Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:22][C:23]([CH3:26])([O-])[CH3:24].[K+]>ClCCl.CN(C=O)C.C1COCC1>[C:23]([O:14][C:13]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:15])([CH3:26])([CH3:24])[CH3:22]
Reactant: Cc1ccc(C2(C(=O)O)CCCC2)cc1
Reactant: CC(C)(C)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc(C2(C(=O)OC(C)(C)C)CCCC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a suspension of 1-(4-methylphenyl)cyclopentane carboxylic acid (3.00 g, 14.7 mmol) in dichloromethane (50 ml,) at 0° C. was added oxalyl chloride (1.54 mL, 17.4 mmol) and DMF (2 drops). The mixture was stirred at 0° C. for 1 hour, and at rt for 2 hours. The solution was concentrated, diluted with THF (40 mL), and cooled to 0° C. Potassium t butoxide (1.80 g, 16.2 mmol) in THF (20 mL) was slowly added, and the mixture was stirred overnight at rt. Additional potassium t butoxide (0.660 g, 5.88 mmol) was added. After 20 minutes the solution was concentrated to dryness, and taken up in ethyl acetate. The organic phase was washed with 10% citric acid, saturated NaHCO3 and brine, dried (MgSO4), and concentrated. Flash column chromatography (10% ethyl acetate/hexane) gave 1-(4-methylphenyl)cyclopentane carboxylic acid t butyl ester (3.27 g, 87%).
Reaction SMILES: C([N:18]1[CH2:23][CH2:22][C:21](C)([C:24]([OH:26])=[O:25])[CH2:20][CH2:19]1)(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.C(Cl)(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>>[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=[O:25])[CH2:20][CH2:19]1
Reactant: CC1(C(=O)O)CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Agent: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Product: O=C(O)C1CCNCC1

Procedure:
Preparation of N-FMOC-4-methyl-4-piperidinecarboxylic acid was prepared as described in Step D of Preparation 2 utilizing the product of Step B as starting material, except as follows. After stirring the reaction mixture overnight in the presence of FMOCCl the mixture was concentrated in vacuo to remove dioxane. The aqueous phase was diluted with water and extracted with ether. The desired product was extracted into the ether phase (salt is soluble in ether). The combined ether and aqueous phase were acidified and extracted with ether. The combined ethereal phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography over silica gel eluting with 5%MeOH/CH2Cl2 to give the desired product. 1H-NMR (CDCl3, 400 Mhz):1.22 (s, 3H); 1.40 (bm, 2H); 2.02 (bs, 2H); 3.05 (bs,2H); 3.75 and 3.85 (bs, 1H); 4.21 (t, 1H); 4.41 (d, 2H) 7.29 (t, 2H); 7.38 (t, 2H); 7.55 (d, 2H); 7.75 (d, 2H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][C:12]([NH:14][C:15]2[CH:16]=[C:17]([C:21]3[N:30]=[C:29]([NH:31][C:32]4[CH:33]=[C:34]5[C:38](=[CH:39][CH:40]=4)[N:37](C(OC(C)(C)C)=O)[N:36]=[CH:35]5)[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[CH:18]=[CH:19][CH:20]=2)=[O:13])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:37]1[C:38]2[C:34](=[CH:33][C:32]([NH:31][C:29]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=[C:21]([C:17]4[CH:16]=[C:15]([NH:14][C:12](=[O:13])[CH2:11][CH2:10][N:7]5[CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:9][CH2:8]5)[CH:20]=[CH:19][CH:18]=4)[N:30]=3)=[CH:40][CH:39]=2)[CH:35]=[N:36]1
Reactant: CC(C)N1CCN(CCC(=O)Nc2cccc(-c3nc(Nc4ccc5c(cnn5C(=O)OC(C)(C)C)c4)c4ccccc4n3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1CCN(CCC(=O)Nc2cccc(-c3nc(Nc4ccc5[nH]ncc5c4)c4ccccc4n3)c2)CC1

Procedure:
To tert-butyl 5-(2-(3-(3-(4-isopropylpiperazin-1-yl)propanamido)phenyl)-quinazolin-4-ylamino)-1H-indazole-1-carboxylate (60 mg, 0.094 mmol) was added a solution of 1:1 TFA:CH2Cl2 (4 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the crude product was purified by prep HPLC (method 10-35—90 mins) to afford N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-3-(4-isopropylpiperazin-1-yl)propanamide. (61 mg, 0.11 mmol, 100%).
Reaction SMILES: C(O[C:4](=[O:27])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:10][CH:9]=1)=[O:6])C.[O:28]([C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CC(C)([O-])C.[Li+]>C1(C)C(C)=CC=CC=1>[CH2:15]([O:14][C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:5](=[O:6])[C:4]([NH:39][C:38]2[CH:37]=[CH:36][C:35]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:41][CH:40]=2)=[O:27])=[CH:13][CH:12]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCOc1ccc(NC(=O)C(=O)OCC)cc1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCCCOc1ccc(NC(=O)C(=O)Nc2ccc(Oc3ccccc3)cc2)cc1
Reaction time: 3 h
Yield: 85.6 %

Procedure:
A solution of N-(4-dodecyloxyphenyl)oxalamic acid ethyl ester (10 g, 0.026 mol), 4-phenoxyaniline (5 g, 0.026 mol) and lithium t-butoxide (0.2 g, 0.0026 mol) in xylene (50 mL) isheated to gentle reflux. A distillate of ethanol/xylene is slowly collected; the reaction volumn is kept at 50 mL by adding xylene. Heating and distillation continued for 3 hours. The reaction mixture is cooled, the solids are collected and washed sequentially with warm ethyl acetate, ethanol, water and finally ethanol. There is obtained 11.5 g white solid mp: 179–181.
Reaction SMILES: C(=O)([S:3][CH:4]([C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1)[C@@H:5]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH3:6])C.[OH-].[Na+]>CO>[F:22][C:21]([F:23])([F:24])[C:19]1[CH:20]=[C:15]([CH:4]([SH:3])[C@@H:5]([NH:7][C:8](=[O:9])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH3:6])[CH:16]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:18]=1
Reactant: CC(=O)SC(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H](C)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](NC(=O)OC(C)(C)C)C(S)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The S-((2S)-1-(3,5-bis(trifluoromethyl)phenyl)-2-((tert-butoxycarbonyl)amino)propyl) ethanethioate (580 mg, 1.30 mmol) in MeOH (30 ml) was thoroughly degassed and degassed NaOH solution (1.43 ml, 1.43 mmol) was added dropwise. The reaction was stirred at r.t. for 30 minutes under a N2 atmosphere to yield tert-butyl ((2S)-1-(3,5-bis(trifluoromethyl)phenyl)-1-mercaptopropan-2-yl)carbamate. To the same reaction was added TFA (0.502 ml, 6.51 mmol), and the reaction mixture was stirred for 10 min., and then MeOH was removed. The residue was redissolved in DCM (6.0 ml), TFA (50% in DCM) (4.0 ml, 26.0 mmol) was added, and the mixture was stirred for 40 minutes at room temperature to yield (2S)-2-amino-1-(3,5-bis(trifluoromethyl)phenyl)propane-1-thiol. The reagents were removed, and the residue was dried under high vacuum. The reaction was dissolved in DCM (12.00 ml), degassed, and was cooled to 0° C. DIPEA (0.682 ml, 3.91 mmol) was added, followed by triphosgene (155 mg, 0.521 mmol), which was predissolved in DCM (6.0 ml) under N2 atmosphere dropwise. The reaction was stirred for 30 minutes to yield ((4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methylthiazolidin-2-one. The reaction was diluted with DCM, washed with 1N NaHCO3 solution, then brine. The organic layer was then dried over Na2SO4, filtered, and concentrated to yield (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-4-methylthiazolidin-2-one. 1H NMR (500 MHz, CDCl3): δ 7.90 (s, 1H); 7.86 (s, 2H); 5.00 (d, J=6.9 Hz, 1H); 4.41-4.42 (m, 1H); 0.99 (d, J=6.6 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]3[CH:22]([C:23]([F:26])([F:25])[F:24])[CH2:21][CH2:20][CH:19]([C:27]([NH:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:28])[CH2:18]3)[CH:10]=2)=[CH:5][C:4]=1F)#[N:2].O.[NH2:39][NH2:40]>C(O)C>[NH2:2][C:1]1[C:3]2[C:4](=[CH:5][C:6]([C:9]3[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]4[C@H:22]([C:23]([F:24])([F:26])[F:25])[CH2:21][CH2:20][C@H:19]([C:27]([NH:29][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[O:28])[CH2:18]4)[CH:10]=3)=[CH:7][CH:8]=2)[NH:40][N:39]=1
Reactant: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2CC(C(=O)NCc3ccccc3)CCC2C(F)(F)F)n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CNc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2C[C@@H](C(=O)NCc3ccccc3)CC[C@H]2C(F)(F)F)n1
Yield: 39.9 %

Procedure:
To a solution of 1-[6-(4-cyano-3-fluorophenyl)-2-(methylamino)-4-pyrimidinyl]-N-(phenylmethyl)-6-(trifluoromethyl)-3-piperidinecarboxamide (66 mg, 0.129 mmol) in ethanol (2 mL) into a 5 mL microwave vial was added hydrazine monohydrate (0.121 mL, 3.86 mmol). The reaction was capped and heated overnight. Since the reaction was not completed, additional 50 uL of hydrazine monohydrate was added and heated overnight. The reaction was concentrated then re-dissolved in 1 mL of DMSO and purified on HPLC (HPLC condition: open-access Gilson using Unipoint software with a Varian Polaris 5u C18(2) 100A, 50×30.00 mm 5 micron. 10-minute run (35 mL/min, 25% CH3CN/H2O, 0.1% TFA to 50% CH3CN/H2O, 0.1% TFA) with UV detection at 254 nm). Product fractions were combined and the volume was reduced under vacuum until most of the CH3CN was removed. Saturated aqueous NaHCO3 (10 mL) was added, and the resulting mixture was extracted with EtOAc (3×10 mL). The organics were combined, washed with brine, dried over MgSO4, filtered, and concentrated. The resulting material was transferred into a vial and water was added and freeze dried overnight to afford the title compound (27 mg) as a light yellow solid. LC-MS (ES) m/z=525 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.81-1.88 (m, 3H), 2.06-2.14 (m, 1H), 2.43-2.49 (m, 1H), 2.84 (bs, 3H), 3.14 (bs, 1H), 4.20-4.43 (m, 2H), 5.40 (s, 2H), 6.80 (bs, 1H), 7.22-7.31 (m, 3H), 7.31-7.38 (m, 2H), 7.62-7.69 (m, 1H), 7.71-7.75 (m, 1H), 8.02 (bs, 1H), 8.54 (t, J=5.9 Hz, 1H), 11.53 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9](B3OC(C)(C)C(C)(C)O3)[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:26])[O:4][N:3]=1.Br[C:28]1[N:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:31]=[CH:30][C:29]=1[CH3:39].COCCOC.C([O-])([O-])=O.[Cs+].[Cs+]>O>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:28]3[N:32]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:31]=[CH:30][C:29]=3[CH3:39])[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1cc(B2OC(C)(C)C(C)(C)O2)c2[nH]c(=O)[nH]c2c1
Reactant: Cc1cnn(-c2ccccc2)c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: Cc1cnn(-c2ccccc2)c1-c1cc(-c2c(C)noc2C)cc2[nH]c(=O)[nH]c12
Temperature: 130 °C
Yield: 12 %

Procedure:
6-(3,5-dimethylisoxazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one (30 mg, 0.084 mmol) and 5-bromo-4-methyl-1-phenyl-1H-pyrazole (30 mg, 0.13 mmol) was added to a solvent mixture of 1,2-dimethoxyethane (2 ml) and water (1 ml). To the above mixture were added PEPPSI-Ipr (5.4 mg, 0.008 mmol) and Cs2CO3 (83 mg, 0.25 mmol). The reaction mixture was heated at 130° C. in microwave reactor for 30 mins. The reaction mixture was then filtered and organic solvent was evaporated and the residue was purified with Prep HPLC (0-100% CH3CN/H2O) to afford 3.9 mg product 6-(3,5-dimethylisoxazol-4-yl)-4-(4-methyl-1-phenyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazol-2(3H)-one (yield=12%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23](=[O:38])[CH2:24][Sn](CCCC)(CCCC)CCCC)[CH3:21]>CN(C=O)C.CCOC(C)=O.[Br-].[Zn+2].[Br-]>[CH2:20]([O:22][C:23](=[O:38])[CH2:24][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)[CH3:21]
Reactant: CCCC[Sn](CCCC)(CCCC)CC(=O)OCC
Reactant: Brc1cc(OCc2ccccc2)cc2ccccc12
Agent: [Br-]
Agent: [Zn+2]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cc(OCc2ccccc2)cc2ccccc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
3-Benzyloxy-1-bromo-naphthalene (5.64 g, 18.01 mmol) is dissolved under an atmosphere of argon in dry DMF (100 ml). Tributylstannanyl-acetic acid ethyl ester (7.47 g, 19.81 mmol) is added, as well as [bis(tri-ortho-tolyl-phosphine)]palladium (II) dichloride (2.83 g, 3.60 mmol) and zinc(II) bromide (5.27 g, 23.41 mmol). The reaction mixture is heated to 80° C. for 3 h. The reaction mixture is diluted with EtOAc and washed twice with diluted brine (back extracted). The combined organic layers are dried over Na2SO4, the solvent is removed, and the residue is purified by FCC (hexane/EtOAc 100:0 to 97.5:2.5 to 95:5 to 90:10). The resulting oil, still containing tin residues, is stirred in a 1:1 mixture of EtOAc/1N NaOH (200 ml) for 1 h. The mixture is extracted twice with EtOAc. The combined organic layers are washed twice with H2O (back extracted), dried over Na2SO4 and concentrated. The residue is purified by FCC (hexane/EtOAc 100:0 to 97:3 to 95:5 to 93:7 to 92:8 to 90:10) to yield the title compound. 1H NMR (DMSO, 400 MHz) δ 1.18 (t, J=7.2 Hz, 3H), 4.10 (q, J=7.2 Hz, 2H), 4.11 (s, 2H), 5.25 (s, 2H), 7.21 (d, J=3.0 Hz, 1H), 7.41 (m, 8H), 7.53 (d, J=6.6 Hz, 1H), 7.84 (dd, J=7.2 Hz, 1H); ES-MS: 320 [M+H]+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH:23]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:24][C:25](=[CH2:41])[CH2:26][C:27]([NH:38][CH:39]=[O:40])([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N+]=[N-].O>O1CCCC1>[NH2:20][CH:23]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:24][C:25](=[CH2:41])[CH2:26][C:27]([NH:38][CH:39]=[O:40])([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: C=C(CC(N=[N+]=[N-])C(=O)OCC)CC(NC=O)(C(=O)OCC)C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C=C(CC(N)C(=O)OCC)CC(NC=O)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.5 %

Procedure:
10.9 g of triphenylphosphine were added to a solution of 13 g of the product of Step 3 in 250 ml of tetrahydrofuran at approximately -5° C. and the mixture was stirred for 5 hours at room temperature. 8.5 ml of water were added and the mixture was stirred for 24 hours at room temperature. The tetrahydrofuran was evaporated off and the residue was taken up in methylene chloride. The mixture was poured into ice-cold 2N hydrochloric acid, followed by extraction with 2N hydrochloric acid, neutralization with sodium bicarbonate and extraction with methylene chloride. The extract was washed with saline solution, dried and evaporated to dryness to obtain 10 g of the expected product melting at 50° C. after crystallization from isopropyl ether.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[OH:9].Br[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([CH2:11][O:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([OH:9])[CH:4]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1ccc(O)cc1O
Reactant: BrCC1CCCCC1
Product: Cc1ccc(OCC2CCCCC2)cc1O

Procedure:
Alkylation of 4-methylbenzene-1,3-diol using (bromomethyl)cyclohexane following the method used in Example 154 gave 5-(cyclohexylmethoxy)-2-methylphenol as a light yellow oil. Yield (0.15 g, 8.5%): 1H NMR (400 MHz, CDCl3) δ 6.96 (d, J=8.4 Hz, 1H), 6.36-6.41 (m, 2H), 3.68 (d, J=6.4 Hz, 2H), 2.16 (s, 3H), 1.64-1.89 (m, 6H), 1.14-1.34 (m, 3H), 0.96-1.08 (m, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)=[C:9]([CH3:11])[N:10]=1)=[O:5])C.[OH-].[Na+]>O.C1COCC1>[CH3:11][C:9]1[N:10]=[C:6]([C:4]([OH:5])=[O:3])[S:7][C:8]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1nc(C)c(-c2cccc3ccccc23)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(C(=O)O)sc1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-methyl-5-naphthalen-1-yl-thiazole-2-carboxylic acid ethyl ester (30 mg, 0.10 mmol) in water (1 ml) and THF (1 ml) is added sodium hydroxide (0.2 mL, 1M, 0.20 mmol). The reaction mixture is stirred at rt for 1 hr, and then extracted with ethyl ether (30 mL). The aqueous layer is acidified to pH<7.0 by phosphate buffer and then extracted with EtOAc (2×50 mL). The combined organic layers are washed with brine, dried over MgSO4, and then concentrated. The crude product is used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[I:11]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([I:11])=[CH:9][N:10]=2)[N:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1ccc2nccn2n1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Clc1ccc2ncc(I)n2n1
Reaction time: 8 h
Yield: 90.8 %

Procedure:
6-chloroimidazo[1,2-b]pyridazine (2.0 g, 13.0 mmol, 1.0 equiv) in chloroform (20 mL) at room temperature was added N-iodosuccinimide (2.9 g, 13.0 mmol, 1.0 equiv) then stirred vigorously overnight. The reaction mixture was diluted in water and extracted with ethyl acetate. Purification using column chromatography gave 3.3 g of the yellow solid, 90%: 1H NMR δ 8.21 (d, J=7.6 Hz, 1H), 7.96 (s, 1H), 7.41 (d, J=7.6 Hz, 1H).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]2[N:10]=[CH:11][CH:12]=[C:8]2[N:7]=[C:6]([S:13][CH3:14])[C:5]=1[C:15]#[N:16].CN(C=O)C.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH2:22]([NH:3][C:4]1[N:9]2[N:10]=[CH:11][CH:12]=[C:8]2[N:7]=[C:6]([S:13][CH3:14])[C:5]=1[C:15]#[N:16])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: CSc1nc2ccnn2c(N)c1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc2ccnn2c(NCc2ccccc2)c1C#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.2 %

Procedure:
100 mg of sodium hydride (60%) was added to 500 mg of 7-amino-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile and 8 ml of DMF, followed by stirring at room temperature for about 10 minutes, and then 420 mg of benzyl bromide was added thereto, followed by stirring at about 50° C. for about 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, about 50 ml of water was added thereto, and the precipitated crystals were collected by filtration, washed with water and dried to obtain crude crystals. The crude crystals were purified by silica gel column chromatography to obtain 570 mg of 7-benzylamino-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile (compound No. 2) having a melting point of 165° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[O:13][CH3:14])(=[O:3])[CH3:2].S(=O)(=O)(O)O.[Br:20]Br>O>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([Br:20])=[CH:7][C:6]=1[O:13][CH3:14])(=[O:3])[CH3:2]
Reactant: COc1ccc(OC)c(NC(C)=O)c1
Reactant: BrBr
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1cc(NC(C)=O)c(OC)cc1Br

Procedure:
300 Parts of 1-acetylamino-2,5-dimethoxybenzene were introduced at about 5°C in 1500 parts of 95 % sulfuric acid while stirring, 127 Parts of bromine were added dropwise at about 5°C with outside cooling. The mixture was stirred at 20°C for about 3 hours, 6000 parts by volume of water were added dropwise (a temperature of 25°C is not to be exceeded), the precipitate was suction-filtered and dried. 381 parts of 1-acetylamino-2,5-dimethoxy-4-bromobenzene (=90.4 % of the theory) were obtained.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([C:12](=O)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)[C:2]#[C:3][CH3:4].Cl.[CH:21]([O:24][NH2:25])([CH3:23])[CH3:22].Cl>N1C=CC=CC=1>[CH:21]([O:24][N:25]=[C:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]1[CH:7]=[C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])[N:11]=[CH:10][N:9]=1)([CH3:23])[CH3:22]
Reactant: CC(C)ON
Reactant: CC#CCOc1cc(C(=O)c2ccccc2)ncn1
Agent: Cl
Solvent: c1ccncc1
Product: CC#CCOc1cc(C(=NOC(C)C)c2ccccc2)ncn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 3 ml of pyridine were added 0.3 g of 6-(2-butynyloxy)-4-benzoylpyrimidine and 0.20 g of O-isopropylhydroxylamine hydrochloride, followed by stirring at room temperature for 3 hours. The reaction mixture was then poured into 10% hydrochloric acid and extracted three times with ethyl acetate. The organic layers were combined and washed with a saturated aqueous sodium chloride solution, and the combined organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give two isomers of (6-(2-butynyloxy)-4-pyrimidyl)phenylketone O-isopropyloxime (referred to as isomers A and B).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([NH:12][C:13]([C:15]1[C:20]([I:21])=[C:19]([N:22]2[CH2:26][CH2:25][CH:24](Br)[C:23]2=[O:28])[C:18]([I:29])=[C:17]([C:30]([NH:32][CH:33]([CH2:39][O:40][C:41](=[O:43])[CH3:42])[CH2:34][O:35][C:36](=[O:38])[CH3:37])=[O:31])[C:16]=1[I:44])=[O:14])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2]>C(O)(=O)C.C([O-])(=O)C.[Ag+]>[C:1]([O:4][CH2:5][CH:6]([NH:12][C:13]([C:15]1[C:20]([I:21])=[C:19]([N:22]2[CH2:26][CH2:25][CH:24]([O:4][C:1](=[O:3])[CH3:2])[C:23]2=[O:28])[C:18]([I:29])=[C:17]([C:30]([NH:32][CH:33]([CH2:39][O:40][C:41](=[O:43])[CH3:42])[CH2:34][O:35][C:36](=[O:38])[CH3:37])=[O:31])[C:16]=1[I:44])=[O:14])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(COC(C)=O)NC(=O)c1c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c(I)c(N2CCC(Br)C2=O)c1I
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CC(=O)OCC(COC(C)=O)NC(=O)c1c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c(I)c(N2CCC(OC(C)=O)C2=O)c1I
Yield: 163.4 %

Procedure:
N,N'-bis-[2-acetyloxy-1-)acetyloxymethyl)ethyl]-5-[3-bromo-2-oxo-1-pyrrolidinyl]-2,4,6-triiodo-1,3-benzenedicarboxamide (4.00 g, 3.92 mmol) of example 4a was dissolved in glacial acetic acid (40 ml) and treated with silver acetate (3.25 g, 19.50 mmol) at 133°-135° for 26 hours under a nitrogen atmosphere. The suspended solids were filtered off and the solvent was removed in vacuo. The resulting crude residue was treated with acetic anhydride (30 ml) and pyridine (42 ml), after which the volatile components were completely removed under high vacuum. The resulting product was purified by silica gel flash chromatography to obtain N,N'-bis-[2-acetyloxy-1-(acetyloxymethyl)ethyl]-5-[3-acetyloxy-2-oxo-1-pyrrolidinyl]-2,4,6-triiodo-1,3-benzenedicarboxamide as a pale orange foam (3.20 g, 82% yield).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[C:8](OC)=[O:9].CO.O>C1COCC1>[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[CH2:8][OH:9]
Reactant: COC(=O)[C@H](C)Nc1ccc(F)c(F)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](CO)Nc1ccc(F)c(F)c1F
Reaction time: 1 h

Procedure:
At room temperature, sodium borohydride (35.7 mg) was suspended in THF (0.2 ml). Then a solution (0.8 ml) of methyl (2S)-2-(2,3,4-trifluoroanilino)propionate (200 mg, 99.8% ee) in THF was added to the solution. After adding methanol (137.4 mg), the liquid reaction mixture was stirred for 1 hour. Then water was added to the liquid reaction mixture followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of ammonium chloride and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography to thereby give 176 mg (99.8% ee) of the title compound as an oily substance. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 51.