Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([CH2:27][CH2:28][NH:29][CH:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:33][CH2:32][CH2:31]3)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:40]([CH:45]=O)[CH2:41][C:42]([OH:44])=[O:43].CC(O)=O.[BH3-]C#N.[Na+]>CO.O>[C:23]([O:22][C:20]([C@@H:19]([NH:18][C:16]([O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:17])[CH2:27][CH2:28][N:29]([CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32][CH2:31]1)[CH2:45][CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: O=CCCC(=O)O
Reactant: CC(C)(C)OC(=O)[C@H](CCNC1CCCc2ccccc21)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)[C@H](CCN(CCCC(=O)O)C1CCCc2ccccc21)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.9 %

Procedure:
To a solution of tert-butyl (2S)-2-[[(9H-9-fluorenylmethoxy)carbonyl]amino]-4-(1,2,3,4-tetrahydro-1-naphthylamino)butanoate (16 mg,0.030 mmol) in MeOH (0.5 ml) were added succinic semialdehyde (15 wt. % solution in water, 48 μl, 0.077 mmol), HOAc (2 μl, 0.035 mmol) and NaBH3CN (2.3 mg, 0.074 mmol), and the mixture was stirred at RT for 6 h. After adding water, the mixture was extracted with chloroform, washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under vacuum to dryness, and the residue was adsorbed on a plate of silica gel and then developed with 10% methanol/chloroform to afford 4-[[(3S)-3-(tert-butoxycarbonyl)-3-[[(9H-9-fluorenylmethoxy)carbonyl]amino]propyl](1,2,3,4-tetrahydro-1-naphthyl)amino]butanoic acid (18 mg, 98%): MS(ES+) m/e 613 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 7.98 (br, 1H), 7.76 (d, J=7.3 Hz, 2H), 7.61 (m, 3H), 7.40 (t, J=7.3 Hz, 2H), 7.31 (m, 2H), 7.15 (m, 2H), 7.06 (d, J7.6 =Hz, 1H), 5.64 (br, 1H), 4.36 (m, 2H), 4.22 (m, 3H), 2.75-2.17 (m, 8H), 2.10-1.65 (m, 8H), 1.42 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH2:11]([O:13][C:14](=[O:23])[CH2:15][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=O)[CH3:12].[CH2:24]([O:26][C:27](=[O:32])/[CH:28]=[C:29](\[NH2:31])/[CH3:30])[CH3:25]>C(O)C>[CH2:24]([O:26][C:27]([C:28]1[CH:6]([C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:15]([C:14]([O:13][CH2:11][CH3:12])=[O:23])=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:31][C:29]=1[CH3:30])=[O:32])[CH3:25]
Reactant: COc1cccc(C=O)c1
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Reactant: CCOC(=O)/C=C(/C)N
Solvent: CCO
Product: CCOC(=O)C1=C(C(=O)OCC)C(c2cccc(OC)c2)C(C(=O)OCC)=C(C)N1

Procedure:
27.2 g of 3-methoxybenzaldehyde, 38 g of oxalacetic acid diethyl ester and 26 g of β-aminocrotonic acid ethyl ester in 120 ccs of ethanol are heated to the boil overnight and evaporated in vacuo. Oil (orange).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:22][CH:6]2[C:7](=[O:21])[N:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)[CH2:9][CH:5]2[CH2:4]1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30](Cl)(=[O:32])=[O:31].CCN(CC)CC>ClCCl>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH:2][CH:3]1[CH2:22][C@@H:6]2[C:7](=[O:21])[N:8]([C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:19])[F:20])=[CH:14][CH:15]=3)[CH2:9][C@@H:5]2[CH2:4]1)(=[O:32])=[O:31]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: NC1CC2CN(c3ccc(OC(F)(F)F)cc3)C(=O)C2C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1[C@H]2CC(NS(=O)(=O)c3ccccc3Cl)C[C@H]2CN1c1ccc(OC(F)(F)F)cc1
Reaction time: 8 h
Yield: 35.1 %

Procedure:
5-Amino-2-(4-trifluoromethoxy-phenyl)-hexahydro-cyclopenta[c]pyrrol-1-one, hydrochloride (60 mg, 0.18 mmol), 2-chlorobenzene-1-sulfonyl chloride (76 mg, 0.36 mmol) and Et3N (82 mg, 0.81 mmol) were added to dichloromethane (2 mL), the mixture was stirred for overnight. The solvent was removed, and the crude product was purified by prep-TLC (petroleum ether/ethyl acetate=1:1) to yield the title compound (30 mg, 33%). 1H NMR (300 MHz, CDCl3): δ 8.14-8.11 (m, 1H), 7.68-7.49 (m, 5H), 7.26-7.22 (m, 2H), 5.04 (d, 1H, J=6.6 Hz), 4.05 (t, 1H, J=9.0 Hz), 3.68-3.62 (m, 2H), 3.08-3.06 (m, 1H), 2.79-2.76 (m, 1H), 2.26-2.19 (m, 2H), 1.95-1.93 (m, 1H), 1.73-1.65 (m, 1H); LC-MS: 475.0 [M+1]+.
Reaction SMILES: [C:1]([C:3]1[C:7]([CH:8]2[CH2:11][CH:10](O)[C:9]2([Cl:14])[Cl:13])=[CH:6][N:5]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][C:16]=2[Cl:26])[N:4]=1)#[N:2].C(N([CH2:32][CH3:33])CC)C.[C:34]1(C)[CH:39]=C[C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>C(Cl)Cl>[C:1]([C:3]1[C:7]([CH:8]2[CH2:11][CH:10]([S:40]([C:37]3[C:32]([CH3:33])=[CH:39][CH:34]=[CH:35][CH:36]=3)(=[O:42])=[O:41])[C:9]2([Cl:14])[Cl:13])=[CH:6][N:5]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][C:16]=2[Cl:26])[N:4]=1)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(CC)CC
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C1CC(O)C1(Cl)Cl
Solvent: ClCCl
Product: Cc1ccccc1S(=O)(=O)C1CC(c2cn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)nc2C#N)C1(Cl)Cl
Temperature: 0 °C
Reaction time: 18 h
Yield: 15.9 %

Procedure:
3-Cyano-4-(2,2-dichloro-3-hydroxycyclobutyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (628 mg, 1.41 mmol, Preparation 2) was dissolved in anhydrous DCM and cooled to 0° C. Triethylamine (0.27 ml, 1.98 mmol) was added dropwise followed by p-toluenesulfonyl chloride (297 mg, 1.56 mmol). The cooling bath was removed and the reaction mixture was stirred 18 hr at room temperature. The reaction mixture was poured into an equal volume of water and extracted with DCM (2×30 ml). The combined organics were washed successively with saturated sodium bicarbonate, brine then dried (Na2SO4), filtered and the solvent removed in vacuo. The residue was purified by silica chromatography (eluting with 33% DCM/hexane) to yield 131 mg of the title compound as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][OH:20])[O:16][N:15]=2)=[CH:12][CH:13]=1.[C:33](O)(=[O:41])[C:34]1[CH:39]=[CH:38][CH:37]=[N+:36]([O-:40])[CH:35]=1.C(N=C=NC(C)C)(C)C>CN(C)C1C=CN=CC=1.CN(C=O)C.CO.C(OCC)C>[C:33]([O:20][CH2:19][C@H:17]1[O:16][N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]3[CH:6]=[CH:5][C:4]([N:21]4[CH2:25][C@H:24]([CH2:26][N:27]5[CH:31]=[CH:30][N:29]=[N:28]5)[O:23][C:22]4=[O:32])=[CH:3][C:2]=3[F:1])=[CH:9][N:10]=2)[CH2:18]1)(=[O:41])[C:34]1[CH:39]=[CH:38][CH:37]=[N+:36]([O-:40])[CH:35]=1
Reactant: O=C(O)c1ccc[n+]([O-])c1
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1)c1ccc[n+]([O-])c1
Reaction time: 24 h
Yield: 53.6 %

Procedure:
(5R)-3-(3-fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1: 130 mg, 0.30 mMol), nicotinic acid 1-oxide (100 mg, 0.72 mMol), 1,3-diisopropylcarbodiimide (290 mg, 2.3 mMol), and 4-dimethylaminopyridine (5 mg, 0.04 mMol) were suspended in 2 ml of DMF at room temperature. The mixture was stirred one day, diluted with methanol (2 ml), stirred 5 minutes and then further diluted with diethyl ether (20 ml) to give a suspension. The solids were collected and rinsed with diethyl ether, then suspended in acetonitrile:methanol (1:1, 150 ml), the mixture was warmed and stirred a few minutes, then allowed to cool. The suspension was filtered and the filtrate was concentrated to a volume of 10 ml to give a suspension. The solids were collected, rinsed with acetonitrile, then diethyl ether and dried under vacuum to yield the title compound as an off-white solid (90 mg), melting point: 255° C.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]([Mg]Cl)[C:11]([CH3:14])([CH3:13])[CH3:12]>C1COCC1.[NH4+].[Cl-]>[CH3:10][C:11]([CH3:14])([CH3:13])[CH2:12][CH:6]([C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=1)[OH:7]
Reactant: Cc1ccc(C=O)cc1
Reactant: CC(C)(C)C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(C(O)CC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
To a stirred solution of 4-methylbenzaldehyde (1.51 g, 12.6 mmol) in THF (30 mL) at 0° C., add neopentyl magnesium chloride (33.0 mL, 16.34 mmol, 0.5-1M in ether) and continue stirring at 0° C. for 1 h. Dilute with saturated aqueous NH4Cl, extract three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (95:5) to give the desired intermediate as a colorless oil (2.15 g, 89%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)=[CH:8][CH:7]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.Cl>>[N:23]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]3[O:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C1CCNCC1
Reactant: ClCCCOc1ccc(/C=C/c2nc3ccccc3o2)cc1
Agent: Cl
Product: C(=C/c1nc2ccccc2o1)\c1ccc(OCCCN2CCCCC2)cc1
Yield: 41 %

Procedure:
The procedure of Example 8 was followed starting with (C) of Example 8 (2.0 g, 6.4 mmol) and using piperidine in place of dibutylamine to produce 1.1 g, (41% yield) of the named compound as the HCl salt, mp 127°-128° C. IR(KBr): 3400, 1600 cm-1. MS: 363(MH+). 1H NMR (CD3OD): δ 7.89-6.81 (m, 10H), 4.24 (t, J=5.5 Hz, 2H), 2.65 (m, 6H), 1.75 (m, 8H).
Reaction SMILES: [F:1][C:2]1([F:16])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[CH:12][C:13](O)=[O:14])=[CH:10][C:4]=2[O:3]1.C(Cl)(=O)C(Cl)=O.[NH3:23]>O1CCCC1.CN(C)C=O>[F:1][C:2]1([F:16])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[CH:12][C:13]([NH2:23])=[O:14])=[CH:10][C:4]=2[O:3]1
Reactant: N
Reactant: O=C(O)C=Cc1ccc2c(c1)OC(F)(F)O2
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: NC(=O)C=Cc1ccc2c(c1)OC(F)(F)O2
Reaction time: 2 h
Yield: 90 %

Procedure:
To a suspension of 8.00 g (35.1 mmol) 3-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-acrylic acid in 40 ml tetrahydrofurane and 0.4 ml N,N-dimethyl formamide, 3.86 ml (45.0 mmol) oxalyl chloride was added dropwise at 0° C. within 10 min. Stirring was continued at 0–5° C. for 30 min. and 2 h at room temperature thereafter. The resulting solution was cooled to 0–5° C. again and then added within 15 min. to 34 ml of an 25% aqueous solution of ammonia. After stirring for 30 min. the precipitated amide was collected, washed with water and dried at 40° C. in vacuo. 7.20 g (90%) 3-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-acrylamide were obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:13][C:14]1([F:20])[CH2:16][CH:15]1[C:17](O)=[O:18].C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.O[Li].O>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:17]([CH:15]3[CH2:16][C:14]3([F:20])[F:13])=[O:18])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)C1CC1(F)F
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li]O
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)C1CC1(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.4 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol; Example 1, Step H), 2,2-difluorocyclopropanecarboxylic acid (212 mg, 1.74 mmol), and triethylamine (606 μL, 4.35 mmol) in CH2Cl2 (5 mL) at room temperature was treated with BOP—Cl (162 mg, 1.74 mmol). The mixture was stirred at room temperature for 18 hours. 2M LiOH.H2O (3 mL) was then added to the mixture and stirred for 30 minutes. Water (10 mL) was added, and the formed solid was filtered, washed with additional water (3×5 mL), and dried to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-difluorocyclopropanecarboxamide (158 mg, 54% yield) as a solid. LCMS (APCI+) m/z 334, 336 (M+H)+.
Reaction SMILES: CO[C:3]([CH2:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]([OH:17])=O)=[O:7])=O.[C:18]1([NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH2:24]>>[NH:24]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:25]=[C:3]1[C:5]1[C:6](=[O:7])[NH:8][C:9]2[C:14]([C:15]=1[OH:17])=[CH:13][CH:12]=[N:11][CH:10]=2
Reactant: COC(=O)CC(=O)Nc1cnccc1C(=O)O
Reactant: Nc1ccccc1N
Product: O=c1[nH]c2cnccc2c(O)c1-c1nc2ccccc2[nH]1
Temperature: 150 °C

Procedure:
3-[2-(Methoxycarbonyl)acetylamino]pyridine-4-carboxylic acid (1.1 equivalents) was combined with 1,2-phenylenediamine (1.0 equivalent) and heated at 150° C. for 3 hours. The crude product was purified by reversed-phase HPLC (DMSO/5% TFA). LC/MS m/z 279.3 (MH+), Rt 1.73 minutes.
Reaction SMILES: [CH3:1][CH:2]([OH:9])[CH2:3][NH:4][CH2:5][CH:6]([OH:8])[CH3:7].[S:10](Cl)([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[OH2:21].Cl>N1C=CC=CC=1>[S:10]([N:4]([CH2:5][CH:6]([O:8][S:10]([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH3:7])[CH2:3][CH:2]([O:9][S:10]([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:11])=[O:21])[CH3:1])([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: O
Reactant: CC(O)CNCC(C)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC(C)CN(CC(C)OS(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1
Reaction time: 72 h

Procedure:
A solution of 53.2 g (0.4 mole) of diiso-propanolamine in 50 cm3 of pyridine is added dropwise with cooling to a solution of 248 g (1.3 mole) of tosyl chloride in 200 cm3 of pyridine at 0° C. so that the temperature is maintained between 0° and 5° C. The mixture is left at this temperature for 72 h. It is then poured into 2 l of water plus ice and 250 cm3 of concentrated hydrochloric acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[C:22]([O:26][C:27]([C@@H:29]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=1[Cl:41])[C:30](O)=[O:31])=[O:28])([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C)C=O>[C:22]([O:26][C:27]([C@@H:29]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=1[Cl:41])[C:30]([NH:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])=[O:31])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: Cc1cc(-c2cc(N)cc(C(=O)OC(C)(C)C)c2)ccn1
Reactant: CC(C)(C)OC(=O)[C@@H](Cc1ccc(Cl)cc1Cl)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2cc(NC(=O)[C@H](Cc3ccc(Cl)cc3Cl)C(=O)OC(C)(C)C)cc(C(=O)OC(C)(C)C)c2)ccn1
Temperature: 80 °C
Reaction time: 4 h
Yield: 100.5 %

Procedure:
A mixture of tert-butyl 3-amino-5-(2-methylpyridin-4-yl)benzoate (100 mg, 0.35 mmol), (S)-2-(tert-butoxycarbonyl)-3-(2,4-dichlorophenyl)-propanoic acid (152 mg, 0.45 mmol), HBTU (174 mg, 0.45 mmol) and N-ethyl-N-isopropylpropan-2-amine (92 μl, 0.53 mmol) in N,N-dimethylformamide (0.70 mL) was allowed to stir at 80° C. for 4 hours. Upon completion, the mixture was directly purified by HPLC to give 206 mg of tert-butyl 3-((S)-2-(tert-butoxycarbonyl)-3-(2,4-dichlorophenyl)propanamido)-5-(2-methylpyridin-4-yl)benzoate 49.1C. LCMS (ES+) m/z 601.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14](O)[CH3:15]>>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:14][CH3:15])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: CCO
Product: CCOC(=O)c1ccc(C)c([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 98 %

Procedure:
4-Methyl-3-nitrobenzoic acid (71 g, 0.39 mol) is dissolved in dry ethanol (600 mL) and dry HCl gas is bubbled into the solution for 5 min. The reaction mixture is heated to 90° C. under N2 for 20 h. The solvent is removed under vacuum to afford the title compound as a straw-colored liquid (80.0 g, 98%).
Reaction SMILES: [F:1][C:2]([F:53])([F:52])[C:3]1[CH:4]=[C:5]([C:13]([CH3:51])([CH3:50])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:31]3[C@H:40]([CH2:41][O:42][Si](C(C)(C)C)(C)C)[CH2:39][N:38]4[C@H:33]([CH2:34][O:35][CH2:36][CH2:37]4)[CH2:32]3)=[CH:22][C:23]=2[C:24]2[CH:25]=[N:26][CH:27]=[CH:28][C:29]=2[CH3:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl>CO>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C:13]([CH3:51])([CH3:50])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:31]3[C@H:40]([CH2:41][OH:42])[CH2:39][N:38]4[C@H:33]([CH2:34][O:35][CH2:36][CH2:37]4)[CH2:32]3)=[CH:22][C:23]=2[C:24]2[CH:25]=[N:26][CH:27]=[CH:28][C:29]=2[CH3:30])[CH3:17])=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:53])[F:52])[CH:8]=1
Reactant: Cc1ccncc1-c1cc(N2C[C@H]3COCCN3C[C@H]2CO[Si](C)(C)C(C)(C)C)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CO
Product: Cc1ccncc1-c1cc(N2C[C@H]3COCCN3C[C@H]2CO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
2-[3,5-bis(trifluoromethyl)phenyl]-N-{6′-[(7S,9aS) -7-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H) -yl]-4-methyl-3,4′-bipyridin-3′-yl}-N,2-dimethylpropanamide (D53, 86 mg) was dissolved in dry MeOH (4 mL), cooled in an ice/salt bath to ˜0° C. before adding c.HCl solution. The mixture was stirred at −0° C. for 45 mins before allowing to warm up to R.T. and stirring for a further 2 hrs. Placed on a 5 g SCX column, washed with MeOH ×3, before eluting compound off with NH3 in MeOH. Solvent evaporated.
Reaction SMILES: Cl.[N:2]1([C:7]2[N:12]=[C:11]([CH2:13][NH2:14])[CH:10]=[C:9]([CH3:15])[N:8]=2)[CH:6]=[CH:5][N:4]=[CH:3]1.C(N(CC)CC)C.[C:23]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[C:23](=[N:14][CH2:13][C:11]1[CH:10]=[C:9]([CH3:15])[N:8]=[C:7]([N:2]2[CH:6]=[CH:5][N:4]=[CH:3]2)[N:12]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cc1cc(CN)nc(-n2ccnc2)n1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(CN=C(c2ccccc2)c2ccccc2)nc(-n2ccnc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
A mixture of (2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl)methanamine hydrochloride (20.4 g, 90.3 mmol) and triethylamine (60.0 mL, 452 mmol) in dichloromethane (300 mL) was stirred at room temperature for 30 min then the mixture was concentrated under vacuum. The residue was dissolved in toluene (500 mL) then benzophenone (57.5 g, 316 mmol) and p-toluenesulfonic acid monohydrate (4.50 g, 23.7 mmol) were added to the solution. The mixture was heated to 110° C. for 12 h then concentrated under vacuum. The residue was extracted with ethyl acetate (2×500mL), washed with water (2×100 mL), dried over anhydrous sodium sulfate and concentrated. The product was purified using column chromatography (1:10 EtOAc/hexanes to EtOAc) to afford benzhydrylidene-(2-imidazol-1-yl-6-methyl-pyrimidin-4-ylmethyl)-amine as a yellow solid (14.0 g, 42.6%).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=O)=[CH:11][CH:10]=2)[CH2:3]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][C:32]2[CH:33]=[C:34]([NH2:37])[NH:35][N:36]=2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1.C[Al](C)C>ClCCl>[CH3:29][O:28][C:26]1[CH:25]=[C:24]([CH2:30][CH2:31][C:32]2[CH:33]=[C:34]([NH:37][C:13](=[O:15])[C:12]3[CH:11]=[CH:10][C:9]([N:4]4[CH2:5][C@H:6]([CH3:8])[NH:7][C@H:2]([CH3:1])[CH2:3]4)=[CH:19][CH:18]=3)[NH:35][N:36]=2)[CH:23]=[C:22]([O:21][CH3:20])[CH:27]=1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: CCOC(=O)c1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1
Agent: C[Al](C)C
Solvent: ClCCl
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4C[C@@H](C)N[C@@H](C)C4)cc3)[nH]n2)cc(OC)c1
Yield: 50.2 %

Procedure:
N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-[(3R,5S)-3,5-dimethylpiperazin-1-yl]benzamide was prepared following the procedure as for Example 155, but starting with ethyl 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzoate (0.525 g, 2 mmol), 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.495 g, 2.00 mmol) and 2M trimethylaluminium (2.5 ml, 5.0 mmol in toluene). The crude mixture was chromatographed on a SCX column, eluting with 7N ammonia in methanol. Fractions containing product were combined and evaporated to give an oil. The oil was suspended in dichloromethane (20 ml) and product slowly crystallised out. This was filtered to give the title compound (0.465 g, 50.2%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])[C:10]([O:12]CC)=[O:11])=[CH:5][CH:4]=1)[CH3:2].[OH-].[Na+]>CO.C1COCC1.O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C@@H:15]([CH3:20])[C:16]([F:17])([F:18])[F:19])[C:10]([OH:12])=[O:11])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(c1ccc(CC)cc1)[C@@H](C)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc(C(C(=O)O)[C@@H](C)C(F)(F)F)cc1
Temperature: 40 °C
Reaction time: 9 h

Procedure:
3.0 g of (3R)-ethyl 2-(4-ethylphenyl)-4,4,4-trifluoro-3-methylbutanoate (about 88% pure, about 9.16 mmol; diastereomer mixture) were dissolved in a mixture of 12.4 ml each of methanol, THF and water, and 5.49 g (137.35 mmol) of sodium hydroxide were added a little at a time. The reaction mixture was stirred at 40° C. for 9 h. After cooling, the volatile solvents were substantially removed under reduced pressure, and the residue was diluted with water. The mixture was acidified by addition of hydrochloric acid, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated under reduced pressure, and the residue was dried under high vacuum. This gave 2.61 g of the title compound as a crude product which was not purified any further (diastereomer ratio about 9:1).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]([O:9][C:10](=[O:13])[CH:11]=[CH2:12])([CH3:8])([CH3:7])[CH3:6].[CH2:14]([O:21][C:22](ON1C(=O)CCC1=O)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>O1CCCC1.O>[C:5]([O:9][C:10](=[O:13])[CH2:11][CH2:12][N:4]([C:22]([O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:23])[CH2:3][CH2:1][OH:2])([CH3:8])([CH3:7])[CH3:6]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: NCCO
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)CCN(CCO)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
6.11 g (100 mmol) of ethanolamine were cooled (0° C.), treated with 14.52 ml (100 mmol) of ter-butyl-acrylate and stirred 15 min at this temperature. During warming up to room temperature the reaction started and was kept with cooling at 25-30° C. and then stirred 18 h at room temperature. The oil was dissolved in 500 ml of tetrahydrofuran and 500 ml of water, 27.42 (110 mmol) of N-(benzyloxycarbonyloxy)succinimide were added at 0° C. followed by 27.88 ml (200 mmol) of triethlamine. The reaction was stirred at room temperature over 3 h, then partitioned between 10% aq. potassium hydrogensulfate solution and diethyl ether (3×). The organic phases were washed with 10% aq. potassium hydrogensulfate solution, sat. aq. sodium hydrogencarbonate solution, 10% aq. sodium chloride solution, dried over Na2SO4 evaporated and purified by flash silica gel column (n-heptane/ethyl acetate 4:1 to 1:1) to yield 27.53 g (85%) of the titled compound as light yellow oil. MS: 324.2 (MH+).