method. tert-Butyl 4-[1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl]piperazine-1-carboxylate (65 mg, 0.18 mmol) was dissolved in THF (1.8 mL). 4-(Iodomethyl)-3-methoxy-2-naphthonitrile (70 mg, 0.22 mmol) was added followed by NaH (9 mg, 0.36 mmol). After reacting at RT overnight, water (60 mL) was added. The mixture was extracted with EtOAc (40 mL). The organic phase was dried over Na2SO4, filtered through a pad of diatomaceous earth and the volatiles removed under reduce pressure. Chromatography of the residue on SiO2 (0-30% EtOAc:hexane) afforded the title compound (99 mg). MS m/z 554.6 (M+H)+. The requisite tert-butyl 4-[1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl]piperazine-1-carboxylate was synthesized using the following method.
Reaction SMILES: C1N2CN3CN(C2)CN1C3.[I-].[Na+].Cl[CH2:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:17]2[CH2:18][CH2:19][C:16]=12.C([OH:25])C>O>[CH:14]([C:15]1[CH:22]=[CH:21][CH:20]=[C:17]2[CH2:18][CH2:19][C:16]=12)=[O:25]
Reactant: CCO
Reactant: ClCc1cccc2c1CC2
Agent: C1N2CN3CN1CN(C2)C3
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: O=Cc1cccc2c1CC2
Reaction time: 2.5 h

Procedure:
To a hot solution of hexamethylene tetramine (14 g) and sodium iodide (16 g) in 140 g of ethanol was added 4-chloromethylbenzocyclobutene (15.2 g) with stirring. After standing at ambient temperature for 2-3 h, the mixture was diluted with 150 ml of water and then heated at reflux for 2 h. The resulting mixture was steam distilled and the distillate was extracted three times with ether. The combined ether extract was washed with water, dried over magnesium sulfate, and fractionally distilled to give 4-formylbenzocyclobutene: 1H NMR (CDCl3) δ 3.17 (s, 4), 7.15 (d, 1), 7.51 (s, 1), 7.67 (d, 1) and 9.86 ppm (s, 1).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[I:21]I.S(S([O-])=O)([O-])(=O)=O.[K+].[K+]>C(Cl)Cl.C1COCC1>[C:1]1([NH:7][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[I:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: II
Reactant: O=C(Nc1ccccc1)c1ccncc1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)c1ccncc1I
Temperature: -69 °C
Reaction time: 14 h

Procedure:
Into a 4-necked RBF equipped with an overhead stirrer and a J-Kem internal temperature probe was placed N-phenylisonicotinamide (35.1 g, 0.18 mol) and anhydrous THF (700 ml). All material appeared to go into solution. This mixture was cooled to −69° C. in a dry ice/IPA bath. To this was slowly added nBuLi (156 ml of a 2.5 M in Hexanes) in two portions. While adding the first equivalent of nBuLi, an exotherm was observed raising the temperature to approx. −41° C. The orange reaction mixture was slightly heterogeneous. This was allowed to slowly warm to 12° C. over 2 h. This mixture was re-cooled to −70° C. At this point, a THF solution (175 ml) of iodine (47.2 g, 0.19 mol) was added. This was allowed to warm and stirred at room temperature for 14 h. To this solution was added 150 ml of a saturated solution of potassium meta-bisulfite and diluted with CH2Cl2. The two layers were separated and the organic layer was extracted with brine. The two layers were separated and the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give a black oil. This material was purified by SiO2 column chromatography using 40% ethyl acetate/Hexane as eluent. Concentration gave 38.6 g (67% th) of an off-white solid.