Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:4]=1[CH2:5][NH:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26](O)=[O:27])=[CH:20][CH:19]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[CH2:7]([N:6]([CH2:5][C:4]1[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:3]=1[O:2][CH3:1])[C:26](=[O:27])[CH2:25][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([OH:17])=[CH:19][CH:20]=1)[CH2:8][CH2:9][CH3:10]
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: CCCCNCc1cccc(OC)c1OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCN(Cc1cccc(OC)c1OC)C(=O)CCc1ccc(O)cc1
Temperature: 0 °C
Yield: 120.6 %

Procedure:
N-(2,3-dimethoxybenzyl)butan-1-amine (0.59 g, 2.65 mmol) was dissolved in DMF (10 ml), 3-(4-hydroxyphenyl)propanoic acid (0.4 g, 2.41 mmol), was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (0.85 g, 2.65 mmol) and diisopropylethylamine (0.65 g, 5.05 mmol) was added. The mixture was allowed to warm to room temperature and stirred over night. EtOAc (15 ml) was added and the organic phase was washed with two portions of sodium hydrogencarbonate (aq, 10 ml). EtOAc was removed by evaporation and the crude was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions was pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two potions of brine and dried (MgSO4). The solvent was removed by evaporation and gave 1.08 gram of N-butyl-N-(2,3-dimethoxybenzyl)-3-(4-hydroxyphenyl)propanamide (yield 82.3%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Cl[CH2:18][C:19]1[N:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[O:21][N:20]=1>>[CH3:1][C:2]1[N:3]([CH2:18][C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=3)[O:21][N:20]=2)[C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
Alternatively, 2-Methyl-4-(trifluoromethyl)-1-({5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}methyl)-1H-indole-5-carbonitrile was synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:15])([F:14])[F:13])[C:3]=1[C:4](O)=[O:5].CO>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:14])([F:13])[F:15])[C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1c(Br)cccc1OC(F)(F)F
Solvent: CO
Solvent: C1CCOC1
Product: OCc1c(Br)cccc1OC(F)(F)F
Yield: 100.7 %

Procedure:
To a stirred solution of 2-bromo-6-[(trifluoromethyl)oxy]benzoic acid (1.116 g, 3.92 mmol, Parkway Scientific), in THF (45 ml), under nitrogen, was added 1.0 M borane-tetrahydrofuran complex (12 ml, 12 mmol) carefully over about 2 minutes. The solution was then heated at gentle reflux for 24 h and allowed to cool. Methanol (20 ml) was added dropwise. The solution was heated at reflux for 30 min and allowed to cool. The solvent was evaporated in vacuo and acidified with dilute aqueous HCl. The mixture was extracted with chloroform and then filtered through a hydrophobic frit. The chloroform was evaporated in vacuo to give {2-bromo-6-[(trifluoromethyl)oxy]phenyl}methanol as a colourless oil (1.07 g). {2-bromo-6-[(trifluoromethyl)oxy]phenyl}methanol (1.06 g, 3.91 mmol) in dichloromethane (14 ml) under nitrogen was stirred and cooled to −10° C. A solution of phosphorus tribromide (0.37 ml, 3.91 mmol) in DCM (3.5 ml) was then added dropwise over about 12 min. The temperature was allowed to rise to ambient temperature over about 3 h then stirred for a further 2 h. Saturated aqueous sodium bicarbonate (12 ml) was then added in portions with stirring and the mixture left in a fridge over weekend. The mixture was extracted into chloroform three times. The combined chloroform extracts were filtered through a hydrophobic frit and the solvent was evaporated in vacuo to give 1-bromo-2-(bromomethyl)-3-[(trifluoromethyl)oxy]benzene as a colourless oil (0.6 g).
Reaction SMILES: Br[C:2]1[C:3]([C:29]#[N:30])=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25](=[O:28])[O:26][CH3:27])[CH:19]=2)[S:5][C:6]=1[C:7]1[N:11]=[CH:10][N:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[N:8]=1.[CH:31]([B-](F)(F)F)=[CH2:32].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.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:29]([C:3]1[C:2]([CH:31]=[CH2:32])=[C:6]([C:7]2[N:11]=[CH:10][N:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[N:8]=2)[S:5][C:4]=1[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25](=[O:28])[O:26][CH3:27])[CH:19]=1)#[N:30]
Reactant: COC(=O)Nc1cc(-c2sc(-c3ncn(C4CCCCO4)n3)c(Br)c2C#N)ccn1
Reactant: C=C[B-](F)(F)F
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: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1c(-c2ncn(C3CCCCO3)n2)sc(-c2ccnc(NC(=O)OC)c2)c1C#N
Temperature: 140 °C

Procedure:
A mixture of methyl (4-{4-bromo-3-cyano-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-2-thienyl}pyridin-2-yl)carbamate (1.14 g, 2.33 mmol), potassium vinyltrifluoroborate (0.624 g, 4.66 mmol), tetrakis(triphenylphosphine)platinum (0) (0.145 g, 0.116 mmol) and potassium carbonate (0.967 g, 7.00 mmol) in N,N-dimethylformamide (14.0 mL) and water (5.0 mL) in a microwave vial was heated under nitrogen atmosphere at 140° C. in a microwave for 15 min. The mixture was cooled to room temperature, quenched with water, extracted with DCM, washed with water then brine, dried over Na2SO4, filtered and rotavaped to give a crude product. Purification on a silica gel column using MeOH/DCM (0/100 to 5/95) afforded the desired product (1.16 g, with PPh3 and O═PPh3 contaminated) with Rf on TLC (MeOH/DCM 5/95) of 0.4, and de-carbamide product (0.627 g, yield 58%). LC/MS: (FA) ES+ 437. 1H NMR (400 MHz, d-chloroform) δ 8.52 (s, 1H), 8.45 (s, 1H), 8.41 (m, 1H), 8.33 (s, 1H), 7.51-7.59 (m, 1H), 7.46-7.49 (m, 1H), 6.28-6.33 (m, 1H), 5.66-5.69 (m, 1H), 5.51-5.54 (m, 1H), 4.09-4.12 (m, 1H), 3.86 (s, 3H), 3.75-3.78 (m, 1H), 2.00-2.20 (m, 3H), 1.68-1.77 (m, 3H).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][C@@H:6]([CH3:27])[NH:7][C:8](=[O:26])[CH2:9][N:10]([C:14](=[O:25])[CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[CH:19]=1)[CH:11]1[CH2:13][CH2:12]1)C.[Li+].[OH-]>C1COCC1>[NH2:24][C:20]1[CH:19]=[C:18]([CH2:17][CH2:16][CH2:15][C:14]([N:10]([CH:11]2[CH2:12][CH2:13]2)[CH2:9][C:8]([NH:7][C@H:6]([CH3:27])[CH2:5][C:4]([OH:28])=[O:3])=[O:26])=[O:25])[CH:23]=[CH:22][N:21]=1
Reactant: CCOC(=O)C[C@@H](C)NC(=O)CN(C(=O)CCCc1ccnc(N)c1)C1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@H](CC(=O)O)NC(=O)CN(C(=O)CCCc1ccnc(N)c1)C1CC1
Reaction time: 8 h

Procedure:
Ester 9-3 (44 mg, 0.11 mmol) was dissolved in 1.1 mL THF, then 1 N LiOH (0.28 mL, 0.28 mmol) was added. After stirring overnight the reaction mixture was loaded directly onto a flash chromatography column (silica, eluting with 7:20:1:1 EtOAc/EtOH/H2O/NH4OH) providing 9-4 as a white solid.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[NH:2][NH2:3].C(=O)(O)[O-].[Na+].[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[C:12]1([S:18]([NH:3][NH:2][C:1]([O:5][CH3:6])=[O:4])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)NNS(=O)(=O)c1ccccc1

Procedure:
180 g. (0.2 mole) of methyl carbazate (from hydrazine and dimethyl carbonate) is placed in a liter flask. 20.0 g. (0.24 mole) of sodium bicarbonate and 100 ml. water are added. The mixture is stirred and dropped in 35.2 g. (0.2 mole) of benzene sulfonyl chloride. Then the mixture is stirred for 16 hours. The crystals that have formed are filtered off, washed with water, and dried in air. Yield = 34.5 g.; m.p. 149°-154° C. Upon recrystallization from ethanol 26 g. of material is recovered which melts sharply at 155° C.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=C[C:30]=2[O:35]C)=CSC=1C(OC)=O.[CH:41](OCC)(OCC)[O:42]CC.COC1C=CC(N)=CC=1>C(O)(=O)C>[CH3:30][O:35][C:22]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:16]1[C:10]2[N:9]=[CH:8][N:7]([C:1]3[CH:6]=[CH:5][C:4]([O:42][CH3:41])=[CH:3][CH:2]=3)[C:12](=[O:13])[C:11]=2[S:14][CH:15]=1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: CCOC(OCC)OCC
Reactant: COC(=O)c1scc(-c2ccccc2OC)c1N
Solvent: COc1ccc(N)cc1
Solvent: CC(=O)O
Product: COc1ccc(-n2cnc3c(-c4ccccc4OC)csc3c2=O)cc1
Yield: 56.7 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(2-methoxyphenyl)thiophene-2-carboxylate (40 mg, 0.15 mmol), triethyl orthoformate (0.33 ml), p-anisidine (34.8 mg, 0.28 mmol), and acetic acid (0.04 ml) were used to give 31 mg (0.09 mmol, 56.7% yield) of the title compound.
Reaction SMILES: C(N(C(C)C)[P:5]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(C)C.[F:25][C:26]1([F:60])[CH2:29][C:28]([CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH:44]=[CH:43][N:42]=[C:41]([S:45][C:46]4[CH:51]=[CH:50][C:49]([O:52][C:53]([F:56])([F:55])[F:54])=[CH:48][CH:47]=4)[C:40]3=[O:57])=[CH:35][C:34]=2[O:58][CH3:59])([OH:30])[CH2:27]1.N1C=NC=N1.[OH:66]O>ClCCCl.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>[P:5]([O:30][C:28]1([CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH:44]=[CH:43][N:42]=[C:41]([S:45][C:46]4[CH:47]=[CH:48][C:49]([O:52][C:53]([F:55])([F:54])[F:56])=[CH:50][CH:51]=4)[C:40]3=[O:57])=[CH:35][C:34]=2[O:58][CH3:59])[CH2:29][C:26]([F:25])([F:60])[CH2:27]1)([O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:66]
Reactant: COc1cc(-n2ccnc(Sc3ccc(OC(F)(F)F)cc3)c2=O)ccc1OCC1(O)CC(F)(F)C1
Reactant: OO
Reactant: CC(C)N(C(C)C)P(OCc1ccccc1)OCc1ccccc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: c1nc[nH]n1
Solvent: ClCCCl
Solvent: O
Product: COc1cc(-n2ccnc(Sc3ccc(OC(F)(F)F)cc3)c2=O)ccc1OCC1(OP(=O)(OCc2ccccc2)OCc2ccccc2)CC(F)(F)C1
Temperature: 25 °C
Yield: 77 %

Procedure:
To a mixture of dibenzyl diisopropylphosphoramidite (135 mg, 0.390 mmol), 1-(4-((3,3-difluoro-1-hydroxycyclobutyl)methoxy)-3-methoxyphenyl)-3-(4-(trifluoromethoxy)phenylthio)pyrazin-2(1H)-one (Example 75) (69 mg, 0.130 mmol) and 1H-1,2,4-triazole (27.0 mg, 0.390 mmol) in DCE (20 mL) was stirred at reflux for 6 hours. The mixture was cooled to RT. 30% hydrogen peroxide in water (10 ml) was slowly added and the mixture was stirred at RT for 30 min. The mixture was diluted with a solution of aqueous 10% sodium thiosulfate (40 ml) and was extracted with DCM (50 ml). The DCM layer was dried over sodium sulfate and concentrated. The crude product was purified by ISCO silica gel Column (40 g) and the product was eluted with hexane to 100% ethyl acetate in 10 min. Yield dibenzyl 3,3-difluoro-1-((2-methoxy-4-(2-oxo-3-(4-(trifluoromethoxy)phenylthio)pyrazin-1(2H)-yl)phenoxy)methyl)cyclobutyl phosphate (79 mg, 0.100 mmol, 77% yield) as off-white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.57-7.66 (2H, m), 7.27-7.39 (12H, m), 7.13 (1H, d, J=4.53 Hz), 6.81-7.00 (4H, m), 4.97-5.14 (4H, m), 4.29 (2H, s), 3.75 (3H, s), 2.93-3.20 (4H, m).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([O:13][CH3:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.C([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]1[C:27](O)=[O:28])(=O)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl.O>[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]1[C:27]([NH:1][C:2]1[S:3][C:4]([O:13][CH3:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1)=[O:28]
Reactant: CC(=O)n1c(C(=O)O)cc2ccccc21
Reactant: COc1sc(N)nc1-c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1sc(NC(=O)c2cc3ccccc3[nH]2)nc1-c1ccccc1
Temperature: 25 °C

Procedure:
3.15 g of 2-amino-5-methoxy-4-phenylthiazole are dissolved in 60 ml of CH2Cl2. 3.26 g of 1-acetylindole-2-carboxylic acid, 8.12 g of BOP and 1.86 g of triethylamine are added, and the reaction mixture is stirred at room temperature for one week. 50 ml of water are added and the organic phase is decanted, dried over Na2SO4, filtered and concentrated under vacuum. The residue is taken up in 100 ml of methanol, and 10 g of K2CO3 are added and the mixture is stirred overnight at room temperature. The mixture is concentrated under vacuum, and the residue is taken up in water, and the precipitate formed is separated by filtration and washed with CH2Cl2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:9][C:10]([NH:12][CH2:13][C:14]([O:16]CC)=[O:15])=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C.Cl>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[CH:9][C:10]([NH:12][CH2:13][C:14]([OH:16])=[O:15])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CNC(=O)C=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CNC(=O)C=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
A mixture of 1.0 g. of ethyl N-[3,3-bis(p-chlorophenyl)acryloyl]glycinate, 106 mg. of sodium hydroxide, 18 ml. of ethanol, and 2 ml. of water is stirred under reflux for one hour, allowed to cool, diluted with 80 ml. of water, and acidified with 20 ml. of 1N hydrochloric acid. The solid is collected, dried in vacuo at 50° C., and then stirred with 50 ml. of dichloromethane and 50 ml. of water. The solid which fails to dissolve is collected and dried at 50° C., giving 150 mg. of the desired product as a white solid, m.p. 166°-168° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]([C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=2)=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(CC)CC)C.[CH3:33][O:34][C:35](=[O:39])[CH2:36][CH2:37][NH2:38].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:33][O:34][C:35](=[O:39])[CH2:36][CH2:37][NH:38][C:21](=[O:22])[C:20]1[CH:19]=[CH:18][C:17]([C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Br:1])[CH:3]=2)=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:25][CH:24]=1
Reactant: CCCCCC=C(c1ccc(C(=O)O)cc1)c1ccc(OC)c(Br)c1
Reactant: COC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCC=C(c1ccc(C(=O)NCCC(=O)OC)cc1)c1ccc(OC)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-[1-(3-bromo-4-methoxy-phenyl)-hept-1-enyl]-benzoic acid (380 mg, 0.94 mmol) in methylene chloride (9 mL) are added triethyl amine (0.39 mL, 2.81 mmol), DMAP (5.0 mg), 3-amino-propionic acid methyl ester (197 mg, 1.41 mmol) and EDCI (541 mg, 2.81 mmol) at room temperature. The reaction mixture is stirred at room temperature overnight, loaded on silica gel, eluted with eluted with hexanes with a gradient from 0% of ethyl acetate to 100% of ethyl acetate giving the titled compound (321 mg).
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][N:7]([CH:9]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:8]=1)(=O)[NH2:2].O=P(Cl)(Cl)Cl.O>CN(C=O)C>[C:1]([C:4]1[N:5]=[CH:6][N:7]([CH:9]([CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:8]=1)#[N:2]
Reactant: CCOC(=O)C(CCc1ccccc1)n1cnc(C(N)=O)c1
Solvent: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)C(CCc1ccccc1)n1cnc(C#N)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 101.2 %

Procedure:
A solution of ethyl 2-(4-carbamoyl-1-imidazolyl)-4-phenyl-butyrate (obtained in Preparation 2) in DMF (5 ml) was added to an ice-cooled solution of POCl3 (0.71 ml) in DMF (6 ml) under nitrogen atmosphere. After 1.5 h, the solvent was poured into water (50 ml) and the solution was neutralized with saturated NaHCO3aq. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel (16 g) column chromatography eluting with chloroform/methanol (100:1) to give ethyl 2-(4-cyano-1-imidazolyl)-4-phenylbutyrate (435 mg, 101.2%).
Reaction SMILES: O([C:5]([CH3:7])=[O:6])C(C)=O.[CH3:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:8][N:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:5](=[O:6])[CH3:7]
Reactant: CNc1ccccc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N(C)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.7 %

Procedure:
(CH3CO)2O (50 g, 480.77 mmol) was added to N-methylbenzenamine (10.7 g, 100.00 mmol), and the resulting solution was stirred at room temperature for 15 hours. The reaction mixture was then quenched by adding 200 mL of iced water. The resulting solution was extracted with dichloromethane (2×100 mL), and the organic layers were combined and concentrated to afford 11 g (70%) of N-methyl-N-phenylacetamide as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[C:13]3[CH:21]=[CH:20][N:19]([S:22]([C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=4)(=[O:24])=[O:23])[C:14]=3[N:15]=[C:16]([Cl:18])[N:17]=2)[C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O>C1COCC1>[ClH:18].[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:6])[N:17]1[C:16]([Cl:18])=[N:15][C:14]3[N:19]([S:22]([C:25]4[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=4)(=[O:23])=[O:24])[CH:20]=[CH:21][C:13]=3[C:12]1=[N:11]2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(Br)c4C(=O)O)nc(Cl)nc32)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3c2nc(Cl)n2c(=O)c4c(Br)cccc4nc32)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of 2-bromo-6-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzoic acid (1.5 g, 2.87 mmol) in THF(200 ml) was added oxalyl chloride (4.31 ml, 8.62 mmol, 2.0M DCM) and the reaction was stirred at rt for 1 hr. The reaction was concentrated on rotovap, redissolved in THF, evaporated again, and high vacced prior to next step to yield 8-bromo-5-chloro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one hydrogen chloride (1.3 g, 90%). ESIMS (M+H)+=503.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:3]=1[N:4]([CH3:6])[CH3:5].[CH3:17][I:18]>C(#N)C>[I-:18].[CH3:6][N:4]([CH3:5])[C:3]1[CH:7]=[CH:8][C:9]([C:11]2[CH:12]=[CH:13][N+:14]([CH3:17])=[CH:15][CH:16]=2)=[CH:10][C:2]=1[F:1]
Reactant: CN(C)c1ccc(-c2ccncc2)cc1F
Reactant: CI
Solvent: CC#N
Product: CN(C)c1ccc(-c2cc[n+](C)cc2)cc1F
Product: [I-]
Temperature: 25 °C
Yield: 21 %

Procedure:
2-Fluoro-N,N-dimethyl-4-(pyridin-4-yl)aniline (0.5 g, 2.3 mmols) was dissolved in acetonitrile (50 ml) and methyl iodide (3 ml) was added. The mixture was heated at reflux for 2 hrs. This was cooled to ambient temperature and evaporated the product was purified by recrystallization from ethanol/diethyl ether. To give 0.2 g of 4-(4-(dimethylamino)-3-fluorophenyl)-1-methylpyridinium iodide 21% yield as a red solid. 1H NMR (DMSO-d6) δ 3.0 (s, 6H), 4.25 (s, 3H), 7.02 (t, 1H), 7.90 (m, 2H), 8.90 (d, 2H), 8.90 (d, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:11])=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.Br[CH:13]([CH3:21])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[C:3]([O:11][CH:13]([CH3:21])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1
Reactant: COC(=O)c1scc(Br)c1O
Reactant: CC(Br)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1scc(Br)c1OC(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of methyl 4-bromo-3-hydroxythiophene-2-carboxylate (1.42 g), tert-butyl 2-bromopropanoate (1.2 mL), potassium carbonate (2.45 g) and DMF (30 mL) was stirred at 50° C. for 2 hr. The reaction mixture was cooled to room temperature, and poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and hexane to give the title compound (2.16 g, 99%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1([F:14])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11](=[O:13])[CH3:12])=[CH:10][C:4]=2[O:3]1.[CH:15]1([Mg]Br)[CH2:17][CH2:16]1.C1(C(C2C=CC(Cl)=CC=2)(O)C)CC1>O1CCCC1>[CH:15]1([C:11]([C:9]2[CH:8]=[CH:7][C:5]3[O:6][C:2]([F:1])([F:14])[O:3][C:4]=3[CH:10]=2)([OH:13])[CH3:12])[CH2:17][CH2:16]1
Reactant: CC(=O)c1ccc2c(c1)OC(F)(F)O2
Reactant: Br[Mg]C1CC1
Agent: CC(O)(c1ccc(Cl)cc1)C1CC1
Solvent: C1CCOC1
Product: CC(O)(c1ccc2c(c1)OC(F)(F)O2)C1CC1

Procedure:
The title compound was prepared starting from 0.75 g (3.75 mmol) of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)ethanone and 15.0 ml (7.50 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran in analogy to the synthesis of the compound from Example 138A. 0.67 g (74% of theory) of the title compound was obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:8]=[C:9]([N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[CH2:16][CH3:17])[CH:10]=1)=[O:4].O[Li].O>C1COCC1.O>[CH2:16]([C:12]1[N:11]([C:9]2[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[C:7]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[CH:8]=2)[CH:15]=[CH:14][N:13]=1)[CH3:17]
Reactant: CCc1nccn1-c1cc(C(=O)OC)cc(-c2ccc(C)cc2)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CCc1nccn1-c1cc(C(=O)O)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-(2-Ethyl-imidazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid methyl ester (750 mg) was dissolved in THF (14 mL) and water (8 mL), and LiOH hydrate (128 mg, 3.1 mmol) was added as one portion. The reaction mixture was stirred at room temperature for 3 hours, then THF was removed under reduced pressure. Concentrated HCl was added into the remaining aqueous solution to adjust the pH to ˜6. The solution was extracted with EtOAc, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 5-(2-ethyl-imidazol-1-yl)-4′-methyl-biphenyl-3-carboxylic acid
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([CH:11]=O)[S:10][C:3]=12.[NH2:13][OH:14].Cl>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([CH:11]=[N:13][OH:14])[S:10][C:3]=12
Reactant: O=Cc1cc2nccc(Cl)c2s1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: O
Product: ON=Cc1cc2nccc(Cl)c2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a solution of aldehyde 14 (scheme 3) in MeOH was added NH2OH×HCl (227 mg, 3.26 mmol) in water (0.5 mL) and the mixture was stirred at room temperature for 0.5 h. The solvents were removed by under reduced pressure and the residue was partitioned between EtOAc and water. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness to afford the title compound 125 (458 mg, 85% yield) as a white solid. MS (m/z) 213.1/215.1 (M+H).