Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:40])([C:31]([F:39])([F:38])[C:32]([F:37])([F:36])[CH:33]([F:35])[F:34])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](=[O:30])[NH:28][CH:27]=[N:26]2)=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:28]1[CH:27]=[N:26][N:25]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]([F:15])([F:40])[C:31]([F:38])([F:39])[C:32]([F:37])([F:36])[CH:33]([F:35])[F:34])=[CH:24][CH:23]=2)[C:29]1=[O:30])[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]cnn1-c1ccc(OCC(F)(F)C(F)(F)C(F)(F)C(F)F)cc1
Product: C[C@@H](n1cnn(-c2ccc(OCC(F)(F)C(F)(F)C(F)(F)C(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 61.7 %

Procedure:
In the same manner as in Reference Example 5, starting from 345 mg of (1S)-[(2R)-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 410 mg of 2-[4-(2,2,3,3,4,4,5,5-octafluoropentoxy)phenyl]-3(2H,4H)-1,2,4-triazolone, 371 mg of 4-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-2-[4-(2,2,3,3,4,4,5,5-octafluoropentoxy)phenyl]-3(2H,4H)-1,2,4-triazolone was obtained as colorless prisms.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[F:23])[C:17](O)=[O:18])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.S(Cl)(Cl)=O.NC1C=C(C=CC=1F)C([NH:34][CH2:35][CH2:36][N:37]1[C@H:42]([CH3:43])[CH2:41][CH2:40][CH2:39][C@@H:38]1[CH3:44])=O>C1(C)C=CC=CC=1.N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([C:17](=[O:18])[NH:34][CH2:35][CH2:36][N:37]4[C@H:42]([CH3:43])[CH2:41][CH2:40][CH2:39][C@@H:38]4[CH3:44])[CH:20]=[CH:21][C:22]=3[F:23])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: O=C(O)c1ccc(F)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Reactant: C[C@@H]1CCC[C@H](C)N1CCNC(=O)c1ccc(F)c(N)c1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C[C@@H]1CCC[C@H](C)N1CCNC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7-Bromoimidazo[1,2-a]pyridine-3-carboxylic acid (Intermediate 1A step 3) (1.150 g, 4.77 mmol) was suspended in toluene (10 ml) and treated with thionyl chloride (1.045 ml, 14.32 mmol). The mixture was at 100° C. for 2 hrs. The solvent was removed in vacuo and the solid was added to a stirred solution of 3-amino-N-(2-(2,6-cis-dimethyl piperidin-1-yl)ethyl)-4-fluorobenzamide (1.4 g, 4.77 mmol) in dry pyridine (5 ml) containing oven dried molecular sieves. The mixture was stirred at RT under nitrogen atmosphere overnight. The solvent was removed in vacuo and purification of the crude product by chromatography on silica eluting with 0-20% MeOH in DCM afforded the title compound;
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[K+].[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH:21](Cl)[CH3:22])=[CH:17][CH:16]=1.C1(C)C=CC=CC=1>CO.O>[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:16]=[CH:17][C:18]([CH:21]([S:1][CH2:2][C:3]([OH:5])=[O:4])[CH3:22])=[CH:19][CH:20]=1
Reactant: O=C(O)CS
Reactant: CC(Cl)c1ccc(-c2ccccc2F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: CC(SCC(=O)O)c1ccc(-c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55 %

Procedure:
6.35 gm (0.055 mol) of 80% mercaptoacetic acid were admixed in 70 ml of methanol with a solution of 6.2 gm (0.11 mol) of potassium hydroxide in 6.2 ml of water. To the solution of the dipotassium salt, 11.7 gm (0.05 mol) of 1-(2'-fluoro-4-biphenylyl)-1-chloro-ethane were added, the reaction mixture was rinsed with 20 ml of methanol and stirred for 18 hours at room temperature. Subsequently, the mixture was evaporated, the residue was digested with acetone, and the precipitated potassium salt was suction-filtered off. The free acid was obtained by dissolving the salt in water and acidifying the solution. M.p. 128°-130° C (from toluene). Yield: 55% of theory.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].C(Cl)(=O)C(Cl)=O.CS(C)=O.CCN(CC)CC>C(Cl)Cl>[CH:2]([C:3]1[CH:4]=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:1]
Reactant: COC(=O)c1cc(CO)ccc1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(C=O)ccc1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.9 %

Procedure:
A solution of 377 mg of methyl 5-(hydroxymethyl)-2-methylbenzoate and 0.8 mL (9.17 mmol) of oxalyl chloride in 20 mL of CH2Cl2 was cooled to −78° C. To this solution was added 1.1 mL (15.5 mmol) of DMSO dropwise, and after stirring for 10 min., 3.2 mL of Et3N was added and stirring was continued at −78° C. for 10 min. The dry ice-acetone bath was removed, and the mixture was allowed to warm to r.t. and after 2 h, 30 mL of sat. NH4Cl solution was added. The organic layer was washed with 25 mL of brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (10% EtOAc/hexanes) provided 268 mg of methyl 5-formyl-2-methylbenzoate as a red liquid in 71% yield with some impurity.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([NH:12][CH2:13][C:14]([F:17])([F:16])[F:15])[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].[CH2:18](I)[CH3:19].[H-].[Na+].O1CCCC1>CN(C)C=O>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([N:12]([CH2:18][CH3:19])[CH2:13][C:14]([F:16])([F:17])[F:15])[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CCI
Reactant: CC#CCOc1cc(NCC(F)(F)F)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC#CCOc1cc(N(CC)CC(F)(F)F)ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
In 2 ml of N,N-dimethylformamide were dissolved 40 mg of 4-(2-butynyloxy)-6-(2,2,2-trifluoroethylamino)pyrimidine and 31 mg of ethyl iodide, to which 8 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 1 hour. Then, 6 ml of tetrahydrofuran was added, and the mixture was further stirred at room temperature for 4.5 hours. Then, ice water was added to the reaction mixture, from which the tetrahydrofuran was distilled out under reduced pressure. The residue was extracted with tert-butyl methyl ether. The organic layer was washed twice with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel thin layer chromatography to give 37 mg of 4-(2-butynyloxy)-6-(N-ethyl-N-2,2,2-trifluoroethylamino)pyrimidine (the present compound (115)).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].CCN(CC)CC>COC(O)C>[ClH:1].[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH:20][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Clc1ncnc2cc3ccccc3cc12
Reactant: Nc1cccc(Br)c1
Agent: COC(C)O
Solvent: CCN(CC)CC
Product: Brc1cccc(Nc2ncnc3cc4ccccc4cc23)c1
Product: Cl
Yield: 18.4 %

Procedure:
4-Chlorobenzo[g]quinazoline (214 mg, 1.0 mmol), 3-bromoaniline (213 mg, 1.25 mmol) and NEt3 (202 mg, 2.0 mmol) in stirred methoxyethanol (5 mL) were heated under N2 at 95° C. for 6 h. The volatiles were removed under reduced pressure and the residual solid was triturated with MeOH. The solid was recrystallized at 0° C. from an EtOH/dilute hydrochloric acid mixture (1:4, 0.05M acid, 50 mL) after celite filtration to give 4-(3-bromoanilino)-benzo[g]quinazoline hydrochloride (71 mg, 18%) as a yellow-green solid. 1H NMR (DMSO) δ14.0 (1H brs), 9.65 (1H, s), 9.01 (1H, s), 8.47 (1H, s), 8.29 (1H, d, J=8.4 Hz), 8.24 (1H, d, J=8.4 Hz), 8.18 (1H, slbrs), 7.9-7.82 (2H, m), 7.78 (1H, t, J=7.5 Hz), 7.58 (1H, d, J=8 Hz), 7.51 (1H, t, J=8 Hz). ##STR21##
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]3=[N:17][C:18]([CH3:22])=[CH:19][C:20]([CH3:21])=[C:15]3[N:14]=[C:13]2[CH2:23][CH3:24])=[CH:8][C:7]=1[Cl:25])=[N+]=[N-].[NH4+].[Cl-]>C(O)C.O.[Fe]>[Cl:25][C:7]1[CH:8]=[C:9]([N:12]2[C:16]3=[N:17][C:18]([CH3:22])=[CH:19][C:20]([CH3:21])=[C:15]3[N:14]=[C:13]2[CH2:23][CH3:24])[CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][NH2:1]
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCN=[N+]=[N-])c(Cl)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCN)c(Cl)c1
Reaction time: 1 h
Yield: 98.8 %

Procedure:
To a solution of methyl 3-[4-(2-azidoethyl)-3-chlorophenyl-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (step 10, 430 mg, 1.2 mmol) in ethanol/water (4/1) were added Fe (335 mg, 6.0 mmol) and NH4Cl (409 mg, 7.8 mmol). The mixture was stirred for 1 h under reflux temperature. The solvent was removed and the residue was diluted with CH2Cl2. The mixture was washed with brine, dried (MgSO4) and concentrated to give 390 mg of title compound as orange oil.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25](SC)=[CH:24][C:23]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[C:22]([I:33])[CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:34]1C=C(Cl)C=C(C(OO)=O)C=1.C([O-])(O)=O.[Na+].[O-][S:51]([O-:54])(=S)=[O:52].[Na+].[Na+]>C(Cl)Cl>[Si:1]([O:18][CH2:19][C:20]1[C:25]([S:51]([CH3:34])(=[O:54])=[O:52])=[CH:24][C:23]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[C:22]([I:33])[CH:21]=1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CSc1cc(NS(C)(=O)=O)c(I)cc1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)[Si](OCc1cc(I)c(NS(C)(=O)=O)cc1S(C)(=O)=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A suspension of crude N-(4-(((tert-butyldiphenylsilyl)oxy)methyl)-2-iodo-5-(methylthio)phenyl)methanesulfonamide, mCPBA (8.9 g, 51.6 mmol) in CH2Cl2 (100 mL) was stirred for 2 h at rt. Sat. aq. NaHCO3 (50 mL) and Na2S2O3 (50 mL) were added and the layers separated. The aqueous layer was extracted with CH2Cl2 (2×100 mL). Combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography over silica gel eluting with EtOAc/hexanes (3/7) to provide N-(4-(((tert-butyldiphenylsilyl)oxy)methyl)-2-iodo-5-(methylsulfonyl)phenyl)methanesulfonamide (8.8 g, 80% yield for two steps). For N-(4-(((tert-butyldiphenylsilyl)oxy)methyl)-2-iodo-5-(methylthio)phenyl)methanesulfonamide: LC-MS m/z 612 [M+H]+. For N-(4-(((tert-butyldiphenylsilyl)oxy)methyl)-2-iodo-5-(methylsulfonyl)phenyl)methanesulfonamide: LC-MS m/z 644 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 8.25 (s, 1H), 8.08 (s, 1H), 7.67-7.65 (m, 4H), 7.46-7.37 (m, 6H), 6.77 (s, 1H), 5.05 (s, 2H), 3.11 (s, 3H), 2.83 (s, 3H), 1.12 (s, 9H).
Reaction SMILES: [C:1]([NH2:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH-].[Na+].Cl[C:10]([O:12][CH2:13][CH3:14])=[O:11].Cl>O1CCOCC1.O>[C:1]([NH:6][C:10](=[O:11])[O:12][CH2:13][CH3:14])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(N)=O
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C=C(C)C(=O)NC(=O)OCC
Reaction time: 1 h
Yield: 18.2 %

Procedure:
In 41 g of dioxane, 2.5 g of methacrylamide and 1.18 g of NaOH were dissolved and the solution was stirred for 1.0 hour at the temperature of 25° to 27° C. Then, 4.0 g of ethyl chloroformate was dissolved in 10 g of dioxane and the solution was added to the reaction mixture at once. After stirring the solution for 15 minutes, water was added thereto and the solution was neutralized by adding conc. hydrochloric acid and filtered. The filtrate was extracted with chloroform and the extract was evaporated in vacuo. The crude product was subjected to column chromatography for purification, thereby obtaining 0.841 g of ethyl N-methacryloylcarbamate. Melting point (mp.) of the compound was 73°-74° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@H:9]1[C:16](=[O:17])[N:15]2[C@@H:11]([S:12][CH2:13][C@H:14]2[C:18]#[N:19])[CH2:10]1.C(O)(=O)C.[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:24]([NH:8][C@H:9]1[C:16](=[O:17])[N:15]2[C@@H:11]([S:12][CH2:13][C@H:14]2[C:18]#[N:19])[CH2:10]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=Cc1ccccc1
Reactant: N#C[C@@H]1CS[C@H]2C[C@@H](N)C(=O)N12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: ClCCCl
Product: N#C[C@@H]1CS[C@H]2C[C@@H](NCc3ccccc3)C(=O)N12
Temperature: 45 °C

Procedure:
20 mg of (3R,6R,7aS)-6-amino-5-oxohexahydropyrrolo[2,1-b]thiazole-3-carbonitrile trifluoroacetate were dissolved in 1 ml of 1,2-dichloroethane. 2 μl of acetic acid, 7 μl of benzaldehyde and 29 mg of sodium triacetoxyborohydride were successively added. The mixture was heated at 45° C. for 2 h. The solvent was then removed in vacuo. The residue was purified by preparative HPLC (Merck RP18, acetonitrile/water (0.5% trifluoroacetic acid), linear gradient (0–>80% acetonitrile)).
Reaction SMILES: CCN(C1C=C[C:9]2[CH:12]=[C:13](/[CH:17]=[N:18]\[NH:19][C:20]3[N:25]=CC=CC=3)C([O:16][C:8]=2C=1)=O)CC.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[O:38][C:37]([C:39]([OH:41])=O)=[CH:36][CH:35]=2)=[CH:30][CH:29]=1.FC1C=CC=CC=1C1[O:53]C(C(Cl)=O)=CC=1>>[O:16]1[CH:8]=[CH:9][CH:12]=[C:13]1[C:17]1[O:53][C:20]([NH:25][C:39]([C:37]2[O:38][C:34]([C:31]3[CH:30]=[CH:29][C:28]([O:27][CH3:26])=[CH:33][CH:32]=3)=[CH:35][CH:36]=2)=[O:41])=[N:19][N:18]=1
Reactant: CCN(CC)c1ccc2cc(/C=N\Nc3ccccn3)c(=O)oc2c1
Reactant: O=C(Cl)c1ccc(-c2ccccc2F)o1
Reactant: COc1ccc(-c2ccc(C(=O)O)o2)cc1
Product: COc1ccc(-c2ccc(C(=O)Nc3nnc(-c4ccco4)o3)o2)cc1

Procedure:
The title compound was synthesized in accordance with the synthesis method of compound Ic-2 described below, using an acid chloride prepared from commercially available 5-(4-methoxyphenyl)-2-furancarboxylic acid by a routine method instead of 5-(2-fluorophenyl)-2-furancarbonyl chloride.
Reaction SMILES: [H-].[Na+].CS(C)=O.[Cl-].[C:8]([CH2:11][CH2:12][CH2:13][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:10])=[O:9].[F:33][C:34]1[CH:48]=[CH:47][C:37]([C:38]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)=O)=[CH:36][CH:35]=1>O1CCCC1>[F:33][C:34]1[CH:48]=[CH:47][C:37]([C:38]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)=[CH:13][CH2:12][CH2:11][C:8]([OH:10])=[O:9])=[CH:36][CH:35]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: O=C(O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: O=C(O)CCC=C(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 69.4 %

Procedure:
The reaction was performed as in Example 87 using sodium hydride (56% dispersion in oil; 9.5 g) dimethylsulfoxide (100 mL), (3-carboxypropyl)triphenylphosphonium chloride (35 g), 4,4'-difluorobenzophenone (23.8 g) and tetrahydrofuran (100 mL). After the usual work up, the crude product was crystallized from ether-hexane to furnish 18.2 g of 5,5-bis(4-fluorophenyl)-4-pentenoic acid, mp 100°-100° C. Anal. Calculated for C17H14F2O2 : C, 70.82; H, 4.89. Found: C, 70.77; H, 5.00.
Reaction SMILES: [CH2:1]([C:3]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[OH:21])=[CH:11][CH:10]=2)[C:7](=[O:22])[C:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:40][C:39](=[O:41])[O:38][N:37]=3)=[CH:26][CH:25]=2)=[C:5]([CH2:42][CH2:43][CH3:44])[N:4]=1)[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.O>[CH2:1]([C:3]1[N:8]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])=[CH:13][CH:14]=2)[C:7](=[O:22])[C:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:40][C:39](=[O:41])[O:38][N:37]=3)=[CH:26][CH:25]=2)=[C:5]([CH2:42][CH2:43][CH3:44])[N:4]=1)[CH3:2]
Reactant: CCCc1nc(CC)n(-c2ccc(OC3CCC[C@H]3O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CCCc1nc(CC)n(-c2ccc(OC3CCCC3=O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 2 h
Yield: 65.2 %

Procedure:
To a solution of 2-ethyl-3-(4-{[(2R)-2-hydroxycyclopentyl]oxy}phenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one (0.2 g) in dichloromethane (4 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.22 g), and the mixture was stirred for 2 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred for 30 min and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.13 g, 65%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[O:8])=[CH:5][C:4]=1[CH3:22].[Br:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30]Br)[CH:25]=1>>[Br:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=1)[CH2:30][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][N:13]=2)[C:18](=[O:19])[C:9]([C:7](=[O:8])[C:6]2[CH:20]=[CH:21][C:3]([O:2][CH3:1])=[C:4]([CH3:22])[CH:5]=2)=[CH:10]1
Reactant: COc1ccc(C(=O)c2c[nH]c3ncccc3c2=O)cc1C
Reactant: BrCc1cccc(Br)c1
Product: COc1ccc(C(=O)c2cn(Cc3cccc(Br)c3)c3ncccc3c2=O)cc1C
Yield: 21.6 %

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 50 mg (0.17 mmol) of 3-(4-Methoxy-3-methyl-benzoyl)-1H-[1,8]naphthyridin-4-one, and 1-Bromo-3-bromomethyl-benzene 55 mg (0.22 mmol), to give 17 mg of desired compound. LCMS (M+H)+: 463.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[S:10](=[C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH2:14]1)(=[O:12])=[O:11].[CH2:22](OCC)C>>[CH3:9][C:4]1[CH:5]=[C:6]([C:16]2[CH:17]=[CH:18][C:13]([S:10]([CH3:22])(=[O:12])=[O:11])=[CH:14][CH:15]=2)[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: CCOCC
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: O=S(=O)=C1C=CC(B(O)O)=CC1
Product: Cc1cc(-c2ccc(S(C)(=O)=O)cc2)nc(N)n1

Procedure:
The title compound is synthesized according to general procedure GP4 (A) starting from 1.5 g (10 mmol) 2-amino-4-chloro-6-methylpyrimidine and 2.7 g (14 mmol) 4-sulfonyl-phenyl boronic acid. After treatment of the precipitated product with diethyl ether 2.3 g (75%) of the desired product are obtained.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)(C)(C)C.Br[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1>>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][CH:16]=[C:15]2[N:10]1[CH2:11][CH2:12][C@H:8]([NH2:7])[CH2:9]1
Reactant: COc1ccc2nccc(Br)c2c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Product: COc1ccc2nccc(N3CC[C@H](N)C3)c2c1

Procedure:
Starting from (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (commercial) and 4-bromo-6-methoxy-quinoline (commercial) the title compound was prepared according to procedure F followed by procedure E and was isolated as a brown oil (801 mg, 78% over two steps).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[CH2:10][N:11]1[C:19]2[CH2:18][CH2:17][NH:16][CH2:15][C:14]=2[N:13]=[CH:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[BH3-][C:24]#N.[Na+].CC(O)=O>CO.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:20])[CH2:10][N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH3:24])[CH2:15][C:14]=2[N:13]=[CH:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cn1cnc2c1CCNC2)OCc1ccccc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: CN1CCc2c(ncn2CC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.6 %

Procedure:
To a solution of (4,5,6,7-tetrahydro-imidazo[4,5-c]pyridin-1-yl)-acetic acid benzyl ester (176 mg) in MeOH was added formaldehyde (36.5% in water, 0.052 mL) followed by NaBH3CN (29 mg) and AcOH (0.5 mL). The reaction mixture was stirred at RT overnight. DCM was added and the mixture was washed with sat. NaHCO3. The aq. layer was extracted with DCM, the combined org. layers were dried (MgSO4), filtered off and evaporated to dryness. The residue was purified by CC (Biotage, SNAP 10 g cartridge, solvent A: DCM; solvent B: DCM/MeOH 8/2; gradient in % B: 25 for 3CV, 25 to 50 over 2CV, 50 for 5CV, 50 to 100 over 3CV, 100 for 2CV) to afford (5-methyl-4,5,6,7-tetrahydro-imidazo[4,5-c]pyridin-1-yl)-acetic acid benzyl ester (39 mg, yellow oil). LC-MS (B): tR=0.46 min; [M+H]+: 286.16.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[C:29](Cl)[CH:28]=[CH:27][C:26]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:38]([O:55][CH2:56][CH2:57][N:58]([CH2:88][CH3:89])[CH2:59][CH2:60][C@@H:61]([NH:70][C:71]1[CH:76]=[CH:75][C:74]([S:77]([NH2:80])(=[O:79])=[O:78])=[CH:73][C:72]=1[S:81]([C:84]([F:87])([F:86])[F:85])(=[O:83])=[O:82])[CH2:62][S:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)([C:51]([CH3:54])([CH3:53])[CH3:52])([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(Cl)C[Cl:92]>CN(C1C=CN=CC=1)C>[Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:92])=[CH:34][CH:33]=1)[CH:10]1[CH2:11][CH2:12][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:80][S:77]([C:74]3[CH:75]=[CH:76][C:71]([NH:70][C@H:61]([CH2:60][CH2:59][N:58]([CH2:57][CH2:56][O:55][Si:38]([C:51]([CH3:52])([CH3:54])[CH3:53])([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH2:88][CH3:89])[CH2:62][S:63][C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=4)=[C:72]([S:81]([C:84]([F:86])([F:87])[F:85])(=[O:82])=[O:83])[CH:73]=3)(=[O:78])=[O:79])=[O:22])=[CH:18][CH:17]=2)[CH2:14][CH2:15]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: ClCCCl
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](c1cc(Cl)ccc1-c1ccccc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: CCN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Agent: CN(C)c1ccncc1
Product: CCN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](O[Si](C)(C)C(C)(C)C)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.5 %

Procedure:
(R)-4-(4-((tert-butyldimethylsilyloxy)(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 13, 160 mg, 0.3 mmol), (R)-4-(4-((2-(tert-butyldiphenylsilyloxy)ethyl)(ethyl)amino)-1-(phenylthio)butan-2-yl amino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 25, 216 mg, 0.27 mmol), DMAP (100 mg, 0.82 mmol), and EDC (104 mg, 0.54 mmol) were placed in a 50 ml flask and flushed with nitrogen. DCM (3 ml) was added, and the solution was stirred at room temperature overnight. The reaction mixture was diluted with DCM (40 ml) and washed with 1N aq. sodium bisulfate (35 ml) followed by a saturated aq. sodium bicarbonate (40 ml). The organic layer was dried (Na2SO4), filtered, and evaporated under reduced pressure to give a residue, which was purified by column chromatography (ISCO, 40 g silica gel column, eluting with 0→25% EtOAc/hexanes) to give 4-(4-((R)-(tert-butyldimethylsilyloxy)(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)-N-(4-((R)-4-((2-(tert-butyldiphenylsilyloxy)ethyl)(ethyl)amino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonyl)benzamide (EXAMPLE 4A, STEP 1, 140 mg), that was used in the preparation of EXAMPLE 4A, STEP 2, without further purification.