Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:20][CH2:21][CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[O:32][C:33]3[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=3[N:35]=2)=[CH:27][CH:26]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:40].CCO>CCO>[ClH:40].[O:32]1[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=[C:31]1[C:28]1[CH:29]=[CH:30][C:25]([CH2:24][O:23][CH2:22][CH2:21][NH2:20])=[CH:26][CH:27]=1
Reactant: c1ccc(C(NCCOCc2ccc(-c3nc4ccccc4o3)cc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCO
Product: NCCOCc1ccc(-c2nc3ccccc3o2)cc1
Temperature: 80 °C

Procedure:
N-trityl-2-[4-(benzoxazol-2-yl)benzyloxy]ethylamine (9.1 g; 17.8 mmol) is suspended in EtOH and treated with HCl/EtOH until acidic by pH paper. The reaction mixture is heated at 80° C. for 3 hours keeping the reaction acidic. The reaction mixture is then cooled and the solid is filtered and washed with EtOH to give 2-[4-(benzoxazol-2-yl)benzyloxy]ethylamine hydrochloride (m.p. 232°-233° C.) as a white solid which is used directly in Step F.
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[NH:5][C:4]=1[C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=O.C1(P(=[CH:37][C:38]([O:40][CH3:41])=[O:39])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[C:38]([CH:37]=[CH:1][C:3]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[NH:5][C:4]=1[C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)([O:40][CH3:41])=[O:39]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc(-c2cccs2)[nH]c1-c1cccs1
Solvent: Cc1ccccc1
Product: COC(=O)C=Cc1cc(-c2cccs2)[nH]c1-c1cccs1
Temperature: 60 °C
Reaction time: 16 h
Yield: 79.7 %

Procedure:
To a solution of 100 mg (0.386 mmole) of 3-formyl-2,5-dithienylpyrrole in toluene (3 mL) was added methyl (triphenylphosphoranylidene)acetate (129 mg, 0.386 mmol) at room temperature. The reaction mixture was then stirred at 60° C. for 16 hours. The reaction solvent was evaporated under reduced pressure, and the crude product then purified on 50 g of silica gel. Elution with hexane-ethyl acetate, 5:1, gave the title compound (97 mg) in 58% yield.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([CH:24]([CH3:26])[CH3:25])[C:21]=1[O:22]C)[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:18])(=[O:17])[CH2:9]1)=[O:7])#[N:2].[Cl-].[Li+].Cl>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([CH:24]([CH3:26])[CH3:25])[C:21]=1[OH:22])[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:18])(=[O:17])[CH2:9]1)=[O:7])#[N:2]
Reactant: COc1c(C#N)cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc1C(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(C)c1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(C#N)c1O
Temperature: 100 °C
Reaction time: 20 h
Yield: 84.1 %

Procedure:
3-(3-cyano-5-isopropyl-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (434 mg) was dissolved in N,N-dimethylformamide (5 mL), and lithium chloride (496 mg) was added to the solution, and then the mixture was stirred at 100° C. for 20 hours. To the reaction solution, 1N hydrochloric acid was added, and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was crystallized from n-hexane-chloroform to obtain the title compound (351 mg) as a colorless crystal.
Reaction SMILES: C(O)(=O)C.[O:5]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N+:20]([CH3:23])([O-:22])=[O:21].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.O>[N+:20](/[CH:23]=[CH:15]/[C:14]1[CH:17]=[CH:18][CH:19]=[C:12]([O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:13]=1)([O-:22])=[O:21]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])/C=C/c1cccc(Oc2ccccc2)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 98.8 %

Procedure:
To an acetic acid (20.0 mL) solution of 3-phenoxybenzaldehyde (3.00 g, 15.1 mmol) were added nitromethane (4.61 g, 75.5 mmol) and ammonium acetate (2.33 g, 30.2 mmol) under nitrogen atmosphere at room temperature, which was stirred for 3 hours at 100° C. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (3.60 g) as a crude product.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:3]>CO.[Pd]>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:11][C:12]2[N:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:1]
Reactant: CC(C)Oc1cccc(Oc2ccc([N+](=O)[O-])cn2)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)Oc1cccc(Oc2ccc(N)cn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
To a solution of 2-({3-[(1-methylethyl)oxy]phenyl}oxy)-5-nitropyridine (Intermediate 28, 670 mg, 2.45 mmol) in methanol (50 mL) was added Pd/C (10%, 100 mg, 0.1 wet. e.g.) and the flask was filled in with H2. The resulting mixture was stirred at room temperature under H2 atmosphere overnight and filtered. The filtrate was concentrated under vacuum to afford the title compound as a brown solid (560 mg).
Reaction SMILES: [C:1]1([C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][C:17](=[CH2:20])[CH2:18][OH:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[CH2:39]([O:57][C:58](Cl)=[O:59])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56].CCOCC>C(Cl)Cl>[CH2:39]([O:57][C:58]([O:19][CH2:18][C:17](=[CH2:20])[CH2:16][O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:7]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:59])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56]
Reactant: CCCCCCCCCCCCCCCCCCOC(=O)Cl
Reactant: C=C(CO)COCCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C(COCCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1)COC(=O)OCCCCCCCCCCCCCCCCCC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-[6-(triphenylmethoxy)hexyloxy]-2-metylenepropane-1-ol (from Preparation 46) (1.5 g) and pyridine (4.5 ml) in methylene chloride (15 ml) was cooled in an ice/water bath and octadecyloxycarbonyl chloride (1.3 g) was added. After stirring for 10 minutes at 0° C. the temperature was raised to 22° C. for 5 hours. Ether (15 ml) was added, and the mixture was filtered. The filtrate was evaporated to dryness in vacuo, and the residue was purified through a column of silica gel 60 (70-230 mesh, 15 g) eluting with ether/methylene chloride 1:1. Further purification was achieved by chromatography on Waters PrepLC®/System 500A using a prepPAK®-500/SILICA cartridge with ether/methylene chloride/pentane 1:1:3 as eluent.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19]Cl.Cl.[OH-].[Na+]>C1COCC1>[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1
Reactant: O=Cc1ccc(O)cn1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(C=O)nc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 51 %

Procedure:
A mixture of the above 5-hydroxypyridin-2-carboxaldehyde (4 g, 0.032 mol), K2CO3 (14 g, 0.097 mol) in THF (100 mL) was heated at 60° C. for 2 h under N2. 2-Dimethylaminoethylchloride was freshly prepared from the corresponding HCl salt (9.4 g, 0.06 mol) to which was added drop-wise 20% NaOH solution (2 equivalent) at 0° C. it was then added drop-wise to the above reaction mixture at 60° C. The reaction mixture was allowed to stir 6 h at the same temperature. Upon completion, the reaction mixture was cooled down to RT, the solid was filtered off and the filtrate was concentrated under vacuum to give expected crude product. It was then purified by column chromatography over silica gel (gradient methanol in chloroform from 0.1% to 2%) to give the desired aldehyde (XVI*), e.g., 5-[2-(dimethylamino)ethoxy]pyridine-2-carboxaldehyde (3.25 g, 51%) as a colorless liquid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.FC(F)(F)C(O)=O.[F:16][C:17]1[C:32]([F:33])=[CH:31][C:20]2[NH:21][C:22]([NH:24][C:25]3[C:29]([CH3:30])=[CH:28][S:27][CH:26]=3)=[N:23][C:19]=2[CH:18]=1>C(O)(=O)C>[Br:1][C:26]1[S:27][CH:28]=[C:29]([CH3:30])[C:25]=1[NH:24][C:22]1[NH:21][C:20]2[CH:31]=[C:32]([F:33])[C:17]([F:16])=[CH:18][C:19]=2[N:23]=1
Reactant: Cc1cscc1Nc1nc2cc(F)c(F)cc2[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1csc(Br)c1Nc1nc2cc(F)c(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At room temperature, a solution of N-bromosuccinimide (8 mg) in glacial acetic acid (0.5 ml) was added dropwise to a solution of (5,6-difluoro-1H-benzimidazol-2-yl)-(4-methylthiophen-3-yl)amine trifluoroacetic acid salt (15 mg, example 45) in glacial acetic acid (0.5 ml) in a ReactiVial, and the mixture was stirred at room temperature for 0.5 h. The acetic acid was then removed under reduced pressure and saturated potassium carbonate solution and ethyl acetate were added to the residue. The organic phase was removed and the aqueous phase was then extracted twice with ethyl acetate. The combined organic phases were dried using magnesium sulfate and the drying agent was then filtered off. The residue that remained after removal of the solvent under reduced pressure was purified by preparative chromatography. The product-containing fractions were combined and freed from acetonitrile, saturated sodium bicarbonate solution was added to the residue and the mixture was extracted three times with ethyl acetate. The organic phases were combined, dried (MgSO4) and filtered. After removal of the ethyl acetate under reduced pressure, the residue was coevaporated with toluene and then dried under high vacuum. This gave 8.1 mg of the desired compound.
Reaction SMILES: Cl.Cl[C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[NH:17]1[CH2:25][CH2:24][CH:20]([C:21]([NH2:23])=[O:22])[CH2:19][CH2:18]1.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH3:9][C:8]1[C:3]([N:17]2[CH2:25][CH2:24][CH:20]([C:21]([NH2:23])=[O:22])[CH2:19][CH2:18]2)=[N:4][CH:5]=[N:6][CH:7]=1
Reactant: NC(=O)C1CCNCC1
Reactant: Cc1cncnc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cncnc1N1CCC(C(N)=O)CC1
Reaction time: 0.25 h
Yield: 25.2 %

Procedure:
To a solution of 5-methyl-4-chloropyrimidne hydrochloride 22 (75 mg, 0.45 mmol) in DMF (2 mL) was added triethylamine (0.63 mL, 4.5 mmol). After stirring for 15 min, a solution of isonipecotamide (64 mg, 0.50 mmol) in DMF (2 mL) was added and the mixture was stirred at r.t. for a further 20 h. The mixture was poured into a saturated solution of sodium hydrogen carbonate (50 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts were washed with water (25 mL), brine (25 mL), dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (CH2Cl2, MeOH, gradient 98:2 to 9:1) to furnish the title compound as a white solid (25 mg, 25%), m.p. 182-184° C.; umax (CHCl3)/cm−1 3024, 1678, 1581, 1439, 1359, 1147, 948; m/z (ESI) C11H17N4O requires 221.1397, found [M+H]+ 221.1394.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Si:11]([O:28][CH2:29][C@@H:30]1[C@@H:34]([CH2:35][O:36][Si:37]([C:50]([CH3:53])([CH3:52])[CH3:51])([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:33][CH2:32][C:31]1=[O:54])([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.P([O-])([O-])([O-])=O.C(Cl)Cl>C1(C)C=CC=CC=1.CCCCCC>[Si:11]([O:28][CH2:29][C@@H:30]1[C@@H:34]([CH2:35][O:36][Si:37]([C:50]([CH3:53])([CH3:52])[CH3:51])([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:33][CH2:32][C@@H:31]1[OH:54])([C:24]([CH3:25])([CH3:26])[CH3:27])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)[Si](OC[C@H]1CCC(=O)[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](OC[C@H]1CC[C@H](O)[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)(c1ccccc1)c1ccccc1
Reaction time: 0.25 h
Yield: 79902.2 %

Procedure:
In an atmosphere of argon gas, 1M solution of diisobutylaluminum hydride in toluene (2.7 ml, 2.7 mmoles) was slowly added at -78° C. to solution of (2S,3S)-2,3-bis-(t-butyldiphenylsilyloxymethyl)-1-cyclopentanone (1.40 g, 2.25 mmoles) in toluene (23 ml), and the resulting mixture was stirred at that temperature for 15 minutes. Then, 0.2M phosphate buffer solution (pH 7) was added to the reaction mixture and stirred for a while, after which an excessive amount of methylene chloride was added and the inorganic matter was filtered off. The filtrate was subjected to extraction with methylene chloride and an extract solution was dried on anhydrous sodium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane=1:10, v/v) to obtain (1S,2S,3S)-2,3-bis(t-butyldiphenylsilyloxymethyl)-1-cyclopentanol (1,120 g, Yield 80%):
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C([Li])CCC.C([O:18][B:19](OC(C)C)[O:20]C(C)C)(C)C.Cl>O1CCCC1.CCCCCC.[Cl-].[Na+]>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([B:19]([OH:20])[OH:18])=[CH:3][CH:4]=1)#[N:7]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: N#Cc1ccc(Br)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#Cc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 24.8 %

Procedure:
A solution of 10.0 g (54.9 mmol) of 4-bromobenzonitrile in 100 mL of tetrahydrofuran was cooled to −85° C. whereupon 36.0 mL (57.6 mmol) of 1.6 M solution of n-butyllithium in hexane was added. The mixture was stirred for five minutes and 19.0 mL (82.4 mmol) of triisopropylborate was added. The mixture was stirred at −85° C. for 30 minutes then warmed to ambient temperature over one hour. To the mixture was added 35 mL of 5 N hydrochloric acid and stirring was continued for 2.5 hours. The mixture was diluted with 100 mL of saturated aqueous sodium chloride and extracted three times with 100 mL each of ethyl ether. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. The residue was recrystallized from water and filtered to afford 2.0 g (25%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.C(N=[N+]=[N-])C.[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][NH2:20]>CC#N>[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][NH:20][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CN(C)CCN
Agent: CCN=[N+]=[N-]
Solvent: CC#N
Product: CN(C)CCNc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-chloro-5-nitropyridine 106-A and EtN3 (4.7 g, 46.5 mmol) in CH3CN (150 ml) was added N,N-dimethylethlenediamine 106-B (4.1 g, 46.5 mmol). The solution was stirred at room temperature for 3 hours, extracted with EtOAc, washed (brine), dried(MgSO4) and concentrated to give N,N-dimethyl-N′-(5-nitropyridin-2-yl)ethane-1,2-diamine 106-C (5.2 g) as a yellow solid.
Reaction SMILES: [H-].[Na+].[CH:3]([N:16]1[CH2:19][CH:18]([OH:20])[CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:22]1[CH:27]=[CH:26][C:25]([I:28])=[CH:24][N:23]=1.[Cl-].[NH4+]>CN(C)C=O>[CH:3]([N:16]1[CH2:19][CH:18]([O:20][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][N:23]=2)[CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Clc1ccc(I)cn1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Ic1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.3 %

Procedure:
Sodium Hydride (60 wt % dispersion in mineral oil, 6.36 g, 0.156 mol) was added in portions to a solution of 1-benzhydryl-azetidin-3-ol (25.38 g, 0.106 mol) in anhydrous dimethylformamide (400 mL) under a Nitrogen atmosphere. This caused a precipitate to form and effervescence to occur. When addition was complete the reaction mixture was stirred at ambient temperature for 15 min. A solution of 2-chloro-5-iodopyridine (25.40 g, 0.106 mol) in dimethylformamide (100 mL) was added to the reaction mixture via a dropping funnel over 15 minutes. When addition was complete the reaction mixture was heated to 70° C. and stirred, under nitrogen atmosphere, for 4.5 hr. Reaction mixture was then allowed to cool to ambient temperature and a sat. aqueous ammonium chloride solution (30 mL) was added. The solvents were removed in vacuo and the residual solid was partitioned between ethyl acetate (600 mL) and sat. aqueous sodium bicarbonate solution (500 mL). The phases were separated and the organic phase was washed with sat. aqueous sodium chloride solution (3×300 mL), dried over sodium sulphate, filtered and filtrate solvents removed in vacuo to afford a yellow-brown solid which was triturated with diethyl ether, filtered and dried in vacuo to afford the title compound as a beige-coloured solid (33.41 g, 71%)
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[OH-].[K+].C1(C=CC(O)=CC=1)O.O>C(O)C.C(O)(=O)C>[CH:3]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)(=[O:11])=[O:12])=[CH:8][CH:9]=1)=[CH2:2]
Reactant: Cc1cccnc1NS(=O)(=O)c1ccc(CCBr)cc1
Agent: Oc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: C=Cc1ccc(S(=O)(=O)Nc2ncccc2C)cc1

Procedure:
4-(2-Bromoethyl)-N-(3-methyl-2-pyridinyl)benzenesulfonamide (183 g, 0.5 mol) and potassium hydroxide (120 g, 1.83 mol) and hydroquinone (1 g) in ethanol (2 l) was refluxed for 1 h. 5 l water was added and the solution acidified with acetic acid. The precipitated product was collected by filtration, washed with water and dried. Yield 137 g (quantitative).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].[OH-].[Li+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[CH2:24]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:20])(=[O:21])[NH2:19])[C:10]=1[S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Sc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)O)cc(NCc2ccccc2)c1Sc1ccccc1

Procedure:
A suspension of 3-amino-4-phenylthio-5-sulphamyl-benzoic acid (4.05 g) in water (100 ml) was adjusted to pH 7.5 by addition of 1N lithium hydroxide. Benzyl bromide (2.2 g) was added and, under stirring, the pH was kept at 7.5 by automatic titration with lithium hydroxide. After the base consumption had become negligible, the pH was adjusted to 2.5 by addition of dilute hydrochloric acid. The precipitated 3-benzylamino-4-phenylthio-5-sulphamyl-benzoic acid was collected and recrystallized from ethanol, whereafter the compound was obtained with a melting point of 224°-225° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[CH:12]=[CH:11][C:10]=1[N:20]1[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]1)C1C=CC=CC=1.B(Br)(Br)Br.O>C(Cl)Cl>[OH:8][C:9]1[CH:14]=[C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[CH:12]=[CH:11][C:10]=1[N:20]1[S:24](=[O:26])(=[O:25])[NH:23][C:22](=[O:27])[CH2:21]1
Reactant: O=C1CN(c2ccc(-c3nccs3)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C1CN(c2ccc(-c3nccs3)cc2O)S(=O)(=O)N1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 5-(2-benzyloxy-4-thiazol-2-yl-phenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (50 mg, 0.125 mmol) in CH2Cl2 (5 mL) at −10° C. is added BBr3 (1.0M in CH2Cl2, 0.68 mL) dropwise. The yellow mixture is stirred at −10° C. for 30 min. Water is added to the reaction mixture and the aqueous layer is separated and neutralized with 1N NaOH. The water is removed under reduced pressure and the residue is purified by reverse phase HPLC (MeCN/water/0.1% TFA) to afford the title compound as a light yellow solid: 1H NMR (D24.45 (s, 1H), 7.48-7.54 (m, 3H), 7.61 (d, J=4 Hz, 1H), 7.85 (d, J=4 Hz, 1H); (M−1)−=310.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21]C)=[C:17]([F:23])[CH:16]=2)=[CH:11][N:10]=[C:9]1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([F:23])[CH:16]=2)=[CH:11][N:10]=[C:9]1[NH:24][C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2cnc(Nc3ccc(F)cc3)n(Cc3ccccc3)c2=O)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1c(-c2ccc(O)c(F)c2)cnc(Nc2ccc(F)cc2)n1Cc1ccccc1
Reaction time: 0.83 h

Procedure:
3-benzyl-5-(3-fluoro-4-methoxyphenyl)-2-(4-fluorophenylamino)pyrimidin-4(3H)-one (563.4 mg, 1.343 mmol) was suspended in DCM (12 ml) and cooled in an ice water bath. Then, BBr3 (1.0 M in DCM, 2.2 ml, 2.2 mmol) was added, and the reaction was stirred at 0 C. After 50 minutes, more BBr3 added (2.5 ml, 2.5 mmol) and stirring was continued at room temperature. After 35 minutes, the reaction was cooled to 0 C and quenched with NaOH (5 N, 2.0 ml). The pH of the solution was adjusted with 5 N HCl and saturated sodium bicarbonate to around 7, and the suspension was allowed to stand at room temperature. The suspension was then treated with 1:1 DCM/MeOH and filtered. The solid was washed with this solution and the filtrate was concentrated, treated with EtOAc, and filtered again. The solid was again washed with DCM and MeOH and filtered, and the filtrate was concentrated. This last washing and filtration sequence was repeated a few more times to remove sodium salts (NaCl; NaBr). Finally, the filtrate was concentrated and dried in vacuo to afford the desired 3-benzyl-5-(3-fluoro-4-hydroxyphenyl)-2-(4-fluorophenylamino)pyrimidin-4(3H)-one, which was taken to the next step. MS (ESI pos. ion) m/z: 406 (MH+). Calc'd exact mass for C23H17F2N3O2: 405.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.CO.S(Cl)([Cl:19])(=O)=O>C(Cl)Cl>[Cl:19][C:7]1[CH:6]=[C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]=[CH:3][C:2]=1[OH:1]
Reactant: CCOC(=O)Cc1ccc(O)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(O)c(Cl)c1
Yield: 60 %

Procedure:
To a stirred solution of ethyl 2-(4-hydroxyphenyl)acetate (20 g, 0.076 molo) in 200 ml of DCM was added MeOH (3.4 ml, 0.84 mol). The mixture was brought to reflux and sulfuryl chloride (6.8 ml 0.846 mol) dissolved in DCM (50 mL) was slowly added under over 10 min. The reaction mixture was refluxed further for 5 h, upon which the reaction mixture was poured onto crushed ice and extracted with DCM (×2). The combined organic layers were washed with 10% NaHCO3 solution and water. The organic layer was dried over Na2SO4, filtered and evaporated under vacuum to give compound ethyl 2-(3-chloro-4-hydroxyphenyl)acetate in 60% yield. (13.6 g).