Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C([Li])CCC.[C:16]1(=[O:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.CCCCCC>O1CCCC1>[OH:22][C:16]1([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: O=C1CCCCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C2(O)CCCCC2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 11.4 %

Procedure:
To a solution of 4-bromobenzoic acid (3.00 g, 14.9 mmol) in tetrahydrofuran (54 mL) at −78° C. was added n-butyllithium (19.1 mL of 1.6 M in hexanes, 30.6 mmol) dropwise while maintaining the internal temperature below −65° C. The mixture was stirred at −78° C. for 30 min. Cyclohexanone (1.55 mL, 14.9 mmol) was added dropwise while maintaining the reaction temperature below −65° C. The mixture was stirred at −78° C. for 10 min then allowed to warm to room temperature and stirred for 2 h. The reaction mixture was quenched with saturated NH4Cl (50 mL) and 1N HCl (25 mL). The mixture was extracted with ethyl acetate (3×100 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The residue was stirred with 1:1 dichloromethane/hexane (20 mL) to provide a white solid, which was filtered and discarded. The filtrate was concentrated in vacuo and purified by silica gel chromatography (0-5% methanol/dichloromethane) to provide an off-white solid. The solid was stirred with hexane, filtered, and dried to provide 4-(1-hydroxycyclohexyl)benzoic acid (375 mg, 11%). ESI-MS m/z calc. 220.1. found 221.3 (M+1)+; Retention time: 1.18 minutes (3 min run). 1H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H), 7.88 (d, J=8.3 Hz, 2H), 7.60 (d, J=8.5 Hz, 2H), 4.84 (s, 1H), 1.81-1.46 (m, 9H), 1.35-1.17 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:14])=[N:4][C:5]([NH:8][CH2:9][CH2:10][S:11][CH2:12][CH3:13])=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>CO.C(Cl)Cl>[NH2:1][C:2]1[C:3]([OH:14])=[N:4][C:5]([NH:8][CH2:9][CH2:10][S:11]([CH2:12][CH3:13])=[O:23])=[N:6][CH:7]=1
Reactant: CCSCCNc1ncc(N)c(O)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: CCS(=O)CCNc1ncc(N)c(O)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
3.2 gm of 5-amino-2-(2'-ethylmercapto-ethylamino)4-hydroxy-pyrimidine (0.015 mol) were dissolved in a mixture of 60 ml of absolute methanol and 60 ml of absolute methylene chloride. The solution was admixed with a solution of 2.89 gm (0.015 mol) of m-chloro-perbenzoic acid in 50 ml of methylene chloride at -15° C. After stirring for 8 hours at 0° C., the mixture was evaporated in vacuo to nearly dryness and was fractionated on a silicagel column with a methylene chloride/methanol mixture of at first 10:1, then 5:1. 1.42 gm (41.1%) of a uniform product were obtained.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[C:8]([Cl:15])=[CH:7][C:6]=1[Cl:16])=[O:4].[CH2:17]([NH:19][C:20]([NH:22][CH2:23][CH3:24])=[S:21])[CH3:18]>>[BrH:1].[CH2:23]([N:22]1[C:3]([C:5]2[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[C:8]([Cl:15])=[CH:7][C:6]=2[Cl:16])([OH:4])[CH2:2][S:21][C:20]1=[N:19][CH2:17][CH3:18])[CH3:24]
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)c(Cl)cc1Cl
Reactant: CCNC(=S)NCC
Product: Br
Product: CCN=C1SCC(O)(c2cc(S(N)(=O)=O)c(Cl)cc2Cl)N1CC

Procedure:
was obtained in a manner analogous to that described in Example 1 d) from 3.5 g of 2-bromo-2',4'-dichloro-5'-sulfamoyl-acetophenone and 1.3 g of 1,3-diethyl-thiourea. M.p. 202° C (decomposition).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]2[CH2:14][C:13](=[O:15])[NH:12][C:9]2=[N:10][CH:11]=1.[C:16]([O:19][CH:20](OCC)OCC)(=O)[CH3:17]>>[CH2:16]([O:19][CH:20]=[C:14]1[C:8]2[C:9](=[N:10][CH:11]=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[CH:7]=2)[NH:12][C:13]1=[O:15])[CH3:17]
Reactant: O=C1Cc2cc(-c3ccco3)cnc2N1
Reactant: CCOC(OCC)OC(C)=O
Product: CCOC=C1C(=O)Nc2ncc(-c3ccco3)cc21

Procedure:
This compound was synthesized from 5-(2-furyl)-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one and diethoxymethyl acetate according to Procedure A. 1H NMR 400 MHz (DMSO-d6): δ 10.96 (s, 1H); 8.36 (s, 1H); 7.87–7.84 (m, 2H); 7.72 (s, 1H); 6.87 (d, 1H); 6.56 (m, 1H); 4.42 (m, 2H); 1.36 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C[Si](C)(C)C1C=CC([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH:21]=[CH:22][CH2:23]3)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH:21]=[CH:22][CH2:23]3)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: C[Si](C)(C)c1ccc(-c2cccc3c2C=CC3)cc1
Product: Clc1ccc(-c2cccc3c2C=CC3)cc1
Yield: 69 %

Procedure:
The synthesis was performed by the same procedure as in Metallocene Compound A (1-1) by using 4-chlorophenylboronic acid in place of 4-trimethylsilylphenylboronic acid in the synthesis of 4-(4-trimethylsilyl-phenyl)-indene to obtain a white solid of 4-(4-chloro-phenyl)-indene in a yield of 69%.
Reaction SMILES: [CH:1]1([O:11][CH2:12][C:13]#[C:14][C:15]2[C:23]3[C:18](=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])[CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]=2[C:31]([O:33]CC)=[O:32])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>O1CCCC1.CO>[CH3:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[NH:17][C:16]([C:31]([OH:33])=[O:32])=[C:15]2[C:14]#[C:13][CH2:12][O:11][CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1[nH]c2c(-c3ccccc3C)cccc2c1C#CCOC1CCCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cccc2c(C#CCOC3CCCc4ccccc43)c(C(=O)O)[nH]c12

Procedure:
To a solution of EXAMPLE 564B (180 mg) and 1-(prop-2-ynyloxy)-1,2,3,4-tetrahydronaphthalene (165 mg) in triethylamine (5 ml) was added bis(triphenylphosphine)palladium(II) dichloride (18.71 mg) and copper(I) iodide (4.23 mg). The reaction mixture was stirred at 70° C. for 3 hours, cooled and concentrated. The residue was dissolved in dichloromethane and purified by flash chromatography, eluting with dichloromethane, to provide ethyl 3-(3-(1,2,3,4-tetrahydronaphthalen-1-yloxy)prop-1-ynyl)-7-o-tolyl-1H-indole-2-carboxylate. This ester was hydrolyzed with aqueous NaOH in tetrahydrofuran and methanol to provide the title compound. 1H NMR (400 MHz, methanol-d4) 7.76 (dd, J=7.98, 1.23 Hz, 1 H), 7.52 (dd, J=6.75, 2.46 Hz, 1 H), 7.34-7.40 (m, 2 H), 7.27-7.31 (m, 2 H), 7.26 (d, J=7.98 Hz, 1 H), 7.13-7.19 (m, 3 H), 7.07-7.12 (m, 1 H), 4.97 (t, J=3.99 Hz, 1 H), 4.52-4.71 (m, 2 H), 2.79-2.90 (m, 1 H), 2.68-2.78 (m, 1 H), 2.14-2.21 (m, 1 H), 2.12 (s, 3 H), 1.91-2.06 (m, 2 H), 1.73-1.84 (m, 1 H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]1[S:13][C:12]([C:14]2[CH:19]=[C:18]([NH:20][CH:21]3[CH2:23][CH2:22]3)[N:17]3[N:24]=[CH:25][C:26]([CH:27]=[O:28])=[C:16]3[N:15]=2)=[CH:11][CH:10]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.O>CN(C=O)C>[CH:21]1([NH:20][C:18]2[N:17]3[N:24]=[CH:25][C:26]([CH:27]=[O:28])=[C:16]3[N:15]=[C:14]([C:12]3[S:13][C:9]([CH2:8][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:10][CH:11]=3)[CH:19]=2)[CH2:23][CH2:22]1
Reactant: C1CCNC1
Reactant: O=Cc1cnn2c(NC3CC3)cc(-c3ccc(CBr)s3)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cnn2c(NC3CC3)cc(-c3ccc(CN4CCCC4)s3)nc12
Temperature: 60 °C
Yield: 50.5 %

Procedure:
Potassium carbonate (30 mg, 0.20 mmol) was added to 5-(5-(bromomethyl)thiophen-2-yl)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (25 mg, 0.07 mmol) dissolved in DMF (0.7 mL). Pyrrolidine (6 μL, 0.07 mmol) was added and the reaction was heated to 60° C. for 4 h. Water (3 mL) was added and the orange precipitate was filtered and dried in vacuo to give 7-(cyclopropylamino)-5-(5-(pyrrolidin-1-ylmethyl)thiophen-2-yl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (13 mg, 54%) which was used without further purification. LCMS (ES): >85% pure, m/z 368 [M+1]+.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[S:15])[CH:6]([O:13][CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH:2]=[CH2:3].[CH2:16]=O.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[CH2:1]([NH:4][C:5](=[S:15])[C:6]([O:13][CH3:14])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[CH2:16][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH:2]=[CH2:3]
Reactant: C=CCNC(=S)C(OC)c1ccccn1
Reactant: C1COCCN1
Reactant: C=O
Product: C=CCNC(=S)C(CN1CCOCC1)(OC)c1ccccn1

Procedure:
Reacting N-allyl-2-methoxy-2-(2-pyridyl)thioacetamide with formaldehyde and morpholine by the procedure of Example 1 gives N-allyl-2-methoxy-3-morpholino-2-(2-pyridyl)thiopropanamide.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[O:4][C:5]1[C:10](C=O)=[CH:9][N:8]=[C:7]([NH:13][C:14]2[S:15][CH:16]=[C:17]([CH3:19])[N:18]=2)[CH:6]=1.[CH3:25][O:26][C:27](=[O:48])[CH:28]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:49]1COCC1>>[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]([NH:13][C:14]2[S:15][CH:16]=[C:17]([CH3:19])[N:18]=2)[N:8]=[CH:9][C:10]=1/[CH:49]=[CH:28]/[C:27]([O:26][CH3:25])=[O:48]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1csc(Nc2cc(Oc3c(F)cccc3F)c(C=O)cn2)n1
Reactant: C1CCOC1
Product: COC(=O)/C=C/c1cnc(Nc2nc(C)cs2)cc1Oc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 25 mL round-bottomed flask is charged with 4-(2,6-difluorophenoxy)-6-(4-methylthiazol-2-ylamino)nicotinaldehyde (534 mg, 1.54 mmol) and THF (10 mL). Methyl(triphenylphosphoranylidene)acetate (668 mg, 2.00 mmol) is added and the reaction mixture is stirred at room temperature. After 4 hours, additional methyl(triphenylphosphoranylidene)acetate (668 mg, 2.00 mmol) is added and the reaction mixture is and stirred overnight. The precipitate is filtered, concentrated, and purified by silica gel chromatography (1:1 EtOAc in hexanes) to afford (E)-methyl 3-(4-(2,6-difluorophenoxy)-6-(4-methylthiazol-2-ylamino)pyridin-3-yl)acrylate.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(N(CC)CC)C.[S:18](Cl)([CH3:21])(=[O:20])=[O:19]>C(Cl)Cl>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N1CCC(OS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
1-Isopropyl-4-hydroxypiperidine (1 g, 6.98 mmol), DCM (10 ml) and triethylamine (1.08 ml, 7.68 mmol) were cooled to 0-5° C. and mesyl chloride (0.54 ml, 6.98 mmol) was added dropwise under N2. The reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched with sat. NaHCO3 (20 ml) and the aqueous phase extracted with DCM (2×5 ml). The combined organic extracts were dried over MgSO4, filtered, washed with DCM and concentrated in vacuo to give the title compound (1.55 g, 100%) as a pale yellow oil.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=[C:15]([OH:17])C=CC=1O.[CH3:18][OH:19]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]1([C:7]#[C:8][C:18]([O:17][CH3:15])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccc(O)c(Cl)c1
Reactant: CO
Reactant: C#Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: COC(=O)C#Cc1ccccc1

Procedure:
A solution of phenylacetylene (10, 2 mmol), chlorohydroquinone(HQ-Cl) (0.4 mmol), molybdovanadophosphate (NPMoV) (35 mg) and palladium (II) acetate (50 mg) in methanol (10 mL) is stirred under CO/O2 (10 atm/0.5 atm) at 25° C. for 15 h. The reaction is then quenched with wet ether and the product is extracted with n-hexane. After removal of the solvent under reduced pressure, the product is isolated by column chromatography over silica gel (hexane:ethyl acetate 5:1) to give pure methyl phenylpropiolate.
Reaction SMILES: [C:1]1(=[O:7])[CH:5]=[CH:4][C:3](=[O:6])[CH2:2]1.[CH3:8][C:9]1[O:10][CH:11]=[CH:12][CH:13]=1>CO>[CH3:8][C:9]12[O:10][CH:11]([CH:12]=[CH:13]1)[CH:4]1[CH:5]2[C:1](=[O:7])[CH2:2][C:3]1=[O:6]
Reactant: Cc1ccco1
Reactant: O=C1C=CC(=O)C1
Solvent: CO
Product: CC12C=CC(O1)C1C(=O)CC(=O)C12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 4-cyclopentene-1,3-dione (10 g, 104 mmol) and 2-methylfuran (15 ml) are stirred at room temperature for 3 days. Methanol (50 ml) is then added and the solid is collected and dried on a Buchner funnel to give 1-methyl-10-oxa-tricyclo[5.2.1.0*2,6*]dec-8-ene-3,5-dione (14.3 g)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[Cl:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(CC)CC)C.[C:20](Cl)(=[O:24])[CH:21]([CH3:23])[CH3:22]>ClCCl.CO>[Cl:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[NH:1][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22]
Reactant: Nc1cnc2ccccc2c1Cl
Reactant: CC(C)C(=O)Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)Nc1cnc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
A solution of 3-amino-4-chloroquinoline (8.5 g, 48 mmol) in dichloromethane (100 mL) was cooled to 0° C. Triethylamine (42 mL, 0.30 mol) was added followed by a solution of isobutyryl chloride (9.6 mL, 0.10 mol) in dichloromethane (35 mL), which was added dropwise. The reaction was stirred overnight at room temperature. An analysis by LC/MS indicated the presence of starting material, and the reaction was heated at reflux for two hours. The reaction was still incomplete. The volatiles were removed under reduced pressure, and the residue was dissolved in dichloromethane (75 mL). Additional isobutyryl chloride (9.6 mL, 0.10 mol) was added, the reaction was stirred for three days at room temperature. The reaction was still incomplete, and additional isobutyryl chloride (3 mL) was added. The reaction was stirred overnight, diluted with methanol (10 mL), stirred for 30 minutes, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (150 mL), and the solution was washed with saturated aqueous sodium bicarbonate (3×50 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide 9.6 g of N-(4-chloroquinolin-3-yl)-2-methylpropanamide as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]1[C:19]2[S:32][CH:31]=[CH:30][C:20]=2[N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:39][CH2:40][CH2:41][CH2:42]Br>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:42][CH2:41][CH2:40][Br:39])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]1[C:19]2[S:32][CH:31]=[CH:30][C:20]=2[N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:22]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCCCBr
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3cc(O)ccc3n2C(=O)OC(C)(C)C)c2sccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(C)OC(=O)n1nc(-c2cc3cc(OCCCBr)ccc3n2C(=O)OC(C)(C)C)c2sccc21
Temperature: 100 °C
Yield: 42 %

Procedure:
To a solution of 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-5-hydroxy-indole-1-carboxylic acid tert-butyl ester (195 mg, 0.43 mmol, Example 5D) in 1,3-dibromopropane (2 mL) is added cesium carbonate (350 mg, 1.08 mmol). The resulting suspension is heated at 100° C. for 30 minutes. It is then filtered and concentrated. The residue is chromatographed through silica gel (ethyl acetate-n-heptane, 05:95 to 20:80 as eluant) to provide 103 mg (42%) of 5-(3-bromo-propoxy)-2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-indole-1-carboxylic acid tert-butyl ester as a yellow glass. LC/MS: RT=4.38 minutes, 576.11 m/e.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[N:14]=[CH:13][C:12]([NH:15][C:16](=[O:26])[C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH3:27])[N:3]=1>[Pd].CO.C1COCC1>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]([NH:15][C:12]2[CH:13]=[N:14][C:9]([NH:8][C:6]3[CH:5]=[C:4]([CH3:27])[N:3]=[C:2]([NH2:1])[N:7]=3)=[CH:10][CH:11]=2)=[O:26])=[CH:18][CH:19]=1
Reactant: Cc1cc(Nc2ccc(NC(=O)c3ccc([N+](=O)[O-])cc3)cn2)nc(N)n1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Nc2ccc(NC(=O)c3ccc(N)cc3)cn2)nc(N)n1
Reaction time: 20 h
Yield: 95.9 %

Procedure:
To a suspension of 11 (790 mg, 2.16 mmol) in 1:1 MeOH/THF (100 ml) was added 10% Pd/C (100 mg) and hydrogenated at 45 Hg mm. for 20 h. The reaction mixture was filtered and evaporated to dryness and recrystallized from DCM/Pert.ether to give 12 (695 mg, 96%); mp (DCM/pet.ether)>300° C.; 1H NMR [(CD3)2SO] δ 9.78 (s, 1 H, NH), 9.45 (s, 1 H, NH), 8.63 (dd, J=2.4, 0.3 Hz, 1 H, H-2′), 8.09 (d, J=9.0 Hz, 1 H, H-5′), 7.98 (dd, J=9.0, 2.6 Hz, 1 H, H-4′), 7.72 (d, J=8.7 Hz, 2 H, H-2,6), 6.61 (d, J=8.7 Hz, 2 H, H-3,5), 6.43 (s, 1 H, H-5″), 6.13 (s, 2 H, NH2), 5.73 (s, 2 H, NH2), 2.12 (s, 3 H, CH3); HRMS (FAB+) calc. for C17H18N7O (M+1) m/z 336.1573, found 336.1578; Anal. calc. for C17H17N7O-0.25H2O: C, 60.1; H, 5.2; N, 28.9; C, 60.2; N, 5.3; N, 29.0%.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1.C(N(CC)CC)C>O1CCOCC1.O>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([S:18]([NH:1][C@@H:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4])(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)[C@@H](N)C(=O)O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cccc(S(=O)(=O)N[C@@H](C(=O)O)C(C)(C)C)c1
Yield: 93.4 %

Procedure:
D-tert-leucine (3 g, 22.9 mmol), 3-methoxy benzenesulfonyl chloride (4.68 g, 22.6 mmol) and triethylamine (6.4 ml, 45.7 mmol) are stirred in dioxane-water (1:1, 60 ml) at ambient temperature for 20 minutes. The reaction mixture is concentrated in vacuo and the residue is re-dissolved in Ethyl Acetate and washed with 1 N HCl. The organics are separated and washed with brine. The organic layer is dried over MgSO4 and concentrated to afford the title compound as a white solid (6.36 g, 92% yield). 1H-NMR (CDCl3, 400 MHz): δ 7.49 (d, 1H, J=8), 7.39 (s, 1H), 7.32 (t, 1H, J=8.11), 7.00 (m, 1H), 5.67 (d, 1H, J=12), 3.86 (s, 3H), 3.42 (d, 2H, J=8), 1.01 (s, 9H). Mass spectrum (302.0; M+1, 300.0; M−1).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:9]=2[CH3:18])=[C:5]([NH2:19])[NH:4][N:3]=1.O=[C:21]([C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)[CH2:22][C:23]#[N:24]>C(O)(=O)C>[CH3:1][C:2]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:17])[F:16])[C:9]=2[CH3:18])=[C:5]2[N:19]=[C:21]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[CH:22]=[C:23]([NH2:24])[N:4]2[N:3]=1
Reactant: Cc1n[nH]c(N)c1Cc1cccc(C(F)(F)F)c1C
Reactant: N#CCC(=O)c1ccncc1
Solvent: CC(=O)O
Product: Cc1nn2c(N)cc(-c3ccncc3)nc2c1Cc1cccc(C(F)(F)F)c1C
Temperature: 140 °C
Reaction time: 0.67 h

Procedure:
To a suspension of 3-methyl-4-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-5-amine (100 mg, 0.37 mmol) in acetic acid (2 mL) was added 3-oxo-3-(4-pyridinyl)propanenitrile (54.3 mg, 0.37 mmol). The reaction mixture was irradiated (microwave) and stirred at 140° C. for 40 minutes. Reaction mixture was cooled down, diluted with acetic acid (2 mL) and stood still overnight. Precipitate was collected by filtration. The crude product was purified with column chromatography to provide titled product. (23 mg, 16%); LC/MS: MS (ES+) m/e 398 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.57 (s, 3H) 1.72 (s, 3H) 3.44 (s, 2H) 6.01 (s, 1H) 6.45 (d, J=7.58 Hz, 1H) 6.50-6.55 (m, 1H) 6.73 (d, J=7.58 Hz, 1H) 7.72-7.80 (m, 2H) 8.03-8.10 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:15](=[CH:16][CH:17]=1)[C:9]1([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[NH:8][CH2:7][CH2:6]2.[F:18][C:19]([F:32])([F:31])[C:20]1[CH:30]=[CH:29][CH:28]=[CH:27][C:21]=1[CH:22]=[CH:23][C:24](O)=[O:25].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:15](=[CH:16][CH:17]=1)[C:9]1([CH2:10][CH2:11][N:12]([C:24](=[O:25])/[CH:23]=[CH:22]/[C:21]3[CH:27]=[CH:28][CH:29]=[CH:30][C:20]=3[C:19]([F:31])([F:32])[F:18])[CH2:13][CH2:14]1)[NH:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCNC21CCNCC1
Reactant: O=C(O)C=Cc1ccccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc2c(c1)CCNC21CCN(C(=O)/C=C/c2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of 6-methoxy-3,4-dihydro-2H-spiro[isoquinoline-1,4′-piperidine] (570 mg, 2.45 mmol) in CH2Cl2 (20 mL) were added ortho-(trifluoromethyl)cinnamic acid (132 mg, 0.61 mmol), i-Pr2NEt (0.43 mL, 2.45 mmol), HOBt (99 mg, 0.73 mmol) and EDC.HCl (141 mg, 0.73 mmol). The mixture was stirred at rt for 3 d. The mixture was diluted with EtOAc (80 mL), washed with water (30 mL) and satd aq NaHCO3 (30 mL), and dried over Na2SO4. Removal of the solvent left an orange oil (378 mg). A portion of the oil was purified by preparative HPLC to afford (E)-1-(6-methoxy-3,4-dihydro-2H-spiro[isoquinoline-1,4′-piperidine]-1′-yl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one. LC-MS Method 1 tR=1.37, min, m/z=431; 1H NMR (CDCl3) 2.25 (m, 4H), 3.16 (br s, 2H), 3.39 (m, 1H), 3.45 (br s, 2H), 3.78 (s, 3H), 3.84 (m, 1H), 4.11 (m, 1H), 4.78 (m, 1H), 4.9 (1H), 6.65 (s, 1H), 6.83 (m, 2H), 7.12 (d, 1H), 7.4-7.75 (4H), 7.98 (d, 1H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:16]([O:18][CH3:19])=[O:17].ClCCl>O>[CH3:19][O:18][C:16]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4][CH2:5]1)=[O:17]
Reactant: OCC1CCNCC1
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)N1CCC(CO)CC1
Temperature: 5 °C
Yield: 90 %

Procedure:
4-Hydroxymethylpiperidine (47.6 g, 1.0 eq) and water (300 mL) were charged to a flask. The resulting mixture was cooled to 0-10° C. Potassium carbonate (85.7 g, 1.5 eq) dissolved in water (150 mL) and methyl chloroformate (38.4 mL, 1.1 eq) were added while maintaining the temperature at below 10° C. When the addition was complete, the reaction mixture was warmed up to 20-30° C. for 1 hour. After the reaction was complete, dichloromethane (500 mL) was added to the reaction mixture. The organic layer was collected and washed with 1 M phosphoric acid solution (200 mL), saturated sodium bicarbonate solution (200 mL) and saturated sodium chloride solution (200 mL). The organic layer was dried over sodium sulfate (50 g, 1 w/w eq) and then distilled under vacuum to produce the title intermediate. (67.0 g, 90% yield)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@@H:4]([O:23][CH2:24][CH3:25])[C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][C:8]=1[O:21][CH3:22])O.O.O.C(O)(=O)C(O)=O>C(O)(C)C.[Pd]>[CH3:1][O:2][C:3](=[O:26])[C@@H:4]([O:23][CH2:24][CH3:25])[CH2:5][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[O:21][CH3:22]
Reactant: CCO[C@H](C(=O)OC)[C@H](O)c1ccc(OCc2ccccc2)cc1OC
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CC(C)O
Product: CCO[C@@H](Cc1ccc(O)cc1OC)C(=O)OC
Yield: 85 %

Procedure:
A solution of (2S,3R)-3-(4-benzyloxy-2-methoxy-phenyl)-2-ethoxy-3-hydroxy-propionic acid methyl ester (100 mg, 200 μmol) and oxalic acid dihydrate (150 mg, 1.2 mmol) in isopropanol (2 ml) was hydrogenated at a pressure of 50 atmospheres over 10% palladium on charcoal (20 mg) at ambient temperature for 6.5 h. The catalyst was filtered off and the solvent evaporated under reduced pressure. The residue was dissolved in ice water/aqueous sodium bicarbonate solution 1/1 and extracted two times with ethyl acetate. The combined extracts were washed two times with ice water/brine 1/1 and dried over sodium sulfate. The solvent was removed under reduced pressure to give a yellow liquid which was purified by column chromatography (silica gel, cyclohexane/AcOEt) to yield 43 mg (170 μmol, 85%) of the title compound as light yellow liquid.