Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.C1(C([NH:31][CH:32]2[C:57](=[O:58])[N:34]3[CH:35]([C:40]4[N:41](CC5C=CC(OC)=CC=5)[C:42](=[O:47])[CH2:43][C:44](=[O:46])[N:45]=4)[C:36]([CH3:39])([CH3:38])[S:37][C@H:33]23)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+].[OH-].[K+].C(N(CC)CC)C>O>[NH2:31][CH:32]1[C:57](=[O:58])[N:34]2[CH:35]([C:40]3[NH:41][C:42](=[O:47])[CH2:43][C:44](=[O:46])[N:45]=3)[C:36]([CH3:38])([CH3:39])[S:37][C@H:33]12
Reactant: COc1ccc(CN2C(=O)CC(=O)N=C2C2N3C(=O)C(NC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@H]3SC2(C)C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)S[C@@H]2C(N)C(=O)N2C1C1=NC(=O)CC(=O)N1

Procedure:
The tosylate salt of Example 8 is coverted to the free base form by neutralization with one equivalent of base such as sodium hydroxide, potassium hydroxide or triethylamine in water followed by freeze-drying of the aqueous mixture.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.[CH2:15](Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O.Cl>[OH-].[Na+].CS(C)=O>[CH2:15]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: CCCCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCOc1ccc2cc(C(=O)O)ccc2c1
Temperature: 80 °C

Procedure:
A solution of 6-hydroxy-2-naphthoic acid (1.04 g) in a mixture of 10% sodium hydroxide aqueous solution (4.44 ml) and dimethyl sulfoxide (18 ml) was stirred for half an hour at 80° C. Then heptyl bromide (0.872 ml) was added thereto and stirred for 5 hours at 60° C. The reaction mixture was added to water (50 ml) and the mixture was adjusted to pH 3 with conc. hydrochloric acid. The resultant precipitate was collected by filtration and dried to give 6-heptyloxy -2-naphthoic acid (1.39 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[I:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34]([OH:36])=O>C(Cl)Cl>[I:30][C:31]1[CH:32]=[C:33]([C:34]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[O:36])[CH:37]=[CH:38][CH:39]=1
Reactant: O=C(O)c1cccc(I)c1
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN1CCN(C(=O)c2cccc(I)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.2 %

Procedure:
1-Methylpiperazine (0.58 mL, 5.2 mmol), HOBt (0.70 g, 5.2 mmol) and EDCl (1.0 g, 5.2 mmol) were added to a solution of 3-iodobenzoic acid (1.0 g, 4.0 mmol) in dry DCM (40 mL). The mixture was stirred at room temperature for 16 h, washed with saturated aqueous sodium bicarbonate (30 mL), water (15 mL), brine, dried over sodium sulphate, and evaporated to afford the title compound (1.27 g, 96%).
Reaction SMILES: [C:1]([OH:6])(=[O:5])C(O)=O.[NH2:7][CH2:8][CH2:9][C@@H:10]([O:14][C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=1[C:17]#[N:18])[CH2:11][O:12]C.[BH4-].[Li+].CO>O1CCCC1>[Cl:23][C:21]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([CH:22]=1)[O:14][C@@H:10]([CH2:11][OH:12])[CH2:9][CH2:8][NH:7][C:1](=[O:5])[O:6][C:16]([CH3:19])([CH3:17])[CH3:15]
Reactant: COC[C@@H](CCN)Oc1cc(Cl)ccc1C#N
Reactant: O=C(O)C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCC[C@H](CO)Oc1cc(Cl)ccc1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 148.6 %

Procedure:
The product from step (c) (881 mg, 2.39 mmol) was dissolved in anhydrous tetrahydrofuran (20 ml) and lithium borohydride (2M solution in tetrahydrofuran, 2.6 ml, 5.26 mmol) added dropwise. The mixture was stirred at room temperature for 18 h. Methanol (5 ml) was added and the reaction stirred for 15 minutes. The solvent was removed in vacuo and the residue chromatographed on flash silica, eluting with hexane:ethyl acetate (3:2, then 1:1) to give the title compound as a colourless oil (605 mg, 74%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]([CH2:15][N:16]3[CH:20]=[C:19]([C:21]([O:23]CC)=[O:22])[CH:18]=[N:17]3)[S:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[OH-].[Na+].Cl>C(O)C.O1CCCC1.[Cl-].[Na+].O>[C:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]([CH2:15][N:16]3[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[N:17]3)[S:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cccc(C(C)=O)c3)cs2)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cccc(-c2csc(Cn3cc(C(=O)O)cn3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a mixed solution of the compound (188 mg, 0.53 mmol) obtained in Example 30d in ethanol-tetrahydrofuran (v/v=2/1) was added 2N aqueous sodium hydroxide solution (1.5 mL, 3.0 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with 1N aqueous hydrochloric acid solution, saturated brine was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained crude product was purified by recrystallization (ethyl acetate-hexane) to give the title compound (145 mg, 84%) as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:7]1)[CH3:2].Br[C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[Cl:31]>>[Cl:31][C:23]1[CH:24]=[CH:25][C:26]([N+:28]([O-:30])=[O:29])=[CH:27][C:22]=1[NH:11][C:10]1[N:6]([CH2:5][CH:4]([O:18][CH2:19][CH3:20])[O:3][CH2:1][CH3:2])[N:7]=[C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:9]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Br)c1
Reactant: CCOC(Cn1nc(-c2cccnc2)cc1N)OCC
Product: CCOC(Cn1nc(-c2cccnc2)cc1Nc1cc([N+](=O)[O-])ccc1Cl)OCC

Procedure:
Analogously to the process described in Example 9A/Step 1, 1.0 g (3.62 mmol) of the compound of Example 4A and 941 mg (3.98 mmol) of 1-bromo-2-chloro-5-nitrobenzene gave 1.26 g (80% of theory) of the title compound. In this case, the reaction time in the microwave reactor was 1 h at a temperature of 140° C. Chromatographic isolation of the product was by MPLC (mobile phase cyclohexane/ethyl acetate 1:2).
Reaction SMILES: [C:1]1([C:7]2[C:11]3[CH:12]=[CH:13][C:14]4[O:18][CH:17]([CH2:19][OH:20])[CH2:16][C:15]=4[C:10]=3[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:24])(=O)=O>C(Cl)Cl>[Cl:24][C:13]1[C:14]2[O:18][CH:17]([CH2:19][OH:20])[CH2:16][C:15]=2[C:10]2[O:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]=2[CH:12]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: OCC1Cc2c(ccc3c(-c4ccccc4)noc23)O1
Solvent: ClCCl
Product: OCC1Cc2c(c(Cl)cc3c(-c4ccccc4)noc23)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.2 %

Procedure:
A portion (10 g) of the 7,8-dihydro-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-methanol prepared in Example 1 was dissolved in 300 ml of methylene chloride. To the ice-cooled solution, sulfuryl chloride (9 g) was added over time under agitation. The mixture was thereafter stirred for 8 hours at room temperature. The solvent was distilled off and the resulting residue was purified by column chromatography using methylene chloride as an eluant, whereupon 3.3 g of 5-chloro-7,8-dihydro-3-phenylfuro[2,3-g]-1,2benzisoxazole-7-methanol was obtained. This compound (3.3 g) was dissolved in 100 ml of acetone and, to the stirred solution, a mixture of chromium (VI) oxide (4 g), water (6 ml) and concentrated sulfuric acid (5.9 g) was added dropwise over time, and the solution was stirred for 2.5 hours at room temperature. The insolubles were filtered off by suction. After distilling off the acetone, water was added to the residue and the mixture was subjected to extraction with ether. The ether layer was washed with water and dried, followed by distilling off of the solvent. The residue was recrystallized with acetonitrile to yield 1 g of 5-chloro-7,8-dihydro-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-carboxylic acid. m.p. 221°-224° C. This compound exhibited a mass spectrum having a molecular ion peak at m/e 315.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[O:27]1[CH2:32][CH2:31][CH2:30][CH:29]([C:33](O)=[O:34])[CH2:28]1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:33]([CH:29]5[CH2:30][CH2:31][CH2:32][O:27][CH2:28]5)=[O:34])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)C1CCCOC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)C1CCCOC1

Procedure:
The title compound, off-white solid (91 mg, 83%), MS (ISP) m/z=441.4 [(M+H)+], mp 222° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydro chloride (intermediate B) (100 mg, 0.25 mmol) and (RS)-tetrahydro-pyran-3-carboxylic acid.
Reaction SMILES: [CH3:1][P:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:13]=[C:14]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[S:36]([CH:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])[C:15]3[CH:20]=[CH:19][N:18](COCC[Si](C)(C)C)[C:16]=3[N:17]=2)=[C:7]([O:42][CH3:43])[CH:6]=1)([CH3:4])=[O:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(N)CN>[CH3:4][P:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:13]=[C:14]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[S:36]([CH:39]([CH3:40])[CH3:41])(=[O:37])=[O:38])[C:15]3[CH:20]=[CH:19][NH:18][C:16]=3[N:17]=2)=[C:7]([O:42][CH3:43])[CH:6]=1)([CH3:1])=[O:3]
Reactant: COc1cc(P(C)(C)=O)ccc1Nc1nc(Nc2ccccc2S(=O)(=O)C(C)C)c2ccn(COCC[Si](C)(C)C)c2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: NCCN
Product: COc1cc(P(C)(C)=O)ccc1Nc1nc(Nc2ccccc2S(=O)(=O)C(C)C)c2cc[nH]c2n1
Temperature: 60 °C

Procedure:
To a solution of compound N2-[4-(dimethylphosphoryl)-2-methoxyphenyl]-N4-[2-(propan-2-ylsulfonyl)phenyl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine in THF (1 mL) was added tetrabutylammonium fluoride (TBAF) in THF (1.0 M, 3 mL) and ethylenediamine (0.1 mL). The solution was heated at 60° C. for 24 hrs. About 40% conversion was observed by HPLC monitoring. Volatile components were removed on rotavap and the residue was subjected to prep-HPLC purification. The desired product was determined by NMR to be contaminated with TBAF, which was removed by water wash (4 times). Evaporation of EtOAc gave the pure compound (14 mg). MS/ES+: m/z=514.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]2[CH:14]=[CH:13][NH:12][C:8]=2[N:9]=[CH:10][N:11]=1.CN(C)C=O.[I:20]N1C(=O)CCC1=O.O>ClCCl>[I:20][C:14]1[C:7]2[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[N:11][CH:10]=[N:9][C:8]=2[NH:12][CH:13]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COCCOc1ncnc2[nH]ccc12
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCCOc1ncnc2[nH]cc(I)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
To 4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidine (24, 5.70 g, 29.5 mmol) in 150.0 mL of dichloromethane, N,N-dimethylformamide (6.0 mL, 78 mmol) and N-iodosuccinimide (7.22 g, 32.1 mmol) are added and the reaction stirred at room temperature for 2 hours. The reaction is poured into water and extracted with ethyl acetate. The organic layer is dried with sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is washed with ethyl acetate and hexane to provide the desired compound (25, 6.75 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][N:10]=[C:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][N:10]=[C:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[N:24]1[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]1
Reactant: Fc1ccccc1C(Cl)=NNc1ccc(Cl)cc1Cl
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Product: CN1CCN(C(=NNc2ccc(Cl)cc2Cl)c2ccccc2F)CC1
Reaction time: 16 h
Yield: 118.8 %

Procedure:
To a stirred mixture of α-chloro-2-fluorobenzaldehyde 2,4-dichlorophenylhydrazone (51.0 g, 0.16 mol) and tetrahydrofuran (500 ml) under N2 was added dropwise, 1-methylpiperazine (35.4 g, 0.35 mol). The reaction was allowed to stir for 16 hours and then was cooled in an ice bath for 30 minutes. The mixture was filtered and washed with cold tetrahydrofuran leaving behind the insoluble 1-methylpiperazine hydrochloride. The filtrate was concentrated to afford 72.5 g of 1-{[(2,4-dichlorophenyl) hydrazono](2-fluorophenyl)methyl}-4-methylpiperazine as an oil. To a stirred mixture of the oil (72.5 g, 0.19 mol) and tetrahydrofuran (200 ml), under N2, was added dropwise, potassium tert-butoxide (23.5 g, 0.21 mol) dissolved in tetrahydrofuran (400 ml). The reaction was allowed to stir at ambient temperature for 58 hours. The reaction mixture was concentrated to an oily residue, which was partitioned between ether and H2O. The ether extract was washed with H2O, dried with MgSO4 and concentrated to 58.0 g of an oil. A 9.0 g sample of the oil was flash chromatographed over 500 g silica gel eluting with 20% methanol-CH2Cl2. Concentration of appropriate fractions afforded 5.7 g (55%) of an oil. The oil was dissolved in anhydrous ether and fumaric acid (2.0 g, 1.1 eq) was added. The mixture was stirred overnight and the solid was collected by filtration to afford 4.6 g of product. A 3.8 g sample was recrystallized twice from ethyl acetate to afford 2.2 g of 1-(2,4-dichlorophenyl)-3-(4-methyl-1-piperazinyl)-1H-indazole, m.p. 150°-152° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[S:10]1[CH:14]=[CH:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]1=2>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][C:14]1[S:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=1
Reactant: c1ccc2sccc2c1
Reactant: O=Cc1cccc(Br)c1
Product: Brc1cccc(Cc2cc3ccccc3s2)c1

Procedure:
Preparation was performed in a similar manner as in Preparation Example 4 using 3-bromobenzaldehyde and benzo[b]thiophene.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])(O)[CH2:10][CH2:9]1)=O)(C)(C)C.S(=O)(=O)(O)O.[OH-].[Na+]>C1(C)C=CC=CC=1>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[C:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(F)cc2F)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Fc1ccc(C2=CCNCC2)c(F)c1
Reaction time: 8 h
Yield: 80.3 %

Procedure:
4-(2,4-Difluoro-phenyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.4 g) was dissolved in toluene (10 mL). Concentrated sulphuric acid (0.3 mL) was added and the mixture was heated at reflux for 2 hours and then allowed to stand at room temperature overnight. A solution of aqueous sodium hydroxide (1 N, 30 mL) was added and the products extracted into ethyl acetate. The organic solution was dried with magnesium sulphate, filtered and the solvent removed by evaporation under vacuum to give the title compound as a dark oil (0.2 g) which was used without further purification. LCMS m/z 196.1 [M+H]+. R.T.=2.12 min (Analytical Method 4).
Reaction SMILES: Cl.[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3].[C:17]1([C:27](Cl)=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:27]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)=[O:28])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3]
Reactant: CC(C)NCC(=O)c1ccc(O)c(O)c1
Reactant: O=C(Cl)c1cccc2ccccc12
Agent: Cl
Product: CC(C)NCC(=O)c1ccc(OC(=O)c2cccc3ccccc23)c(O)c1

Procedure:
Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and 1-naphthalenecarbonyl chloride instead of isovaleryl chloride, there is obtained 3-hydroxy-4-(1-naphthalenecarbonyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-hydroxy-4-(1-naphthalenecarbonyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]([CH3:32])=[C:22]([CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][C@H:27]3[CH3:31])[N:23]=2)=[CH:15][CH:14]=1>>[CH3:32][C:21]1[O:20][C:19]([C:16]2[CH:17]=[CH:18][C:13]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:8]=3)=[CH:14][CH:15]=2)=[N:23][C:22]=1[CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][C@H:27]1[CH3:31]
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCC[C@H]1C
Reactant: N#Cc1cccc(B(O)O)c1
Product: Cc1oc(-c2ccc(-c3cccc(C#N)c3)cc2)nc1CCN1CCC[C@H]1C

Procedure:
The title compound is prepared in a manner substantially analogous to example 133 starting from 3-Cyanobenzene boronic acid (211 mg, 1.43 mmol) and 2-(4-Bromo-phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]-oxazole (100 mg, 0.287 mmol) to give 50 mg (47%). MS (m/e) 372.2 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:20]=[C:19]([CH3:21])[C:13]2[N:14]=[C:15]([NH2:18])[N:16]=[N:17][C:12]=2[CH:11]=1.Br[C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:32][CH2:33][CH2:34][N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:20]=[C:19]([CH3:21])[C:13]2[N:14]=[C:15]([NH:18][C:23]3[CH:28]=[CH:27][C:26]([S:29]([NH:32][CH2:33][CH2:34][N:35]4[CH2:36][CH2:37][CH2:38][CH2:39]4)(=[O:31])=[O:30])=[CH:25][CH:24]=3)[N:16]=[N:17][C:12]=2[CH:11]=1
Reactant: O=S(=O)(NCCN1CCCC1)c1ccc(Br)cc1
Reactant: COc1ccc(Cl)c(-c2cc(C)c3nc(N)nnc3c2)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc(Cl)c(-c2cc(C)c3nc(Nc4ccc(S(=O)(=O)NCCN5CCCC5)cc4)nnc3c2)c1
Yield: 95.4 %

Procedure:
In a dry 25 mL round bottom flask, 7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamine (0.157 g, 0.523 mmol, 1 equiv), 4-bromo-N-(2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide (0.261 g, 0.785 mmol, 1.5 equiv), cesium carbonate (0.512 g, 1.57 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.061 g, 0.10 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.048 g, 0.052 mmol, 0.1 equiv) were combined. The reactants were flushed with argon, diluted with dioxane (5 mL) and outfitted with reflux condenser. The reaction was heated to reflux for 18 hours, then filtered hot, and the solvents were diluted with ethyl acetate and washed with brine. The brine layer was back extracted once with fresh ethyl acetate. The organic phases were combined and dried over sodium sulfate (Na2SO4). Filtration followed by evaporation provided slightly impure product. Solids were diluted in minimum amount of DCM and precipitated out using excess hexanes. The resulting solids were filtered off and dried to yield a yellow powder (0.276 g, 95% yield). MS (ESI+): m/z=553.3, LC retention time: 2.77 min.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=[C:5]2I.[CH3:17][Sn](C)(C)C>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.C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=[C:5]2[CH3:17]
Reactant: C[Sn](C)(C)C
Reactant: COC(=O)c1ccc(I)c2cc(O)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C)c2cc(O)ccc12
Temperature: 90 °C
Reaction time: 24 h

Procedure:
A resealable tube was charged with methyl 6-hydroxy-4-iodo-1-naphthoate (0.302 g, 0.920 mmol), toluene (5.0 ml), tetramethyltin (0.40 g, 0.30 mL, 2.2 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.042 g, 0.036 mmol). The system was purged with argon and the tube was sealed. The mixture stirred at 90° C. for 24 h and was cooled to RT. The mixture was partitioned between EtOAc and water. The aqueous phase was separated and extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford an orange solid. This material was purified via column chromatography on silica gel (eluting with 0-50% ethyl acetate-hexane) to afford methyl 6-hydroxy-4-methyl-1-naphthoate as an orange brown solid. MS (ESI, pos. ion) m/z: 217.1 (M+H). Mass Calc'd for C13H12O3: 216.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH3:12])[C:9]1([CH2:20][CH:21]=C(C)C)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:25]=[O+][O-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl.CO.C(Cl)(Cl)Cl.O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH3:12])[C:9]1([CH2:20][CH:21]=[O:25])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)=CCC1(C(=O)OC(C)(C)C)C(C)CN1C(=O)OC(C)(C)C
Reactant: O=[O+][O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC1CN(C(=O)OC(C)(C)C)C1(CC=O)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A solution of an optically-active compound of 3-methyl-2-(3-methyl-but-2-enyl)-azetidine-1,2-dicarboxylic acid di-tert-butyl ester (44.5 g) in chloroform/methanol (310 ml/310 ml) cooled to −70° C. was flowed ozone air for 1 hour. To the reaction mixture was added a solution of triphenylphosphine (44.7 g) in chloroform (45 ml) in small batches, and the mixture was warmed to room temperature. To the mixture were added saturated aqueous sodium thiosulfate solution (200 ml) and water (300 ml), and the mixture was extracted with chloroform (500 ml). The separated organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the titled compound (95.0 g), which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][S:35]([NH2:38])(=[O:37])=[O:36]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:38][S:35]([CH3:34])(=[O:37])=[O:36])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(c4cccs4)CC3)cnc12
Reactant: CS(N)(=O)=O
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(c4cccs4)CC3)cnc12
Yield: 30.9 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-[4-(thiophen-2-yl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.06 g, 0.12 mmol) obtained in step 2 and methanesulfonamide (0.057 g, 0.600 mmol), the title compound (0.02 g, 31%) was obtained.