Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C@H:11]([OH:14])[CH2:12][CH3:13])[CH2:3][CH3:4].N1C=CC=CC=1.[C:21]1([P:27](Cl)(Cl)=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>CC(OC)(C)C>[CH2:3]([C@H:2]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C@H:11]([CH2:12][CH3:13])[O:14][P:27](=[O:28])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:1]1)[CH3:4]
Reactant: CC[C@@H](O)c1ccccc1[C@@H](O)CC
Reactant: O=P(Cl)(Cl)c1ccccc1
Agent: Cl
Solvent: COC(C)(C)C
Solvent: c1ccncc1
Product: CC[C@@H]1OP(=O)(c2ccccc2)O[C@@H](CC)c2ccccc21
Temperature: 25 °C

Procedure:
A solution of (R,S)-1-[2-(1-Hydroxy-propyl)-phenyl]-propan-1-ol (4.0 g, 20.6 mmol) in pyridine (4.89 g, 61.7 mmol) was cooled with an ice-bath. Then phenyl phosphonic acid dichloride (4.03 g, 20.6 mmol) was added drop wise. The mixture was allowed to warm to ambient temperature, and stirred over night. To the mixture was then added HCl (ca. 20 ml 4N solution) and TBME (ca. 50 ml). The organic layer was separated, dried (sodium sulfate), and after removal of the solvent the product remained as a colourless oil. Yield: 5.88 g (90.3%). 1H/13C-NMR (CDCl3, HSQC/HMBC) δ/δ 1.05 (tr, J=7.4 Hz)/11.05 (CH3); 1.13 (tr, J=7.6 Hz)/10.48 (CH3); 2.05-2.21 (m)/27.82 (d, J=8.9 Hz), 30.61 (d, J=9.4 Hz) (2 CH2Me); 5.42 (ddd, J=4.7 Hz, J=5.8 Hz, J=8.5 Hz)/80.30 (d, J=7.6 Hz) (CHEt); 5.75 (ddd, J=3.8 Hz, J=5.3 Hz, J=7.4 Hz)/80.47 (d, J=7.3 Hz) (CHEt); 7.24/126.73 (Ar CH); 7.24/127.18 (Ar CH); 7.24/128.12 (Ar CH); 7.31/128.59 (Ar CH); 7.40/128.47 (d, J=15.2 Hz) (Ph meta-CH); 128.93 (d, J=192 Hz) (Ph ipso-C); 7.51/132.47 (d, J=3.1 Hz) (Ph para-CH); 7.73/131.74 (d, J=9.8 Hz) (Ph ortho-CH); 137.66, 138.92 (2 Ar ipso-C). 31P-NMR (CDCl3) δ 19.26.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[S:23])=[CH:3][CH:2]=1.Cl[CH2:25][CH2:26][CH2:27][CH2:28][S:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1.C1CCN2C(=NCCC2)CC1.O>CN(C)C=O>[N:33]1[CH:34]=[CH:35][C:30]([S:29][CH2:28][CH2:27][CH2:26][CH2:25][N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21](=[O:22])[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][S:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[C:13]2=[S:23])=[CH:31][CH:32]=1
Reactant: ClCCCCSc1ccncc1
Reactant: O=c1c2ccccc2[nH]c(=S)n1CCCCSc1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2ccccc2n(CCCCSc2ccncc2)c(=S)n1CCCCSc1ccncc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 0.1 %

Procedure:
To a solution of 515 mg (1.5 mmol) of 3-[4-(4-pyridylthio)butyl]quinazoline-2 (1H)-thion-4(3H)-one and 332 mg (1.65 mmol) of 4-(4-chlorobutylthio)pyridine in 15 ml of dimethylformamide, 0.25 ml (1.65 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene was added, and the mixture was stirred at 80° C. for 16 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried and the solvent was distilled off. The residue was purified by flash column chromatography (eluent: ethyl acetate/ethanol =25:1 to 10:1) to give 0.694 mg of the desired product (97.1% yield; colorless oil).
Reaction SMILES: [CH2:1]([N:8]([CH2:11][CH2:12][CH2:13][CH:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[CH:17][C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]1=2)CC)[C:2]1C=CC=CC=1>[Pd]>[CH2:1]([NH:8][CH2:11][CH2:12][CH2:13][CH:14]1[C:15]2[CH:28]=[CH:27][CH:26]=[CH:25][C:16]=2[CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]1=2)[CH3:2]
Reactant: CCN(CCCC1c2ccccc2C=Cc2ccccc21)Cc1ccccc1
Agent: [Pd]
Product: CCNCCCC1c2ccccc2C=Cc2ccccc21

Procedure:
5-[3-(N-Benzyl-N-ethylamino)-propyl]-5H-dibenzo[a,d]cycloheptene is dissolved in absolute alcohol and hydrogenated over palladium on alumina catalyst at 40°-60°C. The catalyst is separated and the product isolated by evaporating the solvent.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:3]=1[CH2:4][NH:5][CH2:6][CH3:7].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][C:3]=1[CH2:4][N:5]([CH2:6][CH3:7])[C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1Br
Product: CCN(Cc1cc(C(F)(F)F)ccc1Br)C(=O)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2-bromo-5-trifluoromethyl-benzyl)-ethyl-amine and benzoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[CH2:16]([O:8][C:7]1[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Oc1cccnc1Cl
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Clc1ncccc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a solution of 2-chloropyridin-3-ol (16.3 g, 125 mmol) and K2CO3 (24.3 g, 176 mmol) in acetone (150 ml) was added dropwise (bromomethyl)benzene (17.9 ml, 151 mmol). The mixture was stirred overnight at 50° C. and then concentrated to dryness. Water (100 ml) was added and the mixture extracted with CH2Cl2. The organics were dried over Na2SO4, and concentrated to a crude residue that was dissolved in 20 ml CH2Cl2. Et2O (250 ml) was added and then the solvent was decanted from the residue. The residue was then purified on a silica gel plug by eluting with 25% EtOAc/Hexanes to give 3-(benzyloxy)-2-chloropyridine (22.3 g, 80% yield) as a solid.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[S:17]([NH2:27])(=[O:26])([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)=[O:18]>CO>[NH2:27][S:17]([C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:14]([C:10]2[CH:9]=[C:8]([NH:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[N:13]=[CH:12][N:11]=2)=[O:16])=[CH:23][CH:24]=1)(=[O:18])=[O:26]
Reactant: O=C(O)c1cc(NC2CCCCC2)ncn1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Solvent: CO
Product: NS(=O)(=O)c1ccc(NC(=O)c2cc(NC3CCCCC3)ncn2)cc1

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexylamino)pyrimidine-4-carboxylic acid (Intermediate 4) and sulfanilamide (Acros), the title compound was obtained as a white solid after trituration in methanol.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14](OC)=[O:15])=[CH:10][C:9]=2[OH:18])[N:3]=1.[BH4-].[Li+].O>O1CCCC1>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][C:9]=2[OH:18])[N:3]=1
Reactant: COC(=O)c1ccc(-n2nc(C)cc2C)c(O)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)n(-c2ccc(CO)cc2O)n1
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 10.6 %

Procedure:
132 mg of methyl 4-(3,5-dimethyl-1H-pyrazol-yl)-3-hydroxybenzene carboxylate was dissolved in 2.6 ml of tetrahydrofuran, and 58 mg of lithium borohydride was added and stirred at 50° C. for 3.5 hours. To the reaction mixture was added 20 ml of water, and extracted with 20 ml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and purified using preparative thin-layer silica gel column chromatography (hexane:ethyl acetate=1:2) to yield 12.4 mg of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([C:10](=[O:12])[CH3:11])[C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.O>C1COCC1>[S:22]([N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([C:10](=[O:12])[CH3:11])[C:4]=2[CH:3]=[CH:2]1)([C:19]1[CH:20]=[CH:21][C:16]([CH3:15])=[CH:17][CH:18]=1)(=[O:24])=[O:23]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)c1nccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1nccc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
To a mixture of 1-(1H-pyrrolo[3,2-c]pyridin-4-yl)ethanone (680 mg, 4.25 mmol) in anhydrous THF (40 mL) at 0° C. was added NaH (60% in mineral oil, 204 mg, 5.1 mmol). After the mixture was stirred at 0° C. for 30 min, 4-methylbenzene-1-sulfonyl chloride (850 mg, 4.46 mmol) was added. The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into water (150 mL), extracted with EtOAc (3×50 mL) and concentrated under reduced pressure to afford 1.32 g (98.9%) of 1-(1-tosyl-1H-pyrrolo[3,2-c]pyridin-4-yl)ethanone as yellow solid: MS (ESI) m/z: 315.2 [M+1]+.
Reaction SMILES: [CH:1]([C:13]([O:15][CH2:16][CH3:17])=[O:14])([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[N+:20]([C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:24]=1[CH2:25]Cl)([O-:22])=[O:21].CN(C)C=O>C1C=CC=CC=1>[C:8]([C:1]([C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH2:25][C:24]1[C:27]([CH3:31])=[CH:28][CH:29]=[CH:30][C:23]=1[N+:20]([O-:22])=[O:21])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)CC(C(=O)OCC)C(=O)OCC
Reactant: Cc1cccc([N+](=O)[O-])c1CCl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)CC(Cc1c(C)cccc1[N+](=O)[O-])(C(=O)OCC)C(=O)OCC

Procedure:
The title compound was prepared by the same procedure as described in example 1 for 1a (R2 = R3 = H), using triethyl 1,1,2-ethanetricarboxylate (9.85 g; 0.04 mole), NaH (1.6 g; 0.04 mole) and 2-nitro-6-methylbenzyl chloride (7.4 g; 0.04 mole) in 20 ml. 10% dimethylformamide (DMF) in benzene. The crude product so obtained was used directly in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2C(OC(C)(C)C)=O)=[CH:6][CH:5]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:24][C:2]([F:1])([F:25])[O:3][C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][NH:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(OC(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc(OC[C@@H]2CCCN2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.8 %

Procedure:
A mixture of tert-butyl (S)-2-(4-trifluoromethoxyphenoxymethyl)pyrrolidine-1-carboxylate (2.31 g, 6.39 mmol) prepared in Reference Example 62, trifluoroacetic acid (20 ml), and methylene chloride (20 ml) was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was neutralized with 10% sodium hydroxide aqueous solution and the mixture was extracted with methylene chloride, and the extract was dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford (S)-2-(4-trifluoromethoxyphenoxymethyl)-pyrrolidine (1.65 g, yield 99%) as a pale brown oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:21])[C:5]([C:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C:15]3=[O:20])[CH2:10][CH:9]=2)=[N:6][CH:7]=1.[CH3:22][C:23]1[N:27]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=2)[N:26]=[CH:25][C:24]=1[C:38]([NH2:40])=[O:39].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[NH4+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.O1CCOCC1>[CH3:22][C:23]1[N:27]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][N:29]=2)[N:26]=[CH:25][C:24]=1[C:38]([NH:40][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C:15]3=[O:20])[CH2:10][CH:9]=2)=[C:4]([CH3:21])[CH:3]=1)=[O:39]
Reactant: Cc1c(C(N)=O)cnn1-c1ccc(C(F)(F)F)cn1
Reactant: Cc1cc(Br)cnc1C1=CCC(N2CCOCC2=O)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1=CCC(N2CCOCC2=O)CC1
Temperature: 110 °C
Reaction time: 5 h
Yield: 73.5 %

Procedure:
1,4-Dioxane (2 ml) was added to 4-[4-(5-bromo-3-methylpyridin-2-yl)cyclohex-3-en-1-yl]morpholin-3-one (150 mg) described in Reference Example 187, 5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (115 mg) described in Reference Example 120, palladium (II) acetate (3.8 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (14.8 mg) and cesium carbonate (195 mg) and stirred at 110° C. for five hours. After the reaction, the reaction solution was cooled to room temperature, a saturated aqueous solution of ammonium chloride was added and the precipitated solid was filtered. The resulted solid was purified with a silica gel column chromatography (chloroform/methanol), suspended and washed with ethanol to give the titled compound (169 mg) as a white solid.
Reaction SMILES: FC1C=CC(C2N=C(C(=O)C)SN=2)=CC=1.[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][CH:18]=1.Cl[C:27]([S:29]Cl)=[O:28]>>[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]2[O:22][C:27](=[O:28])[S:29][N:23]=2)=[CH:19][CH:18]=1
Reactant: O=C(Cl)SCl
Reactant: NC(=O)c1ccc(F)cc1
Agent: CC(=O)c1nc(-c2ccc(F)cc2)ns1
Product: O=c1oc(-c2ccc(F)cc2)ns1

Procedure:
In still a further embodiment, 1-(3-(4-fluorophenyl)-1,2,4-thiadiazol-5-yl)ethanone may be prepared according to the methodology and reagents of Scheme 16A. In this embodiment, a 1,3,4-oxathiazol-2-one ring fragment is generated and subsequently converted to a 1,2,4-thiadiazole ring fragment during the preparation of 1-(3-(4-fluorophenyl)-1,2,4-thiadiazol-5-yl)ethanone. Specifically, 4-fluoro-benzamide is reacted with chlorocarbonylsulfenyl chloride to provide 5-(4-fluoro-phenyl)-1,3,4-oxathiazol-2-one. In one embodiment, the reaction is performed in toluene. In another embodiment, the reaction is performed at elevated temperatures of about 80° C. for about 3 hours. 5-(4-Fluorophenyl)-1,3,4-oxathiazol-2-one is then reacted with acetyl cyanide to provide 1-(3-(4-fluorophenyl)-1,2,4-thiadiazol-5-yl)-ethanone. In one embodiment, this reaction is performed in 1,2-dichlorobenzene. In another embodiment, this reaction is performed at elevated temperatures of about 160° C. for about 20 hours. 1-(3-(4-Fluorophenyl)-1,2,4-thiadiazol-5-yl)ethanone is then converted to a compound of Formula (I-A) by the methods described herein, such as Scheme 1.
Reaction SMILES: [F:1][C:2]1([F:16])[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[Si](C)(C)C.[Br:29]Br>CN(C=O)C>[Br:29][CH:9]([CH2:8][CH:5]1[CH2:4][CH2:3][C:2]([F:16])([F:1])[CH2:7][CH2:6]1)[C:10](=[O:15])[C:11]([F:13])([F:14])[F:12]
Reactant: BrBr
Reactant: O=C(CCC1CCC(F)(F)CC1)C(F)(F)F
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(C(Br)CC1CCC(F)(F)CC1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
4-(4,4-Difluorocyclohexyl)-1,1,1-trifluorobutan-2-one (100 mg, 0.410 mmol) obtained in step 1 was dissolved in DMF (1.0 mL). Under ice-cooled condition, triethylamine (0.110 mL, 0.788 mmol) and chlorotrimethylsilane (0.0570 mL, 0.450 mmol) were added, and the mixture was stirred at 0° C. for 30 minutes. The reaction mixture was extracted with hexane after adding saturated sodium hydrogen carbonate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The residue was dissolved in dichloromethane (1.0 mL). Under ice-cooled condition, bromine (73.0 mg, 0.456 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered through a Presep (registered trademark; diatomaceous earth, granular type M, 4.5 g/25 mL) after adding a saturated sodium hydrogen carbonate aqueous solution and sodium thiosulfate aqueous solution. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20) to give 3-bromo-4-(4,4-difluorocyclohexyl)-1,1,1-trifluorobutan-2-one (73.8 mg, yield 56%).
Reaction SMILES: CO.C([NH:10][C:11]1[C:16]([F:17])=[C:15]([CH3:18])[C:14]([F:19])=[C:13]([F:20])[N:12]=1)C1C=CC=CC=1>[Pd].C(O)(=O)C>[NH2:10][C:11]1[C:16]([F:17])=[C:15]([CH3:18])[C:14]([F:19])=[C:13]([F:20])[N:12]=1
Reactant: Cc1c(F)c(F)nc(NCc2ccccc2)c1F
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1c(F)c(N)nc(F)c1F
Reaction time: 24 h

Procedure:
To 4 ml of methanol were added all amount of the crude 2-benzylamino-3,5,6-trifluoro-4-methylpyridine as described above together with 0.18 g of 10% palladium on carbon and 2 ml of acetic acid, and the mixture was hydrogenated at 50° C. for one day. The catalyst was separated by filtration, and the solvent and the like were distilled off under reduced pressure to obtain 1.35 g of the title compound as a colorless solid.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][C:6](=[O:9])[NH:5][C:4]1=[O:10].CC(O)=O.[NH2:15][C:16]1[C:24]([OH:25])=[CH:23][CH:22]=[C:18]([C:19](O)=[O:20])[C:17]=1[C:26](O)=[O:27]>C(N(CC)CC)C>[NH2:15][C:16]1[C:24]([OH:25])=[CH:23][CH:22]=[C:18]2[C:17]=1[C:26](=[O:27])[N:2]([CH:3]1[CH2:8][CH2:7][C:6](=[O:9])[NH:5][C:4]1=[O:10])[C:19]2=[O:20]
Reactant: Nc1c(O)ccc(C(=O)O)c1C(=O)O
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: Nc1c(O)ccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 51 %

Procedure:
3-Aminopiperidine-2,6-dione hydrochloride (9.58 g, 58.4 mmol) was dissolved in triethylamine (TEA) (14.7 g) and the mixture was stirred at room temperature for 4 hrs. HOAc (150 mL) and 3-amino-4-hydroxyphthalic acid C1-5 (9.6 g, 48.7 mmol) were added. The mixture was stirred at 120° C. for 20 mins. TEA was added until the white solid was dissolved completely. The mixture was stirred at 120° C. for 2 hrs. After cooling, the solution was extracted with ethyl acetate (500 mL×4). The combined organic layers were dried over Na2SO4, filtered, and concentrated to a dark solid. The dark solid was washed with EA (300 mL) and dried to give compound 1 as a dark solid (7.2 g, yield: 51%). 1H NMR (DMSO-d6, 400 MHz) δ: 11.05 (s, 1H), 10.82 (s, 1H), 6.98 (d, J=8 Hz, 1H), 6.92 (d, J=7.6 Hz, 1H), 5.95 (s, 2H), 5.03-4.98 (m, 1H), 2.91-2.83 (m, 1H), 2.60-2.44 (m, 2H), 2.01-1.98 (m, 1H); MS (ESI+): m/z 290 (M+1); Elem. Anal. Calcd. for C13H11N3O5: C, 53.98; H, 3.83; N, 14.53. Found: C, 53.67; H, 3.80; N, 14.44.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].O.[CH:13](O)([CH3:15])[CH3:14]>>[Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O:9][CH:13]([CH3:15])[CH3:14])=[O:8]
Reactant: CC(C)O
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Solvent: O
Product: CC(C)OC(=O)c1cnc(Cl)c(Cl)c1

Procedure:
5,6-Dichloronicotinic acid (2.00 g, 10.4 mmol) was dissolved in 50 mL isopropanol to which was added BF3 -diethyl etherate (3.84 mL, 3 eq). The solution was refluxed overnight. When cooled, the solution was poured into 100 mL water and extracted with Et2O (2×100 mL) The organics were collected, washed with water, brine, 1.0 N NaOH, dried over MgSO4, and concentrated to give isopropyl 5,6-dichloronicotinate (0.62 g) as a cream solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[CH:32]=[C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][CH2:44][N:43]([CH:46]4[CH2:49][O:48][CH2:47]4)[CH2:42][C@@H:41]3[CH2:50][CH3:51])=[CH:36][N:35]=2)[C:30](=[O:52])[N:29]([CH3:53])[CH:28]=1)(=O)C.[Li+].[OH-]>CC(O)C.C1COCC1.O>[CH2:50]([C@H:41]1[CH2:42][N:43]([CH:46]2[CH2:47][O:48][CH2:49]2)[CH2:44][CH2:45][N:40]1[C:37]1[CH:38]=[CH:39][C:34]([NH:33][C:31]2[C:30](=[O:52])[N:29]([CH3:53])[CH:28]=[C:27]([C:7]3[C:6]([CH2:5][OH:4])=[C:11]([N:12]4[CH2:24][CH2:23][N:15]5[C:16]6[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=6[CH:22]=[C:14]5[C:13]4=[O:25])[CH:10]=[C:9]([F:26])[CH:8]=3)[CH:32]=2)=[N:35][CH:36]=1)[CH3:51]
Reactant: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(N4CCn5c(cc6c5CCCC6)C4=O)c3COC(C)=O)cn(C)c2=O)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: CC[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(N4CCn5c(cc6c5CCCC6)C4=O)c3CO)cn(C)c2=O)nc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 26.4 %

Procedure:
A mixture of 105a (220 mg, 0.30 mmol) and LiOH (72 mg, 3.0 mmol) in iPrOH/THF (1:1, 4 mL) and H2O (1 mL) was stirred at 30° C. for 1 h. The mixture was evaporated in vacuo and the residue was extracted with EtOAc (10 mL×2). The combined EtOAc extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 105 (54 mg, 25%) as a white solid. LCMS: [M+H]+ 682. 1H NMR (500 MHz, CDCl3) δ 8.54 (t, J=2.5, 1H), 7.91 (s, 1H), 7.80 (s, 1H), 7.47 (d, J=1.5, 1H), 7.26-7.24 (m, 1H), 7.18-7.15 (m, 1H), 6.95 (dd, J=2.5, 9.0, 1H), 6.87 (s, 1H), 6.81 (d, J=7.5, 1H), 4.72-4.61 (m, 4H), 4.54 (d, J=11.5, 1H), 4.33-4.30 (m, 2H), 4.20-4.14 (m, 3H), 3.92-3.90 (m, 1H), 3.71 (s, 3H), 3.53 (t, J=5.5, 1H), 3.31 (s, 1H), 3.12 (s, 2H), 2.61-2.56 (m, 5H), 2.44 (s, 2H), 2.35 (s, 1H), 1.91-1.89 (m, 2H), 1.80-1.79 (m, 2H), 1.67 (s, 1H), 1.43-1.37 (m, 1H), 0.82 (t, J=5.5, 3H)
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:6][CH:5]=1.CO.[OH-].[Na+]>C1COCC1>[N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:12]=1[CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:22])=[O:2])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(CCc2ccc3ccccc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(CCc2ccc3ccccc3n2)cc1
Reaction time: 4 h
Yield: 85 %

Procedure:
To a solution of 4-(2-Quinolin-2-yl-ethyl)-benzoic acid methyl ester (680 mg) in THF (11 ml)/methanol (3 ml) was added 1N sodium hydroxide solution (4.67 ml). The reaction mixture stirred for 4 h. and the pH adjusted to 3. The white solid was filtered to provide the title compound (550 mg, 86%). MS: (M+H m/z=278.1).
Reaction SMILES: Cl[C:2]1[C:10]2[C:9]3[CH2:11][NH:12][CH2:13][CH2:14][C:8]=3[NH:7][C:6]=2[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.[OH-].[K+]>C(O)(C)(C)C.CCOC(C)=O.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:2]2[C:10]3[C:9]4[CH2:11][NH:12][CH2:13][CH2:14][C:8]=4[NH:7][C:6]=3[N:5]=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: Nc1ccc(F)cc1
Reactant: Clc1ccnc2[nH]c3c(c12)CNCC3
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)(C)O
Product: Fc1ccc(Nc2ccnc3[nH]c4c(c23)CNCC4)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 25.8 %

Procedure:
4-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (100 mg, 0.48 mmol), 4-fluoroaniline (0.14 mL, 1.44 mmol), Pd(OAc)2 (5 mg, 0.02 mmol), 2-X-Phos (23 mg, 0.05 mmol), and KOH (162 mg, 2.89 mmol) were dissolved in tert-butanol (2.0 mL), and stirred overnight at 100° C. The reaction mixture diluted with EtOAc/H2O, and filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude material was triturated with EtOAc, filtered, washed with EtOAc, and dried under vacuum to provide 5 (35 mg, 26% yield) as a brown solid. LC-MS (M+H=283, obsd.=283).