Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:3][CH2:4][CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)[CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=O.P(Cl)(Cl)([Cl:24])=O.Cl>C(#N)C.C(O)C.CCOCC>[ClH:24].[CH3:21][O:20][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[CH:1]=[N:3][CH2:4][CH:5]2[CH2:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)CCCC(CNC=O)c1cccc(OC)c1
Agent: Cl
Solvent: CCOCC
Solvent: CC#N
Solvent: CCO
Product: CCOC(=O)CCCC1CN=Cc2ccc(OC)cc21
Temperature: 60 °C

Procedure:
The formaldehyde obtained in Step C (6.8 g; 23 mmol) is dissolved in 100 ml of acetonitrile, then the reaction mixture is heated to approximately 60° C. Phosphorus oxychloride (7 ml) is added to the solution, which is heated at reflux for 6 hours with stirring and then evaporated under reduced pressure. The residue obtained is taken up twice in ethanol and evaporated under reduced pressure, and is then taken up in water. The aqueous phase is washed with dichloromethane and then rendered alkaline with a saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The organic phase is dried over magnesium sulphate, filtered and evaporated under reduced pressure. The oil obtained is taken un in ether saturated with HCl(g) and then evaporated under reduced pressure. The residue is taken up in toluene in the heated state and is stirred until precipitation occurs. The precipitate obtained is then suction-filtered off and the title product is obtained in the form of a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[C:25](=[O:26])[N:24]([CH2:27][CH2:28][CH3:29])[N:23]=[CH:22]4)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1>Br>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:16]=[CH:17][C:18]([N:21]4[C:25](=[O:26])[N:24]([CH2:27][CH2:28][CH3:29])[N:23]=[CH:22]4)=[CH:19][CH:20]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: CCCn1ncn(-c2ccc(N3CCN(c4ccc(OC)cc4)CC3)cc2)c1=O
Agent: Br
Product: CCCn1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Yield: 97 %

Procedure:
This compound was synthesized as a white amorphous solid from 4c (53.6 mg, 0.136 mmol) in 48% aqueous HBr (1.5 mL) in 97% yield by following general procedure 1.4: 1H NMR (400 MHz, CDCl3, δH) 7.62 (s, 1H), 7.38 (d, J=8.6 Hz, 2H), 7.06-6.90 (m, 4H), 6.74 (d, J=8.4 Hz, 2H), 3.83 (t, J=7.1 Hz, 2H), 3.37-3.31 (m, 4H), 3.24-3.18 (m, 4H), 1.83 (dd, J=14.5, 7.2 Hz, 2H), 0.98 (t, J=7.3 Hz, 3H). MALDI-MS: 380.2 (M+H+), 402.2 (M+Na+).
Reaction SMILES: C(O[C:4]([CH:6]1[C:14](=[O:15])[C:13]2[N:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:7]1=[O:16])=[O:5])C.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([NH:25][C:4]([CH:6]2[C:14](=[O:15])[C:13]3[N:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:7]2=[O:16])=[O:5])[CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)C1C(=O)c2cccnc2C1=O
Reactant: COc1cccc(N)c1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1cccc(NC(=O)C2C(=O)c3cccnc3C2=O)c1
Temperature: 25 °C

Procedure:
5,7-Dioxo-6,7-dihydro-5H-[1]pyrindine-6-carboxylic acid ethyl ester (100 mg) (see D. Binder, Monatshefte für Chemie, Vol. 105, Pp. 179-186, 1974), m-anisidine (0.124 ml) and acetic acid (0.052 ml) were suspended in toluene (5 ml). This mixture was refluxed for 2 hours under nitrogen. The mixture was cooled to room temperature and the ppt was collected with suction. The ppt was washed with toluene and dichloromethane and dried under reduced pressure to give a brown powder (112 mg). ESI−MS: m/z 297 (MH+); 1H-NMR (DMSO-d6): δ3.74 (3H, s), 6.54 (1H, dd, J=8.5 Hz, J=2.5 Hz), 7.04 (1H, bd, J=8.5 Hz), 7.16 (1H, t, J=8.5 Hz), 7.38 (1H, dd, J=7.0 Hz, 4.5 Hz), 7.44 (1H, t-like, 2.5 Hz), 7.70 (1H, dd, J=7.0 Hz, 1.5 Hz), 8.57 (1H, dd, J=4.5 Hz, 1.5 Hz), 10.79 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:6]=2[CH:22]=1.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][N:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:18][CH2:17]3)[C:6]=2[CH:22]=1
Reactant: Clc1ccc2c(c1)C(N1CCNCC1)=Nc1ccccc1O2
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C2=Nc3ccccc3Oc3ccc(Cl)cc32)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
A mixture of 2.20 g of 2-chloro-11-(1-piperazinyl)dibenz[b,f][1,4]oxazepine, 0.76 g of ethyl chloroformate and 0.97 g of potassium carbonate in 20 ml of N,N-dimethylformamide was stirred at 80° C. for 3 hrs. Ice water was added to the reaction mixture and extracted with ether. The etheral layer was washed with water, dried and concentrated. The residue was chromatographed on silica gel using a mixture of n-hexane and ethyl acetate (1:2) as eluents to give 2.62 g of colorless crystals, which were recrystallized from isopropyl ether to give colorless prisms, mp 121.5°-122.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[O:13])[CH:5]=[CH:4][N:3]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C>ClCCl>[CH3:29][S:30]([N:1]([S:30]([CH3:29])(=[O:32])=[O:31])[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[CH:16]=2)=[O:13])[CH:5]=[CH:4][N:3]=1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(CNc2ccccc2C(=O)Nc2cccc(C(F)(F)F)c2)ccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N(c1cc(CNc2ccccc2C(=O)Nc2cccc(C(F)(F)F)c2)ccn1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 49.2 %

Procedure:
193 mg (0.5 mmol) of 2-[(2-amino-pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-benzamide is mixed in 3 ml of dichloromethane with 69 mg (0.6 mmol) of methanesulfonic acid chloride and 61 mg (0.6 mmol) of triethylamine and stirred together for 1.5 hours at room temperature. Then, it is washed once with dilute sodium bicarbonate solution, dried, filtered and concentrated by evaporation. The residue is chromatographed via flash chromatography (5 g of Isolute) with a gradient of cyclohexane:ethyl acetate=100:0 to 50:50 as an eluant. 80 mg (30% of theory) of 2-[(2-bismethanesulfonylamino-pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-benzamide is obtained as a resin.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][P:25]([CH3:29])(=[O:28])[CH2:24][CH2:23]3)=[CH:18][C:17]=2[O:30][CH3:31])=[N:4][C:5]([NH:8][CH2:9][C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.NCC1SC=CC=1[S:39]([N:42]([CH2:45][CH3:46])[CH2:43][CH3:44])(=[O:41])=[O:40]>>[Cl:1][C:2]1[C:3]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][P:25]([CH3:29])(=[O:28])[CH2:24][CH2:23]3)=[CH:18][C:17]=2[O:30][CH3:31])=[N:4][C:5]([NH:8][CH2:9][C:10]2[S:11][CH:12]=[CH:13][C:14]=2[S:39]([N:42]([CH2:45][CH3:46])[CH2:43][CH3:44])(=[O:41])=[O:40])=[N:6][CH:7]=1
Reactant: COc1cc(N2CCP(C)(=O)CC2)ccc1Nc1nc(NCc2cccs2)ncc1Cl
Reactant: CCN(CC)S(=O)(=O)c1ccsc1CN
Product: CCN(CC)S(=O)(=O)c1ccsc1CNc1ncc(Cl)c(Nc2ccc(N3CCP(C)(=O)CC3)cc2OC)n1

Procedure:
The compound can be prepared as in Example 32 by reacting 2,5-dichloro-N-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]pyrimidin-4-amine (as described in Example 47) with 2-(aminomethyl)-N,N-diethylthiophene-3-sulfonamide.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][NH:8][C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[C:11]([O:18][CH2:19][CH2:20][CH3:21])[N:10]=1)[CH2:4][CH3:5])[CH3:2].Cl[C:23](OCC)=[O:24].Cl>>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:6][CH2:7][N:8]1[C:9]2[N:10]=[C:11]([O:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:13][C:14]=2[N:15]=[C:23]1[OH:24])[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CCCOc1ccc([N+](=O)[O-])c(NCCN(CC)CC)n1
Agent: Cl
Product: CCCOc1ccc2nc(O)n(CCN(CC)CC)c2n1

Procedure:
The compound was produced in a manner analogous to Example 4 (or Example 5) starting from 36 grams of 2-(diethylaminoethylamino)-3-nitro-6-n-propoxypyridine and 13.5 grams of ethyl chloroformate produced. Yield: 24 grams M.P. of the hydrochloride 210°-212° C.
Reaction SMILES: [CH:1]([O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19](C(OCC)=O)=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)([CH3:3])C.[CH3:27][O:28][C:29](=[O:38])[CH2:30]C1C=CC(I)=CC=1>C(N(CC)CC)C.[Cu]I.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>[CH3:27][O:28][C:29](=[O:38])[CH2:30][C:19]1[CH:25]=[CH:26][C:16]([C:15]#[C:14][C:11]2[CH:10]=[CH:9][C:8]([C:5]3([O:4][CH2:1][C:3]4[CH:9]=[CH:8][CH:5]=[CH:6][CH:7]=4)[CH2:7][CH2:6]3)=[CH:13][CH:12]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(OC(C)C)CC3)cc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 161.4 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-benzyloxycyclopropyl)-benzene (Intermediate 71, 60.0 mg, 0.20 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 66.0 mg, 0.24 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (15.0 mg, 0.08 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (56 mg, 0.08 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-7% EtOAc—hexanes) afforded 64.0 mg (81%) of the title compound as a yellow oil.
Reaction SMILES: C([O-])([O-])=[O:2].[K+].[K+].[C:7]([C:9]1[C:10]([NH:15][C:16](=O)[CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:11][CH:12]=[N:13][CH:14]=1)#[N:8].OO>CO.CS(C)=O.C(OCC)(=O)C>[C:21]1([CH2:20][CH2:19][CH2:18][CH2:17][C:16]2[NH:8][C:7](=[O:2])[C:9]3[C:10]([N:15]=2)=[N:11][CH:12]=[N:13][CH:14]=3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cncnc1NC(=O)CCCCc1ccccc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=c1[nH]c(CCCCc2ccccc2)nc2ncncc12
Yield: 1.8 %

Procedure:
Under an atmosphere of nitrogen, K2CO3 (3.057 g) was added to a solution of 5-phenyl-pentanoic acid (5-cyano-pyrimidin-4-yl)-amide (1.00 g) in MeOH (5 ml) and DMSO (1.2 ml). The mixture was cooled (ice bath) and hydrogen peroxide (35% in H2O, 1.5 ml) was added dropwise. The mixture was taken up in ethyl acetate and washed with water. The organic layer was dried (Na2SO4), filtered, and the solvent was evaporated. 2-(4-Phenyl-butyl)-3H-pyrimido[4,5-d]pyrimidin-4-one (18 mg, 1.8%) was obtained from the residue by subsequent column chromatography (silica gel, eluent gradient n-heptan/ethyl acetate=100:0-60:40) and preparative, reverse-phase HPLC (Agilent Zorbax XdB C18 column, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 7 min, flow rate 30 ml/min). MS: m/e=279.3 [M−H−]. 1H NMR (d6-DMSO): δ 1.62-2.00 (m, 4H), 2.55-2.80 (m, 4H), 7.17-7.18 (m, 2H), 7.26-7.28 (m, 3H), 9.56 (d, 1H), 9.64 (d, 1H), 11.13 (bs, 1H).
Reaction SMILES: Cl[CH:2]([CH:6](OC)OC)[C:3](=[O:5])[CH3:4].[C:11]([NH2:19])(=[NH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(=O)C.[Na+]>O1CCOCC1>[C:12]1([C:11]2[NH:19][C:2]([C:3](=[O:5])[CH3:4])=[CH:6][N:18]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(OC)C(Cl)C(C)=O
Reactant: N=C(N)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)c1cnc(-c2ccccc2)[nH]1
Temperature: 110 °C
Yield: 41 %

Procedure:
To a solution of 1 (2.2 g, 13.3 mmol) in 20 ml 1,4-dioxane was added benzamidine (3.24 g, 20.0 mmol) and sodium acetate (2.83 g, 33.3 mmol). The reaction was refluxed in an oil bath at 110° C. over 60 hours. After the reaction was cooled to room temperature, the salt was removed through a plug of celite and the filtrate was concentrated to a red oil. This oil was then taken up in ethyl acetate (50 ml) and extracted with 1N HCl (17 ml×3). The combined aqueous layers were basified with aqueous Na2CO3 and then were extracted with ethyl acetate (50 ml×3). The combined organic layers were dried over Na2SO4 and the solvent was removed. Purification by chromatography using CH2Cl2/MeOH (95:5/v:v) afforded 2′ (1.02 g) as the desired product in 41% yield. 1H NMR (acetone-d6, ppm) δ: 7.4-8.1 (m, 7H) and 2.42 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:21][CH2:20][C:11]2[NH:12][C:13]3[C:14](I)=[CH:15][CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][OH:34]>C(Cl)Cl.[Cu]I>[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][O:34][C:14]1[C:13]2[NH:12][C:11]3[CH2:20][CH2:21][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C:10]=3[C:18]=2[CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3c(I)cccc3c2C1
Reactant: CN(C)CCO
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CN(C)CCOc1cccc2c3c([nH]c12)CCN(C(=O)OC(C)(C)C)C3
Temperature: 150 °C
Yield: 67.1 %

Procedure:
tert-Butyl-6-iodo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (500 mg, 1.26 mmol), copper(I) iodide (71.7 mg, 0.38 mmol) and tri-potassium orthophosphate (533 mg, 2.51 mmol) were suspended in 2-dimethylaminoethanol (10 ml, 99.40 mmol) and sealed into a microwave tube. The reaction was heated to 150° C. for 1 hour in the microwave reactor and cooled to RT. The reaction mixture was diluted with DCM (100 mL), and washed with 2N NaOH (3×50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by preparative HPLC (0.1% NH3, CH3CN/H2O gradient) to afford tert-butyl 6-(2-(dimethylamino)ethoxy)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (304 mg, 67%) as a yellow gum.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:16][C:14]=3[CH:15]=2)=[C:7]([C:27]#[N:28])[CH:6]=1)C.[BH4-].[Na+].[Cl-].[Ca+2].[Cl-].O>C(O)C>[CH2:20]([C:17]1[CH:18]=[CH:19][C:13]2[O:12][C:11]([C:8]3[CH:9]=[CH:10][C:5]([CH2:4][OH:3])=[CH:6][C:7]=3[C:27]#[N:28])=[CH:15][C:14]=2[CH:16]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1ccc(-c2cc3cc(Cc4ccccc4)ccc3o2)c(C#N)c1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: N#Cc1cc(CO)ccc1-c1cc2cc(Cc3ccccc3)ccc2o1
Yield: 75 %

Procedure:
A solution of Ethyl-4-(5-benzylbenzofuran-2-yl)-3-cyanobenzoate (0.05 g, 0.13 mmol), sodium borohydride (0.01 g, 0.26 mmol) and calcium chloride (0.015 g, 0.13 mmol) in ethanol (2.5 mL) were stirred at room temperature for 1 hour. Water was added and the aqueous layer was extracted with ethyl acetate (×2, 10 mL). Organic layer was washed with water and brine and dried over sodium sulphate in 75% yield: 1H NMR (400 MHz, CDCl3) δ 8.06 (d, 1H), 7.79 (s, 1H), 7.64 (d, 1H), 7.63 (s, 1H), 7.43-7.21 (m, 8H), 4.78 (s, 2H), 4.06 (s, 3H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15]>>[CH:11]([C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]=1)=[CH:12][CH2:13][CH2:14][CH3:15]
Reactant: C1=Cc2ccccc2C1
Reactant: C=CCCCBr
Product: CCCC=CC1=CCc2ccccc21

Procedure:
Metallocenes MET 1, MET 3, and MET 4 were produced using suitable procedures. MET 2 was synthesized by first reacting lithiated indene with 5-bromo-1-pentene. Pure 3-(1-pentenyl) indene was obtained via vacuum distillation as a pale yellow oil. One mole of 3-(1-pentenyl) indene was added to diethyl ether and cooled to −74° C., and one mole of n-butyllithium was added. The reaction mixture was stirred at 21° C. for 3 hr, then cooled again to −74° C., followed by the addition of a diethyl ether solution of dichloro(diisopropylamino) boron, and then stirred for 12 hr while warming to 21° C. The resulting yellow slurry was centrifuged, and the bright yellow solution was poured off and solvent removed under reduced pressure. Monochloro(diisopropylamino)-3-(1-pentenyl)indenylboron was obtained as a yellow oil. One mole of monochloro(diisopropylamino)-3-(1-pentenyl)indenylboron was added to tetrahydrofuran and cooled to 0° C., followed by the addition of one mole of sodium cyclopentadiaenide, producing a yellow slurry, which was stirred at 21° C. for 12 hr. The reaction solution was centrifuged and then decanted off. Concentration under reduced atmosphere yielded the ligand shown below as a yellow oil:
Reaction SMILES: [C:1]([C:4]1[C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[N:28])[CH:22]=2)=[C:6]([Cl:20])[N:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][C:8]=12)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl>[Cl:20][C:6]1[N:7]2[CH2:12][CH2:11][NH:10][CH2:9][C:8]2=[C:4]([C:1]([NH2:2])=[O:3])[C:5]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[N:28])[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c(Cl)c(-c3cccc(C#N)c3)c(C(N)=O)c2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(-c2c(C(N)=O)c3n(c2Cl)CCNC3)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a solution of 2.90 g (7.23 mmol) of tert-butyl 8-carbamoyl-6-chloro-7-(3-cyanophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate in 7 ml of dichloromethane are added slowly 7 ml (72 mmol) of trifluoroacetic acid. After stirring for 1 hour at room temperature, the solvent is evaporated off under reduced pressure, the residue is taken up in water and the aqueous phase is basified by addition of aqueous ammonia. The white solid formed is separated out by filtration, rinsed with water and triturated in acetonitrile to give 1.7 g of 6-chloro-7-(3-cyanophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide in the form of a white powder after separating out by filtration and drying under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=2)[C:17]([O:19]C)=[O:18])=[N:6][C:7]=1[C:8]([NH:10][CH:11]1[CH2:13][CH2:12]1)=[O:9].[OH-].[Na+]>CO>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=2)[C:17]([OH:19])=[O:18])=[N:6][C:7]=1[C:8]([NH:10][CH:11]1[CH2:13][CH2:12]1)=[O:9]
Reactant: COC(=O)c1cccc(-c2cnc(N)c(C(=O)NC3CC3)n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ncc(-c2cccc(C(=O)O)c2)nc1C(=O)NC1CC1
Temperature: 92.5 °C
Yield: 15 %

Procedure:
Methyl 3-{5-amino-6-[(cyclopropylamino)carbonyl]pyrazin-2-yl}benzoate (480 mg, 1.5 mmol) was suspended in a 20 mL of 1:1 MeOH-5% aqueous sodium hydroxide and heated at 90-95° C. for 4 hours. The homogeneous reaction mixture was cooled to room temperature, concentrated to half the initial volume, cooled in an ice-bath, and acidified to pH 4 with concentrated HCl. A white solid precipitated and was collected by filtration, washed with water and dried in vacuo to give the intermediate 3-{5-amino-6-[(cyclopropylamino)carbonyl]pyrazin-2-yl}benzoic acid. The acid (40 mg, 0.13 mmol) was dissolved in DMF (1 mL) and 1-hydroxybenzotriazole (30 mg, 0.22 mmol), 1-[(3-dimethylamino)propyl]pyrazin-2-ethylcarbodiimide hydrochloride (30 mg, 0.16 mmol), and 4-methylmorpholine (30 mg, 0.28 mol) were added sequentially. After one hour 2-chloro-6-fluorobenzylamine (30 mg, 0.19 mmol) was added to the reaction mixture and stirring was continued at room temperature for 18 hours. It was then diluted with ethyl acetate (10 mL), washed with water, saturated sodium bicarbonate solution, and brine, dried over sodium sulfate, filtered, and concentrated. The oily residue was purified by flash chromatography (silica gel, eluted with ethyl acetate-hexanes gradient from 15% to 80% yield) to give 3-amino-6-[3-({[(2-chloro-6-fluorophenyl)methyl]amino}carbonyl)phenyl]-N-cyclopropyl-pyrazine-2-carboxamide (a tan color solid, 23 mg, 56% yield): 1H NMR (400 MHz, DMSO-d6): 8.87-8.86 (t, 1H), 8.85-8.83 (b, 1H), 8.65-8.64 (d, 1H), 8.45 (s, 1H), 7.83-7.81 (d, 1H), 7.53-7.51 (t, 1H), 7.41-7.39 (m, 2H), 7.26-7.21 (t, 1H), 4.63-4.61 (d, 2H), 2.85-2.81 (m, 1H), 0.73-0.64 (m, 4H); MS (EI) for C22H19ClFN5O2: 440 (MH+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[C:11]2([CH2:16][CH2:15][CH:14]([CH2:17][C:18](OCC)=[O:19])[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1.[F-].[Na+].O>O1CCCC1.ClCCl>[OH:19][CH2:18][CH2:17][CH:14]1[CH2:15][CH2:16][C:11]2([O:7][CH2:8][CH2:9][O:10]2)[CH2:12][CH2:13]1
Reactant: CCOC(=O)CC1CCC2(CC1)OCCO2
Agent: [Al+3]
Agent: [F-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: OCCC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.5 %

Procedure:
To a mixture of lithium aluminium hydride (831 mg) and anhydrous tetrahydrofuran (70 ml) at 0° C. was added a solution of ethyl 1,4-dioxaspiro[4.5]decane-8-acetate of Example 90 (2) (5.0 g) in anhydrous tetrahydrofuran (30 ml). The mixture was gradually warmed to about 25° C., stirred for 3 hours, and then sodium fluoride, water and dichloromethane were added to the reaction mixture. The precipitate was filtrated off with Celite, the filtrated organic layer was dried over sodium sulfate. The solvent was removed in vacuo from the organic layer to give 4.18 g of 8-(2-hydroxyethyl)-1,4-dioxaspiro[4.5]decane.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]12[CH2:12][CH2:11][C:8]([C:13]3[N:17]([CH3:18])[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])=[N:15][N:14]=3)([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)[NH2:4].[F:29][C:30]1([F:37])[CH2:33][CH:32]([C:34](O)=O)[CH2:31]1.C(N1C=CN=C1)(N1C=CN=C1)=O>C(Cl)Cl>[F:29][C:30]1([F:37])[CH2:33][CH:32]([C:34]2[O:1][N:2]=[C:3]([C:5]34[CH2:12][CH2:11][C:8]([C:13]5[N:17]([CH3:18])[C:16]([C:19]6[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=6[C:25]([F:28])([F:27])[F:26])=[N:15][N:14]=5)([CH2:9][CH2:10]3)[CH2:7][CH2:6]4)[N:4]=2)[CH2:31]1
Reactant: O=C(O)C1CC(F)(F)C1
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C12CCC(C(N)=NO)(CC1)CC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C12CCC(c3noc(C4CC(F)(F)C4)n3)(CC1)CC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N′-Hydroxy-4-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}bicyclo[2.2.2]octane-1-carboximidamide (1-G) (120 mg, 0.305 mmol) was added to a pre-stirred solution of 3,3-difluorocyclobutanecarboxylic acid 2-D (166 mg, 1.22 mmol) and carbonyldiimidazole (198 mg, 1.22 mmol) in CH2Cl2 (8 ml). The resulting mixture was stirred at room temperature for 48 h, then concentrated. The solid was resuspended in toluene and refluxed under nitrogen atmosphere for 3 h. The product was purified by C-18 reverse phase HPLC eluting with 30-80% acetonitrile/water with 0.1% TFA to yield 2-E as a white powder. MS (ESI+)=494.2 (M+1); 1H NMR (500 MHz, CDCl3): δ 2.09 (6H, m), 2.31 (6H, m), 3.03-3.11 (4H, m), 3.57-3.61 (4H, m), 7.56 (1H, m), 7.71 (2H, m), 7.86 (1H, m) ppm. Shh-Light II Assay: IC50: 1.4 μM.