Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[NH2:35][C:36]1[CH:37]=[C:38]([CH:51]=[CH:52][C:53]=1[N:54]1[CH2:59][CH2:58][N:57]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=2[CH3:66])[CH2:56][CH2:55]1)[C:39]([NH:41][CH2:42][CH2:43][CH2:44][N:45]1[CH2:49][CH2:48][CH2:47][C:46]1=[O:50])=[O:40].Br[C:68]1[N:73]=[CH:72][CH:71]=[CH:70][N:69]=1>CC(O)(C)C.C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[O:50]=[C:46]1[CH2:47][CH2:48][CH2:49][N:45]1[CH2:44][CH2:43][CH2:42][NH:41][C:39](=[O:40])[C:38]1[CH:51]=[CH:52][C:53]([N:54]2[CH2:59][CH2:58][N:57]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=3[CH3:66])[CH2:56][CH2:55]2)=[C:36]([NH:35][C:68]2[N:73]=[CH:72][CH:71]=[CH:70][N:69]=2)[CH:37]=1
Reactant: Brc1ncccn1
Reactant: Cc1ccccc1N1CCN(c2ccc(C(=O)NCCCN3CCCC3=O)cc2N)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: Cc1ccccc1N1CCN(c2ccc(C(=O)NCCCN3CCCC3=O)cc2Nc2ncccn2)CC1

Procedure:
N-[3-(2-Oxo-pyrrolidin-1-yl)-propyl]-3-(pyrimidin-2-ylamino)-4-(4-o-tolyl-piperazin-1-yl)-benzamide (compound no. 242) was prepared as follows: In a microwavable glass tube, Pd(OAc)2 (0.0025 g, 0.0115 mmol) and X—PHOS (5.4 mg, 0.0115 mmol) were taken in a mixture of t-BuOH:toluene (1:5) (2.0 mL) and stirred. This solution was evacuated for 5 min and purged with nitrogen. 3-Amino-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide (0.05 g, 0.115 mmol) and 2-bromo-pyrimidine (2.7 mg, 0.172 mmol) were added to this, evacuated and nitrogen purged. This mixture was stirred at 140° C. under MW for 30 min. LC-MS indicated the product formation along with some other by-products. The reaction mixture was concentrated, dissolved in methanol and purified on preparative HPLC using water/methanol as eluent to give desire product (10.0 mg, 17%).
Reaction SMILES: [CH3:1][C:2]1[C:9]([NH2:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#N.[C:11](OC(=O)C)(=[O:13])[CH3:12].C(O)(=[O:20])C>>[CH3:1][C:2]1[C:9]([NH:10][C:11](=[O:13])[CH3:12])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:20]
Reactant: Cc1c(N)cccc1C#N
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O
Product: CC(=O)Nc1cccc(C=O)c1C

Procedure:
39 g (0.3 mole) of 2-methyl-3-amino-benzonitrile were dissolved in 75 ml of acetic acid, 30 ml (0.3 mole) of acetic anhydride were added, the mixture was heated with reflux for 5 minutes, and cooled. The solid obtained was filtered off an the evaporation of the solvent furnished an additional quantity of solid which was added to the preceding one. After recrystallisation of the whole from toluene, 44 g (95%) of colourless flakes were obtained, with a melting point of 160° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:11]=[CH:12][C:13]([CH2:21][OH:22])=[N:14][C:15]=1[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.O>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:11]=[CH:12][C:13]([CH:21]=[O:22])=[N:14][C:15]=1[CH2:16][C:17]([CH3:18])([CH3:20])[CH3:19]
Reactant: COc1ccc(F)c(-c2ccc(CO)nc2CC(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(F)c(-c2ccc(C=O)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.4 %

Procedure:
To a solution of (5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)methanol (2.90 g) and triethylamine (13.3 mL) in DMSO (45 mL) was added sulfur trioxide pyridine complex (6.08 g), and the mixture was stirred at room temperature for 10 min. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After silica gel filtration, the solvent was evaporated under reduced pressure to give the title compound (2.69 g) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:3]2[O:14][CH2:13][O:12][C:9]([C:10]=1[F:11])=[CH:8][C:4]=2[C:5](O)=[O:6].C(Cl)(=O)C([Cl:18])=O>C(OCC)C.CN(C)C=O>[F:1][C:2]1[C:3]2[O:14][CH2:13][O:12][C:9]([C:10]=1[F:11])=[CH:8][C:4]=2[C:5]([Cl:18])=[O:6]
Reactant: O=C(O)c1cc2c(F)c(F)c1OCO2
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(Cl)c1cc2c(F)c(F)c1OCO2
Temperature: 0 °C
Reaction time: 60 h
Yield: 101.4 %

Procedure:
A solution of 15.0 grams (0.0742 mole) of 3,4-difluoromethylenedioxybenzoic acid in 200 mL of diethyl ether was stirred and cooled to 0° C. To this was added one drop of dimethylformamide followed by the dropwise addition of 11.3 grams (0.0890 mole) of oxalyl chloride. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature where it stirred for 60 hours. After this time the reaction mixture was concentrated under reduced pressure to yield 16.6 grams of 3,4-difluoromethylenedioxybenzoyl chloride.
Reaction SMILES: [CH3:1][Si:2]([CH3:8])([CH3:7])NC(=O)C.[C:9]([NH:17][CH:18]1[C:30](=[O:31])[N:20]2[C:21]([C:27]([OH:29])=[O:28])=[C:22]([CH3:26])[CH2:23][S:24](=[O:25])[C@H:19]12)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.NS(O)(=O)=O.[Br:37]N1C(=O)CCC1=O>ClCCl>[C:9]([NH:17][CH:18]1[C:30](=[O:31])[N:20]2[C:21]([C:27]([O:29][Si:2]([CH3:8])([CH3:7])[CH3:1])=[O:28])=[C:22]([CH2:26][Br:37])[CH2:23][S:24](=[O:25])[C@H:19]12)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)N[Si](C)(C)C
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)c3ccccc3)[C@H]2S(=O)C1
Reactant: O=C1CCC(=O)N1Br
Agent: NS(=O)(=O)O
Solvent: ClCCl
Product: C[Si](C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2C(NC(=O)c3ccccc3)C(=O)N12
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
208 mg of N-trimethylsilylacetamide (1.59 mmoles) were added to a suspension of 383 mg (1.14 mmoles) of 7-benzamido-3-methyl-3-cephem-4-carboxylic acid-1-oxide in 25 ml of dichloromethane, and after stirring for 11/2 hours at room temperature, a clear solution was obtained, which was diluted with dichloromethane to 50 ml. 200 mg of amidosulfonic acid (1.04 mmoles) were added thereto and the mixture was cooled in an ice-bath. Bromination was carried out in half an hour using 310 mg (1.74 mmoles) of N-bromosuccinimide as the brominating agent to obtain a 48% yield of trimethylsilyl 7-benzamido-3-bromomethyl-3-cephem-4-carboxylate-1-oxide.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[N:13]1([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[N:14]1>>[CH3:12][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([NH:1][C:22](=[O:23])[C:21]3[CH:20]=[CH:19][C:18]([N:13]4[CH:17]=[CH:16][CH:15]=[N:14]4)=[CH:26][CH:25]=3)=[CH:3][CH:4]=2)[N:9]=1
Reactant: Cc1ccc2ccc(N)cc2n1
Reactant: O=C(O)c1ccc(-n2cccn2)cc1
Product: Cc1ccc2ccc(NC(=O)c3ccc(-n4cccn4)cc3)cc2n1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-amino-2-methylquinoline (D66) (33 mg, 0.21 mmol) and 4-(1-pyrazolyl)benzoic acid (47 mg, 0.25 mmol) as an off-white solid. MS (ES): MH+ 329, M-H+ 327.
Reaction SMILES: [OH-].[Na+].CN(C=O)C.[CH2:8]([SH:10])[CH3:9].Br[C:12]1[CH:13]=[N:14][CH:15]=[C:16]([Br:18])[CH:17]=1>O>[Br:18][C:16]1[CH:15]=[N:14][CH:13]=[C:12]([S:10][CH2:8][CH3:9])[CH:17]=1
Reactant: CCS
Reactant: Brc1cncc(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 80.5 %

Procedure:
Under a nitrogen atmosphere, NaOH (1.25 g, 31.3 mmol) was added to anhydrous DMF (40 mL). Ethanethiol (2.60 mL, 2.20 g, 35.5 mmol) was then added by syringe and the mixture was stirred for 6 h at 25° C. while the NaOH dissolved. The solution was cooled to 0° C., and 3,5-dibromopyridine (5.92 g, 25.0 mmol) was added. After stirring for 15 min at 0° C. and 45 min at 25° C., the mixture was poured into water (250 mL) and extracted with ether (2×100 mL). Drying (Na2SO4) and evaporation of the ether, followed by vacuum distillation of the crude product gave 4.39 g (80.6% yield) of colorless oil, bp 91-95° C. at 0.30 mm Hg.
Reaction SMILES: [CH:1]([C:3]1[C:4]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[N:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[CH:8]=1)=[O:2].[NH2:24][C:25]1[CH:30]=[C:29]([F:31])[C:28]([Cl:32])=[CH:27][C:26]=1[NH2:33].C(C1C(NC(=O)C(C)(C)C)=NC=C(C2C=CC=CC=2)C=1)=O.COC1C=C(B(O)O)C=CC=1>>[ClH:32].[Cl:32][C:28]1[C:29]([F:31])=[CH:30][C:25]2[NH:24][C:1]([C:3]3[C:4]([NH2:17])=[N:5][CH:6]=[C:7]([C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=4)[CH:8]=3)=[N:33][C:26]=2[CH:27]=1.[CH:1]([C:3]1[C:4]([NH:17][C:18](=[O:23])[C:19]([CH3:21])([CH3:20])[CH3:22])=[N:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[CH:8]=1)=[O:2]
Reactant: Nc1cc(F)c(Cl)cc1N
Agent: CC(C)(C)C(=O)Nc1ncc(-c2ccccc2)cc1C=O
Agent: COc1cccc(-c2cnc(NC(=O)C(C)(C)C)c(C=O)c2)c1
Agent: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2cnc(N)c(-c3nc4cc(Cl)c(F)cc4[nH]3)c2)c1
Product: Cl

Procedure:
The title compound was synthesized using the procedure recited in Example 2, except that N-(3-formyl-5-(3-methoxyphenyl)pyridin-2-yl)-2,2-dimethylpropanamide and 1,2-diamino-4-chloro-5-fluorobenzene were utilized. N-(3-formyl-5-(3-methoxyphenyl)pyridin-2-yl)-2,2-dimethylpropanamide was synthesized using the sequence of steps (a), (b), and (c) of Example 1, utilizing 3-methoxyphenylboronic acid in step (a).
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:22])[N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[SH:23][C:24]1[N:25]([CH3:29])[CH:26]=[CH:27][N:28]=1>>[CH:10]1([N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:8]([NH:7][C:5]2[S:6][C:2]([S:23][C:24]3[N:25]([CH3:29])[CH:26]=[CH:27][N:28]=3)=[CH:3][N:4]=2)=[O:22])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C(Nc1ncc(Br)s1)N(C1CCCCC1)C1CCCCC1
Reactant: Cn1ccnc1S
Product: Cn1ccnc1Sc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1

Procedure:
Prepared as described in general procedure (E) using 3-(5-bromo-thiazol-2-yl)-1,1-dicyclohexyl-urea and 2-mercapto-1-methyl-1H-imidazole.
Reaction SMILES: [CH3:1][Mg]Br.C([O:6][CH2:7][CH3:8])C.[Br:9][C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1C(OC)=O.[Cl-].[NH4+]>O1CCCC1>[Br:9][C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1[C:7]([OH:6])([CH3:8])[CH3:1]
Reactant: C[Mg]Br
Reactant: COC(=O)c1ccccc1Br
Reactant: CCOCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(O)c1ccccc1Br
Reaction time: 0.25 h

Procedure:
In a nitrogen atmosphere, 49.5 mL of 3.0 M methylmagnesium bromide-diethyl ether solution was dropwise added to tetrahydrofuran (200 mL) solution of 10.7 g of methyl 2-bromobenzoate with cooling with ice. This was stirred at that temperature for 15 minutes, and then stirred at room temperature for 6 days. Aqueous saturated ammonium chloride solution was added to the reaction liquid, and extracted with diethyl ether. The diethyl ether layer was washed with saturated saline water, and then dried with anhydrous magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue was separated and purified through silica gel column chromatography (hexane/ethyl acetate=9/1) to obtain 7.4 g of the entitled compound.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]2)=[N:3][CH:2]=1.[N:17]1[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]1[C:6]2=[N:7][CH:8]=[CH:9][C:5]2=[C:4]([N:10]2[CH2:11][CH2:12][CH:13]([NH:16][C:23]([C:20]3[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=3)=[O:24])[CH2:14][CH2:15]2)[N:3]=[CH:2]1
Reactant: NC1CCN(c2ncnc3[nH]ccc23)CC1
Reactant: O=C(O)c1ccncc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CCN(c2nc[nH]c3nccc2-3)CC1)c1ccncc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinamine D2 (100 mg), 4-pyridinecarboxylic acid (56.7 mg, 0.460 mmol), HATU (210 mg, 0.552 mmol) and HOAt (37.60 mg, 0.276 mmol) in DMF (2.3 mL) was added DIPEA (386 μL, 2.209 mmol). The reaction mixture was stirred at room temperature for 2 hours then the solvent was removed in vacuo. The crude mixture was purified by MDAP using a high pH method to afford E11 (75 mg), 1H NMR (d6-DMSO) δ 11.70 (1H, brs), 8.70 (2H, d), 8.57 (1H, d), 8.17 (1H, s), 7.72 (2H, d), 7.18 (1H, d), 6.60 (1H, d), 4.70 (2H, dt), 4.15 (1H, m), 3.20 (2H, dt), 1.90 (2H, m), 1.60 (2H, m), MS(ES+) 323 [M+H]+.
Reaction SMILES: C(O[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[CH2:18])[CH2:10][CH2:9]1)=[O:7])(C)(C)C.[Cl:19][C:20]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:21]=1[O:22][C:23]1[N:31]=[CH:30][CH:29]=[CH:28][C:24]=1C(O)=O.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>Cl.O1CCOCC1>[Cl:19][C:20]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:21]=1[O:22][C:23]1[C:24]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[CH2:18])[CH2:10][CH2:9]2)=[O:7])=[CH:28][CH:29]=[CH:30][N:31]=1
Reactant: O=C(O)c1cccnc1Oc1cc(Cl)ccc1Cl
Reactant: C=C1CCN(C(=O)OC(C)(C)C)c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C=C1CCN(C(=O)c2cccnc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Temperature: 100 °C
Yield: 6.6 %

Procedure:
A solution of 4-methylene-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (44.2 mg, 0.18 mmol, 1.2 equiv) in 4 M HCl in dioxane (4 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product redissolved in anhydrous DMF (1 mL). To this solution was added 2-(2,5-dichloro-phenoxy)-nicotinic acid (42.6 mg, 0.15 mmol, 1.0 equiv; Example 31, Step 1), N-ethyldiisopropylamine (97 mg, 131 μL, 0.75 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and HATU (68 mg, 0.18 mmol, 1.2 equiv; [CAS RN 148893-10-1]) and the reaction mixture heated by microwave irradiation to 100° C. for 30 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 4.1 mg (7%) of the title compound. MS (ISP): 410.7 [M+H]+.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([F:31])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([O:29]C)=[O:28])[CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CCO>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[C:13]([F:31])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([OH:29])=[O:28])[CH2:24]2)[CH:16]=[CH:15]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1CN(Cc2ccc3c(F)c(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CN4CC(C(=O)O)C4)ccc3c2F)CC1
Temperature: 0 °C

Procedure:
To a solution of methyl 1-((6-((trans)-4-tert-butylcyclohexyloxy)-5-fluoronaphthalen-2-yl)methyl)azetidine-3-carboxylate 40 mg, 0.09 mmol) in EtOH (3 mL) was added aqueous NaOH (2 mL, 1%, 5.0 eq.) and refluxed for 1 h. Then the reaction was cooled to 0° C. the pH of the solution was adjusted to 6 with 1M HCl, concentrated and the residue was washed with DCM and water, dried in vacuum to give product 1-((6-((trans)-4-tert-butylcyclohexyloxy)-5-fluoronaphthalen-2-yl)methyl)azetidine-3-carboxylic acid (30 mg, 78%) as a white solid. EDI-MS (M+1)+: 414.0 HPLC: 91.27%. 1H NMR (400 MHz, CD3OD) δ 8.09-8.01 (m, 2H), 7.74-7.71 (m, 1H), 7.59-7.58 (m, 1H), 7.48 (t, 1H), 4.57 (s, 2H), 4.38-4.32 (m, 5H), 3.76-3.70 (m, 1H), 2.21-2.19 (m, 2H), 1.91-1.88 (m, 2H), 1.53-1.44 (m, 2H), 1.24-1.10 (m, 3H), 0.90 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-])=O)[C:3]=1F.C([O-])([O-])=O.[K+].[K+].[CH3:22][N:23]([CH3:29])[CH2:24][CH2:25][CH2:26][NH:27][CH3:28]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([NH2:12])[C:3]=1[N:27]([CH2:26][CH2:25][CH2:24][N:23]([CH3:29])[CH3:22])[CH3:28]
Reactant: CNCCCN(C)C
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)CCCN(C)c1c(N)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A heterogeneous mixture of 1-chloro-2-fluoro-3-nitro-5-(trifluoromethyl)benzene (1.25 mL, 8.2 mmol), K2CO3 (3.44 g, 24.6 mmol), N1,N1,N3-trimethylpropane-1,3-diamine (1.26 mL, 8.61 mmol) and THF were allowed to stir at RT for 45 min. The THF was removed under reduced pressure and reconstituted in EtOAc (50 ml). The organic layer was washed with water (20 ml), brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated to an oil. The concentrated oil was taken up in EtOH (20 ml) to which Raney nickel (2.5 g wet, washed) was added. The reduction was monitored and after 1 h, another portion of Raney nickel (3.8 g, wet, washed) was added. The reaction was allowed to stir for an additional 30 min., and filtered through Celite, washed with EtOH (10 mL) and concentrated. The crude residue was purified via flash chromatography (silica gel, gradient elution 0 to 25% MeOH in CH2Cl2) to afford 6-chloro-N1-(3-(dimethylamino)propyl)-N1-methyl-4-(trifluoromethyl)benzene-1,2-diamine as a yellow oil. MS m/z=310.1 [M+H]+. Calc'd for C13H19ClF3N3: 309.8.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=2[Cl:16])[N:5]=[CH:4][N:3]=1.[Br:17][CH:18]=[CH:19][CH2:20]Br.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O.CCCC(C)C>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:20][CH:19]=[CH:18][Br:17])[C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=2[Cl:16])[N:5]=[CH:4][N:3]=1
Reactant: BrC=CCBr
Reactant: Cc1ccc(Cl)c(Nc2cc(Cl)ncn2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCCC(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(Cl)c(N(CC=CBr)c2cc(Cl)ncn2)c1
Temperature: 25 °C

Procedure:
4-Chloro-6-(2-chloro-5-methylanilino)pyrimidine (Reference Example 12) (0.5 g, 1.97 mmol) and 1,3-dibromopropene [cis/trans mixture] (0.6 g, 3.0 mmol) were dissolved in NMP (2 ml). Anhydrous potassium carbonate (0.54 g, 4 mmol) was added and the mixture stirred at room temperature for seventeen hours. After aqueous work-up the product was obtained by column chromatography on silica gel using EtOAc/isohexane mixtures (0.68 g, 93%). M/z 372 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(N(CC)CC)C.[Cl:16][C:17]1[N:18]=[C:19](Cl)[C:20]2[N:26]=[CH:25][N:24]=[C:23]([Cl:27])[C:21]=2[N:22]=1.O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([NH:5][C:19]2[C:20]3[N:26]=[CH:25][N:24]=[C:23]([Cl:27])[C:21]=3[N:22]=[C:17]([Cl:16])[N:18]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Clc1nc(Cl)c2ncnc(Cl)c2n1
Reactant: Cc1cccc(N)c1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(Nc2nc(Cl)nc3c(Cl)ncnc23)c1
Reaction time: 1.5 h

Procedure:
0.45 g of 3-methylaniline and 0.42 g of triethylamine are added to 1.0 g of 2,4,8-trichloro-pyrimido[5,4-d]pyrimidine in 20 ml of methylene chloride at 0° to -10° C. and the mixture is stirred at this temperature for 1.5 hours. Water is then added and the organic phase is separated off, dried and concentrated. The residue is purified by chromatography over an aluminium oxide column with petroleum ether/ethyl acetate (10:2).
Reaction SMILES: C([NH:11][C@H:12]([C:21]([OH:23])=O)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)(OCC1C=CC=CC=1)=O.CN1CCOCC1.[C:31]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])(=[O:34])[NH:32][NH2:33]>O1CCCC1>[C:31]([NH:32][NH:33][C:21](=[O:23])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)[NH2:11])([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NNC(=O)[C@@H](N)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of CBZ-L-tyrosine (3.00 gm, 9.11 mmoles), N-methylmorpholine (0.92 gm, 1.00 ml, 9.11 mmoles) in 100 ml dry tetrahydrofuran (THF) was cooled to 0° C. under nitrogen. 2,2,2-Trichloro-1,1-dimethylethylchloroformate (2.18 gm, 9.11 mmoles) was added to the cold solution. After 5 minutes stirring, a solution of t-butyl carbazate (1.20 gm, 9.11 mmoles) in 20 ml dry THF was cooled to 0° C. and added to the reaction mixture. The mixture was allowed to warm slowly to room temperature and was stirred for about 18 hours. The solvent was removed by rotary evaporation and the residue was partitioned between chloroform and water and the layers separated. The organic layer was washed with saturated NaCl dried over Na2SO4, filtered, and solvent evaporated to yield the crude protected product. The CBZ-protected product, CBZ-tyrosine N'-Boc-hydrazide, was purified on silica gel via flash chromatography using a mixture of petroleum ether and ethyl acetate (1:1).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=O)[CH3:2].[Cl:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:15]=1[NH2:16]>C1COCC1>[Cl:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:15]=1[N:16]=[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=[N:16][C:15]2[C:17]([CH3:22])=[CH:18][C:19]([CH3:21])=[CH:20][C:14]=2[Cl:13])[CH3:11])[N:5]=1)[CH3:2]
Reactant: Cc1cc(C)c(N)c(Cl)c1
Reactant: CC(=O)c1cccc(C(C)=O)n1
Solvent: C1CCOC1
Product: CC(=Nc1c(C)cc(C)cc1Cl)c1cccc(C(C)=Nc2c(C)cc(C)cc2Cl)n1
Temperature: 22 °C
Yield: 74.7 %

Procedure:
To a solution of 2,6-diacetylpyridine (35 g, 0.21 mol) in THF (1.21) was added 2-chloro-4,6-dimethylaniline (76.7 g, 2.3 eq) and Sicapent (45 g). The reaction mixture was refluxed overnight. Then additional 2-chloro-4,6-dimethylaniline (25 g, 0.7 eq) and Sicapent (25 g) were added and once again refluxed overnight. The suspension was cooled to 22° C., filtered and washed with two times THF (75 ml). The mother liquor was concentrated (90%) and methanol was added to precipitate the product, which was washed two times with methanol (50 ml) and dried under high vacuum. 68.8 g of a yellow powder was isolated (y=73.1%)
Reaction SMILES: FC(F)(F)C([N:5]([CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.CCOCC.[C:43]([CH:48]([CH:50]([C:52]([O:54][CH2:55][CH3:56])=[O:53])[OH:51])[OH:49])([O:45][CH2:46][CH3:47])=[O:44]>C(=O)([O-])[O-].[K+].[K+]>[CH2:15]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:51][CH:50]([CH:48]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[OH:49])[C:52]([O:54][CH2:55][CH3:56])=[O:53])=[O:11])=[CH:13][CH:14]=1)[CH2:16][CH2:17][CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCC=CCCCN(C(=O)C(F)(F)F)c1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)C(O)C(O)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCCCCCC=CCCCNc1ccc(C(=O)OC(C(=O)OCC)C(O)C(=O)OCC)cc1

Procedure:
N-trifluoroacetyl-4-(4-tetradecenylamino)benzoyl chloride and 1.2 g. triethylamine in 100 ml. warm ether is treated with 2.5 g. diethyl tartrate and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solvent evaporated from the combined filtrate and washings to yield a solid residue. After dissolving in aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields the diethyl tartrate as a white, crystalline solid.