Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([S:4][CH2:5][CH2:6][C:7]([N:9]1[CH2:16][C:15]([O:19][CH3:20])([O:17][CH3:18])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=O)C.N>>[SH:4][CH2:5][CH2:6][C:7]([N:9]1[CH2:16][C:15]([O:19][CH3:20])([O:17][CH3:18])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8]
Reactant: COC1(OC)C[C@@H](C(=O)O)N(C(=O)CCSC(C)=O)C1
Agent: N
Product: COC1(OC)C[C@@H](C(=O)O)N(C(=O)CCS)C1

Procedure:
The product from part (a) is hydrolyzed with concentrated ammonia according to the procedure of Example 4 to yield 1-(3-mercapto-1-oxopropyl)-4,4-dimethoxy-L-proline.
Reaction SMILES: [CH:1]1([CH2:6][C:7]2[N:11]([CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:10]3[CH:17]=[CH:18][C:19]([C:21]([OH:23])=O)=[CH:20][C:9]=3[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C=O)C.C(Cl)(=O)C([Cl:32])=O>ClCCl>[CH:1]1([CH2:6][C:7]2[N:11]([CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:10]3[CH:17]=[CH:18][C:19]([C:21]([Cl:32])=[O:23])=[CH:20][C:9]=3[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCC(CC)n1c(CC2CCCC2)nc2cc(C(=O)O)ccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCC(CC)n1c(CC2CCCC2)nc2cc(C(=O)Cl)ccc21
Reaction time: 16 h
Yield: 100 %

Procedure:
To 8.00 g of 2-cyclopentylmethyl-1-(1-ethyl-propyl)-1H-benzoimidazole-5-carboxylic acid in 100 ml of dichloromethane 0.1 ml of DMF and 4 ml of oxalyl chloride were added. The reaction was stirred at it for 16 h, then concentrated and co-distilled with toluene to obtain 8.45 g (100%) of the crude product as a brown solid, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH2:11])([CH3:10])[CH3:9])=[CH:4][C:3]=1[CH3:12].CC(C)([O-])C.[K+].[I:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](I)[CH:21]=1.CCOCC>COCCOC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:11][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([I:19])[CH:21]=2)([CH3:9])[CH3:10])=[CH:4][C:3]=1[CH3:12]
Reactant: Cc1cc(C(C)(C)N)ccc1Cl
Reactant: Ic1cccc(I)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOCC
Product: Cc1cc(C(C)(C)Nc2cccc(I)c2)ccc1Cl
Temperature: 25 °C

Procedure:
A suspension of amine INT 22 (2.8 g, 15.24 mmol) and potassium tert-butoxide (5.99 g, 53.4 mmol) in DME (25 mL) was purged with argon for 5 minutes. Then, PEPPSI-IPr® (207 mg, 0.305 mmol) and 1,3-diiodobenzene (5.03 g, 15.24 mmol) were added and the flask was closed. The mixture was stirred at room temperature over the weekend. The crude reaction mixture was treated with Et2O (50 mL) and filtered. The residue was washed with more Et2O (30 mL) and the combined filtrates were concentrated. The crude was purified by chromatography on silica gel (cyclohexane/CH2Cl2).
Reaction SMILES: [Br:1][C:2]1[C:3]([S:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH:5]=O.Cl.[NH2:19][OH:20]>C(O)(C)C.O>[Br:1][C:2]1[C:3]([S:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH:5]=[N:19][OH:20]
Reactant: NO
Reactant: CC(C)(C)Sc1c(Br)cc([N+](=O)[O-])cc1C=O
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)Sc1c(Br)cc([N+](=O)[O-])cc1C=NO
Yield: 150.1 %

Procedure:
A solution of 3-bromo-2-tert-butylsulfanyl-5-nitro-benzaldehyde (1.2 g, 3.8 mmol) and hydroxylamine hydrochloride (1.2 g, 7.7 mmol) in isopropanol (36 mL) and water (8 mL) was heated to 90° C. for 16 h. The reaction mixture was cooled and concentrated to remove isopropanol. Water was added to the residue, followed by saturated sodium bicarbonate solution until the pH was ˜8.0. The residue was extracted with dichloromethane (2×30 mL). The combined organic fractions were dried with sodium sulfate, filtered, and concentrated to afford 1.9 g of the crude title compound which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][N:19]=2)(=[O:17])=[O:16])[C:3]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35].[Na]>C(O)CO>[OH:27][CH2:28][CH2:29][O:34][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][N:19]=2)(=[O:17])=[O:16])[C:3]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35]
Reactant: COc1ccccc1Oc1c(Cl)nc(N2CCOCC2)nc1NS(=O)(=O)c1ccc(C(C)C)cn1
Agent: [Na]
Solvent: OCCO
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(N2CCOCC2)nc1OCCO

Procedure:
reacting the product of step d) with sodium in ethylene glycol to form 5-isopropyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-morpholin-4-yl-pyrimidin-4-yl-amide, and
Reaction SMILES: [CH2:1]([N:5]1[CH:10]=[CH:9][C:8](O)=[CH:7][C:6]1=[O:12])[CH2:2][CH2:3][CH3:4].P(Br)(Br)([Br:15])=O>CN(C=O)C>[Br:15][C:8]1[CH:9]=[CH:10][N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6](=[O:12])[CH:7]=1
Reactant: CCCCn1ccc(O)cc1=O
Reactant: O=P(Br)(Br)Br
Solvent: CN(C)C=O
Product: CCCCn1ccc(Br)cc1=O
Temperature: 110 °C
Yield: 92 %

Procedure:
To a solution of intermediate D2 (1.44 g, 8.6 mmol) in DMF (140 ml) was added phosphorus oxybromide (5.4 g, 18.9 mmol) and the mixture was heated at 110° C. for 1 hour. After cooling in an ice bath the solution was partitioned between water and EtOAc. After three extractions with EtOAc the combined organic fractions were dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate D3 (1.82 g, 93%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CC(C)=O>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10]
Reactant: COc1ccc(CCl)cc1
Reactant: CC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(COc2ccc(C(C)=O)c(O)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2′,4′-Dihydroxyacetophenone (11.71 g, 0.077 mol), 4-methoxybenzyl chloride (10.44 ml, 0.077 mol), anhydrous potassium carbonate (11.75 g, 0.085 mol) and potassium iodide (12.78 g, 0.077 mol) are heated together in refluxing dry acetone (80 ml) for 4 hours. The mixture is then cooled to room temperature, poured into water (250 ml) and extracted with ethyl acetate (3×100 ml). The ethyl acetate extracts are combined, washed with saturated brine (100 ml), dried (MgSO4), filtered and concentrated, until crystallization commences. After standing at 4° C. for 16 h, the crystals are recovered by filtration, washed with cold ethyl acetate and then with n-hexane and dried.
Reaction SMILES: [C:1]([C@@H:3]([NH:8][C:9]([C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[NH2:17])=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6])#[N:2].[Cl:18][CH2:19][CH2:20][CH2:21][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[C:31](O)=[O:32]>>[C:1]([C@@H:3]([NH:8][C:9]([C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[NH:17][C:31]([C:23]1[N:22]([CH2:21][CH2:20][CH2:19][Cl:18])[C:30]2[C:25]([CH:24]=1)=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:32])=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6])#[N:2]
Reactant: O=C(O)c1cc2ccccc2n1CCCCl
Reactant: CC(C)C[C@@H](C#N)NC(=O)[C@@H]1CCCC[C@@H]1N
Product: CC(C)C[C@@H](C#N)NC(=O)[C@@H]1CCCC[C@@H]1NC(=O)c1cc2ccccc2n1CCCCl

Procedure:
(1R,2S)-2-Amino-cyclohexanecarboxylic acid ((S)-1-cyano-3-methyl-butyl)-amide was coupled with afford 1-(3-chloro-propyl)-1H-indole-2-carboxylic acid using the procedure of Example 11 to yield 1-(3-chloro-propyl)-1H-indole-2-carboxylic acid [(1S,2R)-2-((S)-1-cyano-3-methyl-butylcarbamoyl)-cyclohexyl]-amide.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:12]1([CH:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:19][NH2:20])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: NCC(c1ccccn1)N1CCOCC1
Product: O=C(NCC(c1ccccn1)N1CCOCC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and (2-morpholin-4-yl-2-pyridin-2-ylethyl)amine.
Reaction SMILES: [C:1]1([S:7][C:8]([S:11](F)(=[O:13])=[O:12])([F:10])[F:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>ClCCCl>[CH2:15]([NH:22][S:11]([C:8]([F:10])([F:9])[S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:13])=[O:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(F)C(F)(F)Sc1ccccc1
Reactant: NCc1ccccc1
Agent: Cl
Solvent: ClCCCl
Product: O=S(=O)(NCc1ccccc1)C(F)(F)Sc1ccccc1

Procedure:
Added to a solution of 1,2-dichloroethane (15 ml), containing the PhSCF2SO2F (1.46 g, 5 mmol) obtained according to the method from example 7, was freshly distilled benzylamine (2.7 ml, 25 mmol). The mixture was stirred and heated at 50° C. for 20 h until the disappearance of PhSCF2SO2F (monitored by TLC and 19F NMR/CDCl3). After returning to ambient temperature, an aqueous solution of HCl (10%) was added to the reaction medium. The aqueous and organic phases were separated and the aqueous phase was extracted with dichloromethane. The organic phases were combined and dried over MgSO4. After filtration and evaporation of the solvents, the residue was purified by chromatography over silica gel (pentane to pentane/AcOEt:4/1). The sulfonamide product was obtained in the form of a white solid (1.5 g, 90%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[N:7]=[C:8]([SH:11])[S:9][CH:10]=1)[CH3:2].[C:13]([O:17][C:18](=[O:22])[CH:19](Br)[CH3:20])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18](=[O:22])[CH:19]([S:11][C:8]1[S:9][CH:10]=[C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:12])[N:7]=1)[CH3:20])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCOC(=O)Cc1csc(S)n1
Reactant: CC(Br)C(=O)OC(C)(C)C
Product: CCOC(=O)Cc1csc(SC(C)C(=O)OC(C)(C)C)n1

Procedure:
The title compound was obtained by an operation similar to that of Example 2 and using (2-mercapto-1,3-thiazol-4-yl)acetic acid ethyl ester synthesized in Example 1 and 2-bromopropionic acid tert-butyl ester to give 2-{[4-(2-ethoxy-2-oxoethyl)-1,3-thiazol-2-yl]thio}propionic acid tert-butyl ester, followed by sequential operations similar to those of Examples 3, 4 and 34.
Reaction SMILES: [C:1]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[CH:5][C:4]([CH:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][N:13](C)[CH2:14]C2C=CC=CC=2)=[CH:3][CH:2]=1.[H][H].[ClH:36].Cl.CC(O)C>CO.[Pd]>[ClH:36].[ClH:36].[C:1]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:6]=[CH:5][C:4]([CH:7]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][NH:13][CH3:14])=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: CN(CCNCCC(c1ccccc1)c1ccc(-c2ccccc2)cc1)Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: CNCCNCCC(c1ccccc1)c1ccc(-c2ccccc2)cc1

Procedure:
A mixture of (±)-N-[3-([1,1′-biphenyl]-4-yl)-3-phenylpropyl]-N′-methyl-N′-(phenylmethyl)-1,2-ethanediamine (0.006 mol) in methanol (150 ml) was hydrogenated at room temperature with palladium on carbon (10%, 1 g) as a catalyst. After uptake of hydrogen (1 equivalent), the catalyst was filtered off and the filtrate was evaporated, giving a residue that was converted into the hydrochloric acid salt (1:2) with HCl/2-propanol, yielding 2.76 g of (±)-N-[3-([1,1′-biphenyl]-4-yl)-3-phenylpropyl]-N′-methyl-1,2-ethanediamine dihydrochloride (comp. 56).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([CH3:34])([S:30]([CH3:33])(=[O:32])=[O:31])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:18][CH:17]=1)=O)(C)(C)C>>[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][C:24]([CH3:34])([S:30]([CH3:33])(=[O:32])=[O:31])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][CH:21]=1
Reactant: CCOC(=O)C(C)(CCc1ccc(NC(=O)OC(C)(C)C)cc1)S(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)(CCc1ccc(N)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
Trifluoroacetic acid (50 mL, 650 mmol) was added to a solution of (+/−)-ethyl 4-{4-[(tert-butoxycarbonyl)amino]phenyl}-2-methyl-2-(methylsulfonyl)butanoate (6.47 g, 16.2 mmol) in dicholoromethane (100 mL) at 0° C. The reaction was allowed to warm to room temperature and was stirred for 2 hours. The reaction was then concentrated; the residue was dissolved in 1N aqueous HCl (100 mL) and washed with ethyl acetate (3×100 mL). The organic layers were discarded. The aqueous layer was made basic with 1N aqueous NaOH, and extracted with ethyl acetate (3×100 mL). The combined organics were washed with water (100 mL), brine (100 mL), dried (MgSO4), filtered, and concentrated in vacuo to afford a crude orange oil. The crude product was purified via flash chromatography using an Analogix SF40-150 g column and an eluant of ethyl acetate in heptane (1:1) to afford the title compound as a yellow oil (3.52 g, 72.6%). LC-MS m/z 300.5 (M+1). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.55 (t, J=7.13 Hz, 3H) 1.88 (s, 3H) 2.24-2.39 (m, 1H) 2.56-2.77 (m, 2H) 2.84-2.98 (m, 1H) 3.31 (s, 3H) 4.42-4.49 (m, 2H) 6.91 (d, J=8.40 Hz, 2H) 7.19 (d, J=8.40 Hz, 2H).
Reaction SMILES: [C:1]([C:3]([C:15]#[N:16])=[C:4]1[CH2:9][CH2:8][C:7](=[C:10]([C:13]#[N:14])[C:11]#[N:12])[CH2:6][CH2:5]1)#[N:2]>[O-2].[O-2].[Mn+4].C1(C)C=CC=CC=1>[CH:5]1[C:4](=[C:3]([C:1]#[N:2])[C:15]#[N:16])[CH:9]=[CH:8][C:7](=[C:10]([C:11]#[N:12])[C:13]#[N:14])[CH:6]=1
Reactant: N#CC(C#N)=C1CCC(=C(C#N)C#N)CC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: N#CC(C#N)=c1ccc(=C(C#N)C#N)cc1

Procedure:
According to the procedure of Fatiadi Synthesis, 1976, 133, incorporated herein by reference, the 1,4-bis(dicyanomethylene)cyclohexane is allowed to react with manganese dioxide in refluxing (110° C.) toluene for ca. 15 minutes to provide TCNQ in ca. 60% yields.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)[CH:2]1[O:4][CH2:3]1.[NH:14]1[CH:19]=[CH:18][CH:17]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[CH2:16][CH2:15]1>>[N:5]1([CH2:1][CH:2]([OH:4])[CH2:3][N:14]2[CH2:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:22][CH:21]=3)[CH2:18][CH2:19]2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1
Reactant: C1=CC(c2c[nH]c3ccccc23)CCN1
Reactant: c1ccc2c(c1)ccn2CC1CO1
Product: OC(CN1CC=C(c2c[nH]c3ccccc23)CC1)Cn1ccc2ccccc21
Yield: 47.6 %

Procedure:
A methanolic solution of 1-N-glycidylindole (0.52 g, 3.0 mmole) from example 4 and 3-(4-tetrahydropyridinyl)indole (0.59 g, 3.0 mmole) was refluxed under nitrogen for 24 hours. The reaction mixture was concentrated in vacuo and the product purified by flash silica gel chromatography (ethyl acetate) to afford the titled compound as a yellow colored solid (0.53 g, 47% yield). Treatment with a 0.25M ethanolic solution of fumaric acid (0.5 equivalents) gave the required product as a yellow colored solid. The product was recrystallized from ethanol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:22][N:12]3[C:13](=[O:21])[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10][CH2:9]2)=[C:4]([CH3:23])[CH:3]=1.C(N(CC)CC)C.[C:31]1([CH3:40])[CH:36]=[CH:35][CH:34]=[C:33]([N:37]=[C:38]=[O:39])[CH:32]=1>C(Cl)Cl>[CH3:23][C:4]1[CH:3]=[C:2]([NH:1][C:38]([NH:37][C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([CH3:40])[CH:32]=2)=[O:39])[CH:7]=[CH:6][C:5]=1[CH:8]1[CH2:22][N:12]2[C:13](=[O:21])[NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:11]2=[N:10][CH2:9]1
Reactant: Cc1cc(N)ccc1C1CN=C2c3ccccc3NC(=O)N2C1
Reactant: Cc1cccc(N=C=O)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(NC(=O)Nc2ccc(C3CN=C4c5ccccc5NC(=O)N4C3)c(C)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
To a mixture of 3-(4-amino-2-methylphenyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,2-c]quinazolin-6-one (92 mg, 0.30 mmol) and triethylamine (0.125 mL, 0.90 mmol) in 2.5 mL CH2Cl2 at rt was added meta-tolyl isocyanate (0.057 mL, 0.45 mmol) and the reaction stirred at rt. After 2 hours, an additional 0.015 mL meta-tolyl isocyanate and 1.5 mL CH2Cl2 was added and the reaction continued for 20 hours. The reaction was quenched with 0.5 mL MeOH, stirred 5 minutes and then evaporated. The mixture was triturated with MeOH, filtered and rinsed with MeOH and EtOAc to give the title compound as an off-white solid (99 mg, 75%). 1H NMR (DMSO-d6) δ: 10.68 (s, 1H), 8.54 (d, J=3.2 Hz, 2H), 7.99 (dd, J=7.9, 1.5 Hz, 1H), 7.40-7.47 (m, 1H), 7.00-7.32 (m, 8H), 6.78 (d, J=7.0 Hz, 1H), 4.15-4.23 (m, 1H), 3.63-3.73 (m, 1H), 3.44-3.55 (m, 2H), 3.04-3.16 (m, 1H), 2.31 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:13](=[O:14])[N:12]([CH2:15][CH2:16][CH2:17][F:18])[N:11]=[N:10]2)=[C:4]([F:19])[CH:3]=1.[N+:20]([O-])([OH:22])=[O:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([F:19])[C:5]([N:9]2[C:13](=[O:14])[N:12]([CH2:15][CH2:16][CH2:17][F:18])[N:11]=[N:10]2)=[C:6]([N+:20]([O-:22])=[O:21])[C:7]=1[OH:8]
Reactant: O=[N+]([O-])O
Reactant: O=c1n(CCCF)nnn1-c1cc(O)c(Cl)cc1F
Product: O=c1n(CCCF)nnn1-c1c(F)cc(Cl)c(O)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-(4-Chloro-2-fluoro-5-hydroxyphenyl)-4-(3-fluoropropyl)-tetrazolinone (2.91 g) was gradually added into an ice-cooled nitric acid (20 ml) and stirred for 30 minutes. Crushed ice was added followed by extraction with ethyl acetate. The ethyl acetate extract was washed with water, dried over sodium sulfate, concentrated, and filtered through a silica gel SPE column (2 g) to give the title compound as a yellow solid (3.4 g).
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[C:12]2[C:13](=[O:17])[N:14]([CH3:16])[CH2:15][C:11]=2[CH:10]=[CH:9][N:8]=1.[OH-].[Na+]>Cl>[NH2:6][C:7]1[C:12]2[C:13](=[O:17])[N:14]([CH3:16])[CH2:15][C:11]=2[CH:10]=[CH:9][N:8]=1
Reactant: COc1ccc(CNc2nccc3c2C(=O)N(C)C3)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN1Cc2ccnc(N)c2C1=O

Procedure:
A solution of 4-[(2,4-dimethoxybenzyl)amino]-2-methyl-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one one (1.8 g, 5.7 mmol) in 37% HCl (7.0 mL) was stirred at rt for 16 hours. The reaction mixture was neutralized with NaOH and extracted with EtOAc (15 mL). The organic layer was washed with water (10 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to yield a red solid. The crude material was purified by silica gel chromatography on the combi-flash Rf system using DCM/MeOH (100:0→95:5) as eluent. The fractions containing product were combined and concentrated under reduced pressure to yield an orange solid, (319 mg, 34%). 1H NMR (DMSO-d6, 400 MHz): δ=2.99 (s, 3H), 4.37 (s, 2H), 6.54 (br. s., 2H), 6.73 (d, J=5.05 Hz, 1H), 8.04 (d, J=5.05 Hz, 1H). MS (ES+): m/z 164.07 [MH+] (TOF, polar).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[N:14][C:13]=3[CH:30]=2)O1.Br[C:33]1[CH:41]=[CH:40][C:36]([C:37]([NH2:39])=[O:38])=[C:35]([F:42])[CH:34]=1>>[C:37]([C:36]1[CH:40]=[CH:41][C:33]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:21][CH2:22]4)=[N:14][C:13]=3[CH:30]=2)=[CH:34][C:35]=1[F:42])(=[O:38])[NH2:39]
Reactant: NC(=O)c1ccc(Br)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(B4OC(C)(C)C(C)(C)O4)ccc3o2)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(C(N)=O)c(F)c4)ccc3o2)CC1
Yield: 16.3 %

Procedure:
Following the General Procedure-3, the titled compound (25 mg) was prepared from Intermediate 8 (150 mg, 0.35 mmol) and 4-bromo-2-fluorobenzamide (77 mg, 0.35 mmol) as a white solid. M.P.: 202-206° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.22 (t, J 8.3, 1H), 7.89 (s, 1H), 7.59-7.49 (m, 3H), 7.37 (dd, J 1.6, 13.24, 1H), 6.71 (d, J 9.5, 1H), 5.85 (s, 1H), 4.15 (d, J 10.7, 2H), 3.20-3.10 (m, 1H), 3.00 (t, J 11.8, 2H), 2.20-2.12 (m, 2H), 1.99-1.85 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[O:9][C:8]2[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:7]=2[CH2:6][O:5]1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>CCOC(C)=O>[CH2:18]([N:2]([CH3:1])[CH2:3][CH:4]1[O:9][C:8]2[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:7]=2[CH2:6][O:5]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CNCC1OCc2ccc(S(C)(=O)=O)cc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CN(Cc1ccccc1)CC1OCc2ccc(S(C)(=O)=O)cc2O1
Yield: 63.9 %

Procedure:
N-methyl-1-[7-(methylsulfonyl)-4H-1,3-benzodioxin-2-yl]methanamine (1.05 g, 4.1 mmol), benzylbromide (0.49 ml, 4.1 mmol), potassium carbonate (0.68 g, 4.9 mmol) and ACN (20 ml) were heated at 50° C. for 12 h. EtOAc was added, the reaction mixture was filtered and concentrated. Purification by flash chromatography (isooctane/EtOAc 1:2) afforded the title compound (0.91 g). 1H-NMR (400 MHz, MeOH): δ 7.38 (1H, dd, J 8.4 Hz, J2 1.6), δ 7.28-7.14 (7H, m), δ 5.17 (1H, t, J 4.0 Hz), δ 4.90 (2H, dd, J 52.0 Hz, J2 19.6 Hz), δ 3.59 (2H, dd, J 18.4 Hz, J2 13.2 Hz), δ 2.99 (3H, s), δ 2.78-2.67 (2H, m), δ 2.29 (3H, s). Chiral separation was performed according to Preparation 16. The flow rate was 30 ml/min. Repeated injections (˜40 mg) every 7-8 min. Totally 25 injections afforded the two different enantiomers. The first eluted peak consisted of (−)-N-benzyl-N-methyl-1-{[7-(methylsulfonyl)-4H-1,3-benzodioxin-2-yl]methanamine (0.37 g, >95% e.e.). The second eluted peak consisted of (+)-N-benzyl-N-methyl-1-{[7-(methylsulfonyl)-4H-1,3-benzodioxin-2-yl]methanamine (0.37 g, >95% e.e.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH:31]([C:33]1[N:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)=[O:32].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7](=[O:8])[C:6]1[CH:20]=[C:2]([C:36]2[CH:37]=[N:38][C:33]([CH:31]=[O:32])=[CH:34][CH:35]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21]
Reactant: O=Cc1ccc(B(O)O)cn1
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCN(c1cc(-c2ccc(C=O)nc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 80 °C
Yield: 55.5 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (1 g, 2.15 mmol) and (6-formylpyridin-3-yl)boronic acid (0.539 g, 2.31 mmol) in dioxane/water mixture (15 mL+3 mL), Na2CO3 (0.82 g, 7.74 mmol) was added and solution purged with argon for 15 min. Then Pd (PPh3)4 (0.288 g, 0.25 mmol) was added and argon was purged again for 10 min. Reaction mass was heated at 80° C. for 2 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford the desired compound (0.60 g, 57%).