Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:6]([CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([O:11][CH3:12])=[O:10])[CH:7]=1)=O.CO.[CH3:27][NH2:28].[BH4-].[Na+].[ClH:31].C(=O)([O-])O.[Na+]>CO>[ClH:31].[ClH:31].[CH3:12][O:11][C:9](=[O:10])[CH:8]([N:6]1[CH:7]=[C:3]([CH2:1][NH:28][CH3:27])[N:4]=[C:5]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)C(c1ccccc1)n1cc(C=O)nc1-c1ccccc1
Reactant: CN
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: CNCc1cn(C(C(=O)OC)c2ccccc2)c(-c2ccccc2)n1
Reaction time: 0.25 h
Yield: 40 %

Procedure:
To a solution of methyl (4-formyl-2-phenyl-1H-imidazol-1-yl)(phenyl)acetate (200 mg) in methanol (10 mL) was added 40% methylamine methanol solution (243 mg) and the mixture was stirred for 15 min. Sodium borohydride (24 mg) was added and the mixture was stirred for 30 min. 1 mol/L Hydrochloric acid was added to the reaction mixture and the mixture was stirred for 5 min. The mixture was neutralized with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate-tetrahydrofuran (1:1). The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent:ethyl acetate) and dissolved in methanol (5 mL). A 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added and the mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, and insoluble materials were collected by filtration to give the title compound as a colorless powder (yield 101 mg, yield 40%).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[C:11]([F:17])=[CH:10][C:9]=2[O:18][CH3:19])=[C:4]([CH2:20][N:21]2[C@@H:25]([CH3:26])[C@@H:24]([C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=3)[O:23][C:22]2=[O:41])[CH:3]=1.N(OC(C)(C)C)=O.C(Br)(Br)[Br:50]>>[F:39][C:37]([F:38])([F:40])[C:29]1[CH:28]=[C:27]([C@H:24]2[O:23][C:22](=[O:41])[N:21]([CH2:20][C:4]3[CH:3]=[C:2]([Br:50])[CH:7]=[CH:6][C:5]=3[C:8]3[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[C:11]([F:17])=[CH:10][C:9]=3[O:18][CH3:19])[C@H:25]2[CH3:26])[CH:32]=[C:31]([C:33]([F:35])([F:36])[F:34])[CH:30]=1
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(N)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: BrC(Br)Br
Agent: CC(C)(C)ON=O
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(Br)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
To a solution (4S,5R)-3-[(4-amino-4′-fluoro-5′-isopropyl-2′-methoxybiphenyl-2-yl)methyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (526 mg, 0.90 mmol) in bromoform (2.5 mL) was added tert-butyl nitrite (186 mg, 1.80 mmol). The resulting mixture was stirred at 80° C. for 20 min. An aliquot indicated completion of the reaction. The reaction crude was purified silica gel to afford the title compound as a yellow glass. LC-MS: 650.09 (M+1)+. 1H NMR (CDCl3, 500 MHz) a 1:1 mixture of rotamers δ 7.85 (s, 1H), 7.69 (s, 2H), 7.60 (s, 0.5H), 7.48-7.53 (m, 1.5H), 7.07-7.11 (m, 1H), 6.93-6.99 (m, 1H), 6.62-6.67 (m, 1H), 5.59 (d, J=8.0 Hz, 0.5H), 5.39 (d, J=7.0 Hz, 0.5H), 4.82 (d, J=6.5 Hz, 0.5H), 4.75 (d, J=6.5 Hz, 0.5H), 3.98 (d, J=16.0 Hz, 0.5H), 3.76-3.85 (m, 1.5H), 3.75 (s, 1.5H), 3.74 (s, 1.5H), 3.13-3.23 (m, 1H), 1.13-1.29 (m, 6H), 0.52 (d, J=6.5 Hz, 1.5H), 0.34 (d, J=7.0 Hz, 1.5H).
Reaction SMILES: [F:1][C:2]1[C:3](I)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:14][CH:15]=[CH:16][C:17]=1[O:18][CH3:19].F[C:22](F)(F)[C:23]([OH:25])=O.C(Cl)Cl>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.CN(C=O)C.CCN(CC)CC.C(Cl)Cl.O>[NH2:14][C@@H:13]([C@H:23]([OH:25])[CH3:22])[C@H:17]([OH:18])[C:16]#[C:15][C:3]1[C:2]([F:1])=[CH:10][CH:9]=[C:8]2[C:4]=1/[C:5](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][C:17]=1[O:18][CH3:19])/[C:6](=[O:11])[NH:7]2
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#C[C@@H](O)[C@@H](N)[C@@H](C)O)c21
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Using Method C above, 4R-(1R-Hydroxy-prop-2-ynyl)-2,2,5R-trimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.2 g, 0.65 mmol) (Example 105A above) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (0.1 g, 0.26 mmol) (Starting Material 6) using (Ph3P)4Pd (30 mg) and Cul (6 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85° C. for 18 h. To above compound in CH2Cl2 (10 mL) was added a 1:1 mixture of trifluoroacetic acid/CH2Cl2 (10 mL) and 5 drops of water at 0° C. and the mixture was stirred at 0° C. for 1.5 h. The mixture was then quenched with conc. NH4OH (10 mL) and diluted with EtOAc. The organic layer was washed with brine and dried with MgSO4. The product was purified via flash column chromatography (10% MeOH in CH2Cl2). (Yield 35 mg, 35%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH3:10])[N:3]=1.[K].[S:12]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=1)(=[O:15])(=[O:14])[NH2:13]>CN1CCCC1=O>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][CH3:10])[N:3]=[C:2]([NH:13][S:12]([C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:25])[CH3:24])=[CH:20][CH:21]=2)(=[O:14])=[O:15])[CH:7]=1
Reactant: CC(=O)Nc1ccc(S(N)(=O)=O)cc1
Reactant: CNc1nc(Cl)cc(Cl)n1
Agent: [K]
Solvent: CN1CCCC1=O
Product: CNc1nc(Cl)cc(NS(=O)(=O)c2ccc(NC(C)=O)cc2)n1
Yield: 69.5 %

Procedure:
2.0 g (0.011 mol) of (4,6-dichlorpyrimidin-2-yl)-methylamine and 5.67 g (0.022 mol) N-(4-sulfamoyl-phenyl)-acetamide potassium salt were stirred in 10 ml of 1-methyl-2-pyrrolidone at 140° C. for 8 hours. Then, the solvent was distilled off in a high vacuum, the residue was partitioned in ethyl acetate/water, the inorganic phase was saturated with sodium chloride and the residual ethyl acetate dissolved in the aqueous phase was distilled off on a rotary evaporator. The aqueous phase was made acid with 1N HCl, the crystals which separated were filtered off under suction and washed with water. After drying there were obtained 2.72 g (68%) of N-[4-(6-chloro-2-methylamino-pyrimidin-4-ylsulfamoyl)-phenyl]-acetamide as beige crystals. m.p.: >240° C. (dec.).
Reaction SMILES: Cl[SiH:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].[CH3:15][NH:16][CH3:17]>CCCCCC>[C:11]([N:3]1[CH:4]=[CH:5][N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[SiH:2]1[N:16]([CH3:17])[CH3:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Reactant: CNC
Solvent: CCCCCC
Product: CN(C)[SiH]1N(C(C)(C)C)C=CN1C(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 91 %

Procedure:
In an argon atmosphere, 3.98 g (17.1 mmol) of Si(tBuNCHCHNtBu)(H)Cl was dissolved in 20 mL of hexane. The resulting solution was deaerated by Freeze-Pump-Thaw cycling and after creating a dimethylamine atmosphere in the reaction vessel by connecting thereto a balloon having an internal volume of 5 L and being filled with dimethylamine, the solution was stirred at room temperature for 20 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 84° C./4.7×102 Pa) to obtain 1,3-di-tert-butyl-2-dimethylamino-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)NMe2) as a colorless liquid (yielded amount: 3.76 g, yield: 91%).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][N:13]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=4)[C:16]([CH3:25])=[CH:15][C:14]3=[O:26])[CH2:7][CH2:6]2)[O:4]CC1.FC(F)(F)C(O)=O>C(O)C>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17]([C:16]([CH3:25])=[CH:15][C:14](=[O:26])[N:13]2[CH2:12][CH2:11][CH:8]2[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]2)=[CH:18][CH:19]=1
Reactant: COc1ccc2c(C)cc(=O)n(CCC3CCC4(CC3)OCCO4)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: COc1ccc2c(C)cc(=O)n(CCC3CCC(=O)CC3)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 1.5 mL of an ethanol solution containing 65 mg of 1-(2-(1,4-dioxaspiro[4.5]decan-8-yl)ethyl)-7-methoxy-4-methylquinolin-2(1H)-one, 0.5 mL of an 80% aqueous trifluoroacetic acid solution was added under cooling with ice, and the mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, and water and ethyl acetate were added thereto. The reaction mixture was adjusted to pH 7.7 with an aqueous saturated sodium hydrogen carbonate solution. The organic layer was separated, washed with an aqueous saturated sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 48 mg of a colorless oily substance, 7-methoxy-4-methyl-1-(2-(4-oxocyclohexyl)ethyl)quinolin-2(1H)-one.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:29][CH3:30])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[F:36].N([O-])=O.[Na+].[BrH:41]>C(#N)C>[Br:41][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:29][CH3:30])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[F:36]
Reactant: Br
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)c(F)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(Br)c(F)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
A suspension of 6-(N-(4-amino-3-fluorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (200 mg, 0.39 mmol) in acetonitrile (5 mL) and aqueous hydrogen bromide solution (5 mL) was treated with an aqueous sodium nitrite (29.6 mg, 0.43 mmol) solution at 0° C. with stirring for 0.5 hours. Cuprous bromide (64.3 mg, 0.45 mmol) was then added to the solution in portions at 0° C., and heated to reflux for 2 hours. The solution was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was separated, dried over sodium sulfate, filtered, concentrated to dryness, and purified by column chromatography to afford 6-(N-(4-bromo-3-fluorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (140 mg, 0.24 mmol, 61% yield) as a white solid. LCMS (m/z, ES+)=575, 577 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:10][NH2:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.Cl>ClCCl.C(OCC)C.O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:10][NH:11][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cl)c1ccccc1
Reactant: NCC(c1ccc(Cl)c(Cl)c1)N1CCCC1
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(NCC(c1ccc(Cl)c(Cl)c1)N1CCCC1)c1ccccc1
Yield: 17.4 %

Procedure:
2-(3,4-Dichlorophenyl)-2-(pyrrolidin-1-yl)ethylamine (2.46 g), benzoyl chloride (1.34 g) and triethylamine (1.92 g) were stirred in dichloromethane (25 mL) at 23° C., for 48 hours. The reaction was poured into water, and the separated organic layer was dried, and evaporated to a brown oil (2.85 g). Chromatography, with chloroform (1200 mL) and then methanol:chloroform (5:95) as the eluent, gave an oil. Trituration of the oil with diethylether gave a white solid which was dissolved in dichloromethane and treated with hydrochloric acid (g)/diethylether. The solution was evaporated to give the title compound as a white glass (330 mg); mp 129° C. (after resolidifying); MS: m/z=636(M+1); NMR: 1.78 (m,4), 2.54 (m,4), 3.5 (m,2), 4 (m,1), 6.16 (broad s,1), 7.21 (m,1), 7.42 (m,5), 7.62 (m,2): Analysis Calculated: C, 55.22; H, 5.49; N, 6.78; Found: C, 55.21; H, 5.24; N, 6.59.
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH2:11][CH3:12])[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9])[CH2:2][CH3:3].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[C:35]([O:39][C:40]([N:42]([CH2:49][C:50]1[CH:58]=[CH:57][C:53]([C:54](O)=[O:55])=[CH:52][CH:51]=1)[CH2:43][C:44]1[NH:45][CH:46]=[CH:47][N:48]=1)=[O:41])([CH3:38])([CH3:37])[CH3:36]>CN(C=O)C.C(Cl)(Cl)Cl.C(N(CC)CC)C>[C:35]([O:39][C:40](=[O:41])[N:42]([CH2:49][C:50]1[CH:51]=[CH:52][C:53]([C:54](=[O:55])[NH:9][CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:10][CH2:11][CH3:12])=[CH:57][CH:58]=1)[CH2:43][C:44]1[NH:48][CH:47]=[CH:46][N:45]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C(=O)O)cc1)Cc1ncc[nH]1
Reactant: CCCN(CCC)CCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCN(CCC)CCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 29.4 %

Procedure:
The compound (203 mg) obtained in Example 1-2 was dissolved in DMF (5.0 ml) and chloroform (5.0 ml), and then added with triethylamine (0.374 ml), WSCI hydrochloride (382 mg), HOBt (200 mg), and the compound (463 mg) obtained in Example 6-1. The whole was stirred at room temperature for 23 hours. After completion of the reaction, the solvent was distilled off. Then, the resultant was added with chloroform and washed with water and a saturated saline solution, followed by drying with anhydrous sodium sulfate. The solvent was distilled off and the residue was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining the subject compound (168 mg) as colorless foam.
Reaction SMILES: C1(O[C:8](=[S:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[Cl:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:26]=[C:27]([Cl:29])[CH:28]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:33]2[CH2:32][CH2:31][N:30]([C:25]3[CH:24]=[C:23]([Cl:22])[CH:28]=[C:27]([Cl:29])[CH:26]=3)[CH2:35][CH2:34]2)=[S:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: Clc1cc(Cl)cc(N2CCNCC2)c1
Reactant: CCc1cc(NC(=S)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=S)N2CCN(c3cc(Cl)cc(Cl)c3)CC2)c(OC)nc1C
Yield: 84 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)thiocarbamate and 1-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [C:1]([O:7]CC)(=O)[CH2:2][C:3]([CH3:5])=O.Cl.[C:11]([NH2:14])(=[NH:13])[CH3:12].[O-]CC.[Na+].C(O)(=O)C>C(O)C>[CH3:12][CH:11]1[NH:14][C:1](=[O:7])[CH2:2][C:3]([CH3:5])=[N:13]1
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC1=NC(C)NC(=O)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.4 %

Procedure:
To a solution of ethyl acetoacetate (0.8 g, 6.14 mmol) in ethanol (8 mL) was added acetamidine hydrochloride (0.6 g, 6.3 mmol) and stirred at r.t. for 10 min. A solution of sodium ethoxide [prepared from sodium (0.28 g, 12.3 mmol) and ethanol (3 mL)] was added dropwise and the whole mixture refluxed for 6 h. The reaction mass was cooled, acidified with acetic acid and concentrated under reduced pressure to give a residue which was washed twice with ethyl acetate to afford 2,6-dimethyl-2,5-dihydro-3H-pyrimidin-4-one (460 mg, 60%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([N:12]1[C:17]3[N:18]=[C:19]([S:22][CH3:23])[N:20]=[CH:21][C:16]=3[CH:15]=[CH:14][C:13]1=[O:24])[CH2:9][CH2:8]2.ClC1C=CC=C(C(OO)=[O:33])C=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([N:12]1[C:17]3[N:18]=[C:19]([S:22]([CH3:23])=[O:33])[N:20]=[CH:21][C:16]=3[CH:15]=[CH:14][C:13]1=[O:24])[CH2:9][CH2:8]2
Reactant: COc1cccc2c1C(n1c(=O)ccc3cnc(SC)nc31)CC2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1cccc2c1C(n1c(=O)ccc3cnc(S(C)=O)nc31)CC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 112.3 %

Procedure:
To a solution of 8-(7-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (0.32 g, 0.94 mmol) in dichloromethane (3 mL) was added 3-chloroperbenzoic acid (70%, 0.18 g, 0.73 mmol) and the mixture was stirred at room temperature for 5 h. The reaction mixture was extracted with saturated sodium bicarbonate solution (2×1.5 mL), the organic layer was dried over sodium sulfate, then filtered and evaporated to give 8-(7-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one as a light brown oil (0.29 g, 0.82 mmol, 87%). ESMS m/z 356 (M+H)+.
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].N1C=CC=CC=1.Cl[C:19]([O:21][CH:22]([Cl:24])[CH3:23])=[O:20]>ClCCl>[C:19](=[O:20])([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[O:21][CH:22]([Cl:24])[CH3:23]
Reactant: CCCCCCCCCCO
Reactant: CC(Cl)OC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCOC(=O)OC(C)Cl
Reaction time: 8 h
Yield: 93 %

Procedure:
To a stirred solution of decanol (6.0 g, 7.23 mmol) in dichloromethane (150 ml) was added dry pyridine (3.66 ml, 45.6 mmol). The solution was cooled in an ice bath. To this was added 1-chloroethyl chloroformate (6.5 g, 45.6 mmol) dropwise. The reaction mixture was allowed to proceed overnight, diluted with dichloromethane and washed with 0.5N HCl solution, twice with a saturated sodium bicarbonate solution and finally with distilled water. The solvent was dried over magnesium sulphate, filtered through silica and concentrated to dryness. Yield: 93%.
Reaction SMILES: [OH:1][C:2]1([C:20]([OH:22])=[O:21])[CH2:11][C:10]2([S:15][CH2:14][CH2:13][S:12]2)[C:9]2[C:4](=[C:5]([O:18][CH3:19])[CH:6]=[CH:7][C:8]=2[O:16][CH3:17])[CH2:3]1.COC1C=C2[C@@]34[C@@H]5C[C@H]6C(CN5CC3)=CCO[C@H]3CC(=O)N([C@H]4[C@@H]63)C2=CC=1OC>C(OCC)(=O)C>[OH:1][C@@:2]1([C:20]([OH:22])=[O:21])[CH2:11][C:10]2([S:15][CH2:14][CH2:13][S:12]2)[C:9]2[C:4](=[C:5]([O:18][CH3:19])[CH:6]=[CH:7][C:8]=2[O:16][CH3:17])[CH2:3]1
Reactant: COc1ccc(OC)c2c1CC(O)(C(=O)O)CC21SCCS1
Agent: COc1cc2c(cc1OC)[C@@]13CCN4CC5=CCO[C@H]6CC(=O)N2[C@H]1[C@H]6[C@H]5C[C@H]43
Solvent: CCOC(C)=O
Product: COc1ccc(OC)c2c1C[C@](O)(C(=O)O)CC21SCCS1
Temperature: 25 °C
Yield: 35.7 %

Procedure:
A suspension of 3.42 g of rac-1',2',3',4'-tetrahydro-2'-hydroxy-5',8'-dimethoxyspiro[1,3-dithiolane-2,4'-naphthalene]-2'-carboxylic acid in 168 ml of ethyl acetate and 4.0 g of brucine was heated under reflux until a clear solution was obtained. After seeding, the solution was left to cool slowly to room temperature. The crystalline precipitate (3.6 g) was collected after 2 days. The precipitate was dissolved in 1500 ml of boiling ethyl acetate, the solution was concentrated to 600 ml and left to cool slowly. The crystalline product [2.7 g [α]D20 =-46.6°, c=0.5% in dimethylformamide] was suspended in 150 ml of ethyl acetate and shaken with three 10 ml portions of 5-M hydrochloric acid and with two 100 ml portions of brine. After drying over magnesium sulphate, the solvent was evaporated to give a colourless oil which was crystallised from diethyl ether to yield 1.22 g of (R)-1',2',3',4'-tetrahydro-2'-hydroxy-5',8'-dimethoxyspiro[1,3-dithiolane-2,4'-naphthalene]-2'-carboxylic acid in the form of colourless crystals of melting point 147°-149° C.; [α]D20 =+13.8° (c=0.5% in dioxan).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:13](=[O:20])[C@H:14]([CH2:16][C:17](O)=[O:18])[CH2:15][C:8]=3[CH:7]=[C:6]([Cl:26])[C:5]=2[NH:4][N:3]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.Cl.[NH:60]1[CH2:65][CH2:64][CH:63]([N:66]2[C:74]3[C:69](=[N:70][CH:71]=[CH:72][CH:73]=3)[NH:68][C:67]2=[O:75])[CH2:62][CH2:61]1>CN(C)C=O>[Cl:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:21][C:22]([F:25])([F:23])[F:24])[C:13](=[O:20])[C@H:14]([CH2:16][C:17](=[O:18])[N:60]4[CH2:61][CH2:62][CH:63]([N:66]5[C:74]6[C:69](=[N:70][CH:71]=[CH:72][CH:73]=6)[NH:68][C:67]5=[O:75])[CH2:64][CH2:65]4)[CH2:15][C:8]=3[CH:7]=[C:6]([Cl:26])[C:5]=2[NH:4][N:3]=1
Reactant: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]nc(Cl)c3c2CN(CC(F)(F)F)C1=O
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(C[C@@H]1Cc2cc(Cl)c3[nH]nc(Cl)c3c2CN(CC(F)(F)F)C1=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
(S)-2-(1,4-Dichloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid (110 mg, 0.268 mmol) was dissolved in N,N-dimethylformamide (2.0 ml). N,N-Diisopropylethylamine (150 μl, 0.861 mmol) was added to the mixture followed successively by TBTU (92 mg, 0.287 mmol) and 1-(piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one dihydrochloride (92 mg, 0.316 mmol). Reaction stirred at room temperature for 5 hours. Reaction was quenched with 50% acetonitrile-water. Material was purified by prep HPLC (water-acetonitrile-trifluoroacetic acid). Acetonitrile was removed from the fractions by roto-vap. Remaining aqueous was made basic with aqueous sodium bicarbonate. Material was extracted twice with ethyl acetate and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as white solid in 70% yield. 1H NMR (500 MHz, DMSO-D6) δ ppm 13.89 (s, 1H) 11.55 (s, 1H) 7.90 (dd, J=5.19, 1.22 Hz, 1 H) 7.64 (dd, J=70.19, 7.93 Hz, 1H) 7.35 (s, 1H) 6.99 (dd, J=7.78, 5.34 Hz, 0.4H) 6.90 (dd, J=7.93, 5.19 Hz, 0.6H) 5.44 (d, J=4.88 Hz, 2H) 4.35-4.62 (m, 3H) 3.95-4.32 (m, 3H) 3.15-3.28 (m, 2H) 2.85-3.12 (m, 2H) 2.61-2.76 (m, 1H) 2.20-2.47 (m, 2H) 1.93-2.12 (m, 1H) 1.64-1.87 (m, 2H). High resolution MS m/e (M+H)+=610.1328.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([NH:14][CH:15]=[O:16])=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Br:13])[CH3:2].[Br:18]N1C(=O)CCC1=O.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])[C:5]([NH:14][CH:15]=[O:16])=[C:6]([Br:18])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Br:13])[CH3:2]
Reactant: CCOC(=O)C(=Cc1ccccc1Br)NC=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC=O)=C(Br)c1ccccc1Br
Temperature: 25 °C
Reaction time: 5 h
Yield: 40 %

Procedure:
A 0.4 M solution of 3-(2-bromo-phenyl)-2-formylamino-acrylic acid ethyl ester (5.3 g; 17.8 mM) in anhydrous CH2Cl2, at 0° C., is added with N-bromosuccinimide (3.48 g; 19.6 mM). The mixture is left to slowly warm to room temperature. The reaction is completed in about 5 hours 30 mm. The equivalent amount of triethylamine is added drop by drop; after 30 minutes the mixture is washed with a NaHCO3 saturated solution and then with a NaCl saturated solution. The organic phase is dried over Na2SO4, the solid is filtered off and the clear solution is evaporated under reduced pressure to a residue. The crude (brownish oil) is purified by flash chromatography, using a 6:4 v/v mixture of hexane and ethyl acetate as eluent, thereby obtaining 2.68 g of 3-bromo-3-(2-bromo-phenyl)-2-formylamino-acrylic acid ethyl ester (white-pale yellow solid). (Yield: 40%).