Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=4)[CH:18]=3)[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[Cl:35][CH2:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39]([C:43]2[CH:48]=[C:47]([O:49][CH3:50])[C:46]([O:51][CH3:52])=[C:45]([O:53][CH3:54])[CH:44]=2)[CH:38]=1>>[ClH:35].[ClH:35].[ClH:35].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[CH:24]=[C:25]([O:33][CH3:34])[C:26]([O:31][CH3:32])=[C:27]([O:29][CH3:30])[CH:28]=4)[CH:18]=3)[CH2:14][CH2:15]2)[CH2:36][C:37]2[CH:42]=[CH:41][N:40]=[C:39]([C:43]3[CH:48]=[C:47]([O:49][CH3:50])[C:46]([O:51][CH3:52])=[C:45]([O:53][CH3:54])[CH:44]=3)[CH:38]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(NC2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)cc1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Product: COc1ccc(N(Cc2ccnc(-c3cc(OC)c(OC)c(OC)c3)c2)C2CCN(Cc3ccnc(-c4cc(OC)c(OC)c(OC)c4)c3)CC2)cc1
Product: Cl

Procedure:
4-(p-Anisidino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (1.56 g) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (1.08 g) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a trihydrochloride which gave the title compound as yellow powder.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.O=C(Cl)[O:25][C:26](Cl)(Cl)Cl.[CH3:31][NH:32][CH2:33][CH2:34][CH3:35]>>[CH3:31][N:32]([CH2:33][CH2:34][CH3:35])[C:26]([N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1)=[O:25]
Reactant: CCCNC
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Product: CCCN(C)C(=O)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and methyl-propyl-amine. MS (ESI): 414.3 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:22][OH:23])[CH2:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:22][O:23][S:32]([CH3:31])(=[O:34])=[O:33])[CH2:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)CCC(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CCC(=O)OCc1ccccc1)COS(C)(=O)=O

Procedure:
10.8 g (33.4 mmol) of benzyl (4R)-4-t-butoxycarbonylamino-5-hydroxypentanoate and 3.4 g (33.4 mmol) of triethylamine were stirred in 200 ml of dichloromethane. 3.83 g (33.4 mmol) of methanesulfonyl chloride was added to the obtained mixture under cooling with ice. Crude benzyl (4R)-4-t-butoxycarbonylamino-5-methanesulfonyloxypentanoate was obtained by an ordinary method with dichloromethane as the extracting solvent. The crude product was stirred together with 7.2 g (170 mmol) of lithium chloride in 50 ml of DMF at 50° C. overnight. The solvent was evaporated, and the crude title compound obtained by an ordinary method with ethyl acetate as the extracting solvent was washed with a solvent mixture of hexane and ethyl acetate to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[NH:7]2.[CH3:14][NH:15][CH3:16].[CH2:17]=O>CN(C)C=O>[CH3:14][N:15]([CH2:17][C:11]1[C:2]([OH:1])=[C:3]2[C:8](=[C:9]([CH3:12])[CH:10]=1)[NH:7][C:6](=[O:13])[CH:5]=[CH:4]2)[CH3:16]
Reactant: CNC
Reactant: C=O
Reactant: Cc1ccc(O)c2ccc(=O)[nH]c12
Solvent: CN(C)C=O
Product: Cc1cc(CN(C)C)c(O)c2ccc(=O)[nH]c12
Reaction time: 12 h
Yield: 94.9 %

Procedure:
5-Hydroxy-8-methylcarbostyril (10.51 g, 60 mmol) and dimethylamine (aqueous 40% solution, 12.07 g, 66 mmol) were dissolved in N,N-dimethylformamide (30 ml). To this solution, formaldehyde (aqueous 37% solution, 5.36 g, 66 mmol) was added slowly at room temperature, and stirred. After 12 hours, dimethylamine (6 g, 33 mmol), formaldehyde (2.79 g, 33 mmol), and N,N-dimethylformamide (20 ml) were added thereto, and the mixture was stirred at room temperature for further 12 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the resultant residue was combined with chloroform and n-hexane. Crystals were collected by filtration, and dried under reduced pressure. As a result, 13.23 g of the title compound was obtained as pale reddish gray crystals (95%).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][O:17][C:18]([CH3:23])([CH3:22])[C:19](O)=[O:20].F[B-](F)(F)F.BrC1C=CC=C[N+]=1CC.CCN(C(C)C)C(C)C>ClCCl>[CH3:16][O:17][C:18]([CH3:23])([CH3:22])[C:19]([NH:15][C:12]1[CH:11]=[CH:10][C:9]([C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:14][N:13]=1)=[O:20]
Reactant: Nc1ccc(C#Cc2ccccc2)cn1
Reactant: COC(C)(C)C(=O)O
Agent: CC[n+]1ccccc1Br
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(C)(C)C(=O)Nc1ccc(C#Cc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 14 h
Yield: 46.2 %

Procedure:
(100 mg, 0.515 mmol) 5-Phenylethynyl-pyridin-2-ylamine (Example 1, step 1) was dissolved in dichloromethane (5 ml) and 2-methoxy-2-methylpropionic acid (91 mg, 0.77 mmol, 1.5 equiv.), 2-bromo-1-ethyl pyridinium tetrafluoroborate (CAS 878-23-9) (211 mg, 0.77 mmol, 1.5 equiv.) and Hunig's Base (0.26 ml, 1.54 mmol, 3 equiv.) were added. The mixture was stirred for 14 hours at room temperature. The reaction mixture was extracted with saturated Na2CO3 solution and dichloromethane. The organic layer was dried over sodium sulfate and evaporated to dryness. The crude product was purified by prep HPLC to afford the desired 2-methoxy-2-methyl-N-(5-phenylethynyl-pyridin-2-yl)-propionamide (70 mg, 46% yield) was obtained as a yellow oil, MS: m/e=295.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([OH:10])=O.S(Cl)(Cl)=O.[NH2:22][CH:23]([C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][CH:32]=1)CC1C=CC=CC=1.[OH-].[Na+]>ClCCl>[CH3:17][O:16][C:12]1[CH:11]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([NH:22][CH2:23][C:31]1[CH:32]=[CH:33][C:34]([C:35]([OH:37])=[O:36])=[CH:38][CH:39]=1)=[O:10]
Reactant: COc1cc(C=CC(=O)O)cc(OC)c1OC
Reactant: NC(Cc1ccccc1)c1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1cc(C=CC(=O)NCc2ccc(C(=O)O)cc2)cc(OC)c1OC
Yield: 113.1 %

Procedure:
3,4,5-trimethoxycinnamic acid (2.38 g, 10 mmol), thionylchloride (4.72 g, 40 mmol), dichloromethane (10 ml), 4-(1-amino-2-phenylethyl)benzoic acid (2.41 g, 10 mmol), and 10 ml of 1 mol/L sodium hydroxide are used according to the method for the production of compound III in Method one to obtain 4.20 g of 4-[(3,4,5-trimethoxycinnamoyl)aminomethyl]benzoic acid (intermediate M-42) as a white solid, with a yield of 91.2%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[F:31][C:32]([F:41])([F:40])[C:33]1[CH:34]=[CH:35][C:36]([NH2:39])=[N:37][CH:38]=1.CN1CCOCC1>ClCCl.CN(C)C=O>[F:24][C:21]1[CH:20]=[CH:19][C:18]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([NH:39][C:36]3[CH:35]=[CH:34][C:33]([C:32]([F:40])([F:31])[F:41])=[CH:38][N:37]=3)=[O:16])[C:9]2=[O:17])=[CH:23][CH:22]=1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Reactant: Nc1ccc(C(F)(F)F)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)Nc1ccc(C(F)(F)F)cn1
Reaction time: 0.5 h

Procedure:
To a suspension of 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (0.158 g, 0.477 mmol; Example 58D) in dichloromethane (2 mL) was added a catalytic amount of N,N-dimethylformamide followed by oxalyl dichloride (2.0 Min dichloromethane) (0.358 mL, 0.715 mmol). After stirring for 30 minutes, the reaction was concentrated. The residue was dissolved in dichloromethane (2 mL) and 5-(trifluoromethyl)pyridin-2-amine (0.066 g, 0.405 mmol) and N-methylmorpholine (0.079 mL, 0.715 mmol) were added. After stirring for 2 hours, the reaction was loaded onto a GraceResolv™ 12 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 75% ethyl acetate/hexanes (Flow=30 mL/minute) over 30 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ 8.55 (d, J=12.2, 1H), 8.25 (d, J=8.8, 1H), 7.92 (dd, J=2.2, 8.8, 1H), 7.33 (ddd, J=2.7, 5.3, 7.1, 4H), 7.06-6.96 (m, 4H), 4.22 (s, 2H), 3.55 (t, J=6.5, 2H), 2.83 (t, J=6.5, 2H); MS (ESI+) m/z 467.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]2[O:13][CH2:14][O:15][C:9]=2[CH:8]=1)[CH3:2].CCCCCC.C([Li])CCC.[CH3:27][S:28]SC.[OH-].[Na+]>C(OCC)C>[CH2:1]([O:3][CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]2[O:13][CH2:14][O:15][C:9]=2[C:8]=1[S:28][CH3:27])[CH3:2]
Reactant: CCOCOCc1ccc2c(c1)OCO2
Reactant: CSSC
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCCCCC
Product: CCOCOCc1ccc2c(c1SC)OCO2
Temperature: 0 °C
Reaction time: 2 h
Yield: 43.8 %

Procedure:
1.05 g of 1-[(ethoxymethoxy)methyl]-3,4-methylenedioxybenzene was dissolved in 10 ml of diethyl ether, 2 ml of a 2.52 M n-butyllithium hexane solution was added thereto at 0° C., and the mixture was stirred for 2 hours, and then 471 mg of methyldisulfide was added dropwise at −70° C. After completing the dropwise addition, the mixture was further stirred at room temperature for 12 hours. A 1N aqueous sodium hydroxide was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (ethyl acetate:hexane=1:20), to give 561 mg of the title compound as a colorless oil.
Reaction SMILES: [OH-].[Na+].CS(C)=O.C[O:8][C:9](=[O:22])[CH:10]([S:19][CH2:20][CH3:21])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.[C:23]([O:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:33][CH:32]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>O.O1CCCC1>[C:23]([O:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][O:18][C:15]2[CH:16]=[CH:17][C:12]([CH2:11][CH:10]([S:19][CH2:20][CH3:21])[C:9]([OH:8])=[O:22])=[CH:13][CH:14]=2)=[CH:33][CH:32]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CCSC(Cc1ccc(O)cc1)C(=O)OC
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: O
Product: CCSC(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 105.8 %

Procedure:
Sodium hydroxide (0.14 g; 3.5 mmole) was pulverized and added to DMSO (15 ml). 2-ethylsulfanyl-3-(4-hydroxyphenyl)propanoic acid methyl ester (described in Example 43b) (0.21 g, 0.87 mmole) was added and the resulting mixture was stirred at room temperature for 10 minutes before addition of 2-(4-(tert-butoxycarbonylamino)phenyl]ethyl-4-methylbenzenesulfonate (described in Example 40a) (0.342 g; 0.87 mmole). The reaction mixture was stirred at room temperature for 4 hours. Sodium hydroxide (1.08 g; 2.7 mmole) was dissolved in water (15 ml) and added to the reaction mixture followed by addition of tetrahydrofuran (5 ml). The reaction mixture was stirred at room temperature over night. Most of the solvents were evaporated. The residue was treated with diethyl ether and water and the phases were separated. The organic phase was dried with sodium sulfate and evaporated. Chromatography of the residue on silica gel using a gradient system of petroleum ether: diethyl ether (90:10, 75:25, 25;75 and 0:100) gave 0.41 g (34% yield) of 3-[4-{2-(4-[tert-butoxycarbonylamino]phenyl)ethoxy}phenyl]-2-ethylsulfanylpropanoic acid.
Reaction SMILES: [NH4+:1].[OH-].[Br-].[CH2:4]([N+:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9]C=1)[CH:5]=[CH2:6].O>C(O)C>[CH2:6]([NH:1][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[S:9][S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:7][CH2:4][CH:5]=[CH2:6])[CH:5]=[CH2:4]
Reactant: [NH4+]
Reactant: C=CC[n+]1csc2ccccc21
Agent: [Br-]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCNc1ccccc1SSc1ccccc1NCC=C
Reaction time: 96 h

Procedure:
NH4OH (28° Be, 100 ml) was added to N-allylbenzothiazolium bromide (10 g, 0.04 mole) in ethanol (100 ml). The resulting solution was held four days at room temperature, then poured into cold water (500 ml) and extracted twice with ethyl ether (2×100 ml). The organic solution was dried over anhydrous Na2SO4, then evaporated to dryness. The oily residue was purified by column chromatography silica gel, eptane:CH2Cl2 1:1) to give the product (yield 5 g).
Reaction SMILES: [O-]CC.[Na+].C(O)C.[CH2:8]([N:15]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[CH2:8]([N:15]1[CH2:16][CH2:17][CH2:18][CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:26](=[O:28])[CH2:25]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:8]([N:15]1[CH2:16][CH2:17][CH2:18][CH2:19][C:20](=[O:21])[CH:25]1[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)CCCCN(CC(=O)OCC)Cc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C1C(=O)CCCCN1Cc1ccccc1
Product: CCOC(=O)C1CCCN(Cc2ccccc2)CC1=O
Reaction time: 1.5 h
Yield: 75 %
Yield: 19 %

Procedure:
Under a nitrogen atmosphere, a 21% wt. sodium ethoxide-ethanol solution (1.23 ml, 3.31 mmol) was added to toluene (100 ml) at room temperature, and the resulting mixture was refluxed by the use of a Dean-Stark trap. A solution of ethyl 5-[benzyl(2-ethoxy-2-oxoethyl)amino]pentanoate (965.9 mg, 3.01 mmol) in toluene (50 ml) was added dropwise thereto over a period of 1.5 hours. After 3 hours, a 21% wt. sodium ethoxide-ethanol solution (1.23 ml, 3.31 mmol) was further added thereto. After another 1 hour, the toluene (30 ml) was distilled off with heating. After 5 hours, the reaction solution was poured into water (200 ml) and extracted with ethyl acetate (100 ml×2), and the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain ethyl 1-benzyl-3-oxoazepane-4-carboxylate (158.5 mg, 19%) and ethyl 1-benzyl-3-oxoazepane-2-carboxylate (213.8 mg, content=about 75%).
Reaction SMILES: C1(CN[C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H]2CC[C@@H](CO)O2)CC1.C(N(CC)CC)C.C1(CC(Cl)=O)C=CC=CC=1>C(#N)C.CN(C)C1C=CN=CC=1>[N:14]1[CH:6]=[C:7]2[C:11]([NH:10][CH:9]=[N:8]2)=[N:12][CH:13]=1
Reactant: OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: c1ncc2nc[nH]c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
6-(Cyclopropylmethylamino)-9-[(2R,5S)-tetrahydro-5-(hydroxymethyl)-2-furyl]-9H-purine (0.5 g, 1.44 mmoles) was dissolved in 20 mL acetonitrile. 4-Dimethylaminopyridine (10.2 mg, 0.08 mmoles) and triethylamine (620 μL, 4.4 mmoles) were added and the flask was chilled in an ice bath under a nitrogen atmosphere. Phenylacetyl chloride (1.11 g, 7.2 mmoles, Aldrich Chemical Co., Madison, Wis.) was added dropwise to the flask over a period of 15 minutes. The reaction was stirred at room temperature for 0.5 hours. The reaction was quenched with methanol and solvents were removed under vacuo. The residue was dissolved in 2 mL CHCL3 /CH3OH (9:1) and chromatographed on a column of silica gel (5×15 cm) in the application solvent. Additional chromatography was performed on the product containing fractions using a Chromatotron 2 mm silica gel plate developed with a hexane:acetone mixture (7:3). Lyophilization of the product containing fractions afforded 0.459 g of 6 -(cyclopropylmethylamino)-9-[(2R,5S)-tetrahydro-5-[(phenylacetyl)methyl]-2-furyl)]-9H-purine as an oil (78% yield): m.p. <25° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:25][C:26](Br)=[O:27].[NH2:29][CH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:25][C:26]([NH:29][CH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31]1)=[O:27]
Reactant: NC1CCc2ccccc21
Reactant: COc1cccc(CC2NCCc3cc(OC)c(OC)cc32)c1
Reactant: O=C(Br)CBr
Product: COc1cccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NC2CCc3ccccc32)c1

Procedure:
prepared by reaction of 1-(3-Methoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline and 2-bromoacetyl bromide with 1-Aminoindan
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([O:12]CC)=[O:11])[N:7]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH2:21][N:20]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:19][CH2:18]3)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].O[Li].O.Cl>C1COCC1.CCO.O>[CH2:28]([O:27][C:25]([N:20]1[CH2:19][CH2:18][C:17]2[C:22](=[CH:23][CH:24]=[C:15]([N:7]3[C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6]3)[CH:16]=2)[CH2:21]1)=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=O)c1cc(C(C)(C)C)nn1-c1ccc2c(c1)CCN(C(=O)OCc1ccccc1)C2
Agent: Cl
Agent: [Li]O
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(=O)O)n(-c2ccc3c(c2)CCN(C(=O)OCc2ccccc2)C3)n1
Reaction time: 3 h
Yield: 106.4 %

Procedure:
To a stirring solution of benzyl 6-(3-t-butyl-5-(ethoxycarbonyl)-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.160 g, 0.347 mmol) in 1:1:1 THF/EtOH/H2O (3 ml) at 22° C. was added LiOH.H2O (0.0727 g, 1.73 mmol). After 3 h, the completed reaction was acidified (pH 2-3) with 1M HCl and extracted with EtOAc (3×). The combined organic phases were washed with brine (2×), dried (MgSO4), filtered and evaporated to afford 1-(2-(benzyloxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-t-butyl-1H-pyrazole-5-carboxylic acid (0.16 g, 106% yield) as an oil which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.41-7.31 (m, 5H), 7.328-7.20 (m, 3H), 6.91 (s, 1H), 5.15 (s, 2H), 4.65 (brm, 2H), 3.66 (brs, 2H), 2.86 (t, 2H, J=6.0 Hz), 1.29 (s, 9H); MS (ESI) m/z: 434.2 (M+H+).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([O:11][CH:12]([CH3:14])[CH3:13])=[C:7](Br)[CH:6]=[N:5]1.[CH3:18][S:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.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>[F:1][C:2]([F:17])([F:16])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([O:11][CH:12]([CH3:14])[CH3:13])=[C:7]([C:23]2[CH:24]=[CH:25][C:20]([S:19][CH3:18])=[CH:21][CH:22]=2)[CH:6]=[N:5]1
Reactant: CC(C)Oc1c(Br)cnn(CC(F)(F)F)c1=O
Reactant: CSc1ccc(B(O)O)cc1
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: [Cs+]
Solvent: COCCOC
Product: CSc1ccc(-c2cnn(CC(F)(F)F)c(=O)c2OC(C)C)cc1
Yield: 80.8 %

Procedure:
A solution of 2-(2,2,2-trifluoroethyl)-4-(2-propoxy)-5-bromo-3(2H)-pyridazinone (1.2 g, 3.8 mmol), 4-(methylthio)phenylboronic acid (704 mg, 4.19 mmol), tetrakis(triphenylphosphine)palladium(0) (220 mg, 5% mmol) and cesium carbonate (2.72 g, 8.3 mmol) in 20 mL of ethylene glycol dimethyl ether was heated to reflux for 5 hours. The mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water, brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (94:6 hexanes/ethyl acetate). The product was obtained as a greenish solid (yield: 1.1 g, 81%). 1H NMR (300 MHz, CDCl3) δ 1.19 (d, J=7.5 Hz, 6H), 2.55 (s, 3H), 4.83 (q, J=9 Hz, 2H), 5.28 (h, J=6 Hz, 1H), 7.32 (d, J=9 Hz, 2H), 7.52 (d, J=9 Hz, 2H), 7.85 (s, 1H). MS (DCI) m/z 359 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:10][C:11]([NH2:15])=[C:12]([NH2:14])[CH:13]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([F:32])[CH:31]=1)[C:26](Cl)=[O:27].N1C=CC=C[CH:34]=1>>[F:22][C:23]1[CH:24]=[C:25]([C:26]([C:34]2[NH:15][C:11]3=[N:10][C:9]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)=[C:8]([C:7]4[CH:6]=[CH:5][N:4]=[CH:3][C:2]=4[F:1])[CH:13]=[C:12]3[N:14]=2)=[O:27])[CH:29]=[C:30]([F:32])[CH:31]=1
Reactant: Nc1cc(-c2ccncc2F)c(-c2cccnc2)nc1N
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Reactant: c1ccncc1
Product: O=C(c1cc(F)cc(F)c1)c1nc2cc(-c3ccncc3F)c(-c3cccnc3)nc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 10 %

Procedure:
To a solution of 3″-fluoro-3,2′:3′,4″-terpyridine-5′,6′-diamine (Intermediate 1, 0.1 g, 0.79 mmol) in pyridine (2 mL), 0.071 mL (0.78 mmol) of 3,5-difluorobenzoyl chloride were added. The mixture was stirred at room temperature for 16 h and the solvent was evaporated. The crude mixture was purified by flash chromatography (95:5 dichloromethane/methanol) to give the title compound (0.015 g, 10% of yield).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:22]#[N:23])=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=3)[N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>N1C=CC=CC=1>[CH2:28]([O:27][C:25](=[O:26])[NH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:22]#[N:23])=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=3)[N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1)[CH3:29]
Reactant: CCOc1ccc(-c2c(C#N)c3ccc(N)cc3n2CC)cc1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc2c(C#N)c(-c3ccc(OCC)cc3)n(CC)c2c1

Procedure:
6-Amino-2-(4-ethoxyphenyl)-1-ethyl-1H-indole-3-carbonitrile (31 mg, 0.1 mmol), compound 833, prepared in example 1BR, step B is treated with ethyl chloroformate (16 mg, 0.15 mmol) in pyridine (1.0 mL) at room temperature overnight to furnish, after purification using column chromatography [3-cyano-2-(4-ethoxyphenyl)-1-ethyl-1H-indol-6-yl]-carbamic acid ethyl ester (30 mg, 79%).