Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:21]=[C:20](O)[N:19]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:20]1[N:19]=[CH:18][C:7]2[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]3[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=3[C:6]=2[N:21]=1
Reactant: Oc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1ccccc1C1=NCc2cnc(Cl)nc2-c2ccc(Cl)cc21

Procedure:
A solution of 1.0 g (0.00294 mol) of 9-chloro-7-(2-fluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-ol in 5 ml of phosphorous oxychloride was heated on the steam bath for 4 hr, and evaporated to dryness. The solid was crystallized from dichloromethane/ether, and the precipitate was partitioned between 50 ml of dichloromethane and 40 ml of saturated solution of sodium bicarbonate. The organic layer was dried, evaporated and crystallized from ether. Recrystallization from dichloromethane/ether gave the end product as off-white prisms, mp 157°-160°.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:8]=1[NH2:9].[C:15]([O:19][C:20]([NH:22][C@@H:23]([CH:38]([CH3:40])[CH3:39])[C:24]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][C@H:27]1[C:35](O)=[O:36])=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16]>N1C=CC=CC=1>[F:6][C:7]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:8]=1[NH:9][C:35]([C@@H:27]1[CH2:28][C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:26]1[C:24](=[O:25])[C@@H:23]([NH:22][C:20](=[O:21])[O:19][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:38]([CH3:40])[CH3:39])=[O:36]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccccc2C[C@H]1C(=O)O
Reactant: Nc1c(F)cccc1F
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccccc2C[C@H]1C(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Yield: 89.2 %

Procedure:
Phosphorus oxychloride (164 mg, 0.1 mL, 1.07 mmol, Eq: 2.16) was added dropwise to a cooled (ice-bath) solution of 2,6-difluoroaniline (264 mg, 0.22 mL, 2.04 mmol, Eq: 4.12) and (S)-1-((S)-2-(tert-butoxycarbonylamino)-3-methylbutanoyl)indoline-2-carboxylic acid (0.18 g, 497 μmol, Eq: 1.00) in pyridine (4 mL). The cooling bath was removed and the reaction was stirred at rt. After 1 h the reaction mixture was diluted with toluene (10 mL) and concentrated in vacuo. The residue was treated with water (10 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with 0.1 M aqueous HCl (10 mL) and brine (10 mL) and then concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 30% EtOAc in hexanes) to give tert-butyl (S)-1-((S)-2-(2,6-difluorophenylcarbamoyl)indolin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (0.21 g), m/z=474 (M+H).
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6](/[CH:8]=[C:9](/[CH2:11]P(OCC)(OCC)=O)\[CH3:10])=[O:7].[C:20]1(=O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.O>CN(C=O)C>[C:20]1(=[CH:11][C:9]([CH3:10])=[CH:8][C:6]([O:5][CH2:4][CH3:3])=[O:7])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCOC(=O)/C=C(\C)CP(=O)(OCC)OCC
Reactant: O=C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C=C(C)C=C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (a 60% liquid paraffin dispersion, 1.8 g, 40 mmol) in DMF (60 mL) was added triethyl 3-methyl-4-phosphonocrotonate (11 g, 41.6 mmol) at 0° C., and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added cyclohexanone (3.93 g, 40 mmol), and the mixture was stirred for 3 hours. Water was added to the reaction solution and the product was extracted with diisopropyl ether. The combined extract was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain oily crude resultant product of ethyl 4-cyclohexylidene-3-methyl-2-butenoate. To a mixed solution of this compound in THF (160 mL) and methanol (40 mL) was added a 12 N aqueous sodium hydroxide solution (4.0 mL) at room temperature, and the mixture was stirred for 16 hours, and then was concentrated under reduced pressure. To the residue was added water and hydrochloric acid, and the mixture was acidified, which was extracted with ethyl acetate. The organic layer was washed with water, and then was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the crude resultant product of 4-cyclohexylidene-3-methyl-2-butanoic acid. To a mixture of this compound (6.1 g, 33.8 mmol) in acetic acid (150 mL) was added sodium acetate (12 g, 33.8 mmol) at room temperature, and the mixture was heated under reflux under argon atmosphere for 24 hours. The solvent was concentrated under reduced pressure, water was added to the residue, which was extracted with ethyl acetate, and the organic layer was washed with a saturated sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10) to obtain 5.1 g (yield 63%) of the title compound. Oily matter.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)=[C:4]([CH:19]=O)[CH:3]=1.[C:21]1([CH2:27][CH2:28][NH2:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([BH3-])#N.[Na+]>C(O)(=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)=[C:4]([CH2:19][NH:29][CH2:28][CH2:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:3]=1
Reactant: NCCc1ccccc1
Reactant: O=Cc1cc(Br)ccc1Oc1cccc(CC(=O)O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(O)Cc1cccc(Oc2ccc(Br)cc2CNCCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
[3-(4-Bromo-2-formyl-phenoxy)-phenyl]-acetic acid (0.4 g, 1.23 mmol), 2-phenylethylamine (0.16 mL, 1.23 mmol), sodium cyanoborohydride (0.189 g, 3.0 mmol), and acetic acid (2 drops) were combined in CH2Cl2 and stirred at room temperature for 10 minutes. Aqueous work-up yielded the title compound.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:16][CH2:17][CH3:18].O>CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:16][CH2:17][CH3:18])[C:4](=[O:8])[CH:3]=1
Reactant: CCCI
Reactant: O=c1cc(I)cc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1ccc(I)cc1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2.0 g (9.05 mmol) 4-iodo-1H-pyridin-2-one and 3.13 g (22.6 mmol) potassium carbonate in 10 mL DMF are added 1.05 mL (10.9 mmol) 1-iodopropane. The mixture is stirred for 2 h at rt. Subsequently the mixture is poured into water and extracted with ethyl acetate (2×). The combined organic layers are washed with sat. NaHCO3-solution. After drying over sodium sulphate, the solvent is removed in vacuo and the residue is purified by HPLC (column: Agilent Stablebond C18, 7 μM; eluent A: water+0.15% HCOOH, eluent B: MeOH) to yield the desired product.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:4]([CH2:19][N:20]([CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:21][CH2:22][CH3:23])[CH2:3]1.CCN(CC)CC.[C:41](Cl)(=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43]>C(Cl)Cl>[F:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][CH2:25][CH2:24][N:20]([CH2:19][C@@H:4]2[CH2:3][C@H:2]([NH:1][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:7][CH2:6][C@H:5]2[NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:21][CH2:22][CH3:23])=[CH:32][CH:31]=1
Reactant: CCCN(CCCc1ccc(F)cc1)C[C@@H]1C[C@H](N)CC[C@H]1NC(=O)OCc1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(CCCc1ccc(F)cc1)C[C@@H]1C[C@H](NC(=O)C(C)(C)C)CC[C@H]1NC(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
A solution of benzyl(1R,2S,4R)-4-amino-2-(((3-(4-fluorophenyl)propyl)(propyl)-amino)methyl)-cyclohexylcarbamate (1.1 g, 2.4 mmol) and Et3N (0.3 g, 3 mmol) in CH2Cl2 (50 ml) was cooled in an ice bath and treated drop-wise with pivaloyl chloride (0.32 g, 2.6 mmol). The solution is stirred for 30 minutes and then washed successively with saturated sodium bicarbonate, 0.5 N NaOH, and brine. The solution was dried over sodium sulfate, filtered and the solvent removed on a rotary evaporator. This chromatographed on silica gel to (0.3:2.7:97 NH4OH/MeOH/CH2Cl2) to give 0.85 g of white solid. MS: (M+H)+=540.38.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[C:12]([N:28]3[CH2:33][CH2:32][CH:31]([C:34]([O:36]CC)=[O:35])[CH2:30][CH2:29]3)=[N:13][C:14]([C:24]([F:27])([F:26])[F:25])=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].O.[OH-].[Li+].Cl>O1CCCC1.O>[NH2:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[C:12]([N:28]3[CH2:33][CH2:32][CH:31]([C:34]([OH:36])=[O:35])[CH2:30][CH2:29]3)=[N:13][C:14]([C:24]([F:27])([F:25])[F:26])=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CCOC(=O)C1CCN(c2nc(C(F)(F)F)nc(-c3ccc(F)cc3)c2-c2cccc(S(N)(=O)=O)c2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NS(=O)(=O)c1cccc(-c2c(-c3ccc(F)cc3)nc(C(F)(F)F)nc2N2CCC(C(=O)O)CC2)c1
Reaction time: 17 h

Procedure:
A solution of ethyl 1-{5-[3-(aminosulfonyl)phenyl]-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-4-yl}piperidine-4-carboxylate (0.4 g, 0.725 mmol) in tetrahydrofuran (4 ml) was treated with lithium hydroxide monohydrate (0.036 g, 0.87 mmol) in water (0.2 ml) and was stirred for 17 hours. Subsequently the reaction mixture was poured onto ice-cold water, acidified with dilute hydrochloric acid and extracted with dichloromethane (25 ml). Evaporation of organic layer furnished the required product. 1H-NMR (DMSO-d6) δ: 1.39 (m, 2H), 1.64 (m, 2H), 2.09 (m, 1H), 2.84-2.89 (m, 2H), 3.66 (m, 2H), 7.02-7.07 (m, 2H), 7.07-7.13 (m, 2H), 7.37-7.39 (m, 2H), 7.49-7.53 (m, 1H), 7.69 (s, 1H), 7.72-7.74 (d, 1H), 12.25 (br, 1H, D2O exchangeable); MS m/z: 525.0 (M++1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:14][CH2:15][CH3:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[Br:17]Br>CC(O)=O>[Br:17][C:7]1[CH:6]=[C:5]([C@H:8]([CH2:14][CH2:15][CH3:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:4]=[CH:3][C:2]=1[OH:1]
Reactant: BrBr
Reactant: CCC[C@H](CC(=O)OC)c1ccc(O)cc1
Solvent: CC(=O)O
Product: CCC[C@H](CC(=O)OC)c1ccc(O)c(Br)c1
Reaction time: 1 h
Yield: 90.8 %

Procedure:
To 10.1 (50 mg, 0.23 mmol) was added Br2 (36 mg, 11.6 μl, 0.23 mmol) in AcOH (1 mL) at room temperature. After 1 hour, the red color disappeared to give a pale orange solution. The solution was concentrated and purified by silica gel chromatography (0 to 50% EtOAc/hexanes) to afford a 27.1 (0.0629 g, 90.8% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[NH:24][CH2:23][CH2:22][C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]1=2>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:24]3[CH2:23][CH2:22][C:21]4[N:20]=[CH:19][CH:18]=[CH:17][C:16]=4[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2ncccc21
Product: CC1c2cccnc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-methyl-5,6,7,8-tetrahydro-[1,6]naphthyridine to provide the title compound in moderate yield.
Reaction SMILES: C(O[C:6]([N:8](C)[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=2)=[O:18])[CH2:13][CH2:12]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:6][NH:8][CH2:9][CH2:10][CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[C:23]([Cl:28])[CH:24]=[C:25]([Cl:27])[CH:26]=2)=[O:18])[CH2:15][CH2:16]1
Reactant: CN(CCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3,5-dichlorobenzyl 4-(2-((tert-butoxycarbonyl)(methyl)amino)ethyl)piperidine-1-carboxylate (step 2) (2.73 g, 6.13 mmol) in DCM (20 mL) was added trifluoroacetic acid (19 ml, 247 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under pressure and the residue was suspended in sat. sodium bicarbonate solution (100 ml). The resultant mixture was extracted with EtOAc (2×100 ml). The organic portion was dried using MgSO4, filtered and concentrated under reduced pressure. The oil was applied to a 40 g silica cartridge in DCM and eluted with 0-20% MeOH/DCM containing 1% aqueous ammonia to afford the title compound;
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:12][NH2:13].C[O-].[Na+].C(O[CH:20]=[C:21]([C:24]#[N:25])[C:22]#[N:23])C>CO>[NH2:25][C:24]1[N:12]([C:3]2[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:7][C:2]=2[F:1])[N:13]=[CH:20][C:21]=1[C:22]#[N:23]
Reactant: CCOC=C(C#N)C#N
Reactant: CS(=O)(=O)c1ccc(NN)c(F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)c1ccc(-n2ncc(C#N)c2N)c(F)c1
Yield: 87.6 %

Procedure:
(2-Fluoro-4-methanesulfonyl-phenyl)-hydrazine (1 g, 4.89 mmol) and sodium methoxide (30 mg, 0.489 mmol) were dissolved in methanol under N2 at room temperature. The mixture was stirred for 10. min and 2-ethoxymethylene-malononitrile (0.6 g, 4.91 mmol) was added. The reaction mixture was stirred for 30 min and then brought to reflux for 2 hours. The solvent was removed under reduced pressure; the residue was suspended in water and extracted with ethyl acetate. The organic layer was washed with water, brine and was dried over sodium sulfate. The solvent was concentrated, affording 5-amino-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazole-4-carbonitrile as a yellow solid (1.2 g, 87.5%). 1H NMR (400MHz DMSO-d6) δ (ppm): 7.96 (d, 1H); 7.93 (m, 1H); 7.80 (s, 1H); 7.74 (m, 1H); 6.89 (s, 2H); 3.24(s, 3H). Exact mass calculated for C11H9FN4O2S 280.04, found 281.30 (MH+, 100%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=2)[O:11][CH2:12][CH2:13][CH2:14][CH:15]=NNC(N)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C=O.C(=O)([O-])[O-:27].[Na+].[Na+]>Cl.O>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=2)[O:11][CH2:12][CH2:13][CH2:14][CH:15]=[O:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: NC(=O)NN=CCCCOc1cccc(CN2CCCCC2)c1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=CCCCOc1cccc(CN2CCCCC2)c1

Procedure:
4-[3-(1-piperidinylmethyl)phenoxy]butanal semicarbazone (9.43 g) and 37% formaldehyde (80 ml) in 2N hydrochloric acid (80 ml) were stirred at room temperature for 2.5 h and then diluted with water. The solution was basified with sodium carbonate and extracted with ether. The organic extract was washed with brine, and distilled to give the title compound as a colourless oil (5.59 g) b.p. 200°, 0.06 mm; tlc methanol Rf 0.7.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[C:3]([C:12]([OH:14])=O)=[CH:2]1.S(Cl)([Cl:17])=O>C1CCCCC1>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[C:3]([C:12]([Cl:17])=[O:14])=[CH:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1coc2ccccc2c1=O
Solvent: C1CCCCC1
Product: O=C(Cl)c1coc2ccccc2c1=O

Procedure:
A mixture of chromone-3-carboxylic acid (1.25 g) and thionyl chloride (6 ml) was heated at reflux for 5 minutes. The reaction mixture was then diluted with cyclohexane (15 ml) and ice-cooled. The crystalline precipitate was collected by filtration, washed with cyclohexane and dried under vacuum to give chromone-3-carbonyl chloride (1.2 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(C)C=O.[Br:17]N1C(=O)CCC1=O>O>[NH2:1][C:2]1[C:10]([Br:17])=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Nc1ccc(F)cc1C(=O)O
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c(Br)cc(F)cc1C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 36.5 %

Procedure:
To a mixture of 0.78 g of 2-amino-5-fluorobenzoic acid and 100 ml of N,N-dimethylformamide was added 1.1 g of N-bromosuccinimide at room temperature, and the mixture was stirred at room temperature for 5 hours. After water was added to the reaction mixture, a deposited precipitate was collected by filtration, and then washed with acetone to obtain 0.43 g of 2-amino-3-bromo-5-fluorobenzoic acid of the formula:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][CH:6]1[C:13]2[CH:12]=[C:11]([C:14]([O:16]C)=[O:15])[NH:10][C:9]=2[CH2:8][CH2:7]1.[OH-].[Li+].CO>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][CH:6]1[C:13]2[CH:12]=[C:11]([C:14]([OH:16])=[O:15])[NH:10][C:9]=2[CH2:8][CH2:7]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1cccc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cccc(CC2CCc3[nH]c(C(=O)O)cc32)c1

Procedure:
The title compound was synthesized from methyl 4-(3-methylbenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (85 mg, 0.31 mmol) and lithium hydroxide (129 mg, 3.10 mmol in 3 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (6 mL) was used. The resulting product was purified by chromatography, eluting with heptane-EtOAc, gradient 0 to 50% EtOAc to afford the title compound. 45 mg, 57% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.07-2.20 (m, J=12.57, 8.44, 6.21, 6.21 Hz, 1H), 2.35 (s, 3H), 2.50-2.84 (m, 5H), 3.26-3.35 (m, 1H), 6.53 (d, J=1.42 Hz, 1H), 6.98-7.07 (m, 2H), 7.17-7.22 (m, 1H), 7.23-7.34 (m, 1H), 8.84 (br. s., 1H). LCMS m/e 256 (M+H). Purity ˜100% (HPLC).
Reaction SMILES: Cl.[C:2]1([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:11][C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:37]>CN(C)C1C=CN=CC=1.ClCCl>[C:39]1([O:38][C:36]([N:9]2[C@H:8]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]2[NH:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)=[O:37])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: Fc1ccc(CNC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)cc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Oc1ccccc1)N1C(NCc2ccc(F)cc2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
To a solution of (cis-4,5-diphenyl-4,5-dihydro-1H-imidazol-2-yl)-(4-fluorobenzyl)amine (86) (100 mg, 0.26 mmol), triethylamine (0.091 mL, 0.656 mmol), 4-dimethylamino-pyridine (10 mg) in dichloromethane (10 mL) is added phenyl chloroformate (0.033 mL, 0.262 mmol), and the mixture is stirred at RT overnight. The reaction mixture is diluted with dichloromethane and washed with water, and the organic layer is dried (MgSO4), filtered, and evaporated. The residue is purified by chromatography on silica gel; gradient elution with heptane:EtOAc (70:30-60:40) gives 100 mg of the product 123. 1H NMR (CDCl3) δ 7.50-7.40 (m, 2 H), 7.40-7.10 (m, 6 H), 7.10-6.90 (m, 8 H), 6.90-6.80 (m, 2 H), 6.70-6.60 (m, 2 H), 5.75-5.55 (m, 2 H), 4.75-4.55 (m, 2 H); MS: m/z 466 (M++1)
Reaction SMILES: F[C:2]1[C:7](F)=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:15][NH:14][C:13](=[O:16])[C@H:12]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH2:10]1.[H][H]>C(O)(=O)C.[Pt]=O>[CH:3]1([C@H:9]2[CH2:15][NH:14][C:13](=[O:16])[C@H:12]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:11][CH2:10]2)[CH2:2][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=O
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C2CCCCC2)CNC1=O
Reaction time: 72 h
Yield: 49.7 %

Procedure:
Platinum oxide (300 mg, 1.32 mmol) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-oxoazepan-3-ylcarbamate (463 mg, 1.36 mmol) in glacial acetic acid (15 mL) and the mixture hydrogenated under 50 psi hydrogen in a Parr apparatus. After 3 d, the mixture was concentrated. Saturated aqueous sodium bicarbonate was added, and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried with magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (hexanes→55% ethyl acetate/hexanes) gave the title compound (210 mg). MS 311.2 (M+1).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:21]=[CH:20][C:19]3=[N:22][C:23]([CH2:25][O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:24][N:18]3[C:17]2=[O:33])=[CH:12][CH:11]=1>CN(C=O)C>[Cl:1][C:24]1[N:18]2[C:17](=[O:33])[N:16]([C:13]3[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=3)[CH:21]=[CH:20][C:19]2=[N:22][C:23]=1[CH2:25][O:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=c1n(-c2ccc(F)cc2)ccc2nc(COc3ccccc3)cn12
Solvent: CN(C)C=O
Product: O=c1n(-c2ccc(F)cc2)ccc2nc(COc3ccccc3)c(Cl)n12
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 56.5 %

Procedure:
N-chlorosuccinimide (32.9 mg, 0.25 mmol) was added to a stirred solution of 6-(4-fluoro-phenyl)-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one (75 mg, 0.22 mmol) in DMF (3.5 mL). The mixture was stirred at 150° C. for 15 minutes under microwave irradiation. The solvent was evaporated in vacuo and the crude product was purified by flash column chromatography (silica; AcOEt in DCM with a gradient of 0/100 to 20/80). The desired fractions were collected and the solvents evaporated in vacuo. The product was triturated with DIPE to yield 3-chloro-6-(4-fluoro-phenyl)-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one (46 mg, 56% yield) as a white solid. 1H NMR (400 MHz, CDCl3) 8 ppm 5.12 (s, 2H), 6.62 (d, J=7.9 Hz, 1H), 6.98 (tt, J=7.4, 0.9 Hz, 1H), 7.03-7.07 (m, 2H), 7.06 (d, J=7.6 Hz, 1H), 7.17-7.25 (m, 2H), 7.27-7.34 (m, 2H), 7.35-7.43 (m, 2H).