Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.[CH3:18][N:19]1[C:24]([N:25]2CCCN(C3C=CC=CC=3[N+]([O-])=O)[CH2:27][CH2:26]2)=[CH:23][C:22](=[O:41])[N:21]([CH3:42])[C:20]1=[O:43].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[CH3:18][N:19]1[C:24]([NH:25][CH2:26][CH2:27][N:5]([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH2:4][CH2:3][CH2:2][OH:1])=[CH:23][C:22](=[O:41])[N:21]([CH3:42])[C:20]1=[O:43]
Reactant: O=[N+]([O-])c1ccc(CCCNCCCO)cc1
Reactant: Cn1c(N2CCCN(c3ccccc3[N+](=O)[O-])CC2)cc(=O)n(C)c1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: Cn1c(NCCN(CCCO)CCCc2ccc([N+](=O)[O-])cc2)cc(=O)n(C)c1=O
Yield: 109.9 %

Procedure:
N-(3-hydroxypropyl)-3-(4-nitrophenyl)propylamine (0.7 g), 0.53 g of 6-(1-aziridinyl)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (compound 6) and 50 mg of p-toluene-sulfonic acid monohydrate were dissolved in 30 ml of acetonitrile, and then the solvent was removed in vacuo. The resultant oil was allowed to react at 80° C. for 3 hours and subjected to silica gel column chromatograph (chloroform/methanol=40:1 (v/v)) for purification: 0.68 g of 1,3-dimethyl-6-{2-[N-(3-hydroxypropyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione was thus obtained.
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[F:16][C:17]([F:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:18]O.C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C>ClCCl.CCCCC>[F:15][C:12]([F:13])([F:14])[S:9]([O:8][CH2:18][C:17]([F:26])([F:16])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:10])=[O:11]
Reactant: OCC(F)(F)c1ccccc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Solvent: ClCCl
Solvent: CCCCC
Product: O=S(=O)(OCC(F)(F)c1ccccc1)C(F)(F)F
Yield: 64.4 %

Procedure:
Add triflic anhydride (1.28 mL, 2.14 g) dropwise to a stirred solution of 2,2-difluoro-2-phenyl-ethanol (0.8 g, 5.06 mmol) and 2,6-di-tert-butyl-4-methylpyridine (1.556 g, 7.59 mmol) in anhydrous dichloromethane (25 mL) at −78° C. Stir the reaction overnight while the temperature warms up. Dilute the mixture with pentane and filter the precipitate over Celite®b. Concentrate the filtrate in vacuo and purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (95:5) to provide the title compound (946 mg, 64%).
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1I)([F:4])[F:3].[CH:13]1([C:16]#[CH:17])[CH2:15][CH2:14]1>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:13]1([C:16]#[C:17][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:2]([F:4])([F:3])[F:1])[CH2:15][CH2:14]1
Reactant: C#CC1CC1
Reactant: FC(F)(F)Sc1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: FC(F)(F)Sc1ccccc1C#CC1CC1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
Bis(triphenylphosphine)palladium(II) dichloride ([(C6H5)3P]2PdCl2, 0.0518 g, 5 mol %), copper(I) iodide (0.0086 g, 3 mol %), and triethylamine (3 ml) were charged into a 25-ml round-bottomed flask equipped with a stirrer, and were suspended by stirring at room temperature. To the suspension, a solution obtained by dissolving 2-trifluoromethylsulfanyliodobenzene (1.08 g, 3.6 mmol) prepared in Reference Example 1 and cyclopropylacetylene (0.35 g, 5.3 mmol) in triethylamine (2 ml) was added dropwise, and the solution was stirred at room temperature overnight. After completion of the reaction, a solvent was removed under reduced pressure, and water was added to the obtained residue. The solution was extracted with ether, and the organic layers were combined together, washed with water, dried over magnesium sulfate, filtered, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography (hexane) to give target 1-cyclopropylethynyl-2-trifluoromethylsulfanylbenzene (0.67 g, yield: 78%) as an oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:23][CH3:24])[C:4]1[CH:22]=[CH:21][C:7]([CH:8]=[N:9][NH:10][C:11](=[O:20])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:2].CCN(C1C=CC(/C=N/NC(C2C=CC(O)=CC=2)=O)=CC=1)CC.Br[CH2:49][C:50]1[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][CH:51]=1>>[CH2:23]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[N:9][N:10]([CH2:49][C:50]2[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][CH:51]=2)[C:11](=[O:20])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:21][CH:22]=1)[CH3:24]
Reactant: Cc1ccc(CBr)cc1
Reactant: CCN(CC)c1ccc(C=NNC(=O)c2ccc(OC)cc2)cc1
Agent: CCN(CC)c1ccc(/C=N/NC(=O)c2ccc(O)cc2)cc1
Product: CCN(CC)c1ccc(C=NN(Cc2ccc(C)cc2)C(=O)c2ccc(OC)cc2)cc1

Procedure:
Referring to FIG. 2, thus, a two-step procedure was explored whereby the amine of compound 1 was protected prior to conversion to compound 3. Specifically, the amino group of compound 1 was protected by reacting with α-bromo-p-xylene to give 4-methoxy-benzoic acid N′-(4-diethylamino-benzylidene)-N-(4-methyl-benzyl)-hydrazide (compound 2). This was followed by the simultaneous demethylation and deprotection of the N-benzyl group of compound 2 by ether cleavage with boron tribromide. This produced compound 3, with an overall yield of 27%.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])[CH2:20][CH:19]3[C:31](=[O:33])[NH2:32])=[O:17])=[C:11]([O:34][CH2:35][C:36]([F:39])([F:38])[F:37])[CH:10]=2)[CH2:4][CH2:3]1.[CH3:40][S:41](Cl)(=[O:43])=[O:42].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:40][S:41]([N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])[CH2:20][CH:19]3[C:31](=[O:33])[NH2:32])=[O:17])=[C:11]([O:34][CH2:35][C:36]([F:37])([F:38])[F:39])[CH:10]=2)[CH2:4][CH2:3]1)(=[O:43])=[O:42]
Reactant: Cc1ccccc1N1CCN(C(=O)Cc2ccc(OC3CCNCC3)cc2OCC(F)(F)F)C(C(N)=O)C1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1N1CCN(C(=O)Cc2ccc(OC3CCN(S(C)(=O)=O)CC3)cc2OCC(F)(F)F)C(C(N)=O)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 1-(4-(4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine hydrochloride (0.20 g, 0.35 mmol) from Example 1 in CH2Cl2 (20 mL) was added methanesulfonoyl chloride (0.045 g, 0.39 mmol) and DIEA (0.14 mL, 0.80 mmol). The solution was stirred at ambient temperature for 6 h and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with 0.25 M aqueous citric acid (25 mL), H2O (25 mL), and saturated aqueous NaHCO3 (25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 97:3 CH2Cl2 :MeOH. The product-containing fractions were combined and the solvent was removed under reduced pressure. The residue was dissolved in CH2Cl2 :hexane, and evaporation of this solution under reduced pressure gave the title compound as an amorphous solid.
Reaction SMILES: [N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:12]/[C:13]1[C:18]([Cl:19])=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:14]=1[Cl:23])=[N+]=[N-]>C1(C)C=CC=CC=1>[Cl:23][C:14]1[CH:15]=[C:16]([N+:20]([O-:22])=[O:21])[CH:17]=[C:18]([Cl:19])[C:13]=1[N:12]1[CH:11]=[C:5]2[CH:6]=[N:7][CH:8]=[C:9]([F:10])[C:4]2=[N:1]1
Reactant: [N-]=[N+]=Nc1c(F)cncc1/C=N/c1c(Cl)cc([N+](=O)[O-])cc1Cl
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(Cl)c(-n2cc3cncc(F)c3n2)c(Cl)c1
Temperature: 105 °C
Yield: 88 %

Procedure:
A suspension of [1-(4-azido-5-fluoropyridin-3-yl)-meth-(E)-ylidene]-(2,6-dichloro-4-nitrophenyl)-amine (5.89 g, 16.6 mmol) in toluene (80 mL) was heated at 105° C. for 4 hours. The resultant mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-5% methanol in DCM) to afford the title compound (4.78 g, 81% yield). 1H NMR (300 MHz, CDCl3): δ 9.13 (d, J=2.2 Hz, 1H), 8.43 (s, 2H), 8.39 (d, J=2.4 Hz, 1H), 8.26 (d, J=3.4 Hz, 1H).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12](=O)[CH3:13])=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[CH2:15]([NH2:18])[CH2:16][NH2:17]>C(O)(=O)C>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([NH:17][CH2:16][CH2:15][NH2:18])[CH3:13])=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: NCCN
Reactant: CC(=O)c1ccc(-n2cnnn2)cc1
Solvent: CC(=O)O
Product: CC(NCCN)c1ccc(-n2cnnn2)cc1

Procedure:
By using 1-[4-(1H-tetrazol-1-yl)phenyl]ethanone (250 mg), ethylenediamine (400 μl) and acetic acid (700 μl) as starting materials, the title compound (60.5 mg) was obtained in the same manner as that of Reference Example 64, (1).
Reaction SMILES: [CH:1]([S:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1)([CH3:3])[CH3:2].C([Li])CCC.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.CCCCCC>[C:16]1([S:22]([N:9]2[CH:5]([S:4][CH:1]([CH3:3])[CH3:2])[CH2:6][CH2:7][C:8]2=[O:10])(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)SC1CCC(=O)N1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)SC1CCC(=O)N1S(=O)(=O)c1ccccc1
Yield: 46 %

Procedure:
To 2.5 g of 5-isopropylthio-pyrrolidin-2-one in 130 cm3 of tetrahydrofuran, there is added at -70° to -65° C., 10.48 cm3 of a 1.5M solution of butyllithium in hexane. This is maintained for 20 minutes at this temperature, then 2.76 g of benzenesulphonyl chloride is added in 25 cm3 of tetrahydrofuran. After allowing to return to ambient temperature, concentrating under reduced pressure, taking up with water, filtering and drying, 2.15 g of the expected product is obtained. m.p., 91°-93° C., crystallized from ethanol.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[O:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OCC)=O.C(OC(N1CCC2(C3C(=CC=CC=3)C(=O)O2)CC1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1C=CC=CC=1>[OH:14][C:11]1([C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][OH:22])[CH2:12][CH2:13][N:8]([CH3:1])[CH2:9][CH2:10]1
Reactant: O=C1OC2(CCN(Cc3ccccc3)CC2)c2ccccc21
Agent: CCOC(=O)Cl
Agent: CCOC(=O)N1CCC2(CC1)OC(=O)c1ccccc12
Agent: [Al+3]
Solvent: c1ccccc1
Product: CN1CCC(O)(c2ccccc2CO)CC1

Procedure:
A solution of 5.8 g. of 1'-benzyl-1,3-dihydrospiro[isobenzofuran-1,4'-piperidine]-3-one, 40 ml. of benzene, and 2.5 ml. of ethyl chloroformate is heated under reflux for 18 hours and concentrated to a solid. Recrystallization from benzene-cyclohexane provides colorless crystals, m.p. 150°-151°, of 1,3-dihydro-1'-ethoxycarbonylspiro[isobenzofuran-1,4'-piperidine]-3-one. Reduction with lithium aluminum hydride by the method described in Example 16b provides 4-hydroxy-4-(α-hydroxy2-tolyl)-1-methylpiperidine, m.p. 118°-119°.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C:7](=[O:8])[C:5](=[O:6])[O:4][CH2:3]1.[H][H]>C1COCC1>[CH3:1][C:2]1([CH3:9])[C@@H:7]([OH:8])[C:5](=[O:6])[O:4][CH2:3]1
Reactant: [H][H]
Reactant: CC1(C)COC(=O)C1=O
Solvent: C1CCOC1
Product: CC1(C)COC(=O)[C@@H]1O
Temperature: 50 °C
Reaction time: 45 h

Procedure:
0.0025 m-mole of rhodium-1,5-cyclooctadienechloride complex and 0.0065 m-mole of one of the asymmetric ligand compounds indicated in Table 2 were dissolved in 10 ml of THF, and 5 m-mole of ketopantolactone was added thereto. Reduction was carried out at a hydrogen atmosphere of 50 atm. The mixture was stirred at 50° C. for 45 hours. The reaction mixture was concentrated under reduced pressure and distilled under reduced pressure to obtain optically active (R)-(-)pantolactone. The results are shown in Table 2.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([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.N1C=CC=CC=1.[Cl:26][C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl.O>ClCCl>[CH:1]([N:14]1[CH2:19][CH2:18][N:17]([C:27]([Cl:26])=[O:29])[CH2:16][CH2:15]1)([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
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: O=C(Cl)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 0.25 h
Yield: 216 %

Procedure:
A solution of 2.522 g (10 mmol) of 1-benzhydrylpiperazine and of 1.62 ml (20 mmol) of pyridine in 15 ml of dichloromethane is added, dropwise, to a solution of 1.187 g (4 mmol) of triphosgene in 10 ml of dichloromethane, cooled to −5° C. under an argon atmosphere. Stirring is continued at −5° C. for 15 minutes and then at ambient temperature for 3 hours. 50 ml of dichloromethane and 50 ml of water are subsequently added. The mixture is separated by settling out and the organic phase is washed with 2×25 ml of water and then 25 ml of a saturated aqueous solution of sodium chloride. The product is dried over sodium sulfate and evaporated under vacuum, so as to obtain 2.72 g of product in the form of a gum, used as it is in the following step.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[N-:10]=[N+:11]=[N-:12].[Na+].Cl.C(N(CC)CC)C.Cl>CN1CCCC1=O>[OH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]2[NH:12][N:11]=[N:10][N:2]=2)=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: Oc1ccc(-c2nnn[nH]2)cc1
Temperature: 140 °C
Yield: 78.6 %

Procedure:
A mixture of 4-cyanophenol (4.8 g, 40 mmol), sodium azide (7.8 g, 120 mmol) and triethylamine hydrochloride (8.24 g, 60 mmol) in 1-methyl-2-pyrrolidinone (40 ml) was stirred and heated in an oil bath at 140° C. for five hours. The cooled solution was acidified with 2M hydrochloric acid (200 ml) and extracted with ethyl acetate (3×100 ml). The combined ethyl acetate extracts were washed with water (3×100 ml), dried over anhydrous magnesium sulphate, filtered and evaporated to a fawn solid which was crystallised from 50% v/v ethyl acetate in isohexane to give the title compound (5.1 g.) NMR d (d6-DMSO) 6.95 (2H,d), 7.85 (2H,d), 10.13 (1H,br); MS[MH]+ 163
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][N:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([O:19][CH3:20])=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]1[CH2:21][C:22](OCC)=O)[CH3:2].CC[O-].[Na+].C(O)C.C([O-])(=O)C.[NH4+:39]>C1CCCCC1>[CH2:1]([O:3][C:4]([C:5]1[CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9]([CH:8]2[CH2:21][C:22]=1[NH2:39])=[CH:10][C:11]([O:19][CH3:20])=[C:12]([O:17][CH3:18])[CH:13]=3)=[O:27])[CH3:2]
Reactant: CCOC(=O)CCN1CCc2cc(OC)c(OC)cc2C1CC(=O)OCC
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: CCO
Product: CCOC(=O)C1=C(N)CC2c3cc(OC)c(OC)cc3CCN2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.2 %

Procedure:
A solution of 3-(1-ethoxycarbonylmethyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-propionic acid ethyl ester (Helv. Chim. Acta 1958, 41, 119; 17.1 g, 45.0 mmol) in cyclohexane (340 mL) was treated with sodium ethylate (9.67 g, 135 mmol) and heated in an oil bath, and the ethanol formed during the reaction was removed by distillation over 30 min, while more cyclohexane was added in order to keep the reaction volume constant. After cooling the reaction mixture was neutralized with acetic acid and concentrated. The residue was dissolved in dichloromethane/water 1:1 and brought to pH 10 with concentrated ammonium hydroxide solution. The organic layer was separated, dried (MgSO4), and evaporated. The residue was dissolved in methanol (270 mL) and ammonium acetate (42.3 g, 548 mmol) was added. After stirring at r.t. for 90 min, the reaction mixture was evaporated and the residue partitioned between dichloromethane and 1 M aq. sodium hydroxide solution. The organic layer was dried (MgSO4), evaporated, and chromatographed (SiO2, CH2Cl2/MeOH/NH4OH 97.5:2.5:0.25) to afford the title compound (9.90 g, 66%). Light yellow solid, MS (ISP) 333.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[C:10]#[N:11].[Br:12]Br>CC(O)=O>[Br:12][C:7]1[C:2]([CH3:1])=[C:3]([C:10]#[N:11])[C:4](=[O:9])[NH:5][C:6]=1[CH3:8]
Reactant: Cc1cc(C)c(C#N)c(=O)[nH]1
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1[nH]c(=O)c(C#N)c(C)c1Br
Reaction time: 1 h
Yield: 72 %

Procedure:
To a stirred suspension of 4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (5 g, 33.78 mmol) in AcOH (25 mL) was dropwise added bromine (2.5 mL) at rt. Resulting solution was stirred for 1 h. Solvent was removed under reduced pressure. Obtained solid was recrystallised in hot EtOH and H2O to give the title compound as a white solid (5.5 g, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:14]2[C:22]3[C:17](=[C:18]([NH:23]C(=O)OC(C)(C)C)[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)([CH2:12][CH3:13])[CH2:9][C:10]#[N:11])=[CH:4][CH:3]=1>Cl.CO>[NH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:17]=1[CH:16]=[CH:15][N:14]2[C:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)([CH2:12][CH3:13])[CH2:9][C:10]#[N:11]
Reactant: CCC(CC#N)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Agent: Cl
Solvent: CO
Product: CCC(CC#N)(c1ccc(Cl)cc1)n1ccc2c(N)cccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The mixture of the product from Step C (250 mg, 0.59 mmol) and 4 N HCl/MeOH (10 mL) was stirred at room temperature for 2 h. After solvent was removed in vacuo, the residue was dissolved in ethyl acetate (20 mL), pH value adjusted to 9-10 with a saturated sodium bicarbonate solution, dried over sodium sulfate, then filtered. After removing the organic solvent, the title compound as a colorless oil was obtained. LC/MS m/z=324.1 [M+H]+.
Reaction SMILES: [Li][C@H]1CC(C(O)=O)N([Li])C1=O.[Li]CCCC.[CH3:17][C:18]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[C:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1.O>CCOCC.CCCCCC>[CH:19]1([CH:18]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH3:17])[CH:23]=[CH:22][CH:21]=[CH:20]1
Reactant: CC(=C1C=CC=C1)c1ccccc1
Agent: [Li]CCCC
Agent: [Li][C@H]1CC(C(=O)O)N([Li])C1=O
Solvent: CCOCC
Solvent: CCCCCC
Solvent: O
Product: CC(c1ccccc1)C1C=CC=C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a solution of 0.77 mL of dilithio (s)-(-)-2-pyrrolidone-5-carboxylic acid (6 mmol) in 40 mL of ether was added 7.8 mL of n-BuLi (1.6M solution in hexanes, 13 mmol) at 0° C. This solution was stirred for 30 min at room temperature. The solvent was removed under vacuum and 25 mL of hexane added. 6-Methyl-6-phenylfulvene, 1.06 (6 mmol) in 5 mL of hexane was added dropwise at -78° C. The resulting yellow solution was stirred for 7 h at -78° C. Water, 25 mL, was added dropwise at -78° C. and the solution warmed to room temperature. The organic layer was separated and washed with aqueous NaHCO3, H2O and then dried over MgSO4. Removal of solvent gave 0.8 g (79% yield) of 1-cyclopentadienyl-1-phenylethane as a light yellow oil. [α]D =2.0 ° (CHCl3), 5.8% ee.
Reaction SMILES: CS(O[CH2:6][C@H:7]([N:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:34])[C:15]=2[NH:19][C:20](=[O:33])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[C:24]([F:32])[CH:23]=2)[C:10]1=[O:35])[CH3:8])(=O)=O.[CH3:36][NH:37][CH2:38][CH:39]=[CH2:40].C(N(CC)CC)C.C(Cl)Cl>>[CH2:38]([N:37]([CH3:36])[CH2:6][C@H:7]([N:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:34])[C:15]=2[NH:19][C:20](=[O:33])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[C:24]([F:32])[CH:23]=2)[C:10]1=[O:35])[CH3:8])[CH:39]=[CH2:40]
Reactant: C=CCNC
Reactant: Cc1ccc2c(=O)n([C@H](C)COS(C)(=O)=O)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCN(C)C[C@@H](C)n1ccc2c(NC(=O)Cc3ccc(C(F)(F)F)c(F)c3)c(C)ccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-2-(5-(2-(3-fluoro-4-(trifluoromethyl)phenyl)acetamido)-6-methyl-1-oxoisoquinolin-2(1H)-yl)propyl methanesulfonate (100 mg, 0.0002 mol), N-methylprop-2-en-1-amine (30 mg, 0.4 mmol), triethylamine (200 mg, 0.002 mol) and methylene chloride (6 mL, 0.09 mol) was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the mixture was purified by reverse phase preparative HPLC to afford the desired product as a white solid.
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=[O:14])=[CH:5]1.Cl.[CH3:17][NH:18][CH3:19].[OH-].[K+]>CO>[OH:1][CH:2]([CH2:15][N:18]([CH3:19])[CH3:17])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=[O:14])=[CH:5]1
Reactant: O=Cc1cn(CC2CO2)c2ccccc12
Reactant: CNC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN(C)CC(O)Cn1cc(C=O)c2ccccc21
Temperature: 25 °C
Yield: 79.6 %

Procedure:
A mixture of 1-(2,3-epoxypropyl)indole-3-carboxaldehyde (0.5 g, 2.5 mmol), N,N-dimethylamine hydrochloride (4 g, 49 mmol) and anhydrous potassium hydroxide (2.75 g, 49 mmol) was stirred in dry methanol (50 ml) at −30° C. for 8 h., then allowed to slowly warm to room temperature. The mixture was concentrated under reduced pressure to half the original volume, then water was added and the mixture was extracted with dichloromethane. After drying with anhydrous sodium sulfate the solvent was removed under reduced pressure, and the oily residue was chromatographed on a silica gel column (eluent dichloromethane:methanol from (9:1) to (8:2)) to yield the entitled product as a yellow oil 0.49 g (80%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+:44]1[C:52]2[C:47](=[N:48][CH:49]=C[CH:51]=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.CN1CC(N)C1>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:44][CH:52]5[CH2:47][N:48]([CH3:49])[CH2:51]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: CN1CC(N)C1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(C(=O)NC2CN(C)C2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.08 h
Yield: 77.6 %

Procedure:
A mixture of 0.045 g (0.1 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (I-22), 0.042 g (0.110 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 ml (0.300 mmole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.01 g (0.12 mmole) of 1-Methyl-azetidin-3-ylamine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with water-acetonitrile (gradient, 0:100-80:20) to give 0.04 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-azetidin-3-yl)-benzamide (I-99), as a white solid.