Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][C@@H:25]2[OH:28])[C@:21]2([CH3:22])[C@@H:16]([CH2:17][C@@H:18]([O:29][CH2:30][CH2:31][N:32]([C:34]4[CH:39]=[CH:38][C:37]([C@H:40]5[CH2:57][C@@:55]6([CH3:56])[C@@H:51]([CH2:52][CH2:53][C@:54]6([OH:61])[C:58]#[C:59][CH3:60])[C@H:50]6[C:41]5=[C:42]5[C:47]([CH2:48][CH2:49]6)=[CH:46][C:45](=[O:62])[CH2:44][CH2:43]5)=[CH:36][CH:35]=4)[CH3:33])[CH2:19][CH2:20]2)[CH2:15][C@H:14]3OCCl)[CH2:11][CH2:10]1)[CH3:8])[C:3]([OH:5])=[O:4].[C:66]([O:70][C:71]([NH:73][CH2:74][CH2:75][CH2:76][C:77]([OH:79])=[O:78])=[O:72])([CH3:69])([CH3:68])[CH3:67].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][CH:2]([CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][C@@H:25]2[OH:28])[C@:21]2([CH3:22])[C@@H:16]([CH2:17][C@@H:18]([O:29][CH2:30][CH2:31][N:32]([C:34]4[CH:39]=[CH:38][C:37]([C@H:40]5[CH2:57][C@@:55]6([CH3:56])[C@@H:51]([CH2:52][CH2:53][C@:54]6([OH:61])[C:58]#[C:59][CH3:60])[C@H:50]6[C:41]5=[C:42]5[C:47]([CH2:48][CH2:49]6)=[CH:46][C:45](=[O:62])[CH2:44][CH2:43]5)=[CH:36][CH:35]=4)[CH3:33])[CH2:19][CH2:20]2)[CH2:15][C@H:14]3[O:78][C:77](=[O:79])[CH2:76][CH2:75][CH2:74][NH:73][C:71]([O:70][C:66]([CH3:69])([CH3:67])[CH3:68])=[O:72])[CH2:11][CH2:10]1)[CH3:8])[C:3]([OH:5])=[O:4]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Reactant: CC#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(N(C)CCO[C@H]4CC[C@@]5(C)[C@@H](C4)C[C@@H](OCCl)[C@@H]4[C@@H]5C[C@H](O)[C@]5(C)[C@@H]([C@H](C)CC(C)C(=O)O)CC[C@@H]45)cc3)C[C@@]21C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC#C[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(N(C)CCO[C@H]4CC[C@@]5(C)[C@@H](C4)C[C@@H](OC(=O)CCCNC(=O)OC(C)(C)C)[C@@H]4[C@@H]5C[C@H](O)[C@]5(C)[C@@H]([C@H](C)CC(C)C(=O)O)CC[C@@H]45)cc3)C[C@@]21C

Procedure:
The compound of Example 8B is dissolved in DMF; 4-tert-butoxycarbonylaminobutanoic acid (1.3 eq) is added, along with 1.2 equivalents of Cs2CO3. The resultant mixture is stirred overnight at ambient temperature. The reaction mixture is partitioned between aqueous phosphoric acid (1N) and ethyl acetate. The organic extract is dried (Na2SO4), filtered, and concentrated in vacuo. The crude material is purified on silica gel using a gradient of ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:18])[C:5]2[O:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:6]=2[CH:17]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][N:24]1[C:28](=[O:29])[C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[S:25]1(=[O:35])=[O:34]>>[O:34]=[S:25]1(=[O:35])[C:26]2[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=2[C:28](=[O:29])[N:24]1[CH2:23][CH2:22][CH2:21][CH2:20][N:14]1[CH2:15][CH2:16][CH:11]([N:7]2[C:6]3[CH:17]=[C:2]([CH3:1])[CH:3]=[C:4]([CH3:18])[C:5]=3[O:9][C:8]2=[O:10])[CH2:12][CH2:13]1
Reactant: Cc1cc(C)c2oc(=O)n(C3CCNCC3)c2c1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCCBr
Product: Cc1cc(C)c2oc(=O)n(C3CCN(CCCCN4C(=O)c5ccccc5S4(=O)=O)CC3)c2c1

Procedure:
From the hydrochloride salt of 4-(5,7-dimethyl-2-oxo-3-benzoxazolinyl)-piperidine and 2-(4-bromobutyl)-1,1-dioxido-1,2-benzothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid: 1H NMR (300 MHz, CDCl3) 8.08 (d, J=7.27 Hz, 1H), 7.90 (m, 3H), 7.65 (br m, 1H), 6.752 (s, 1H), 4.55 (br m, 1H), 3.85 (br t, 2H), 3.70 (br m, 2H), 3.32 (br m, 2H), 3.10 (br m, 2H), 2.87 (br m, 2H), 2.413 (s, 3H), 2.318 (s, 3H), 2.06 (br m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH3:11].[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)=[C:5]2[CH3:11]
Reactant: Cc1c[nH]c2ccc(Cl)cc12
Reactant: c1c[nH]cn1
Product: Cc1c(-n2ccnc2)[nH]c2ccc(Cl)cc12

Procedure:
Condensation of 5-chloro-3-methylindole with imidazole according to the procedure described in the previous examples gives 5-chloro-2-(1-imidazolyl)-3-methylindole, m.p. 212°-215°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[OH-].[Na+].Cl[C:13]([O:15][CH3:16])=[O:14]>O>[C:13](=[O:14])([O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[Cl:1])[O:15][CH3:16]
Reactant: Oc1ccc(F)cc1Cl
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)Oc1ccc(F)cc1Cl
Yield: 115.8 %

Procedure:
2-Chloro-4-fluorophenol (83.4 g) was added to a solution of sodium hydroxide (27.7 g) in water (450 ml), and methyl chloroformate (69.2 g) was dropwise added thereto at a temperature of below 10° C. Precipitated crystals were collected by filtration and washed with water to give methyl (2-chloro-4-fluorophenyl) carbonate (134.8 g). M.P., 69°-71° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH:4]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH2:5][C:6]1[C:7]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:8][C:9](Cl)=[N:10][CH:11]=1.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=1>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:28])[CH:4]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH2:5][C:6]1[C:7]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:8][C:9]([NH:29][C:30]2[CH:35]=[N:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[N:10][CH:11]=1
Reactant: COC(=O)C(Cc1cnc(Cl)nc1Nc1ccccc1)c1ccc(OC)cc1
Reactant: COc1ccc(N)cn1
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1cnc(Nc2ccc(OC)nc2)nc1Nc1ccccc1)c1ccc(OC)cc1
Temperature: 110 °C

Procedure:
A mixture of 3-(2-chloro-4-phenylamino-pyrimidin-5-yl)-2-(4-methoxy-phenyl)-propionic acid methyl ester (40 mg, 0.1 mmol) (from Example 12b supra) and 5-amino-2-methoxypyridine (37.2 mg, 0.3 mmol) (Aldrich) was heated at 110° C. for 4 hours. After cooling, the reaction mixture was diluted with ethyl acetate (50 mL) and successively washed with saturated aqueous ammonium chloride solution (10 mL), water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude 3-[2-(6-methoxy-pyridin-3-ylamino)-4-phenylamino-pyrimidin-5-yl]-2-(4-methoxy-phenyl)-propionic acid methyl ester as a dark-red solid which was used in the next step without further purification. (Yield 47.1 mg, 96.8%).
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[C:11](O)(=[O:13])[CH3:12].O.OS(O)(=O)=O>>[C:11]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:10])(=[O:13])[CH3:12]
Reactant: OCCCCCCCCO
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)OCCCCCCCCO
Temperature: 25 °C
Yield: 92.3 %

Procedure:
A solution of 1.987 g (13.7 mmoles) of 1,8-octanediol in 25 ml (441 mmoles) of glacial acetic acid was mixed with 200 ml (11.11 moles) of H2O containing 4 ml (72 mmoles) of conc. H2SO4. This mixture was extracted continuously for 40 hours using hexane. The monoester is not very soluble in hexane and hence a mixture of hexane-cyclohexane (in which the monoester, but not the starting diol, is soluble) should be recommended if one is interested in developing this process for 1,8-octanediol. After cooling the hexane to room temperature, ether was added to make the organic layer homogeneous. The ether-hexane layer was then dried over anhydrous potassium carbonate and filtered. Removal of the solvent under reduced pressure afforded 2.38 g (~92% yield) of product, GC analysis of which indicated the presence of 2% starting diol and 4% diester. The purity of the desired monoester was therefore 94%.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[CH2:11]([NH:14][C:15]([NH2:17])=[S:16])[CH2:12][CH3:13].C([O-])(=O)C.[Na+].O>C(O)C>[C:5]1([C:3]2[N:17]=[C:15]([NH:14][CH2:11][CH2:12][CH3:13])[S:16][CH:2]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(CCl)c1ccccc1
Reactant: CCCNC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCNc1nc(-c2ccccc2)cs1
Yield: 89.7 %

Procedure:
To a solution of 2-chloroacetophenone (4.45 g, 28.8 mmol) and N-propylthiourea (3.40 g, 28.8 mmol) in ethanol (50 mL) was added sodium acetate (3.07 g, 37.4 mmol), and the mixture was heated under reflux for 1.5 hrs. Water was added to the reaction mixture, and crystals were collected by filtration. The obtained crude crystals were recrystallized from diethyl ether-hexane to give the title compound (5.64 g, 92%) as colorless crystals.
Reaction SMILES: C[O-].[Na+].CS(C)=O.CO[C:10](=[O:24])[CH2:11][CH2:12][C:13]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])=[O:14]>C1(C)C=CC=CC=1>[CH3:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][CH2:16][CH:15]1[C:10](=[O:24])[CH2:11][CH2:12][C:13]1=[O:14]
Reactant: COCCOCCCCC(=O)CCC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: COCCOCCCC1C(=O)CCC1=O
Yield: 82.5 %

Procedure:
In a 5 L 3-neck round bottom flask fitted with mechanical stirrer, a distillation system, a 2 L dropping funnel, and an argon inlet, was poured sodium methoxide solution (25 wt. % solution in methanol, 200 mL). Toluene (1.0 L) was added and methanol was removed off by distillation with an heating mantle. To the sodium methoxide suspension, methyl sulfoxide (13.4 mL, 0.4 eq) was added and a solution of 44 (121.0 g, 0.46 mol) in toluene (2.0 L) was slowly added over a period of 2 h. The distillation was continued during the addition and additional 30 minutes (until 0.5 L residual toluene). The reaction mixture was cooled and water (1 L) was added. Toluene was extracted and thrown away. The aqueous phase was acidified with 10% HCl until pH 1 and extracted with dichloromethane (4×800 mL). The combined organic phase was washed with brine, dried over magnesium sulfate, and rotary evaporated to give the cyclopentanedione 45 (81.3 g, 75%) as a brown heavy oil. 1H NMR (400 MHz, CD3OD) δ 2.42 (t, J=7.1 Hz, 2H), 2.51 (s, 4H), 3.38 (s, 3H), 3.55-3.61 (m, 4H), 3.67 (m, 2H), 4.68 (s, 2H) ppm.
Reaction SMILES: [N:1]([Si](C)(C)C)=[N+:2]=[N-:3].[C:8]([C:10]1[CH:11]=[C:12]([C:16]2[CH:17]=[CH:18][C:19]3[O:23][C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[C:21]([C:31]([NH:33][CH3:34])=[O:32])[C:20]=3[CH:35]=2)[CH:13]=[CH:14][CH:15]=1)#[N:9].C([Sn](CCCC)=O)CCC>C1(C)C=CC=CC=1>[NH:1]1[C:8]([C:10]2[CH:11]=[C:12]([C:16]3[CH:17]=[CH:18][C:19]4[O:23][C:22]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)=[C:21]([C:31]([NH:33][CH3:34])=[O:32])[C:20]=4[CH:35]=3)[CH:13]=[CH:14][CH:15]=2)=[N:9][N:3]=[N:2]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C#N)c3)cc12
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nnn[nH]4)c3)cc12
Temperature: 105 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
Azidotrimethylsilane (161 μL, 1.215 mmol) was added to a stirring solution of 5-(3-cyanophenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (225 mg, 0.607 mmol) and dibutylstannanone (30 mg, 0.121 mmol) in toluene (6 mL) at rt. It was heated to 105° C. and allowed to stir overnight. The reaction, which remained a slurry, resulted in ˜70% conversion. Additional equiv of reagents and solvents were added and the mixture was allowed to stir overnight at 105° C. The reaction was allowed to cool and filtered to give the titled compound (205 mg, 82%). LC-MS retention time: 1.03 min; m/z (MH+): 414. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [OH-].[Li+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH:14]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)[N:13]([CH2:24][C:25]([O:27]C)=[O:26])[C:12](=[O:29])[C@@H:11]1[CH2:30][CH:31]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>O.C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH:14]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)[N:13]([CH2:24][C:25]([OH:27])=[O:26])[C:12](=[O:29])[C@@H:11]1[CH2:30][CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)CN1C(=O)[C@H](CC2CCCCCC2)N(C(=O)OC(C)(C)C)CC1c1cc(F)cc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(c2cc(F)cc(F)c2)N(CC(=O)O)C(=O)[C@@H]1CC1CCCCCC1

Procedure:
10 mg (0.42 mmol) lithium hydroxide in 800 μl water were added to 105 mg (0.21 mmol) (2S)-tert-butyl-2-(cycloheptylmethyl)-5-(3,5-difluorophenyl)-4-(2-methoxy-2-oxoethyl)-3-oxopiperazine-1-carboxylate in 2 ml THF. After 2 h tetrahydrofuran was distilled off and the aqueous solution was neutralised with hydrochloric acid. The aqueous phase was extracted with ethyl acetate. The ethyl acetate phase was dried and evaporated down.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[NH:15][C:14](=O)[C:13]3[CH:23]=[CH:24][CH:25]=[N:26][C:12]2=3)=[O:10])[CH2:4][CH2:3]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:28]>N1C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[NH:15][C:14](=[S:28])[C:13]3[CH:23]=[CH:24][CH:25]=[N:26][C:12]2=3)=[O:10])[CH2:4][CH2:3]1
Reactant: CN1CCN(CC(=O)N2c3ccccc3NC(=O)c3cccnc32)CC1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: CN1CCN(CC(=O)N2c3ccccc3NC(=S)c3cccnc32)CC1

Procedure:
In the manner given in Example 1, 6,11-dihydro-11-[(4-methylpiperazino)acetyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one is reacted with phosphorus pentasulfide in pyridine to give 6,11-dihydro-11-[(4-methylpiperazino)-acetyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-thione.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([CH3:15])=[C:11]([CH3:14])[N+:12]=2[O-])[CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)([Cl:18])=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([CH3:15])=[C:11]([CH2:14][Cl:18])[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1oc(-c2cccc(Br)c2)[n+]([O-])c1C
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1oc(-c2cccc(Br)c2)nc1CCl
Temperature: 25 °C
Yield: 71.9 %

Procedure:
A solution of 2-(3-bromophenyl)-4,5-dimethyloxazole-3-oxide (96.6 g, 0.36 mol) in CHCl3 (0.90 L) was treated dropwise with phosphorous oxychloride (61.1 g, 0.40 mol) allowing the reaction to exotherm and then stirred at reflux for 30 min. The reaction was then cooled to room temperature and washed with water (2×1 L). The combined aqueous washes were back extracted with CH2Cl2 (2×400 mL). The organic layers were dried (MgSO4), and the solvent removed in vacuo to give crude product that was recrystallized from hot hexanes (300 mL), decanting the hot supernate away from a dark oily material. The remaining dark oil was agitated in additional hot hexanes (200 mL) and the combined supernates were cooled to 0° C. to crystallize the product which was isolated by filtration to give 74.2 g (72%) of 2-(3-bromophenyl)-4-(chloromethyl)-5-methyloxazole as a lime-green powder.
Reaction SMILES: [F:1][C:2]1[C:10]2[C:5](=[C:6]([N:11]([CH3:20])[S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:14])=[O:13])[CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:21]1[S:22][CH:23]([CH2:26][C:27]([O:29]CC)=[O:28])[CH2:24][N:25]=1.[OH-].[Na+].Cl>O1CCCC1.C(O)C>[F:1][C:2]1[C:10]2[C:5](=[C:6]([N:11]([CH3:20])[S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:13])=[O:14])[CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:21]1[S:22][CH:23]([CH2:26][C:27]([OH:29])=[O:28])[CH2:24][N:25]=1
Reactant: CCOC(=O)CC1CN=C(c2[nH]c3c(N(C)S(=O)(=O)c4cccs4)cccc3c2F)S1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(c1cccc2c(F)c(C3=NCC(CC(=O)O)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
To a solution of ethyl (2-{3-fluoro-7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (0.1 g) in tetrahydrofuran (1 mL) and ethanol (1 mL) was added 2N aqueous sodium hydroxide solution (0.15 mL), and the mixture was stirred at room temperature for 1 hr, and then at 50° C. for 1 hr. The mixture was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried (MgSO4), and concentrated. The obtained residue was recrystallized from ethyl acetate to give the title compound (0.080 g, yield 85%) as colorless crystals. melting point 213-214° C.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][C:20]3[NH:21][N:22]([CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[C:23](=[O:25])[CH:24]=3)=[C:9]2[CH3:32])=[O:7])=[CH:4][CH:3]=1.[CH:35](=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>N1C=CC=CC=1.N1CCCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][C:20]3[C:24](=[CH:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:23](=[O:25])[N:22]([CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]4)[N:21]=3)=[C:9]2[CH3:32])=[O:7])=[CH:33][CH:34]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc2c(c1)c(Cc1cc(=O)n(C3CCCCC3)[nH]1)c(C)n2C(=O)c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1ccc2c(c1)c(CC1=NN(C3CCCCC3)C(=O)C1=Cc1ccccc1)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Pyrazolone from Example 9 (150 mg, 0.31 mmol) was diluted in 5 mL of pyridine in the presence of 2 drops of piperidine and benzaldehyde (32 μL, 0.31 mmol). The reaction mixture was stirred at room temperature for 5 hours. The solvents are evaporated under reduced pressure and the crude material is purified by column chromatography over silica gel eluting with ethyl acetate/hexanes 1:3. The desired material is isolated as a clear oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]2[CH:24]=[C:23]([CH3:25])[N:22]=[C:21](Cl)[N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:30]=1[CH2:31][NH2:32]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]2[CH:24]=[C:23]([CH3:25])[N:22]=[C:21]([NH:32][CH2:31][C:30]3[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:29]=3[O:28][CH3:27])[N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: Cc1cc(NCC2CCN(C(=O)OCc3ccccc3)CC2)nc(Cl)n1
Product: COc1ccc(CNc2nc(C)cc(NCC3CCN(C(=O)OCc4ccccc4)CC3)n2)c(OC)c1
Temperature: 25 °C

Procedure:
A stirred solution of 4-[(2-chloro-6-methyl-pyrimidin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester (EXAMPLE 57, 0.5 g, 1.33 mmol) in 2,4-dimethoxybenzylamine (1.00 mL, 6.67 mmol) was heated at 100° C. for 6 h, then cooled to rt and purified by silica gel chromatography [1–10 (10% NH4OH in MeOH)/99–90 CH2Cl2)] to give 4-{[2-(2,4-dimethoxy-benzylamino)-6-methyl-pyrimidin-4-ylamino]-methyl}-piperidine-1-carboxylic acid benzyl ester. M.S. (M+1): 506.46
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:7]2[CH:8]=[C:9]([C:12]3[N:16]([CH3:17])[C:15]([C:18]#[N:19])=[C:14](Br)[C:13]=3[CH3:21])[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:22])[O:3]1.[CH3:24][Sn](C)(C)C.O>CN(P(N(C)C)(N(C)C)=O)C>[CH3:1][C:2]1([CH3:23])[C:7]2[CH:8]=[C:9]([C:12]3[N:16]([CH3:17])[C:15]([C:18]#[N:19])=[C:14]([CH3:24])[C:13]=3[CH3:21])[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:22])[O:3]1
Reactant: Cc1c(Br)c(C#N)n(C)c1-c1ccc2c(c1)C(C)(C)OC(=O)N2
Reactant: C[Sn](C)(C)C
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1c(C)c(-c2ccc3c(c2)C(C)(C)OC(=O)N3)n(C)c1C#N
Yield: 85.8 %

Procedure:
A solution of 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-3-bromo-1,4-dimethyl-1H-pyrrole-2-carbonitrile (0.11 g, 0.29 mmol), PhCNPdCl(PPh3)2 (cat., 11 mg) and tetramethyltin (10 eq, 0.53 g, 2.9 mmol) in HMPA (3 mL) was heated to 110° C. for 5 days. The solution was allowed to cool, poured into water (20 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layer was washed with brine, dried over MgSO4 and purified by flash column chromatography on silica gel eluting with 30% ethyl acetate/hexane to give 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1,3,4-trimethyl-1H-pyrrole-2-carbonitrile (77 mg, 85%) as a white solid. 1H NMR (300 MHz, d6-DMSO): δ 1.63 (s, 6H), 1.87 (s, 3H), 2.49 (s, 3H), 3.50 (s, 3H), 6.99 (d, 1H, J=8.2 Hz), 7.25 (dd, 1H, J=8.2, 1.4 Hz), 7.29 (s, 1H), 10.39 (s, 1H). MS (ESI (−)) 308 (M−H)−. Anal. calcd for C18H19N3O4, C, 69.9, H, 6.19; N, 13.6. Found, C, 68.8, H, 6.22; N, 12.9.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[I:11]I.[OH-].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2cn[nH]c2c1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Clc1ccc2c(I)n[nH]c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.9 %

Procedure:
In a round-bottomed flask, 6-chloro-1H-indazole (90 mg, 0.59 mmol) was dissolved in DMF (1.4 mL). Iodine (300 mg, 1.18 mmol) was added followed by potassium hydroxide (128 mg, 2.28 mmol). The dark reaction mixture was stirred at room temperature for 3 h then was quenched with 10% aq NaHSO3 and extracted with diethyl ether (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated to give 169 mg (98%) of 6-chloro-3-iodo-1H-indazole as an orange solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2]>C(OCC)C>[CH3:2][CH:1]([OH:3])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Solvent: CCOCC
Product: CC(O)c1ccccc1
Reaction time: 48 h
Yield: 72 %

Procedure:
Following the set-up of Example 5 and under a nitrogen atmosphere, acetophenone (2.9 g, 3.0 mL, 25 mmol) was added to a solution of (+)-B-chlorodiiso-2-ethylapopinocampheylborane (9.6 g, 27.5 mmol) in EE (ethyl ether, 20 mL) at -25° C. The reaction was complete in 48 h (followed by 11B NMR after methanolysis of an aliquot). The reaction was worked up following the procedure of Example 3 to obtain 2.2 g, 72% of α-phenethyl alcohol which was found to be of ≥99%ee by capillary GC analysis of its MTPA ester.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[N:13][N:14]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[O:23])=[CH:18][CH:17]=4)[CH:15]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:30]([OH:33])[C:31]#[CH:32]>N1CCCC1.C(Cl)Cl.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>[N:24]1([C:22]([C:19]2[CH:18]=[CH:17][C:16]([N:14]3[CH:15]=[C:11]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([C:32]#[C:31][CH2:30][OH:33])=[CH:3][CH:4]=5)[NH:8][N:7]=4)[N:12]=[N:13]3)=[CH:21][CH:20]=2)=[O:23])[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1
Reactant: C#CCO
Reactant: O=C(c1ccc(-n2cc(-c3n[nH]c4cc(Br)ccc34)nn2)cc1)N1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCNC1
Product: O=C(c1ccc(-n2cc(-c3n[nH]c4cc(C#CCO)ccc34)nn2)cc1)N1CCOCC1
Temperature: 80 °C
Yield: 28.3 %

Procedure:
A mixture of {4-[4-(6-Bromo-1H-indazol-3-yl)-[1,2,3]triazol-1-yl]-phenyl}-morpholin-4-yl-methanone (150 mg; 0.33 mmol; 1.0 eq.), propargyl alcohol (39 μl; 0.66 mmol; 2.0 eq.) and Pd(PPh3)4 (19 mg, 0.02 mmol, 0.05 eq.) in pyrrolidine (1.5 mL) was heated O/N at 80° C. in a sealed tube. The reaction mixture was then diluted with DCM and washed with a saturated solution of NH4Cl (three times) and brine. Organic phase was dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC gave the title compound as a beige solid (40 mg, 28%). 1H NMR (300 MHz, DMSO-d6-d6): 13.50 (brs, 1H), 9.42 (s, 1H), 8.34 (dd, J=8.5 Hz, 1.0 Hz, 1H), 8.15 (d, J=8.6 Hz, 2H), 7.70-7.67 (m, 3H), 7.28 (dd, J=8.5 Hz, 1.0 Hz, 1H), 5.40 (t, J=6.0 Hz, 1H), 4.35 (d, J=6.0 Hz, 2H), 3.64 (m, 6H), 3.47 (m, 2H).