Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:12])[CH3:11].[C:13]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2([CH3:27])[CH2:26][O:25]2)=[O:23])=[CH:17][C:16]=1[CH3:28])#[N:14]>>[C:10]([NH:9][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:27][C:24]([OH:25])([CH3:26])[C:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([C:13]#[N:14])=[C:16]([CH3:28])[CH:17]=2)=[O:23])=[CH:7][C:2]=1[F:1])(=[O:12])[CH3:11]
Reactant: Cc1cc(NC(=O)C2(C)CO2)ccc1C#N
Reactant: CC(=O)Nc1ccc(O)cc1F
Product: CC(=O)Nc1ccc(OCC(C)(O)C(=O)Nc2ccc(C#N)c(C)c2)cc1F

Procedure:
3-(4-Acetylamino-3-fluorophenoxy)-N-(4-cyano-3-methylphenyl)-2-hydroxy-2-methylpropionamide was prepared as described in Example 1 starting from N-(2-fluoro-4-hydroxyphenyl)acetamide and 2-methyl-oxirane-2-carboxylic acid (4-cyano-3-methylphenyl)amide. 1H NMR (DMSO-d6): 1.41 (3H, s), 2.02 (3H, s), 2.44 (3H, s), 3.95 (1H, d, J=9.8 Hz), 4.26 (1H, d, J=9.8 Hz), 6.21 (1H, bs), 6.72 (1H, m), 6.86 (1H, m),7.56 (1H, m,) 7.69 (1H, d, J=9.0 Hz), 7.78 (1H, dd, J=9.0 Hz and 2.2 Hz), 7.93 (1H, d, J=2.2 Hz), 9.51 (1H, s), 9.99 (1H, bs).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)[C:3]=12.CC(C)([O-])C.[Na+].[Cl:39][C:40]1[CH:41]=[C:42]([S:46](Cl)(=[O:48])=[O:47])[CH:43]=[CH:44][CH:45]=1.[NH4+].[Cl-]>C1COCC1>[Cl:39][C:40]1[CH:41]=[C:42]([S:46]([NH:1][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]3[S:14][C:15]([NH:25][C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=4)[C:3]=23)(=[O:48])=[O:47])[CH:43]=[CH:44][CH:45]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: CCOC(=O)c1c(C)nc2sc(NC(=O)OC(C)(C)C)c(-c3cccc(OC)c3)c2c1N
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)nc2sc(NC(=O)OC(C)(C)C)c(-c3cccc(OC)c3)c2c1NS(=O)(=O)c1cccc(Cl)c1
Reaction time: 3.5 h
Yield: 28.2 %

Procedure:
To a stirred solution of ethyl 4-amino-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridine-5-carboxylate (Description 82) (1.54 g, 3.37 mmol) in THF (30 mL) was added sodium tert-butoxide (1.294 g, 13.46 mmol) at RT and the mixture stirred for 15 min before 3-chlorobenzenesulfonyl chloride (0.948 mL, 6.73 mmol) was added. The resulting mixture was then stirred for ca. 3.5 h. Saturated NH4Cl solution (50 mL) was then added to the mixture which was extracted with ethyl acetate (30 mL×3). The combined organics were washed with brine (30 mL), dried and concentrated. The residue was purified by normal phase chromatography, eluting with a gradient of 0-30% ethyl acetate in cyclohexane, to give the title compound (600 mg). LCMS (A) m/z: 632 [M+1]+, Rt 1.74 min (acidic).
Reaction SMILES: [CH2:1]([S:3][C:4]1[S:5][C:6]([C:9]([OH:11])=O)=[CH:7][N:8]=1)[CH3:2].C(N(CC)CC)C.C(OC(Cl)=O)C.[NH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH2:31]>O1CCCC1>[CH2:1]([S:3][C:4]1[S:5][C:6]([C:9]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH2:31])=[O:11])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCSc1ncc(C(=O)O)s1
Reactant: C=CCCCCN
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCCCCNC(=O)c1cnc(SCC)s1
Temperature: -30 °C

Procedure:
In this preparation 0.1 mole of 2-ethylthio-5-carboxythiazole is dissolved in 300 ml. of anhydrous tetrahydrofuran, under nitrogen, and 0.1 mole of triethylamine is added and the resulting mixture cooled to -30° C. 0.1 Mole of ethylchloroformate is then added dropwise with stirring and the resulting mixture allowed to warm to 0° C. The mixture is then stirred for ten minutes, then cooled to -30° C and 0.11 mole of 1-aminohex-5-ene in 50 ml. of tetrahydrofuran added dropwise. The mixture is allowed to warm to room temperature (about 20° C), poured in 500 ml. of ethyl acetate, washed with water, then washed with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The mixture is then filtered and the resulting filtrate evaporated under vacuum yielding 2-ethylthio-5-(hex-5-enylaminocarbonyl)thiazole as a solid, which is then further purified by recrystallization from ethyl acetate.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]2([CH2:23][C:22](=[O:24])[C:21]3[C:16](=[CH:17][CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27]([NH:29][OH:30])=[O:28])[CH:20]=3)[O:15]2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BH4-].[Na+]>CO>[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]2([CH2:23][CH:22]([OH:24])[C:21]3[C:16](=[CH:17][CH:18]=[C:19](/[CH:25]=[CH:26]/[C:27]([NH:29][OH:30])=[O:28])[CH:20]=3)[O:15]2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3)CC1)O2)NO
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(/C=C/c1ccc2c(c1)C(O)CC1(CCN(Cc3ccccc3)CC1)O2)NO
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
A mixture of (E)-3-{1′-benzyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-hydroxy-acrylamide hydrochloride (60 mg, 0.14 mmol) and NaBH4 (17.6 mg, 0.459 mmol) in MeOH (5 ml) was stirred at RT. After 3 h, the solution was evaporated under vacuum. The crude residue was purified by preparative HPLC to give (E)-3-{1′-benzyl-4-hydroxy-spiro[chromane-2,4′-piperidine]-6-yl}-N-hydroxy-acrylamide (45 mg) as its trifluoro acetate salt.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[C:4]([CH3:9])[N:3]=1.[CH3:10][N:11]([CH2:13][CH2:14][NH2:15])[CH3:12].[OH-].[Na+]>O>[CH3:10][N:11]([CH3:12])[CH2:13][CH2:14][NH:15][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[C:4]([CH3:9])[N:3]=1
Reactant: CN(C)CCN
Reactant: Cc1ncc(Cl)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ncc(NCCN(C)C)nc1C

Procedure:
2-chloro-5,6-dimethylpyrazine (12.8 g., 0.09 mole) is added to unsym-dimethylethylenediamine (26 g., 0.295 mole) containing cuprous chloride (0.25 g.) and the mixture is heated for 48 hours in an oil bath maintained at 135°-140° C. On cooling, 50 ml of water and a single molar excess of 10N sodium hydroxide are added. The mixture is extracted with methylene chloride. The organic extracts are backwashed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under vacuum. The residual oil is dissolved in hexane, filtered and reconcentrated to obtain the product oil (15.8 g., 0.081 mole).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10].[Br:18]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1(=O)NC(=O)CC1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:17][C:15]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH:16]=1
Reactant: COCCCOc1cc(C)ccc1C(=O)OC
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: COCCCOc1cc(CBr)ccc1C(=O)OC

Procedure:
The mixture of 25.0 g of methyl 2-(3-methoxypropoxy)-4-methylbenzoate, 18.4 g of N-bromosuccinimide, 1.65 g of 2,2′-azobis(2-methylpropionitrile) and 2.46 g of dibenzoyl peroxide in 1.2 l of carbon tetrachloride is heated to reflux with stirring and stirred over 3 hours (succinimide crystallizes out). The reaction mixture is cooled and clarified by filtration, and the filtrate is concentrated by evaporation. The title compound is obtained as a slightly orange oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.30 (1:1 EtOAc-heptane); Rt=17.10 (II).
Reaction SMILES: C(C1NC(C#N)C(C)(C)S1)(C)C.C#N.Cl.Cl.C(C1[NH:24][CH:23]([C:25]([OH:27])=[O:26])[C:22]([CH3:29])([CH3:28])[S:21]1)(C)C.[Cl-].[NH4+]>>[NH2:24][C@H:23]([C:25]([OH:27])=[O:26])[C:22]([SH:21])([CH3:29])[CH3:28]
Reactant: CC(C)C1NC(C(=O)O)C(C)(C)S1
Agent: C#N
Agent: CC(C)C1NC(C#N)C(C)(C)S1
Agent: Cl
Product: CC(C)(S)[C@H](N)C(=O)O

Procedure:
In a process for the production of D,L-penicillamine by the reaction of isobutyraldehyde with sulfur and ammonia to form 2-isopropyl-5,5-dimethylthiazoline-3, conversion of the thiazoline with anhydrous hydrogen cyanide into 2-isopropyl-5,5-dimethylthiazolidine-4-carbonitrile, hydrolysis of the nitrile with hydrochloric acid to 2-isopropyl-5,5-dimethylthiazolidine-4-carboxylic acid hydrochloride and ammonium chloride, working up the mixture and separation of the ammonium chloride and hydrolytically breaking down the 2-isopropyl-5,5-dimethylthiazolidine-4-carboxylic acid to form penicillamine the improvement comprising carrying out the hydrolysis of the 2-isopropyl-5,5-dimethylthiazolidine-4-carbonitrile by (1) converting the 2-isopropyl-5,5-dimethylthiazolidine-4-carbonitrile with the hydrochloric acid into 2-isopropyl-5,5-dimethylthiazolidine-4-carbonamide hydrochloride at a temperature of 0° to 80° C and (2) converting the 2-isopropyl-5,5-dimethylthiazolidine-4-carbonamide hydrochloride into 2-isopropyl-5,5-dimethylthiazolidine-4-carboxylic acid hydrochloride at a temperature of 80° to 150° C.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[CH:21][C:3]=1[CH2:4][C:5]([O:18][CH2:19][CH3:20])([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[F:17])[C:6]([NH2:8])=[O:7].[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:25]([C:23]1[CH:22]=[CH:21][C:3]([CH2:4][C:5]([O:18][CH2:19][CH3:20])([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[F:17])[C:6]([NH2:8])=[O:7])=[C:2]([NH:1][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=1)#[N:26]
Reactant: CCOC(Cc1ccc(C#N)cc1N)(C(N)=O)c1ccc(OC)cc1F
Reactant: OB(O)c1ccccc1
Product: CCOC(Cc1ccc(C#N)cc1Nc1ccccc1)(C(N)=O)c1ccc(OC)cc1F

Procedure:
In analogy to example 30.6 (RS)-(2-amino-4-cyano-benzyl)-2-ethoxy-2-(2-fluoro-4-methoxy-phenyl)-acetamide (example 322.4) was reacted with phenyl boronic acid to give (RS)-(4-cyano-2-phenylamino-benzyl)-2-ethoxy-2-(2-fluoro-4-methoxy-phenyl)-acetamide. Off-white foam. MS 434.1 ([M+H]+)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][CH2:8][CH:9]2[CH2:14][CH2:13][N:12](C(OCC3C=CC=CC=3)=O)[CH2:11][CH2:10]2)=[CH:3][CH:2]=1.[H][H]>[Pd].C(O)C>[NH:12]1[CH2:13][CH2:14][CH:9]([CH2:8][NH:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:10][CH2:11]1
Reactant: O=C(OCc1ccccc1)N1CCC(CNc2ccncc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: c1cc(NCC2CCNCC2)ccn1

Procedure:
Benzyl 4-[(4-pyridinylamino)methyl]-1-piperidinecarboxylate (EXAMPLE 1) (7 g, 21 mmol) was dissolved in abs. Ethanol (150 mL) with 10% palladium on carbon (700 mg) and stirred under 1 atm of hydrogen for 2 h. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to afford the N-(4-piperidinylmethyl)-4-pyridinamine as a clear oil which was used without further purification.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:24][CH2:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[N:6][C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:9]=1)(=O)[CH3:2].N12CCCN=C1CCCCC2>CN(C=O)C>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:7]1[N:6]=[C:5]2[O:24][C:25]([C:26](=[O:31])[C:27]([CH3:29])([CH3:30])[CH3:28])=[C:1]([CH3:2])[C:4]2=[CH:9][C:8]=1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1
Reactant: CC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nc1OCC(=O)C(C)(C)C
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1c(C(=O)C(C)(C)C)oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 150 °C

Procedure:
A mixture of 0.432 g (0.95 mmol) of the product of Step B, 250 A (1.67 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in 2 mL DMF was placed in a 10 mL reaction tube of a CEM Corporation Discover 300 Watt microwave reactor. The reaction vessel was sealed, placed in the microwave reactor and heated at 150° C. for 10 min. After the reaction mixture had cooled to room temperature, it was partitioned between EtOAc and 10% aq. NaHSO4 and extracted. The organic layer was washed with 10% aq. NaHSO4, water, brine, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 0–10% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound. HPLC/MS: 438.1 (M+1), 440.1 (M+3); Rt=4.72 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=O.C[Si](Cl)(C)C.C([BH3-])#N.[Na+]>C(#N)C.ClCCl>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[OH:1])=[CH:11][CH:12]=1
Reactant: COc1ccc(C(=O)c2ccccc2O)cc1
Agent: C[Si](C)(C)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccc(Cc2ccccc2O)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
0.78 g of (2-hydroxyphenyl)(4-methoxyphenyl)methanone is dissolved in acetonitrile and cooled to 0° C. 2 ml of TMSCl are added dropwise to the mixture, and then 1 g of sodium cyanoborohydride is added. The mixture is stirred at room temperature for 3 h. The reaction solution is diluted with dichloromethane and filtered through Celite.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1[C:20]([CH3:21])=[C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:30])[CH:17]=2)[CH:12]=1)=O.Cl>O1CCCC1>[CH2:23]([O:22][C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([F:30])[CH:17]=2)[CH:12]=[C:11]([CH2:9][OH:8])[C:20]=1[CH3:21])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1cc2ccc(F)cc2c(OCc2ccccc2)c1C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1c(CO)cc2ccc(F)cc2c1OCc1ccccc1
Temperature: 60 °C
Yield: 92 %

Procedure:
To a slurry of lithium aluminum hydride (1.8 g, 47.5 mmol) in tetrahydrofuran (50 mL) was added a solution of 4-benzyloxy-6-fluoro-3-methyl-naphthalene-2-carboxylic acid methyl ester (10 g, 30.8 mmol) in tetrahydrofuran (50 mL) at 0° C. under a nitrogen atmosphere. After being heated at 60° C. for 2 hours, the resulting mixture was cooled to 0° C. and treated with 1 N hydrochloric acid to quench the reaction. The aqueous layer was extracted with diethyl ether (100 mL×5). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give (4-benzyloxy-6-fluoro-3-methyl-naphthalen-2-yl)-methanol (8.4 g, 92%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.84 (dd, J=5.6, 9.2 Hz, 1H), 7.70 (dd, J=2.4, 10.0 Hz, 1H), 7.69 (s, 1H), 7.40-7.50 (m, 5H), 7.24 (td, J=2.4, 8.4 Hz, 1H), 4.99 (s, 2H), 4.87 (s, 2H), 2.47 (s, 3H).
Reaction SMILES: [Cl:1][C:2]([Cl:38])([Cl:37])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:36])[C@@H:14]([NH:21][C:22](=[O:35])[C@@H:23]([NH:27][C:28](OC(C)(C)C)=[O:29])[CH:24]([CH3:26])[CH3:25])[CH2:15][N:16]2[CH:20]=[CH:19][CH:18]=[N:17]2)[NH:8]1)=[O:6].FC(F)(F)C(O)=O.[C:46]([O:49][C@@H:50]([C:52]1[CH:61]=[CH:60][C:59]2[C:54](=[CH:55][C:56](/[CH:62]=[CH:63]/[C:64](C)([CH3:68])[C:65](O)=O)=[CH:57][CH:58]=2)[N:53]=1)[CH3:51])(=[O:48])[CH3:47].C(N(CC)C(C)C)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]([Cl:37])([Cl:38])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:36])[C@@H:14]([NH:21][C:22](=[O:35])[C@@H:23]([NH:27][C:28](=[O:29])[C:64]([CH3:68])([CH3:65])/[CH:63]=[CH:62]/[C:56]2[CH:55]=[C:54]3[C:59]([CH:60]=[CH:61][C:52]([C@H:50]([O:49][C:46](=[O:48])[CH3:47])[CH3:51])=[N:53]3)=[CH:58][CH:57]=2)[CH:24]([CH3:25])[CH3:26])[CH2:15][N:16]2[CH:20]=[CH:19][CH:18]=[N:17]2)[NH:8]1)=[O:6]
Reactant: CC(=O)O[C@H](C)c1ccc2ccc(/C=C/C(C)(C)C(=O)O)cc2n1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cn1cccn1)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC(=O)O[C@H](C)c1ccc2ccc(/C=C/C(C)(C)C(=O)N[C@H](C(=O)N[C@@H](Cn3cccn3)C(=O)N3CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N3)C(C)C)cc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.5 %

Procedure:
To (S)-1-[(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-3-pyrazol-1-yl-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (450 mg, 0.75 mmol) in anhydrous dichloromethane (1 mL) at 0° C. and under an atmosphere of nitrogen was added trifluoroacetic acid (0.58 mL, 7.6 mmol). The reaction mixture was warmed to room temperature and stirred for 3 h before concentrating in vacuo and co-evaporating from toluene. This residue was dissolved in anhydrous acetonitrile (7.5 mL) and at 0° C. and under an atmosphere of nitrogen was added (E)-4-[2-((R)-1-acetoxy-ethyl)-quinolin-7-yl]-2,2-dimethyl-but-3-enoic acid (246 mg, 0.75 mmol), N,N-diisopropylethylamine (0.66 mL, 3.76 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (401 mg, 1.05 mmol). The solution was warmed to room temperature and stirred for 2 h. The reaction was cooled to 0° C., diluted with ethyl acetate and quenched with 1 M hydrochloric acid. The organic layer was separated and washed with a saturated aqueous solution of sodium bicarbonate (2×) and brine (1×). The organic layer was then dried through a hydrophobic frit and concentrated in vacuo. The residue was purified by silica gel chromatography using iso-hexanes/ethyl acetate 1:1 then 0:1 to give the title compound (433 mg, 72%) as a viscous clear oil, as a 2:1 mixture of diastereoisomers. LCMS (m/z)=806.3 [M+H], Tr=2.91 min.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:13](=[C:14]([F:16])[CH:15]=1)[C:12]([CH3:18])([CH3:17])[CH2:11][CH2:10]2)(=O)=O.C1(C(C2C=CC=CC=2)=[NH:28])C=CC=CC=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+].Cl.[OH-].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1(C)C=CC=CC=1>[F:16][C:14]1[CH:15]=[C:7]([NH2:28])[CH:8]=[C:9]2[C:13]=1[C:12]([CH3:18])([CH3:17])[CH2:11][CH2:10]2
Reactant: CC1(C)CCc2cc(OS(=O)(=O)C(F)(F)F)cc(F)c21
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)CCc2cc(N)cc(F)c21
Temperature: 80 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
A mixture of 7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl trifluoromethanesulfonate (5.18 g, 16.59 mmol), diphenylmethanimine (3.61 g, 19.91 mmol), Pd2(dba)3 (0.759 g, 0.83 mmol), BINAP (1.033 g, 1.66 mmol), sodium tert-butoxide (2.391 g, 24.88 mmol) and toluene (75 mL) was stirred at 80° C. for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in THF (200 mL), LN hydrochloric acid (83 mL, 82.94 mmol) was added thereto, and the mixture was stirred at room temperature for 30 min, and basified with 1N aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 0→10% ethyl acetate/hexane) to give 7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-amine (1.92 g, 10.71 mmol, 65%) as an orange oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:28])=[C:5]([CH:25]=[CH:26][CH:27]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:23][CH3:24])=[C:14]([O:17][C@H:18]3[CH2:22][CH2:21][NH:20][CH2:19]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>>[Cl:2][C:3]1[C:4]([F:28])=[C:5]([CH:25]=[CH:26][CH:27]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:23][CH3:24])=[C:14]([O:17][C@H:18]3[CH2:22][CH2:21][N:20]([S:30]([CH3:29])(=[O:32])=[O:31])[CH2:19]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCNC1
Agent: Cl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCN(S(C)(=O)=O)C1
Yield: 43 %

Procedure:
Using a similar procedure to that described in Example 29, 4-(3-chloro-2-fluoroanilino)-6-[(3S)-pyrrolidin-3-yloxy]-7-methoxyquinazoline hydrochloride (210 mg) was reacted with methane sulfonyl chloride to give the title product (100 mg, 43%); 1H NMR Spectrum: (DMSO d6) 2.18-2.37 (m, 2H); 2.93 (s, 3H); 3.38-3.52 (m, 3H); 3.69 (dd, 1H); 3.92 (s, 3H); 5.17 (m, 1H); 7.15-7.35 (m, 2H); 7.40-7.60 (m, 2H); 7.80 (s, 1H); 8.38 (s, 1H); 9.58 (s, 1H); Mass Spectrum: (M+H)+ 467.
Reaction SMILES: [CH:1]1[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.CO[C:19]1[CH:27]=[C:26](OC)[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[C:8]1([C:21]([C:20]2[C:19]3[C:27]4=[C:15]5[C:14](=[CH:13][CH:12]=3)[CH:1]=[CH:2][CH:3]=[C:4]5[CH:5]=[CH:6][C:26]4=[CH:25][CH:24]=2)=[O:22])[C:7]2[C:16]3=[C:15]4[C:4](=[CH:5][CH:6]=2)[CH:3]=[CH:2][CH:1]=[C:14]4[CH:13]=[CH:12][C:11]3=[CH:10][CH:9]=1
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Reactant: c1cc2ccc3cccc4ccc(c1)c2c34
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc2ccc3cccc4ccc1c2c34)c1ccc2ccc3cccc4ccc1c2c34
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Pyrene (10,1 g; 0.05 mol) and 2,4-dimethoxybenzoyl chloride (10 g; 0.05 mol) were dissolved in 400 ml of anhydrous methylene chloride. Anhydrous aluminium chloride (6.6 g; 0.05 mol) was added to the reaction mixture in small portions over 1 h at 0° C. with intense stirring. The reaction mixture was stirred for another 2 h at 0° C., 2 h at rt and then poured onto a mixture of ice and HCl (500 ml) and transferred into a separating funnel. The organic layer was washed with water (1×500 ml), saturated NaHCO3 (2×500 ml) and saturated NaCl (1×500 ml). The organic fraction was evaporated and recrystallised from toluene to give pyrenylketone as white solid (15.7 g; 86%). Found: C, 82.09; H, 4.81. C25H18O3 (MW 366.41) requires C, 81.95; H, 4.95%. 1H-NMR (CDCl3, d): 8.65-6.45 (m, 12 H, arom.), 3.91 (s, 3H, OCH3), 3.55 (s, 3H, OCH3). Mass-spectrum, MALDI-TOF: 388.89 (MI+Na; 15), 366.89 (100), 203.82 (40). Calculated exact mass for C25H18O3:366.12559; found 366.12617 [1.6 ppm error].
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C@@H:6]([NH2:8])[CH3:7])=[CH:4][CH:3]=1.C([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][C:36]([C:40](O)=[O:41])=[CH:37][CH:38]=3)[C:33]([CH3:43])=[C:32]2[CH3:44])=[CH:26][CH:25]=1)=[O:17])(C)(C)C>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C@@H:6]([NH:8][C:40]([C:36]2[CH:35]=[C:34]3[C:39](=[CH:38][CH:37]=2)[N:31]([CH2:30][C:27]2[CH:26]=[CH:25][C:24]([C:19]4[C:18]([C:16]([OH:17])=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:29][CH:28]=2)[C:32]([CH3:44])=[C:33]3[CH3:43])=[O:41])[CH3:7])=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3ccc(F)cc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 4-fluoro-α-(S)-methylbenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. LC-MS 521 (M+H).
Reaction SMILES: [N+:1](=[CH2:3])=[N-:2].[C:4]1([CH2:10][C:11](Cl)=[O:12])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CCOCC>[N+:1](=[CH:3][C:11](=[O:12])[CH2:10][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[N-:2]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: [N-]=[N+]=CC(=O)Cc1ccccc1
Yield: 95.2 %

Procedure:
To diazomethane (40 mmol) in ether (100 ml) at 0° C. was added phenylacetyl chloride (2.65 ml, 20 mmol). After 30 min at 0° C. the excess diazomethane and the ether were blown off with nitrogen, and then under vacuum to leave 1-diazo-3-phenyl-2-propanone as a yellow oil (3.05 g, 95%); δH (CDCl3) 7.2 (5H, S, aryl), 5.1 (1H, S, CH=N2), 3.5 (2H, S, CH2).