Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]=O)[CH:5]=[CH:6][CH:7]=1.[C:11]1([NH:17]N)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)(=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:17][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=CCc1cccc(Cl)c1
Reactant: NNc1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: Clc1cccc(-c2c[nH]c3ccccc23)c1

Procedure:
A solution of 2-(3-chlorophenyl)-acetaldehyde (5.80 g, 37.5 mmol) and phenylhydrazine (6.22 g, 57.5 mmol) in glacial acetic acid (150 mL) was saturated with nitrogen by bubbling N2 through the solution. The solution was then refluxed for about 2.5 hours. Solvent was removed in vacuo and the residue obtained was dissolved in DCM and washed with 1N HCl aqueous solution (2 times), saturated NaHCO3 aqueous solution (2 times) and brine (2 times), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica, eluting with EtOAc/hexane 1:6. The title compound was obtained as a reddish oil. Yield: 5.30 g, 62%. Rf=0.26 (silica, EtOAc/hexane 1:4).
Reaction SMILES: O1CCCC1.[Br-].[O:7]1[CH2:12][CH2:11][CH2:10][O:9][CH:8]1[CH2:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[C:40]([C:42]1[CH:47]=[CH:46][C:45]([CH:48]2[CH2:53][CH2:52][CH:51]([CH2:54][CH:55]=O)[CH2:50][CH2:49]2)=[CH:44][CH:43]=1)#[N:41]>CCOCC>[O:9]1[CH2:10][CH2:11][CH2:12][O:7][CH:8]1[CH2:13][CH:14]=[CH:55][CH2:54][CH:51]1[CH2:50][CH2:49][CH:48]([C:45]2[CH:44]=[CH:43][C:42]([C:40]#[N:41])=[CH:47][CH:46]=2)[CH2:53][CH2:52]1
Reactant: N#Cc1ccc(C2CCC(CC=O)CC2)cc1
Reactant: c1ccc([P+](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#Cc1ccc(C2CCC(CC=CCC3OCCCO3)CC2)cc1
Reaction time: 1 h
Yield: 50 %

Procedure:
Tetrahydrofuran (100 ml) was added to 2-(1,3-dioxan-2-yl)ethyltriphenylphosphonium bromide (19.2 g, 42 mmols), followed by suspending, stirring under ice cooling till the liquid temperature reached 10° C. The reaction mixture was added potassium t-butoxide (4.7 g, 42 mmols), followed by elevating the temperature up to room temperature under ice cooling for one hour, stirring for one hour, dropwise adding a tetrahydrofuran (20 ml) solution of 2-(4-(4-cyanophenyl)cyclohexyl)acetaldehyde (9.0 g, 40 mmols) over 30 minutes from the dropping funnel, further stirring the reaction mixture for 5 hours after completion of the dropwise addition, adding ether (100 ml), allowing to stand for one hour, filtering off deposited insoluble substance, concentrating the filtrate under reduced pressure and isolating and purifying the resulting pale brown oil by means of silica gel column chromatography, to obtain white solids (6.8 g, 20 mmols) of 1-(4-(1,3-dioxan-2-yl)-2-butenyl)-4-(4-cyanophenyl)cyclohexane.
Reaction SMILES: FC1C=CC(S[C:9]([S:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[S:10])=CC=1.[H-].[Na+].[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:32])[CH2:29][C:30]#[N:31])=[CH:24][CH:23]=1.CN(C=O)C>C1C=CC=CC=1>[C:30]([CH:29]([C:28]([C:25]1[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=1)=[O:32])[C:9]([S:11][C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)=[S:10])#[N:31]
Reactant: N#CCC(=O)c1ccc(F)cc1
Reactant: Fc1ccc(SC(=S)Sc2ccc(F)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: N#CC(C(=O)c1ccc(F)cc1)C(=S)Sc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.6 %

Procedure:
Trithiocarbonate (0.644 g, 2.15 mmol) from step (i) was added to a stirred suspension of sodium hydride (0.165 g, 0.412 mmol) in benzene (2.0 mL). Then, 3-(4-fluorophenyl)-3-oxopropanenitrile (0.320 g, 1.96 mmol) was added as a solution in benzene (2.0 mL). The reaction mixture was stirred for 5 min then DMF (2.0 mL) was added slowly. After addition was complete the reaction mixture was heated to reflux for 30 min and then allowed to cool to ambient temperature before being partitioned between H2O and Et2O. The aqueous layer was separated and washed with two additional portions of Et2O, then acidified with aqueous 2 N HCl. The acidic aqueous layer was then extracted with two portions of EtOAc, which were combined, washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography, eluting with a gradient of 25-100% EtOAc/hexanes to afford the product as a yellow solid (0.20 g, 0.60 mmol, 31% yield). MS (M−H)− 332.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][CH:18](Cl)[CH3:19].C(=O)=O>CN(C)C=O>[C:3]([C:2]1([C:1]([O:8][CH3:9])=[O:7])[CH2:17][CH:18]1[CH3:19])([O:5][CH3:6])=[O:4]
Reactant: CC(Cl)CCl
Reactant: COC(=O)CC(=O)OC
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1(C(=O)OC)CC1C
Temperature: 118 °C

Procedure:
The apparatus described in Example 1 was charged successively with 132.1 g dimethyl malonate (1.0 mol), 166 g (1.2 mols) finely comminuted potassium carbonate, 339 g 1,2-dichloropropane (3.0 mols) and 250 ml of dimethylformamide. While stirring vigorously, the reaction mixture was heated to 118° C., and the reaction temperature was increased to 125° C. over a period of 15 hours. While releasing carbon dioxide, the reaction mixture distilled off as an azeotrope which was separated into dichloropropane and water in the phase separator and was then drained. Flash distillation was used to separate the salts and high boiling components, and the distillate was separated by way of a column into the fractions 1,2-dichloropropane, dimethylformamide and 1,1-dicarbomethoxy-2-methylcyclopropane. The target product distilled over at 78° C./14 mbar and was identified by means of H-NMR as the desired target product.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7].[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1>CO.[Pd]>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]2[NH:13][C:12]3[CH:11]=[CH:10][CH:9]=[C:5]([C:6]([NH2:8])=[O:7])[C:4]=3[N:3]=2)=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: NC(=O)c1cccc(N)c1N
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NC(=O)c1cccc2[nH]c(-c3ccc(Br)cc3)nc12
Yield: 17 %

Procedure:
To a mixture of 2,3-diaminobenzamide dihydrochloride (synthesized as described in U.S. Pat. No. 6,737,421, column 11, EXAMPLE 2, step (e), 5 g, 22.3 mmol) and 4-bromobenzaldehyde (4.13 g, 22.3 mmol) in methanol (200 mL) was added 10% Pd/C (1.3 g). The mixture was refluxed overnight, then cooled and filtered though a pad of celite. The filtrate was concentrated under vacuum and purified by chromatography on a silica gel column with 0-10% methanol/dichloromethane to provide the title compound (1.2 g, 17%). MS (ESI) m/e 317 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2([CH:40]=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH2:35]2)=[CH:30][C:29]=1[O:42][CH3:43]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([C:34]5([CH:40]=[O:41])[CH:35]=[CH:36][CH:37]=[CH:38][CH2:39]5)=[CH:30][C:29]=4[O:42][CH3:43])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1cc(C2(C=O)C=CC=CC2)ccc1OCCCBr
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C2(C=O)C=CC=CC2)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 86.4 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10 mmol), K2CO3 (2.3 g) and 1-[4-(3-bromopropoxy)-3-methoxyphenyl]phenylmethanone (3.47 g, 10 mmol) in acetonitrile (100 ml) was heated at reflux for 3 hours. At the end of reaction, the acetonitrile was concentrated and the mixture was extracted into dichloromethane (200 ml). The insolubles were filtered off and the solvent was evaporated to an oil. Purification was carried out by flash chromatography over a silica gel column (SiO2, 50 g; eluted with dichloromethane, 600 ml; 1% methanol:dichloromethane, 600 ml; 2% methanol; 98% dichloromethane, 600 ml). The fractions containing the pure product were combined and concentrated to give 4.24 g (87%) of an off-white solid. Recrystallization from ethanol (75 ml) gave 3.9 g of 1-[4-[3-[4-(6-fluoro-1,2-benziosoxazol-3-yl)-1-piperidinyl]-propoxy]-3-methoxyphenyl]phenylmethanone as off-white crystals, m.p.=128°-130° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:4]=1[C:5]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[NH:10][C:9](=[O:18])[C@H:8]1[CH2:19][CH3:20])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:34][CH3:35]>C(#N)C>[CH3:1][O:2][C:3]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:4]=1[C:5]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[N:10]([CH2:34][CH3:35])[C:9](=[O:18])[C@H:8]1[CH2:19][CH3:20])=[O:6]
Reactant: CC[C@@H]1C(=O)Nc2ccc(F)cc2N1C(=O)c1ccc(OC)cc1OC
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC[C@@H]1C(=O)N(CC)c2ccc(F)cc2N1C(=O)c1ccc(OC)cc1OC
Temperature: 89 °C
Reaction time: 12 h
Yield: 70.9 %

Procedure:
To a stirred solution of (3R)-4-(2,4-dimethoxybenzoyl)-3-ethyl-6-fluoro-3,4-dihydroquinoxalin-2(1H)-one (0.25 g, 0.73 mmol) in acetonitrile (6 mL) under nitrogen was added cesium carbonate (0.24 g, 0.74 mmol) and iodoethane (0.19 mL, 0.37 g, 2.4 mmol). The mixture was stirred at 89° C. in a sealed tube for 12 h. The solvent was evaporated, and the residue was partitioned between water and methylene chloride. The layers were separated, and the organic layer was washed twice with water, dried over magnesium sulfate, concentrated in vacuo, and purified via Biotage Horizon® (SiO2, gradient from 7% EtOAc/hexane to 51% EtOAc/hexane) to yield 0.20 g (71%) of (3R)-4-(2,4-dimethoxybenzoyl)-1,3-diethyl-6-fluoro-3,4-dihydroquinoxalin-2(1H)-one.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[NH:11]1[CH:15]=[CH:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[N+:8]([C:4]1[CH:3]=[C:2]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: c1cn[nH]c1
Reactant: O=[N+]([O-])c1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cccc(-n2cccn2)c1
Temperature: 180 °C
Yield: 96 %

Procedure:
A mixture of 1-iodo-3-nitrobenzene (18.7 g, 75 mmol), pyrazol (7.66 g, 113 mmol), potassium carbonate (11.2 g, 81 mmol) and catalytic amounts of cuprous iodide and copper-bronze in dry N-methyl-2-pyrrolidone (50 ml) is heated to 180° C. for 4.5 hours. After cooling the mixture is filtered through celite. The filtrate is poured into ice water (700 ml) and the product is filtered off, washed with water and dried to yield 13.57 g. Yield: 96%. Mp 85-87° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[Cl:21][C:22]1[C:23]([F:38])=[C:24]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[CH2:30][C:31](=[O:37])[NH:32]3)[CH:25]=[CH:26][CH:27]=1>>[Cl:21][C:22]1[C:23]([F:38])=[C:24]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[C:30](=[CH:16][C:13]2[NH:12][C:9]4[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][N:3]([CH2:19][CH3:20])[CH2:1][CH3:2])[C:7](=[O:18])[C:8]=4[C:14]=2[CH3:15])[C:31](=[O:37])[NH:32]3)[CH:25]=[CH:26][CH:27]=1
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Reactant: O=C1Cc2c(cccc2-c2cccc(Cl)c2F)N1
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4cccc(-c5cccc(Cl)c5F)c43)c(C)c2C1=O
Yield: 30 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(3-chloro-2-fluoro-phenyl)-1,3-dihydro-indol-2-one (prepared according to WO2002055517) as starting materials to give 2-[4-(3-chloro-2-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-(2-diethylamino-ethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (30 mg, 30.0%) as a light yellow solid.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.I[CH:13]([CH3:15])[CH3:14].[OH:16][C@@H:17]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:18][CH2:19][C@@H:20]([O:29][CH2:30][CH:31]1[CH2:35][CH2:34][C:33](=[O:36])[NH:32]1)[C:21]1[S:25][C:24]([C:26]([OH:28])=[O:27])=[CH:23][CH:22]=1>CC(C)=O>[CH:13]([O:28][C:26]([C:24]1[S:25][C:21]([C@H:20]([O:29][CH2:30][CH:31]2[CH2:35][CH2:34][C:33](=[O:36])[NH:32]2)[CH2:19][CH2:18][C@@H:17]([OH:16])[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:22][CH:23]=1)=[O:27])([CH3:15])[CH3:14]
Reactant: CC(C)I
Reactant: CCCCC[C@H](O)CC[C@@H](OCC1CCC(=O)N1)c1ccc(C(=O)O)s1
Solvent: CC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCC[C@H](O)CC[C@@H](OCC1CCC(=O)N1)c1ccc(C(=O)OC(C)C)s1
Reaction time: 120 h
Yield: 85.7 %

Procedure:
DBU (9 μL, 0.06 mmol) and 2-iodopropane (62 μL, 0.62 mmol) were added to a solution of acid 6 (12 mg, 0.031 mmol) in acetone (0.3 mL) at room temperature under nitrogen. After 5 days at room temperature, the solvent was removed under a stream of nitrogen. The residue was acidified with 1 N HCl (2 mL) and extracted with EtOAc (3×10 mL). The combined extracts were washed with brine (5 mL) then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica (CH2Cl2→10% MeOH/CH2Cl2) afforded 11.3 mg (85%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].[NH3:14]>Cl[Cu].O>[NH2:14][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: N
Agent: Cl[Cu]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(Cl)cccc1C(=O)O
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution comprising 191 parts of 2,3-dichlorobenzoic acid and 40 parts of NaOH prills in 500 parts of water, and 3 parts of CuCl are initially introduced into a 2 l V4A autoclave. 425 parts of liquid NH3 (d20 : 0.61) are then also forced in, and the autoclave is heated at 165° to 175° C. for 3 hours, during which the pressure drops from initially 50 bar to about 46 bar. When the reaction has ended, the contents of the autoclave are cooled to 25° C. and drained off over the ascending line. The reaction solution is boiled under reflux until a bottom temperature of 100° C. is reached, and the NH3 gas driven off is collected in a waste gas washer. Working up in accordance with Example 1 gives 168 parts (98% of theory) of 2-amino-3-chlorobenzoic acid of melting point 185° to 187 ° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:16][CH2:15][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH2:13][OH:14])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:17]([C:19]1[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[N:23][CH:24]=1)=[CH2:18].[OH-].[K+]>CN1C(=O)CCC1>[OH:14][CH2:13][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:18][CH2:17][C:19]3[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[N:23][CH:24]=3)[C:5]3[CH2:15][CH2:16][N:2]([CH3:1])[CH2:3][C:4]=3[C:12]=2[CH:11]=1
Reactant: CN1CCc2[nH]c3ccc(CO)cc3c2C1
Reactant: C=Cc1ccc(C(=O)O)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(CO)ccc3n2CCc2ccc(C(=O)O)nc2)C1

Procedure:
The title compound is prepared from a mixture of (2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indol-8-yl)methanol, 5-vinylpyridine-2-carboxylic acid and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:19]=[CH:18][C:9]2[NH:10][C:11]([CH2:13][CH2:14][CH2:15][CH2:16]Cl)=[N:12][C:8]=2[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH:20]([NH2:23])([CH3:22])[CH3:21]>>[C:2]([C:6]1[CH:19]=[CH:18][C:9]2[NH:10][C:11]([CH2:13][CH2:14][CH2:15][CH2:16][NH:23][CH:20]([CH3:22])[CH3:21])=[N:12][C:8]=2[CH:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)N
Reactant: CC(C)(C)c1ccc2[nH]c(CCCCCl)nc2c1
Agent: Cl
Product: CC(C)NCCCCc1nc2cc(C(C)(C)C)ccc2[nH]1
Temperature: 25 °C
Yield: 51.3 %

Procedure:
A solution of 5-tert-butyl-2-(4-chloro-butyl)-1H-benzoimidazole hydrochloride (500 mg, 1.66 mmol) in isopropylamine (6 ml, 70.04 mmol) was heated to 80° in a sealed tube overnight. The reaction was cooled to RT and solvent evaporated. The residue was purified by flash column chromatography over silica gel, eluted with MeOH in DCM from 2% to 10% gradually to yield 245 mg (51%) of clean product as a yellow oil; MS (ESI+) for C18H29N3 m/z 1 [M+H]+, 288.50; HPLC purity 99% (ret. time, 1.12 min). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.10 (6H, d, J=6.26 Hz), 1.37 (9H, s), 1.60 (2H, quin, J=7.06 Hz), 1.90 (2H, quin, J=7.25 Hz), 2.66 (2H, t, J=6.79 Hz), 2.82 (1H, spt, J=6.23 Hz), 2.93 (2H, t, J=7.17 Hz), 7.22-7.30 (1H, m), 7.46 (1H, d, J=8.39 Hz), 7.54 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:28]=1[C:9]1([CH2:14][CH2:13][N:12]([C:15]([NH:17][CH:18]3[CH:25]4[CH2:26][CH:21]5[CH2:22][CH:23]([CH2:27][CH:19]3[CH2:20]5)[CH2:24]4)=[O:16])[CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH2:29][CH2:30][OH:31].CCN(CC)CC.[S:39](Cl)([C:42]1[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=1)(=[O:41])=[O:40]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:28]=1[C:9]1([CH2:10][CH2:11][N:12]([C:15]([NH:17][CH:18]3[CH:25]4[CH2:26][CH:21]5[CH2:22][CH:23]([CH2:27][CH:19]3[CH2:20]5)[CH2:24]4)=[O:16])[CH2:13][CH2:14]1)[CH2:8][CH:7]2[CH2:29][CH2:30][O:31][S:39]([C:42]1[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=1)(=[O:41])=[O:40]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)N1CCC2(CC1)CC(CCO)c1cccc(Br)c12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC2CC3(CCN(C(=O)NC4C5CC6CC(C5)CC4C6)CC3)c3c(Br)cccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of (±)-7-bromo-N-(2-adamantyl)-3-(2-hydroxyethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide (40 mg, 0.082 mmol) and Et3N (9.9 mg, 0.098 mmol) in dry CH2Cl2(5 mL) was added TsCl (15.6 mg, 0.082 mmol) at 0° C. The mixture was stirred overnight at rt. The mixture was concentrated to give the crude product, which was purified by preparative TLC to give (±)-7-bromo-N-(2-adamantyl)-3-(2-(p-toluenesulfonyloxy)ethyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxamide (50 mg, crude).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]([CH3:27])[C:17]2=[O:28])=[CH:12][C:3]=1[C:4]([O:6][C@@H:7]([CH3:11])[C:8]([OH:10])=O)=[O:5].S(Cl)([Cl:31])=O>>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[N:18]([CH3:27])[C:17]2=[O:28])=[CH:12][C:3]=1[C:4]([O:6][C@@H:7]([CH3:11])[C:8]([Cl:31])=[O:10])=[O:5]
Reactant: C[C@H](OC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl)C(=O)O
Reactant: O=S(Cl)Cl
Product: C[C@H](OC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl)C(=O)Cl

Procedure:
5.7 g (14 mmol) of (S)-2-[2-chloro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydro-2H-pyrimidin-1-yl)benzoyloxy]-propionic acid from example 3.2 were dissolved in 50 ml of thionyl chloride, and the reaction mixture was heated under reflux for 3.5 hours. The solution was allowed to cool and concentrated, which gave 5.9 g of (S)-2-[2-chloro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6-dihydro-2H-pyrimidin-1-yl)-benzoyloxy]propionyl chloride.
Reaction SMILES: [C:1](OC(=O)NC(C1C=CC(CNC([C@H]2N3C(=O)C(NCC4C=CC=CC=4)=CN=C3CC2)=O)=CC=1)=N)(C)(C)[CH3:2].[CH2:39]([O:46][C:47](=[O:87])[N:48]([CH2:84][CH:85]=[CH2:86])[C:49]1[C:54](=[O:55])[N:53]2[C@H:56]([C:61](=[O:83])[NH:62][CH2:63][C:64]3[CH:69]=[CH:68][C:67]([C:70]([NH:72][C:73]([O:75][CH2:76][C:77]4[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=4)=[O:74])=[NH:71])=[CH:66][CH:65]=3)[CH2:57][C@:58]([NH2:60])([CH3:59])[C:52]2=[N:51][CH:50]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:39]([O:46][C:47](=[O:87])[N:48]([CH2:84][CH:85]=[CH2:86])[C:49]1[C:54](=[O:55])[N:53]2[C@H:56]([C:61](=[O:83])[NH:62][CH2:63][C:64]3[CH:69]=[CH:68][C:67]([C:70]([NH:72][C:73]([O:75][CH2:76][C:77]4[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=4)=[O:74])=[NH:71])=[CH:66][CH:65]=3)[CH2:57][C@:58]([NH:60][CH2:1][CH3:2])([CH3:59])[C:52]2=[N:51][CH:50]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NCc4ccccc4)c(=O)n32)cc1
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@H](C(=O)NCc1ccc(C(=N)NC(=O)OCc3ccccc3)cc1)C[C@@]2(C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Product: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@H](C(=O)NCc1ccc(C(=N)NC(=O)OCc3ccccc3)cc1)C[C@@]2(C)NCC
Yield: 54 %

Procedure:
Following a procedure similar to that for the preparation of intermediate 1k, 26a (30.0 mg, 0.045 mmol), acetaldehyde (2.2 mg, 0.050 mmol) and NaBH(OAc)3 (14.4 mg, 0.068 mmol) yielded 16.9 mg (54%) of 26b. MS (ESI) 692.5 (M+H+).
Reaction SMILES: F[C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:8]([C:13]([F:16])([F:15])[F:14])[O:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:28]1([OH:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C>[CH3:12][C:11]1[C:2]([O:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:3][CH:4]=[C:5]2[C:10]=1[O:9][CH:8]([C:13]([F:16])([F:15])[F:14])[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6]2
Reactant: Oc1ccccc1
Reactant: CCOC(=O)C1=Cc2ccc(F)c(C)c2OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2ccc(Oc3ccccc3)c(C)c2OC1C(F)(F)F
Temperature: 90 °C
Yield: 28.3 %

Procedure:
To 0.304 g (1.00 mmol) of ethyl 7-fluoro-8-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate in 5.0 mL of DMF was added 0.194 g of K2CO3 (1.40 mmol) and 0.105 mL (1.20 mmol) of phenol. The mixture was heated to 90° C. and LC/MS indicated remaining starting material. The mixture was then heated to 110° C. overnight and LC/MS still indicated starting material remaining. Added an additional 0.194 g of K2CO3 (1.40 mmol) and 0.105 mL (1.20 mmol) of phenol. Heated overnight and purified by Gilson reverse phase chromatography to afford 0.107 g (28%) of a pale yellow solid: 1H NMR (CH30D/400 MHz) 1.32 (t, 3H, J=7.2 Hz), 2.15 (s, 3H), 4.24-4.33 (m, 2H), 5.82 (q, 1H, J=7.2 Hz), 6.42 (d, 1H, J=8.4 Hz), 6.94-6.97 (m, 2H), 7.09-7.15 (m, 2H), 7.33-7.37 (m, 2H), 7.75 (s, 1H); MS (ES+) 379.3 (M+H, 100); HRMS (EI+) m/z calcd for (C20H17F3O4) 378.1079, found 378.1062.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)=[C:10]([O:29][CH3:30])[CH:9]=1.[OH:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>CN(C=O)C>[F:43][C:42]([F:45])([F:44])[C:40]([OH:46])=[O:41].[CH3:7][C:4]1[C:3]2[C:8]3[CH:9]=[C:10]([O:29][CH3:30])[C:11]([O:14][CH2:15][CH:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]4)=[CH:12][C:13]=3[C:36]([C:35]3[CH:38]=[CH:39][C:32]([OH:31])=[CH:33][CH:34]=3)=[N:1][C:2]=2[NH:6][N:5]=1
Reactant: COc1cc(-c2c(C)n[nH]c2N)ccc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=Cc1ccc(O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OCC1CCNCC1)c(-c1ccc(O)cc1)nc1[nH]nc(C)c12
Temperature: 75 °C
Yield: 20 %

Procedure:
A mixture of 1,1-dimethylethyl 4-({[4-(5-amino-3-methyl-1H-pyrazol-4-yl)-2-(methyloxy)phenyl]oxy}methyl)piperidine-1-carboxylate (100 mg, 0.24 mmol) and 4-hydroxybenzaldehyde (44 mg, 0.36 mmol) was dissolved in TFA (1 mL) and heated to 75° C. for 15 h. After cooling to rt, the mixture was diluted with DMF and purified by preparative reverse phase HPLC. The fractions containing the desired product were concentrated and lyophilized to yield 4-{1-methyl-8-(methyloxy)-7-[(piperidin-4-ylmethyl)oxy]-3H-pyrazolo[3,4-c]isoquinolin-5-yl)phenol hydrogen trifluoroacetate (26.2 mg, 20% yield). 1H NMR (400 MHz, d6-DMSO): 8.64-8.54 (m, 1H), 8.28-8.18 (m, 1H), 7.64 (s, 1H), 7.57-7.54 (m, 2H), 7.49 (s, 1H), 6.95-6.91 (m, 2H), 4.05 (s, 3H), 3.82 (d, 2H), 3.31 (d, 2H), 2.92 (q, 2H), 2.81 (s, 3H), 2.16-2.04 (m, 1H), 1.94 (d, 2H), 1.53-1.42 (m, 2H); MS (EI) for C24H26N4O3: 419 (MH+).