Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][O:8][N:9]=[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([BH3-])#N.[Na+].B(F)(F)F.CCOCC>CO>[C:1]1([CH2:7][O:8][NH:9][CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccccc2)c2ccccc2N1
Agent: FB(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC(NOCc2ccccc2)c2ccccc2N1
Yield: 88.7 %

Procedure:
4.27 g of the compound obtained in stage A are dissolved in 450 ml of methanol. 12.14 g of sodium cyanoborohydride are subsequently added, followed, dropwise at 0° C., by 20.57 g (18.36 ml) of boron trifluoride etherate. After evaporating the methanol, the residue is treated with NaH2PO4 (1M aqueous solution) and then extraction is carried out with a heptane/AcOEt 1:2 mixture. Washing is subsequently carried out with an acidic aqueous solution and then the organic phase is dried with MgSO4 and the solvent is evaporated. The compound is taken up in an ether/pentane mixture at 0° C. The compound crystallizes. 3.81 g of the expected compound (89%) are isolated.
Reaction SMILES: [H-].[Na+].P(=O)([O-])O[C:5](CC)(CC)[C:6]#[N:7].[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O>CN(C)C=O>[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[CH:5][C:6]#[N:7]
Reactant: CCC(C#N)(CC)O[PH](=O)[O-]
Reactant: O=Cc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC=Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
A stirred solution of sodium hydride (1.8 g, 75 mmol) in dimethylformamide (150 ml) was treated with a solution of diethylcyanomethyl phosphonate (13.3 g, 75 mmol) in dimethylformamide (50 ml). The reaction was stirred 30 min at rt. After this time the reaction was treated with 3-chlorobenzaldehyde (10.54 g, 75 mmol) and stirred 1 hr at rt and 30 min at 60° C. The reaction was then quenched by the addition of water (200 ml). The reaction mixture was transferred to a separatory funnel using diethyl ether (300 ml) and the resulting organic phase washed with water (5×300 ml) and brine. The organic layer was dried over anhydrous potassium carbonate and concentrated to yield 3-chlorocinnamonitrile (11.06 g) as a solid. The solid was dissolved in tetrahydrofuran (50 ml) and treated with excess diborane and stirred 30 min at rt. The reaction was poured over ice/10% HCl. The acidic aqueous phase was washed with diethyl ether (2×200 ml). The aqueous phase was made basic by the addition of 10 N NaOH and extracted with diethyl ether (200 ml). The ether extract was dried over anhydrous potassium carbonate and concentrated to afford 3-(3-chlorophenyl)propylamine as an oil (0.6 g, 3.54 mmol). The 3-(3-chlorophenyl)propylamine (0.60 g, 3.54 mmol), 3′-methoxyacetophenone (0.53 g, 3.54 mmol) and 1.25 molar equivalents titanium(IV) isopropoxide (1.26 g, 4.43 mmol) were mixed 4 hr at rt and the intermediate imine treated with an ethanolic sodium cyanoborohydride (5 ml of 1 M, 5 mmol). The reaction was stirred 16 hr at rt, diluted with diethyl ether (50 ml) and treated with water (0.32 ml, 17.7 mmol). After mixing thoroughly the solution was centrifuged and the ether layer concentrated to a milky solid. This material was suspended in diethyl ether and filtered through a 0.45 μM CR PTFE Acrodisc. The ether wash was concentrated to an oil. Chromatography of this material (silica, preparative thin-layer chromatography) using 3% methanol-dichloromethane (containing 0.1% isopropylamine) afforded N-[3-(3-dichlorophenyl)propyl]-1-(3-methoxyphenyl)ethylamine, 6X; m/z (rel. int.) 303 (M+, 3), 288 (40), 196 (3), 164 (8), 135 (100), 125 (46), 103 (26), 91 (29), 77 (29).
Reaction SMILES: [OH:1][CH:2]1[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][N:9]=2)[C:4](=[O:15])[C:3]1([CH3:17])[CH3:16].N1C=CN=C1.[C:23]([Si:27]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)Cl)([CH3:26])([CH3:25])[CH3:24].C([O-])(O)=O.[Na+]>ClCCl>[C:23]([Si:27]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[O:1][CH:2]1[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][N:9]=2)[C:4](=[O:15])[C:3]1([CH3:17])[CH3:16])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC1(C)C(=O)N(c2ccc(I)cn2)C(=O)C1O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC1(C)C(=O)N(c2ccc(I)cn2)C(=O)C1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(2.4 g, 3.47 mmol, 50%) (4RS)-4-Hydroxy-1-(5-iodo-pyridin-2-yl)-3,3-dimethyl-pyrrolidine-2,5-dione (Example 14, step 2) was dissolved in dichloromethane (20 ml). Imidazole (520 mg, 7.63 mmol) and tert-butyldiphenylchlorosilane (1.0 g, 3.64 mmol) were added at room temperature and the mixture was stirred for 3 hours at room temperature. Sat. NaHCO3 solution was added and the mixture was extracted with dichloromethane. The organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (ethyl acetate/heptane gradient 0:100 to 30:70). The desired compound was obtained as a white solid (1.5 g, 74% yield), MS: m/e=585.1 (M+H+).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:7]1)[CH3:2].C[O:22][C:23](=[O:39])[C:24]([C:27]1[CH:32]=[CH:31][C:30]([C:33](=[O:38])[CH2:34][CH2:35][CH2:36]Cl)=[CH:29][CH:28]=1)([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH:15]2[CH2:16][CH2:17][N:18]([CH2:36][CH2:35][CH2:34][C:33]([C:30]3[CH:31]=[CH:32][C:27]([C:24]([CH3:25])([CH3:26])[C:23]([OH:39])=[O:22])=[CH:28][CH:29]=3)=[O:38])[CH2:19][CH2:20]2)=[CH:7]1)[CH3:2]
Reactant: CCOCCn1cc(C2CCNCC2)c2ccccc21
Reactant: COC(=O)C(C)(C)c1ccc(C(=O)CCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOCCn1cc(C2CCN(CCCC(=O)c3ccc(C(C)(C)C(=O)O)cc3)CC2)c2ccccc21

Procedure:
This compound was prepared following the procedure described in Example 152 (parts D and E) starting with 0.1 g (0.37 mmol) of 1-(2-ethoxyethyl)-3-piperidin-4-yl-1H-indole, 0.142 g (0.48 mmol) of 2-[4-(4-chlorobutyryl)-phenyl]-2-methyl-propionic acid methyl ester, 0.07 g (0.48 mmol) of potassium carbonate and 0.04 g (0.24 mmol) of potassium iodide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][C:5]([CH3:9])([CH3:8])[CH:6]=[CH2:7].[CH3:11][C:12]1[CH:21]=[C:20]([CH2:22][O:23][C:24]2[CH:32]=[CH:31][C:27]([CH:28]=[N:29][OH:30])=[CH:26][CH:25]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1>>[CH3:1][O:2][C:3](=[O:10])[CH2:4][C:5]([CH3:9])([CH:6]1[O:30][N:29]=[C:28]([C:27]2[CH:26]=[CH:25][C:24]([O:23][CH2:22][C:20]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=[C:12]([CH3:11])[CH:21]=3)=[CH:32][CH:31]=2)[CH2:7]1)[CH3:8]
Reactant: C=CC(C)(C)CC(=O)OC
Reactant: Cc1cc(COc2ccc(C=NO)cc2)c2ccccc2n1
Product: COC(=O)CC(C)(C)C1CC(c2ccc(OCc3cc(C)nc4ccccc34)cc2)=NO1
Yield: 100 %

Procedure:
Following a procedure analogous to that used in Example step 1c, but using 3,3-dimethyl-pent-4-enoic acid methyl ester and 4-(2-methyl-quinolin-4-ylmethoxy)-benzaldehyde oxime from step 1b, the crude reaction was partitioned between ethyl acetate and water and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give 3-methyl-3-{3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-butyric acid methyl ester (0.14 g, 100%) as a crude oil. MS found: (M+H)+=433.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40][CH:41]([C:45](O)=[O:46])[C:42](O)=[O:43])([CH3:33])[CH3:32]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:11][C:42](=[O:43])[C:41]([S:40][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[CH:31]([CH3:32])[CH3:33])=[C:45]([OH:46])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccccc1Sc1c(O)cc(-c2ccc(Cl)c(Cl)c2)oc1=O

Procedure:
The title compound was prepared by Method A using 3',4'-dichloroacetophenone (2.46 g, 12.8 mmol), trimethylsilyl triflate (3.0 mL, 15.4 mmol), triethylamine (3.6 mL, 26.0 mmol), methylene chloride (30 mL), and diethyl ester of [(2-isopropylphenyl)thio] propanedioic acid (4.0 g, 12.8 mmol) m.p. 204°-207° C.; 1H NMR (400 MHz, CDCl3) δ 1.33 (d, 6H), 3.55 (m, 1H), 6.71 (s, 1H), 7.00 (m, 1H), 7.08 (m, 1H), 7.20 (m, 1H), 7.30 (m, 1H), 7.56 (d, 1H), 7.69 (m, 1H), 7.74 (br, 1H), 7.98 (s, 1H).
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2/[C:5]/1=[CH:14]\[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:3])[CH3:2]>O1CCCC1.CC#N.CC#N.Cl[Pd]Cl>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2/[C:5]/1=[CH:14]/[C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(/C=C2\C3=C(CCCC3)CCN2C(C)=O)cc1
Agent: Cl[Pd]Cl
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ccc(/C=C2/C3=C(CCCC3)CCN2C(C)=O)cc1
Yield: 95 %

Procedure:
A solution of 0.2 g of (E)-2-acetyl-1,2,3,4,5,6,7,8-octahydro-1-(p-methoxybenzylidene)isoquinoline and 8.7 mg of dichlorobis(acetonitrile)palladium(II) in 10 ml of dry tetrahydrofuran was heated at reflux for 7 hours under argon. The yellow solution was evaporated at 15 mbar and the residue was dissolved in diethyl ether. In order to separate the catalyst, the ether solution was filtered through a thin layer of silica gel. After evaporation of the filtrate there was obtained 0.19 g of (Z)-2-acetyl-1,2,3,4,5,6,7,8-octahydro-1-(p-methoxybenzylidene)-isoquinoline with a m.p. of 101-102° C.; content according to GC 96%:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[CH3:22][C:23]1[N:24]=[CH:25][NH:26][C:27]=1[CH3:28]>>[CH3:22][C:23]1[N:24]=[CH:25][N:26]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])[C:27]=1[CH3:28]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: Cc1nc[nH]c1C
Product: Cc1ncn(-c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2[N+](=O)[O-])c1C
Yield: 48 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with 4,5-dimethyl-1H-imidazole according to the GPB affording 18 mg (48%) of a white powder. Rt=2.43 min.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[CH:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CC(C)=O>[O:13]([CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)C(Cl)C(=O)OCC
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(Oc1ccccc1)C(=O)OCC
Yield: 76.8 %

Procedure:
22.1 g (160 mmol) of potassium carbonate were suspended in 30 ml of acetone, 7.5 g (80 mmol) of phenol in 100 ml of acetone were added, and the mixture was refluxed for 1 hour. 15.5 g (80 mmol) of diethyl 2-chloromalonate in 100 ml of acetone were subsequently added dropwise, the mixture was refluxed for 10 hours and evaporated in vacuo, and the residue was taken up in methylene chloride. The organic phase was washed with saturated NaHCO3 solution and saturated NaCl solution, dried over magnesium sulfate and evaporated. Column chromatography (silica gel, heptane/diethyl ether 2:1) of the residue gave 15.5 g (77% of theory) diethyl 2-phenoxymalonate as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:9][O:8][C:7]2[CH:10]=[CH:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:6]=2[O:5]1.[N+:17]([O-])([OH:19])=[O:18].S(=O)(=O)(O)O.O>C(O)(=O)C>[CH3:1][O:2][CH2:3][CH:4]1[CH2:9][O:8][C:7]2[CH:10]=[C:11]([N+:17]([O-:19])=[O:18])[C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:6]=2[O:5]1
Reactant: O=[N+]([O-])O
Reactant: COCC1COc2ccc(C(=O)O)cc2O1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: COCC1COc2cc([N+](=O)[O-])c(C(=O)O)cc2O1
Reaction time: 0.5 h

Procedure:
The titled compound of Example 3 (0.788 g, 3.51 mmol) was dissolved in 2 ml of acetic acid, and added a mixture of nitric acid (3 ml) and sulfuric acid (3 ml), followed by stirring for 30 min. Then, to the reaction mixture was added 10 ml of water to give a solid, which was then fitered and washed with acetic acid and ether in a sequential order to prepare the titled compound (0.510 g, 54%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[OH-].[K+].[CH3:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Cl.O>CC(N(C)C)=O>[CH3:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:20][C:21]3[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=3[CH3:23])=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1
Reactant: Cc1ccccc1CCl
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccccc1COc1ccc(C(C)(C)c2ccc(OCc3ccccc3C)cc2)cc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
Under an inert atmosphere, 5.23 g Bisphenol A (BPA) (22.9 mmol) and 2.83 g potassium hydroxide (50.4 mmol) were dissolved in 50 mL dimethylacetamide. Stirring was started at 500 rpm and the contents were warmed to 70° C. After 30 minutes, 7.09 g 2-methylbenzyl chloride (50.4 mmol) dissolved in 50 mL dimethylacetamide was added to the reaction mixture. The mixture was then heated at 100° C. for 4 h until no 2-methylbenzyl chloride was noted in the GPC trace. During the course of the reaction, a white precipitate had formed. The reaction mixture was cooled to room temperature and then poured into a 1 L separatory funnel containing 200 mL deionized water. The aqueous layer immediately became opaque. The reaction flask was washed with 50 mL deionized water and this wash was added along with 150 mL toluene to the separatory funnel. The separatory funnel was shaken and the bilayer allowed to settle. The lower, aqueous layer appeared opaque while the upper, organic layer was clear and colorless. The organic layer was separated and the aqueous layer was washed 3 additional times with 100 mL toluene. The combined organic fractions were dried over 20 g magnesium sulfate and filtered into a 1 L round bottom flask. The solvent was removed from the filtered toluene solution on a rotary evaporator initially at room temperature then at 70° C. Following solvent removal, a viscous oil remained in the round bottom flask. This crude product was recrystallized at 0° C. from an acetone solution. The crystalline white solid that had formed was filtered on a 7.0 cm Buchner funnel using Whatman 540 filter paper. The crystals were pulverized into a powder and washed with cold acetone. The white powder was transferred to a 75° C. vacuum oven and dried for 24 h. For Bisphenol A bis(2-methylbenzyl) ether: 52% yield (5.2 g, 12 mmol); white powder; mp 117° C. 1H NMR (500.1 MHz, CD2Cl2, ppm, J=Hz): 7.40 (d, 7.2, 2H, Ph), 7.23 (m, 6H, Ph), 7.17 (m, 4H, Ph), 6.90 (m, 4H, Ph), 5.02 (s, 4H, -PhCH2O—), 2.37 (s, 6H, -PhCH3), 1.65 (s, 6H, —C(CH3)2).
Reaction SMILES: [F:1][C:2]([F:16])([CH3:15])[CH2:3][O:4][C:5]1[N:10]=[N:9][C:8]([C:11](=O)[CH3:12])=[CH:7][C:6]=1[CH3:14].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[F:1][C:2]([F:16])([CH3:15])[CH2:3][O:4][C:5]1[N:10]=[N:9][C:8]([CH:11]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:12])=[CH:7][C:6]=1[CH3:14]
Reactant: CC(=O)c1cc(C)c(OCC(C)(F)F)nn1
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)nnc1OCC(C)(F)F
Yield: 74 %

Procedure:
The title compound is prepared in 74% yield (928 mg, yellow solid) from 1-(6-(2,2-difluoropropoxy)-5-methylpyridazin-3-yl)ethanone (860 mg, 3.74 mmol, Step-5) and (R)-2-methylpropane-2-sulfinamide (679 mg, 5.60 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [OH:1][C@H:2]([C:10]1[CH:19]=[CH:18][C:13]2[C:14](=[O:17])[O:15][CH2:16][C:12]=2[C:11]=1[CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[O:21]1[CH2:23][CH:22]1[C:24]1[CH:32]=[CH:31][C:27]2=[N:28][O:29][N:30]=[C:26]2[CH:25]=1>>[N:28]1[O:29][N:30]=[C:26]2[CH:25]=[C:24]([C@@H:22]([OH:21])[CH2:23][N:7]3[CH2:8][CH2:9][N:4]([CH2:3][C@@H:2]([C:10]4[CH:19]=[CH:18][C:13]5[C:14](=[O:17])[O:15][CH2:16][C:12]=5[C:11]=4[CH3:20])[OH:1])[CH2:5][CH2:6]3)[CH:32]=[CH:31][C:27]=12
Reactant: Cc1c([C@@H](O)CN2CCNCC2)ccc2c1COC2=O
Reactant: c1cc2nonc2cc1C1CO1
Product: Cc1c([C@@H](O)CN2CCN(C[C@H](O)c3ccc4nonc4c3)CC2)ccc2c1COC2=O

Procedure:
The title compounds were prepared as described for the synthesis of EXAMPLES 57-58 starting from 5-[(1R)-1-hydroxy-2-(piperazin-1-yl)ethyl]-4-methyl-2-benzofuran-1(3H)-one and 5-(oxiran-2-yl)-2,1,3-benzoxadiazole. The resulting two diastereomers were resolved by prep SFC on Chiralcel OJ 30×200 mm column eluting with 70 mL/min of 30% methanol (0.2% DEA)/CO2 at 35° C. with pressure of 100 bar.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](C2N3C=CC(C(F)(F)F)=NC3=NC=2)=[CH:4][C:3]=1[C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][N:22]=1.Br[C:29]1[N:33]2[CH:34]=[CH:35][C:36]([C:38]([OH:41])([CH3:40])[CH3:39])=[N:37][C:32]2=[N:31][CH:30]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:29]2[N:33]3[CH:34]=[CH:35][C:36]([C:38]([OH:41])([CH3:40])[CH3:39])=[N:37][C:32]3=[N:31][CH:30]=2)=[CH:4][C:3]=1[C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Reactant: Fc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)cc1-c1ncccc1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ncccc4F)c3)cnc2n1

Procedure:
4-Fluoro-3-(3-fluoropyridin-2-yl)phenylboronic acid (prepared according to Example 80) was coupled with 2-(3-bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol by the method of Example 78. Purification by chromatography on silica gel, eluting with dichloromethane containing 3.5% methanol, gave 2-[3-(4-fluoro-3-(3-fluoropyridin-2-yl)phenyl)imidazo[1,2-α]pyrimidin-7-yl]propan-2-ol which was converted to its hydrochloride salt by treatment with methanolic hydrogen chloride, evaporation, and crystallisation of the residue from isopropanol/ethyl acetate: δH (400 MHz, DMSO) 1.56 (6H, s), 7.62-7.71 (1H, m), 7.70 (1H, dd, J 9 and 2), 7.87 (1H, d, J 7.4), 7.92-8.00 (3H, m), 8.54 (1H, s), 8.61 (1H, m), 9.25 (1H, d, J 7); m/z (ES+) 367 (MH+).
Reaction SMILES: O.[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7](=O)[C:6]2=[O:14].Cl.[C:16]1([NH:22][C:23](=[O:26])[NH:24][NH2:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7](=[N:25][NH:24][C:23]([NH:22][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:26])[C:6]2=[O:14]
Reactant: NNC(=O)Nc1ccccc1
Reactant: O=c1c(=O)c2ccc(O)cc2c1=O
Agent: Cl
Solvent: O
Product: O=C(NN=c1c(=O)c2ccc(O)cc2c1=O)Nc1ccccc1

Procedure:
5-hydroxyindan-1,2,3-trione, monohydrate, 4-phenyl semicarbazide hydrochloride; reflux for 4 hours
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][S:6]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Br:18])[CH:16]=2)[N:11]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:10]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])(=[O:8])=[O:7].[CH3:33][O:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1.C(N(CC)CC)C>ClCCl>[Br:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C:10]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:9]2[S:6]([NH:5][CH2:4][CH2:3][NH:2][C:39](=[O:40])[C:38]1[CH:42]=[CH:43][C:35]([O:34][CH3:33])=[CH:36][CH:37]=1)(=[O:8])=[O:7]
Reactant: CCOC(=O)c1c(S(=O)(=O)NCCN)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1c(S(=O)(=O)NCCNC(=O)c2ccc(OC)cc2)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The product from Example 89, Step A was combined with 1.1 equivalents of 4-methoxybenzoyl chloride and 3.0 equivalents of triethylamine in dichloromethane. The reaction was stirred for 1.5 hours at room temperature and the solvent was removed under a stream of nitrogen to give the titled compound. ESI+ MS: 664 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]([S:8][C:9](=O)[CH3:10])([CH3:7])[CH3:6])[CH3:2].C[O-].[Na+].CS(OCC[C@H:23]1[CH2:27][CH2:26][O:25][CH2:24]1)(=O)=O>C(O)C>[CH3:6][C:5]([S:8][CH2:9][CH2:10][C@H:23]1[CH2:27][CH2:26][O:25][CH2:24]1)([CH3:7])[C:4]([O:3][CH2:1][CH3:2])=[O:12]
Reactant: CS(=O)(=O)OCC[C@H]1CCOC1
Reactant: CCOC(=O)C(C)(C)SC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)SCC[C@H]1CCOC1
Temperature: 80 °C
Yield: 29.4 %

Procedure:
To a solution of 1.13 g (5.94 mmol) of 2-acetylsulfanyl-2-methyl-propionic acid ethyl ester in ethanol (20 mL, degassed) are added 1.28 g (23.7 mmol) of sodium methoxide, followed by 1.13 g (5.94 mmol) of 2-[(3R)-oxolan-3-yl]ethyl methanesulfonate under nitrogen atmosphere. The reaction is heated to 80° C. for 16 h. The solvent is removed under reduced pressure. The residue is dissolved in ethyl acetate (50 mL) and washed with saturated aqueous NaHCO3 solution (2×15 mL) and 1M aqueous HCl solution (2×15 mL). The organic layer is dried over Na2SO4, filtered and the filtrate is concentrated under reduced pressure. The residue is purified twice by column chromatography (silica, eluent: heptanes, ethyl acetate) to afford 0.43 g of ethyl 2-methyl-2-({2-[(3R)-oxolan-3-yl]ethyl}sulfanyl)propanoate (UV purity: 70%). Yield: 21%, m/z 247 [M+H]; 1H NMR (250 MHz, CHLOROFORM-d) δ ppm 1.29 (3 H, t, J=7.08 Hz), 1.43-1.81 (9H, m), 1.95-2.16 (1H, m), 2.20-2.35 (1H, m), 2.53-2.67 (2 H, m), 3.34 (1H, dd, J=8.38, 7.16 Hz), 3.66-3.98 (3H, m), 4.17 (2H, q, J=7.06 Hz)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[C:12]2[NH2:20])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[Cl:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[Cl:37])[C:31](Cl)=[O:32].Cl>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[C:12]2[NH:20][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:36]([Cl:37])=[C:28]([Cl:27])[CH:29]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(CCCn2c(N)nc3ccccc32)CC1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CN1CCN(CCCn2c(NC(=O)c3ccc(Cl)c(Cl)c3)nc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mechanically stirred suspension of 1-[3-(4-methyl-1-piperazinyl)propyl]-2-aminobenzimidazole (123 g., 0.45 mole) and anhydrous potassium carbonate (182 g., 1.35 mole), in methylene chloride (110 ml.) under nitrogen at 0° C. (ice-salt bath), was added 3,4-dichlorobenzoylchloride (113 g., 0.54 mole) at a rate sufficient to maintain the reaction temperature at 0°-3° C. The total time required for the addition was 1 hour. After stirring for 5 hours at ambient temperature, the reaction mixture was cooled to 10° C. and adjusted to pH 2 by the addition of 1N HCl. The precipitated hydrochloride salt was collected by suction filtration and then partitioned between 10% aqueous NaOH (800 ml.) and chloroform (1000 ml.). The phases were separated and the basic aqueous layer was extracted with chloroform (500 ml.). The organic layers were combined, dried (MgSo4), and evaporated in vacuo giving 1-[3-(4-methyl-1 -piperazinyl)propyl]-2-(3,4-dichlorobenzamido)benzimidazole as a pale yellow solid, m.p. 170°-172° C. Treatment with 2 equivalents of methane sulfonic acid in chloroform (500 ml.), removal of solvent and recrystallization from 1-propanol gave 136 g., (47% yield) of 1-[3-(4-methyl-1-piperazinyl)propyl]-2-(3,4-dichlorobenzamido) benzimidazole dimesylate as a white crystalline solid, m.p. 170°-173° C.