Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:10]=[C:11]([C:15]3[N:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][NH:24]C(=O)OC(C)(C)C)=[CH:17][N:16]=3)[CH:12]=[CH:13][CH:14]=2)[N:6]=[C:5]([C:32]2[CH:37]=[C:36]([F:38])[C:35]([F:39])=[C:34]([F:40])[CH:33]=2)[CH:4]=[CH:3]1.FC(F)(F)C(O)=O>ClCCl>[NH2:24][CH2:23][CH2:22][CH2:21][C:18]1[CH:17]=[N:16][C:15]([C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[CH2:8][N:7]2[C:2](=[O:1])[CH:3]=[CH:4][C:5]([C:32]3[CH:37]=[C:36]([F:38])[C:35]([F:39])=[C:34]([F:40])[CH:33]=3)=[N:6]2)=[N:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)NCCCc1cnc(-c2cccc(Cn3nc(-c4cc(F)c(F)c(F)c4)ccc3=O)c2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCc1cnc(-c2cccc(Cn3nc(-c4cc(F)c(F)c(F)c4)ccc3=O)c2)nc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
49.3 70 mg (0.127 mmol) of tert-butyl [3-(2-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yl)propyl]carbamate are dissolved in 3 ml of dichloromethane, and 195 μl (2.54 mmol) of trifluoroacetic acid are added. The reaction mixture is stirred at room temperature for 15 h and evaporated. The residue is digested with diethyl ether and dried in vacuo; yield: 74 mg of “A285”; HPLC: Rt=2.63 min (method C); LC-MS: 452 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:11][C:12]1[CH:13]=[C:14]2[C:18]3=[C:19]([CH2:21][O:22][CH2:23][CH2:24][N:17]3[C@H:16]3[CH2:25][CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][C@@H:15]23)[CH:20]=1>>[CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:11][C:12]1[CH:13]=[C:14]2[C:18]3=[C:19]([CH2:21][O:22][CH2:23][CH2:24][N:17]3[C@H:16]3[CH2:25][CH2:26][NH:27][CH2:28][C@@H:15]23)[CH:20]=1
Reactant: Cc1ccc(C=O)c(C)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Product: Cc1ccc(CNc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCOC3)c(C)c1

Procedure:
Using 2,4-dimethylbenzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate from EXAMPLE 56, Part B was converted into the title compound of EXAMPLE 135. 1H NMR(CDCl3) δ: 9.55 (broad s, 1H), 9.35 (broad s, 1H), 7.18 (d, 1H, J=7.7 Hz), 7.01-6.95 (m, 2H), 6.64 (s, 1H), 6.51 (s, 1H), 4.57 (ABq, 2H), 4.25-4.20 (m, 1H), 4.20 (s, 2H), 3.67 (app t, 1H), 3.50-3.10 (m, 6H), 2.70-2.50 (m, 2H), 2.30 (s, 3H), 2.27 (s, 3H), 2.23-2.10 (m, 2H).
Reaction SMILES: [H-].[Na+].C1[O:18][C:6]2([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9](=[O:17])(=[O:16])[NH:8][CH2:7]2)OC1.[CH2:19]([O:26][CH:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35]Cl)[CH2:29][CH2:28]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>COCCOC.C(Cl)(Cl)Cl.CO.CO>[CH2:19]([O:26][CH:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][N:8]2[CH2:7][C:6](=[O:18])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9]2(=[O:16])=[O:17])[CH2:29][CH2:28]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: ClCCCN1CCC(OCc2ccccc2)CC1
Reactant: O=S1(=O)NCC2(OCCO2)c2ccccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: COCCOC
Product: O=C1CN(CCCN2CCC(OCc3ccccc3)CC2)S(=O)(=O)c2ccccc21
Temperature: 50 °C
Yield: 48.9 %

Procedure:
In 1,2-dimethoxyethane (40 mL) was suspended 60% sodium hydride (180 mg, 4.5 mmol.), and then 2H-1,2-benzothiazin-4(3H)-one 1,1-dioxide ethylene ketal (1.00 g, 4.1 mmol.) was added to the suspension. The suspension was heated for 1 hour under stirring. The reaction liquid was cooled to 50° C., and to this was added a solution of 4-benzyloxy-1-(3-chloropropyl)piperidine (1.11 g, 4.1 mmol.) in 1,2-dimethoxyethane (10 mL). The mixture was further heated for 20 hours under refluxing. The reaction liquid was filtered to remove insolubles and the solvent was distilled off to give a residue. To the residue were added aqueous 9% hydrochloric acid (30 mL) and methanol (30 mL), and the mixture was heated for 15 min. under refluxing. The reaction liquid was placed under reduced pressure to distill methanol off. The residue was treated with ice-water, and the deposited oil was extracted with dichloromethane. The dichloromethane portion was washed with water and an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off to leave a residue. The residue was treated by silica gel column chromatography (chloroform/methanol=30/1) to give the desired compound (860 mg, yield 45%) as a red oil.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:18])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:9]1)=O)(C)(C)C.CN(C=O)C.[H-].[Na+].[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29](F)[C:28]=1[Cl:34].Cl.CCO>>[Cl:26][C:27]1[C:28]([Cl:34])=[CH:29][CH:30]=[CH:31][C:32]=1[O:18][C@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:14][CH:15]([CH3:16])[CH3:17]
Reactant: CC(C)C[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: Fc1cccc(Cl)c1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)C[C@H](Oc1cccc(Cl)c1Cl)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-3-((S)-1-Hydroxy-3-methylbutyl)pyrrolidine-1-carboxylic acid t-butyl ester (50 mg, 0.2 mmol) was dissolved in DMF (940 μL, 12 mmol). Sodium hydride (5.6 mg, 233 μmmol) was then slowly added, and the mixture was stirred at room temperature for 15 minutes. 1,2-Dichloro-3-fluoro-benzene (64.1 mg, 388 μmmol) was added. The mixture was stirred at 70° C. for 3 hours, then concentrated under vacuum. 1.2M HCl in EtOH (1.1 mL, 1.3 mmol) was added, and the mixture was stirred overnight. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt (37.4 mg, 100% purity). MS m/z: [M+H]+ calcd for C15H21Cl2NO, 302.10; found 302.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:5](=[N:6][OH:7])[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:3]1[C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1.Cl.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32]Cl)[CH:27]=1>CN(C=O)C.CCOC(C)=O.O>[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][O:7][N:6]=[C:5]2[C:2]([CH3:24])([CH3:1])[C:3]([C:14]3[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][CH:19]=3)=[C:4]2[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:27]=1
Reactant: ClCc1cccnc1
Reactant: CC1(C)C(=NO)C(c2ccccc2)=C1c1ccc(S(C)(=O)=O)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)C(=NOCc2cccnc2)C(c2ccccc2)=C1c1ccc(S(C)(=O)=O)cc1
Temperature: 80 °C

Procedure:
To a solution of Example 45 (102 mg) in DMF (3 mL) was added Cs2 CO3 (390 mg) and a solution of 3-picolylchloride hydrochloride (154 mg) in DMF (3 mL). The mixture was heated at 80° C. for 18 hr, diluted with EtOAc and H2O. The aqueous phase was extracted with EtOAc, the combined organic phase was washed with brine, dried (MgSO4) and the solvent evaporated. The resulting residue was purified by flash chromatography (silica gel; hexane/EtOAc (40:60)) to give the title compound as white foam; 1H NMR (300 MHz, Ace-d6): δ 1.61 (s,6H), 3.17 (s, 3H), 5.22 (s, 2H), 7.36-7.41 (m, 4H), 7.69 (m, 2H), 7.85 (m, 3H), 7.98 (d, 2H), 8.52 (dd, 1H), 8.68 (br s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]1[C:21]([OH:23])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:48][CH:49]([CH3:52])[CH2:50][NH2:51].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:48][CH:49]([CH3:52])[CH2:50][NH:51][C:21]([C@H:9]1[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:23]
Reactant: CC(C)CN
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CNC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 118.4 %

Procedure:
A 20 mL vial was charged with ((2R)-1,4-bis(tert-butoxycarbonyl)-2-piperazinecarboxylic acid (1.52 g, 4.60 mmol, ASW MedChem Inc., New Brunswick, N.J.), HATU (2.10 g, 5.52 mmol, ChemImpex International Inc., Wood Dale, Ill.), 2-methylpropan-1-amine (0.457 mL, 4.60 mmol, Sigma-Aldrich, St. Louis, Mo.), DIPEA (1.60 mL, 9.19 mmol) and DMF (8 mL). The mixture was stirred at room temperature for 2.5 h. and then partitioned between water (80 mL) and EtOAc (50 mL). The aqueous phase was extracted with EtOAc (50 mL). The combined organic extracts were washed with saturated aqueous NaHCO3 (100 mL), water (100 mL) then brine (100 mL). The organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford di-tert-butyl (2R)-2-((2-methylpropyl)carbamoyl)-1,4-piperazinedicarboxylate (2.10 g) as a light brown foam.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH:5]([NH2:8])[CH2:6][OH:7].C(N(CC)CC)C.[C:16](Cl)(Cl)=[S:17]>C1COCC1>[CH2:4]([CH:5]1[CH2:6][O:7][C:16](=[S:17])[NH:8]1)[CH2:3][CH2:2][CH3:1]
Reactant: S=C(Cl)Cl
Reactant: CCCCC(N)CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCC1COC(=S)N1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
To a stirred cold solution of DL-2-amino-1-hexanol (1.1 ml) in dry THF (10 ml) was added triethylamine (2.8 ml) followed by dropwise addition of thiophosgene (0.81 ml) in dry THF (9 ml). The mixture was then stirred for 18 h at 20° C., evaporated under reduced pressure and the residue partitioned between water and diethyl ether. The ether extract was dried with sodium sulphate filtered and evaporated. The residue was dissolved in the minimum of hot 1:1 dimethylether-hexane and crystallised on cooling to give 4-butyloxazolidine-2-thione, mp 71-2°.
Reaction SMILES: C(O[C:4](=[O:21])[C:5](=[CH:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[N:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:9]([O:8][C:6]([C:5]1[C:4](=[O:21])[C:18]2[C:13](=[N:14][C:15]([CH3:20])=[C:16]([CH3:19])[CH:17]=2)[NH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNc1ccc(C)c(C)n1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2nc(C)c(C)cc2c1=O
Yield: 80.7 %

Procedure:
Experimental conditions analogous to those described for Step 2 of Example 60 were used with 10.61 g (36.29 mmol) of 2-[(5,6-Dimethyl-pyridin-2-ylamino)-methylene]-malonic acid diethyl ester and 150 mL of diphenyl ether to yield 7.21 g of 6,7-Dimethyl-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.C(=O)([O-])[O-].[K+].[K+].[F:16][C:17]([F:26])([F:25])[CH2:18][CH2:19][CH:20]([C:23]#[N:24])[C:21]#[N:22].O>CN(C)C=O>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][C:20]([CH2:19][CH2:18][C:17]([F:16])([F:25])[F:26])([C:21]#[N:22])[C:23]#[N:24]
Reactant: ClCc1ccccn1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccccn1
Yield: 57.7 %

Procedure:
2-(Chloromethyl)pyridine hydrochloride (303 mg) was suspended in N,N-dimethylformamide (3 ml), potassium carbonate (256 mg) was added thereto, and the mixture was stirred. Then, to the suspension was added a solution of (3,3,3-trifluoropropyl)malononitrile (300 mg) in N,N-dimethylformamide (3 ml), and further thereto was added potassium carbonate (256 mg), followed by stirring overnight at room temperature. To the reaction mixture was added water, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography to give 270 mg of 2-((2-pyridyl)methyl)-2-(3,3,3-trifluoropropyl)malononitrile represented by the following formula (hereinafter referred to as the present invention compound (5)).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[C:4]([CH:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=2)[O:2]1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:25][S:26]([O:12][CH2:11][CH:10]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[O:9][CH2:1][O:2][C:3]=12)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCC(CO)c1cccc2c1OCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCC(COS(C)(=O)=O)c1cccc2c1OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
To a solution of 6.65 g (28.1 mmol) of 2-(2, 3-methylenedioxyphenyl)heptanol in 80 ml of methylene chloride was added 4.30 ml (30.9 mmol) of triethylamine, and 2.28 ml (29.5 mmol) of methanesulfonyl chloride was dropwise added. The reaction mixture was stirred at room temperature for 30 minutes, washed with water twice, dried over anhydrous magnesium sulfate and the solvent was evaporated to give 8.76 g of 2-(2, 3-methylenedioxyphenyl)heptyl methanesulfonate as an oil.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15](Br)=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH3:20])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[CH3:26][S:27]SC>C1COCC1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([S:27][CH3:26])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH3:20])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cc2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CSSC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccc2c(c1)cc(C)n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 49.6 %

Procedure:
To a chilled solution of 1-benzenesulfonyl-5-bromo-2-methyl-1H-indole (350 mg, 0.99 mmol) in 4 mL of THF was added 440 μL (1.10 mmol) of n-BuLi (2.5 M solution in hexanes), followed by dimethyl disulfide (100 μL, 1.11 mmol). The mixture was stirred as it warmed to room temperature and was then quenched with ammonium chloride and extracted with three 15 mL portions of ethyl acetate. The combined organic layers were washed with three 15 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was adsorbed onto silica gel and chromatographed on silica gel using ethyl acetate-hexanes (1:99, then 2:98) to afford 156 mg (44.3% yield) of 1-benzenesulfonyl-2-methyl-5-methylsulfanyl-1H-indole as a clear oil.
Reaction SMILES: [Na].[C:2]([O:9][CH3:10])(=[O:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1>CO>[CH3:7][O:6][C:4](=[O:5])[CH:3]([CH2:16][C:15]1[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=1)[C:2]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)CC(=O)OC
Reactant: Fc1ccc(CBr)cc1
Agent: [Na]
Solvent: CO
Product: COC(=O)C(Cc1ccc(F)cc1)C(=O)OC
Reaction time: 0.5 h

Procedure:
To a solution of anhydrous methanol (250 mL) is added sodium metal (2.875 g, 0.125 mol) piecewise until the evolution of gas has deceased. Dimethyl malonate (16.5 g, 0.125 mol) is added dropwise and the mixture is stirred for 30 minutes. 4-Fluoro benzyl bromide (23.8 g, 0.126 mol) is added dropwise, and the reaction is refluxed for 2 hour. The majority of the solvent is removed under vacuum, and aqueous HCl is added. The solution is extracted with CHCl3, dried, and the solvent removed in vacuo. Distillation of the crude material under reduced pressure provides the desired compound which is used without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=CC=3)[C:13]2=[O:23])[S:5][C:6]=1[C:7]([O:9]CC)=[O:8].C1(CN2CCN(C3SC(C(OCC)=O)=C(C)N=3)C2=O)CC1>>[CH:22]1([CH2:17][N:14]2[CH2:15][CH2:16][N:12]([C:4]3[S:5][C:6]([C:7]([OH:9])=[O:8])=[C:2]([CH3:1])[N:3]=3)[C:13]2=[O:23])[CH2:21][CH2:20]1
Reactant: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(CC3CC3)C2=O)nc1C
Product: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)O
Yield: 82 %

Procedure:
Following the procedure as described in Example 6, making variations as required to replace ethyl 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylate with ethyl 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained in 82% yield: 1H NMR (300 MHz, DMSO-d6) δ 3.96 (t, J=7.8 Hz, 2H), 3.67 (t, J=7.8 Hz, 2H), 3.06 (d, J=6.9 Hz, 2H), 2.52 (s, 3H), 0.97-0.84 (m, 1H), 0.53-0.37 (m, 2H), 0.20-0.11 (m, 2H); MS (ES+) m/z 282.2 (M+1).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[CH3:6][C:7]([CH2:9][OH:10])=O.C(N(CC)CC)C>CO>[NH2:4][C:3]1[O:10][CH:9]=[C:7]([CH3:6])[C:2]=1[C:1]#[N:5]
Reactant: CC(=O)CO
Reactant: N#CCC#N
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1coc(N)c1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
To a mixture of malononitrile (0.96 g, 14.6 mmol), acetol (1.08 g, 14.6 mmol) in methanol (10 mL) at 0° C. was added, dropwise, triethylamine (2.0 mL). The reaction mixture was stirred at room temperature overnight. After removal of solvent under reduced pressure the crude solid washed with cold isopropanol to give product as white powder (0.54 g, 30%). HPLC/MS: (M+H)+ 123.3 m/z. Retention time (LC-MS)=1.81 min. 1H NMR (CD3OD): 6.58(s, 1H,); 1.95 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][C@:6]12[CH2:22][CH2:21][C@H:7]1[CH2:8][CH2:9][C:10]1[C:11]3[C:16]([NH:17][C:18]=12)=[C:15]([CH3:19])[C:14]([Cl:20])=[CH:13][CH:12]=3)C.Cl>CCO.[OH-].[Na+]>[Cl:20][C:14]1[C:15]([CH3:19])=[C:16]2[C:11]([C:10]3[CH2:9][CH2:8][C@@H:7]4[CH2:21][CH2:22][C@:6]4([CH2:5][C:4]([OH:23])=[O:3])[C:18]=3[NH:17]2)=[CH:12][CH:13]=1
Reactant: CCOC(=O)C[C@]12CC[C@H]1CCc1c2[nH]c2c(C)c(Cl)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(Cl)ccc2c3c([nH]c12)[C@@]1(CC(=O)O)CC[C@H]1CC3

Procedure:
The ester was dissolved in 22 mL of EtOH and 7 mL of 2.5N NaOH. The solution was refluxed for 30 minutes under nitrogen. The reaction mixture was then acidified with 1N HCl and extracted with 4×50 mL of ethyl acetate. The organic phase was dried over MgSO4 and concentrated in vacuo. Trituration of the resulting thick oil in n-heptane afforded cis-7-chloro-1,2,2a,3,4,9-hexahydro-8-methyl-9bH-cyclobuta[a]carbazole-9b-acetic acid, 1.28 g (50%), m.p. 189°-190° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH3:11][N:12]=[C:13]=[O:14]>C1(C)C=CC=CC=1>[CH3:11][NH:12][C:13]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][CH:2]1[CH3:1])=[O:14]
Reactant: CC1Cc2ccccc2N1
Reactant: CN=C=O
Solvent: Cc1ccccc1
Product: CNC(=O)N1c2ccccc2CC1C
Reaction time: 24 h
Yield: 89 %

Procedure:
1 mole of 2-methylindoline is dissolved in 300 ml of toluene and 1 mole of methyl isocyanate is added, the temperature not rising above 25° c. The mixture is left to stand for 1 day and the resulting precipitate is then filtered off. N-Methylaminocarbonyl-2-methylindoline with a melting point of 158°-160° C. is obtained.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[O:5][C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:7][N:8]=1.C([Li])CCC.[CH2:19]([Sn:23](Cl)([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22]>C1COCC1.CCCCCC>[CH2:28]([Sn:23]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:24][CH2:25][CH2:26][CH3:27])[C:2]#[C:3][C:4]1[O:5][C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:7][N:8]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CC(C)(C)c1cnc(C=C(Br)Br)o1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](C#Cc1ncc(C(C)(C)C)o1)(CCCC)CCCC
Reaction time: 0.5 h
Yield: 109.3 %

Procedure:
To a stirred solution of 1,1-dibromo-2-(5-t-butyl-oxazol-2-yl)ethylene (6.0 g, 19 mmole) in anhydrous THF (80 mL) at −78 deg C. under argon atmosphere. was added with 1.6 M n-butyllithium (32 mL, 51 mmole) in hexane dropwise over 20 min., the reaction mixture, stirred at −78 deg C. for 30 min and treated with tributyltin chloride (5.5 mL, 20 mmole). The reaction mixture was stirred for 30 min, warmed to 0 deg C., stirred at 0 deg C. for 30 min, and then at room temperature for 45 min. The mixture was passed through a short column of silica gel (deactivated with 2% triethylamine in hexane), and eluted with 10% EtOAc in dichloromethane to obtain crude product of 1-tributylstannyl-2-(5-t-butyl-oxazol-2-yl)acetylene as a brown oil (9.10 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CN(C(ON1N=[N:39][C:34]2[CH:35]=[CH:36][CH:37]=N[C:33]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CC1(N)CCC1>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:39][C:34]5([CH3:33])[CH2:37][CH2:36][CH2:35]5)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CC1(N)CCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(C)CCC4)c3n2)c2ccc(F)cc21
Reaction time: 16 h
Yield: 13.9 %

Procedure:
To a stirred solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (59 mg, 0.19 mmol), HATU (91.20 mmol, 0.24 mmol) and DIPEA (49 mg, 0.38 mmol) in 6 mL of DMF, 1-methylcyclobutanamine (21.00 mg, 0.25 mmol) was added in one portion at room temperature and the reaction mixture was stirred for 16 hours. The solvent was evaporated at 80° C. under reduced pressure and the residue was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 48% acetonitrile/52% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 70% acetonitrile/30% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-N-(1-methylcyclobutyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (10 mg, 13.7%) as an off-white solid. MS: (M+H)+=379; 1H NMR (300 MHz, DMSO): δ 12.82 (s, 1H), 9.10 (s, 1H), 8.47-8.38 (m, 2H), 8.24 (s, 1H), 7.70 (d, 1H, J=8.7 Hz), 7.17 (t, 1H, J=9.2 Hz), 4.15 (s, 3H), 2.54-2.45 (m, 2H), 2.15-2.13 (m, 2H), 1.96-1.88 (m, 2H), 1.62 (s, 3H).
Reaction SMILES: [CH:1]1([C:8]2[N:13]3[CH:14]=[CH:15][N:16]=[C:12]3[N:11]=[C:10](O)[C:9]=2[C:18]2[C:23]([F:24])=[CH:22][C:21]([F:25])=[CH:20][C:19]=2[F:26])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:29])=O>>[Cl:29][C:10]1[C:9]([C:18]2[C:19]([F:26])=[CH:20][C:21]([F:25])=[CH:22][C:23]=2[F:24])=[C:8]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[N:11]=1
Reactant: Oc1nc2nccn2c(C2CCCCCC2)c1-c1c(F)cc(F)cc1F
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1cc(F)c(-c2c(Cl)nc3nccn3c2C2CCCCCC2)c(F)c1

Procedure:
A mixture of the above 5-cycloheptyl-6-(2,4,6-trifluorophenyl)imidazo[1,2-a]pyrimidin-7-ol (294 mg) in 2 mL of phosphorous oxychloride is heated at reflux for 6 h. The excess phosphorous oxychloride is removed in vaccuo, and the resulting residue is dissolved in methylene chloride. The organic layer is washed with water, dried over magnesium sulfate, and concentrated. The residue is chromatographed over silica gel, eluting with a gradient of 10% ethyl acetate in hexanes to 33% ethyl acetate in hexanes. Concentration provides 7-chloro-5-cycloheptyl-6-(2,4,6-trifluorophenyl)imidazo[1,2-a]pyrimidine as a white solid (24 mg). MS: m/z 380.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15](=O)[CH3:16])=[CH:4][CH:3]=1.[OH-].[NH4+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[C:4](=[C:15]([CH3:16])[N:14]=[C:9]3[C:8]=2[CH:13]=[CH:12][CH:11]=[CH:10]3)[CH:3]=1
Reactant: CC(=O)Nc1ccccc1-c1ccc(F)cc1
Agent: [NH4+]
Agent: [OH-]
Product: Cc1nc2ccccc2c2ccc(F)cc12
Temperature: 120 °C
Reaction time: 48 h

Procedure:
The N-(4′-fluorobiphenyl-2-yl)acetamide (18.5 g, 80.7 mmol) was mixed with polyphosphoric acid (250 g) and heated at 120° C. with vigorous stirring for 48 hours. The hot reaction mixture was poured onto ice and stirred vigorously until homogeneous. Ammonium hydroxide (28-30%, aqueous) was added until the pH was greater than eight. A white precipitate was filtered, dissolved in ethyl acetate (250 mL), and re-filtered. The combined filtrate was washed with a saturated, aqueous, sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to a brown solid. The brown solid was purified by crystallization from a mixture of ethyl acetate-hexane to yield the title compound as a white, crystalline solid (15.9 g, 94%), m.p. 92-93° C.;