Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][C:7]([CH2:8][C:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)(C(O)=O)[C:10](O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:28][CH:29]([CH2:31][CH2:32][CH2:33][C@H:34]([C@@H:36]1[C@:53]2([CH3:54])[C@H:39]([C@H:40]3[C@H:50]([CH2:51][CH2:52]2)[C@:48]2([CH3:49])[C:43]([CH2:44][C@@H:45]([OH:55])[CH2:46][CH2:47]2)=[CH:42][CH2:41]3)[CH2:38][CH2:37]1)[CH3:35])[CH3:30]>CN(C)C1C=CN=CC=1.ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[C:10]([O:55][CH:45]2[CH2:46][CH2:47][C@@:48]3([CH3:49])[C:43](=[CH:42][CH2:41][C@@H:40]4[C@@H:50]3[CH2:51][CH2:52][C@@:53]3([CH3:54])[C@H:39]4[CH2:38][CH2:37][C@@H:36]3[C@H:34]([CH3:35])[CH2:33][CH2:32][CH2:31][CH:29]([CH3:28])[CH3:30])[CH2:44]2)=[O:11])=[CH:26][CH:27]=1)([O-:3])=[O:2]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C(O)C(Cc1ccc([N+](=O)[O-])cc1)(Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4CC(OC(=O)C(Cc5ccc([N+](=O)[O-])cc5)Cc5ccc([N+](=O)[O-])cc5)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 82.8 %

Procedure:
2.00 g (5.34 mmol) of 2,2-bis(4-nitrobenzyl)malonic acid and 2.07 g (5.35 mmol) 5-cholesten-3β-ol and 65 mg (0.53 mmol) 4-dimethylaminopyridine in 40 ml of dichloromethane were cooled to 0° C. and 1.16 g (5.62 mmol) N,N′-dicyclohexylcarbodiimde were added. The mixture was subsequently allowed to react for 2 hours at 0° C. and 19 hours at 25° C., filtered and concentrated by rotary evaporation. Chromatography of the residue on 50 g silica gel using toluene as eluant and recrystallisation form ethyl acetate yielded 3.09 g (83%) Cholest-5-en-3-yl 2-(4-nitrobenzyl)-3-(4-nitrophenyl)propanoate as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=1)=[O:13].[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][C:27](O)=[O:28].CCN(CC)CC>C(Cl)Cl.N#N>[Br:20][C:16]1[CH:15]=[C:14]([C:12]([C:3]2[CH:4]=[C:5]([O:10][CH3:11])[C:6]([O:8][CH3:9])=[CH:7][C:2]=2[NH:1][C:27](=[O:28])[CH2:26][C:22]2[S:21][CH:25]=[CH:24][CH:23]=2)=[O:13])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc(N)c(C(=O)c2cccc(Br)c2)cc1OC
Reactant: O=C(O)Cc1cccs1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(NC(=O)Cc2cccs2)c(C(=O)c2cccc(Br)c2)cc1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (2-amino-4,5-dimethoxyphenyl)(3-bromophenyl)methanone (5 g, 14.9 mmol) in dry DCM (125 mL) was added thiophen-2-ylacetic acid (2.54 g, 17.9 mmol) and Et3N (6.77, 66.9 mmol) at 0° C. in N2. 10 minutes later, POCK (3.4 g, 22.31 mmol) was added dropwise at 0° C. in N2. The reaction mixture was stirred for 1 hour at 0° C. and then quenched with saturated NaHCO3, and neutralized to pH=8. The mixture was exacted with ACM (30 mL×3). The combined organic layer was dried over anhydrous MgSO4, filtered and concentrated under vacuum to afford N-{2-[(3-bromophenyl)carbonyl]-4,5-dimethoxyphenyl}-2-(thiophen-2-yl)acetamide. MS (M+H)=460 and 462.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](/[CH:15]2[CH2:19][CH2:18][CH2:17][CH:16]2[C:20]([O:22]CC)=[O:21])\[CH3:14])=[C:9]([O:25][CH3:26])[C:8]([CH3:27])=[C:7]2[C:3]=1[C:4](=[O:28])[O:5][CH2:6]2>CCCCCC.C(OCC)(=O)C>[OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](/[CH:15]2[CH2:19][CH2:18][CH2:17][CH:16]2[C:20]([OH:22])=[O:21])\[CH3:14])=[C:9]([O:25][CH3:26])[C:8]([CH3:27])=[C:7]2[C:3]=1[C:4](=[O:28])[O:5][CH2:6]2
Reactant: CCOC(=O)C1CCCC1/C(C)=C/Cc1c(O)c2c(c(C)c1OC)COC2=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1c(C)c2c(c(O)c1C/C=C(\C)C1CCCC1C(=O)O)C(=O)OC2

Procedure:
By following the procedure of Example ZA-6A and substituting methyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran -5-yl)-2,4-dimethyl-4-hexenoate with ethyl (E)-2-[-3-(4-hydroxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-1-methylpropenyl ]-cyclopentane-carboxylate and compounds of Formula I-ZH-A1, prepared e.g, as described in Example ZH-6B, there are obtained (E)-2-[-3-(1,3-dihydro-4-hydroxy -6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-1-methylpropenyl]-cyclopentane-carboxylic acid, mp 157°-158° C. (hexane/ethyl acetate) and the corresponding compounds of Formula I-ZH-A2 as identified in the following table.
Reaction SMILES: [NH2:1][CH:2]1[C:15](=[O:16])[N:4]2[C:5]([C:12]([OH:14])=[O:13])=[C:6]([CH2:9][O:10][CH3:11])[CH2:7][S:8][C@H:3]12.[F:17][C:18]([F:26])([F:25])[CH2:19][S:20][CH2:21][C:22](Cl)=[O:23]>>[F:17][C:18]([F:26])([F:25])[CH2:19][S:20][CH2:21][C:22]([NH:1][CH:2]1[C:15](=[O:16])[N:4]2[C:5]([C:12]([OH:14])=[O:13])=[C:6]([CH2:9][O:10][CH3:11])[CH2:7][S:8][C@H:3]12)=[O:23]
Reactant: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(Cl)CSCC(F)(F)F
Product: COCC1=C(C(=O)O)N2C(=O)C(NC(=O)CSCC(F)(F)F)[C@H]2SC1

Procedure:
Using the procedure of Example 1, 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid is acylated with trifluoroethylmercaptoacetyl chloride to give 7-trifluoroethylmercaptoacetamido-3-methoxymethyl-3-cephem-4-carboxylic acid.
Reaction SMILES: B(F)(F)F.CCOCC.[C:10]([C:12]1[CH:32]=[CH:31][C:15]([C:16]([N:18]([CH2:20][C:21]2([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:24][O:23][CH2:22]2)[CH3:19])=[O:17])=[CH:14][CH:13]=1)#[N:11]>ClCCl>[C:10]([C:12]1[CH:13]=[CH:14][C:15]([C:16]23[N:18]([CH3:19])[CH2:20][C:21]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)([CH2:22][O:23]2)[CH2:24][O:17]3)=[CH:31][CH:32]=1)#[N:11]
Reactant: CN(CC1(C2CCCCC2)COC1)C(=O)c1ccc(C#N)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CN1CC2(C3CCCCC3)COC1(c1ccc(C#N)cc1)OC2
Reaction time: 24 h

Procedure:
Boron trifluoride etherate (37.2 μl) was added to a stirred solution of 3-[N-(4-cyanobenzoyl)-N-methylaminomethyl]-3-cyclohexyloxetane (281 mg) in dichloromethane (3 ml) at -70° C. under nitrogen. After stirring overnight a further portion of boron trifluoride etherate (110 μl) was added. After stirring for a further 24 hours the reaction mixture was poured into dichloromethane (20 ml, saturated with ammonia). Filtration and evaporation of the filtrate gave 1-(4-cyanophenyl)-4-cyclohexyl-7-methyl-2,6-dioxa-7-aza-bicyclo[2,2,2]octane as pale yellow crystals.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:7]([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:18][CH:17]=1
Reactant: CCOC(=O)C(=O)c1cccn1C
Reactant: COc1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=Nc1ccc(OC)cc1)c1cccn1C
Yield: 58 %

Procedure:
To a solution of 4.0 g ethyl 1-methylpyrrole-2-glyoxylate and 2.96 g p-anisidine in 20 ml toluene is added 24 mg p-toluenesulfonic acid. Heating at reflux for 4 days with water being removed with a Dean-Stark trap is followed by washing successively with aqueous hydrochloric acid, aqueous sodium bicarbonate and brine. After drying, evaporation of the solvent affords a dark solid. Recrystallization from isopropanol gives a 58% yield of ethyl α-(4-methoxyphenylimino)-1-methylpyrrole-2-acetate, m.p. 83°-85° C.
Reaction SMILES: [H-].[Na+].[CH:3]1([NH:10][C:11](=[O:13])[CH3:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=[CH:4]1.[CH3:14]I.O>CN(C=O)C>[CH3:14][N:10]([CH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=[CH:4]1)[C:11](=[O:13])[CH3:12]
Reactant: CC(=O)NC1C=CCCCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N(C)C1C=CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.2 %

Procedure:
To a suspension (10 ml) of sodium hydride (0.24 g, 10 mmoles) in DMF was added N-(2-cycloheptenyl)acetamide (1.53 g, 10 mmoles) in DMF (1 ml) at 0° C. After completion of the addition, the temperature of the mixture was raised to room temperature, and after stirring for 15 minutes, methyl iodide (2.84 g, 20 mmoles) was added dropwise. The resulting mixture was stirred at room temperature for 24 hours, poured into water (20 ml) and extracted with ether. The oily product obtained by concentration was purified by chromatography on silica gel to obtain 0.84 g of N-methyl-N-(2-cycloheptenyl)acetamide [Compound (55)].
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[C:26]2[C:6]([CH:7]=[C:8]3[C:25]=2[CH:24]=[C:23]2[C:10]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=4[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=42)=[CH:9]3)=[CH:5][C:4](B2OC(C)(C)C(C)(C)O2)=[CH:3]1.Br[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[N+:44]([O-:46])=[O:45].C([O-])([O-])=O.[Na+].[Na+].CCO>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:36])[C:26]2[C:6]([CH:7]=[C:8]3[C:25]=2[CH:24]=[C:23]2[C:10]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=4[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=42)=[CH:9]3)=[CH:5][C:4]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[N+:44]([O-:46])=[O:45])=[CH:3]1
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(C)C=C(c2ccccc2[N+](=O)[O-])C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Temperature: 90 °C
Yield: 58.5 %

Procedure:
A mixture of 9.5 g (20.2 mmol) of 2-(10,10-dimethyl-10H-indeno[2,1-b]triphenylen-12-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 4.3 g (21 mmol) of 1-bromo-2-nitrobenzene, 0.44 g (0.4 mmol) of tetrakis(triphenyl phosphine)palladium, 30 ml of 2M Na2CO3, 40 ml of EtOH and 80 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. overnight. After finishing the reaction, the mixture was allowed to cool to room temperature. The solution was extracted with 250 ml of ethyl acetate and 1000 ml of water. The organic layer was dried with anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica (Hx-EA) to give product 5.5 g (58%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[CH3:26]I>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:26]
Reactant: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(O)c(F)c3)oc2c1
Reactant: CI
Product: COc1ccc(-c2nc3ccc(OC[C@H](C)NC(C)=O)cc3o2)cc1F

Procedure:
Using N-((2S)-1-((2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)acetamide and methyl iodide, and in the same manner as in Example 5, the title compound was obtained.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][N:9]([CH3:30])[CH2:10][CH2:11][N:12]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]([CH2:27][CH3:28])([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25]C)[CH:20]=2)[C:13]1=[O:29].B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:30][N:9]([CH3:8])[CH2:10][CH2:11][N:12]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]([CH2:27][CH3:28])([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=2)[C:13]1=[O:29]
Reactant: CCC1(c2cccc(OC)c2)CCCCN(CCN(C)C)C1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC1(c2cccc(O)c2)CCCCN(CCN(C)C)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(2-dimethylamino-ethyl)-3-ethyl-3-(3-methoxy-phenyl)-azepan-2-one Trifluoroacetate (as described above in Step A) (0.1 g, 0.23 mmol) in CH2Cl2 (10 mL) at −78° C. was added BBr3 (1M, 0.46 mL, 0.46 mmol). After stirring for 2 hr at 25° C. the reaction mixture was quenched with H2O, the solvents removed in vacuo, and the residue purified by prep RP HPLC to obtain the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[C:40](Cl)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[N:43][CH:42]=1>>[C:40]([O:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1)(=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[N:43][CH:42]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)c3cccnc3)CN2C1=O
Yield: 7.6 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and nicotinoyl chloride (94 mg, 0.53 mmol). The final trituration (diethyl ether/hexane) and filtration gave 9.0 mg (8.0%) of 18-(nicotinoyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 95.0% pure (HPLC), MS m/z 672 (M−H)−, HRMS: calcd. 674.2860 and found 674.2855 (M+H)+, mp 157-159° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14](O)=[O:15])[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[NH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][C:31]=1[C:38]([F:41])([F:40])[F:39]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14]([NH:29][C:30]3[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][C:31]=3[C:38]([F:39])([F:40])[F:41])=[O:15])[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(N)c(C(F)(F)F)c1
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Product: N#Cc1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 22, int. d) from [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid and 4-amino-3-trifluoromethylbenzonitrile. The compound was purified by using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane to n-heptane/ethyl acetate (1:0 to 4:1 v/v) and subsequent purification by preparative HPLC using a Gemini column and a gradient of acetonitrile:water (containing 0.5% formic acid). Colorless foam (47%). MS (ES+): M+H: 573.2.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].N1C(C)=CC=CC=1C.[CH3:14][NH:15][C@H:16]([CH3:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[CH3:14][N:15]([C@@H:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:23])[P:1]([Cl:5])([Cl:3])=[O:2]
Reactant: CN[C@H](C)c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C[C@H](c1ccccc1)N(C)P(=O)(Cl)Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.6 %

Procedure:
To a cooled (ice/water bath) solution of phosphorus oxychloride (2.83 mL, 30.3 mmol) in DCM (30 mL) was added sequentially, dropwise, and with stirring 2,6-lutidine (7.06 mL, 60.6 mmol) and a DCM solution of (R)-(+)-N,a-dimethylbenzylamine (3.73 g, 27.6 mmol). After 5 minutes, the bath was removed and reaction mixture allowed to warm to ambient temperature. After 1 hour, the reaction solution was washed with a citric acid solution (50 mL×3, 10% w/v aq), dried (MgSO4), filtered through SiO2 and concentrated to provide the title compound (3.80 g) as a white foam. ESI/MS calcd. for 1-(4-nitrophenyl)piperazine derivative C19H25N4O4P 404.2. found m/z=403.1 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:19][C:20]3[CH:21]=[C:22]([CH:27]=[C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH:29]=3)[C:23]([O:25]C)=[O:24])=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1.CO.[OH-].[Li+]>C1COCC1>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:19][C:20]3[CH:21]=[C:22]([CH:27]=[C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH:29]=3)[C:23]([OH:25])=[O:24])=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(Nc2c(C)c(-c3ccccn3)nc3cc(F)ccc23)cc(N2CCOCC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(C(=O)O)cc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure T using methyl 3-(7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ylamino)-5-morpholinobenzoate (0.233 g, 0.493 mmol), methanol (2 mL), THF (3 mL), and 1 N aqueous lithium hydroxide (4.9 mL, 4.93 mmol). (Extraction was performed with 20% 2-propanol in chloroform rather than EtOAc). This afforded 3-((7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-amino)-5-(4-morpholinyl)benzoic acid as an orange amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.72-8.76 (1H, m), 8.13 (1H, m), 8.01-8.06 (1H, m), 7.89 (1H, dt, J=7.8, 1.2 Hz), 7.74-7.82 (1H, m), 7.49-7.56 (2H, m), 7.05 (1H, br. s.), 6.79 (1H, br. s.), 6.65 (1H, br. s.), 3.66-3.75 (4H, m), 3.06-3.11 (4H, m), 2.17 (3H, s). Mass Spectrum (ESI) m/e=459.0 (M+1).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C:13]([CH3:27])([CH3:26])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([Cl:25])=[CH:22][C:23]=2I)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.B(O)(O)[C:31]1[C:36]([CH:37]=[O:38])=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([C:13]([CH3:27])([CH3:26])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([Cl:25])=[CH:22][C:23]=2[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:36]=2[CH:37]=[O:38])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=Cc1ccccc1B(O)O
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1-c1ccccc1C=O
Yield: 55 %

Procedure:
2-[3,5-bis(trifluoromethyl)phenyl]-N-(6-chloro-4-iodo-3-pyridinyl)-N,2-dimethylpropanamide (200 mg, 0.363 mmol), benzaldehyde-2-boronic acid (71 mg, 0.472 mmol), sodium carbonate (0.4 mL, 2M solution), tetrakistriphenylphosphinepalladium (4 mg, 0.00363 mmol) in dioxan (2 mL) were heated together in the microwave at 110° C. for 30 minutes. The mixture was partitioned between EtOAc and Brine. The Aqueous layer was extracted with EtOAc×3. The combined extracts were dried and evaporated. The residue was purified on a 25+M column eluting with 0-50% EtOAc/Pet Et2O to afford the title compound as a yellow solid in 55% yield.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:7]2[CH2:18]CC[CH2:15][C:8]=2[S:9][C:10]=1[Si:11]([CH3:14])([CH3:13])[CH3:12])=[O:5])[CH3:2]>C(C(C)=O)C>[CH3:18][C:7]1[C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[C:10]([Si:11]([CH3:13])([CH3:12])[CH3:14])[S:9][C:8]=1[CH3:15]
Reactant: CCNC(=O)c1c([Si](C)(C)C)sc2c1CCCC2
Solvent: CCC(C)=O
Product: CCNC(=O)c1c([Si](C)(C)C)sc(C)c1C

Procedure:
Using the procedures for the synthesis of the compound of Example 270 and methyl ethyl ketone as the starting material, the title compound was obtained as a white solid. m.p. 90°-94° C.
Reaction SMILES: [C:1]([CH:3]([CH3:17])[CH2:4][P:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:9])[O:6][CH2:7][CH3:8])#[N:2].N.[H][H]>C(O)C.[Ni]>[NH2:2][CH2:1][CH:3]([CH3:17])[CH2:4][P:5]([CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:9])[O:6][CH2:7][CH3:8]
Reactant: [H][H]
Reactant: CCOC(OCC)P(=O)(CC(C)C#N)OCC
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOC(OCC)P(=O)(CC(C)CN)OCC

Procedure:
A solution of 17.0 g of ethyl 2-cyanopropyl(diethoxymethyl)phosphinate in 150 ml of ethanol is added to 155 g of an 8% solution of ammonia in ethanol. To this are added 10 ml of Raney Nickel and the resulting mixture is hydrogenated at 1 bar until the theoretical amount of hydrogen has been taken up. The mixture is then filtered, the filtrate is concentrated under reduced pressure and the crude product is distilled under reduced pressure to give ethyl 3-amino-2-methylpropyl(diethoxymethyl)phosphinate, b.p. 150° C./0.01 mbar, 31P=+45.8 and +45.7 ppm (CDCl3).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[C:16]1([CH:12]2[CH2:13][CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[C:23]([F:34])([F:33])[F:22])=[CH:3][CH:4]=3)=[O:9])[CH2:11]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: O=C(c1ccc(Br)cc1)N1CCCC(c2ccccc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(c1ccc(-c2ccccc2C(F)(F)F)cc1)N1CCCC(c2ccccc2)C1
Temperature: 120 °C

Procedure:
This compound could be made in the following manner analogous to Example 60; 1 equivalent of (4-Bromo-phenyl)-(3-phenyl-piperidin-1-yl)-methanone would be combined with 1.5 equivalents of 2-(Trifluoromethyl)phenyl boronic acid, 10 mol % of tetrakis(triphenylphosphine)palladium(0), 6.7 equivalents of 2M sodium carbonate solution, toluene and ethanol. The reaction mixture would be heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture would then be filtered through Celite and concentrated in vacuo. The residue would be diluted with water and extracted with ethyl acetate. The combined organic phases would be washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material would be purified by flash chromatography to afford product.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[C:12]([F:15])([F:14])[F:13])[C:3]#[N:4].[ClH:16].C(O)=[O:18]>>[ClH:16].[NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[C:12]([F:15])([F:13])[F:14])[C:3]([NH2:4])=[O:18]
Reactant: O=CO
Reactant: N#CC(N)c1ccc(F)cc1C(F)(F)F
Agent: Cl
Product: NC(=O)C(N)c1ccc(F)cc1C(F)(F)F
Yield: 25 %

Procedure:
A solution of (RS)-amino-(4-fluoro-2-trifluoromethyl-phenyl)-acetonitrile (4.47 g) in formic acid (15 ml) saturated with hydrogen chloride was stirred at room temperature for 90 min. The mixture was then concentrated in vacuo and the residue was resuspended in acetone whereby white crystals formed The crystals were collected by filtration, washed with acetone and dried in vacuo to afford (RS)-2-amino-2-(4-fluoro-2-trifluoromethyl-phenyl)-acetamide hydrochloride (1.40 g, 25%) as a white solid. MS (ISP): 273.1 ([M+H]+).