Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[O:13])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[Cl:24][CH2:25][C:26](Cl)=[O:27].C(=O)([O-])O.[Na+]>C(Cl)Cl.C1C=CC=CC=1>[Cl:24][CH2:25][C:26]([O:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[O:13])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4])=[O:27]
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(COC(=O)c2ccc(C(O)C(=O)O)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: ClCCl
Product: COc1ccc(COC(=O)c2ccc(C(OC(=O)CCl)C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
1.58 g(5 m mol) of DL-α-hydroxy-4-(p-methoxybenzyloxycarbonyl)phenylacetic acid were suspended in 10 ml of anhydrous methylene chloride and ice-cooled. To this suspension were added dropwise 5 ml of anhydrous methylene chloride solution containing 0.68 g(6 m mol) of chloroacetyl chloride with stirring over the course of 5 minutes. Then the temperature of the solution was raised slowly to ambient temperature, and the solution was stirred for 30 minutes to give a clear solution, The reaction mixture was poured into 20 ml of ice-water and adjusted to pH 2.5 with an aqueous sodium hydrogen carbonate solution. The organic layer was separated and the aqueous layer was extracted several times with methylene chloride. The combined organic layers were washed with water and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give a pale yellow oily residue, which then was dissolved in 20 ml of benzene and left overnight in an ice-box, yielding 1.52 g (78%) of crystalline DL-α-chloroacetoxy-4-(p-methoxybenzyloxycarbonyl)phenylacetic acid of mp. 121°~125° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[O:27]CC1C=CC=CC=1>CO.[Pd]>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:15])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[OH:27]
Reactant: Nc1ncc(-c2ccc(C(=O)N3CCC[C@@H]3CN3CCCC3)cc2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Nc1ncc(-c2ccc(C(=O)N3CCC[C@@H]3CN3CCCC3)cc2)cc1O
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of [4-(6-amino-5-benzyloxy-pyridin-3-yl)-phenyl]-[(2R)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl]-methanone (2.28 g, 5.00 mmol) in methanol (25 mL) was added 10% Pd/C (100 mg). The mixture was degassed and charged with hydrogen for three times, and then stirred under hydrogen balloon overnight. The reaction was filtered through a celite pad, washed with methanol, and condensed. After high vacuum dry, [4-(6-amino-5-hydroxy-pyridin-3-yl)-phenyl]-[(2R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone was obtained (1.74 g, 95% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.79 (s, 1H), 7.54 (m, 3H), 7.46 (m, 2H), 7.14 (s, 1H), 5.68 (s, 2H), 4.22 (m, 1H), 3.45 (m, 2H), 2.66 (m, 1H), 2.52 (m, 4H), 1.96 (m, 2H), 1.84 (m, 3H), 1.64 (m, 4H); MS m/z 367 (M+1).
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[C:15]1([NH:21][C:22]2[O:23][CH:24]=[C:25]([C:27]([N:29]3[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH:30]3[CH2:42][O:43][C:44]3[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=3)=[O:28])[N:26]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[ClH:1].[ClH:1].[C:15]1([NH:21][C:22]2[O:23][CH:24]=[C:25]([C:27]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH:30]3[CH2:42][O:43][C:44]3[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=3)=[O:28])[N:26]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2coc(Nc3ccccc3)n2)C(COc2cccnc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1coc(Nc2ccccc2)n1)N1CCNCC1COc1cccnc1
Reaction time: 8 h
Yield: 83 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(2-(phenylamino)oxazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate TFA salt (64.8 mg, 0.109 mmol) in MeOH (1 mL). After stirring overnight, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The fractions containing the desired product were concentrated under reduced pressure, dissolved in MeOH (1 mL), and treated with 4 M HCl in 1,4-dioxane (6 mL). The mixture was concentrated under reduced pressure to give 41 mg (83%) of the title compound as a white solid. LC-MS: RT=3.29 min, [M+H]+=380.0.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:16]2([F:22])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:23]([O:27][CH3:28])(=[O:26])[CH:24]=[CH2:25]>>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:16]2([F:22])[CH2:17][CH2:18][N:19]([CH2:25][CH2:24][C:23]([O:27][CH3:28])=[O:26])[CH2:20][CH2:21]2)[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C=CC(=O)OC
Reactant: FC1(c2cccc(OCc3ccccc3)c2)CCNCC1
Agent: Cl
Product: COC(=O)CCN1CCC(F)(c2cccc(OCc3ccccc3)c2)CC1
Yield: 86 %

Procedure:
This compound was prepared from 4-(3-benzyloxyphenyl)-4-fluoropiperidine hydrochloride and methyl acrylate as described in Step 1 of Example 4 in 86% yield.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[O:24]1[C:29]2[C:30]([C:34](O)=[O:35])=[CH:31][CH:32]=[CH:33][C:28]=2[NH:27][CH2:26][CH2:25]1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:34]([C:30]2[C:29]3[O:24][CH2:25][CH2:26][NH:27][C:28]=3[CH:33]=[CH:32][CH:31]=2)=[O:35])=[O:10])[N:12]=1
Reactant: O=C(O)c1cccc2c1OCCN2
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3c2OCCN3)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3,4-Dihydro-2H-benzo[1,4]oxazine-8-carboxylic acid. LC-MS (basic): tR=0.82 min; [M+H]+=488.9.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:34]1([C:37]#[C:38][C:39]#[C:40][C:41]2[CH:49]=[CH:48][C:44]([C:45]([OH:47])=O)=[CH:43][CH:42]=2)[CH2:36][CH2:35]1.Cl.[CH3:51][NH:52][C:53](=[O:61])[C@H:54]([C:57](=[O:60])[O:58][CH3:59])[NH:55][CH3:56]>O.C(OCC)(=O)C.CN(C=O)C>[CH:34]1([C:37]#[C:38][C:39]#[C:40][C:41]2[CH:42]=[CH:43][C:44]([C:45](=[O:47])[N:55]([CH:54]([C:53]([NH:52][CH3:51])=[O:61])[C:57]([O:58][CH3:59])=[O:60])[CH3:56])=[CH:48][CH:49]=2)[CH2:35][CH2:36]1
Reactant: O=C(O)c1ccc(C#CC#CC2CC2)cc1
Reactant: CNC(=O)[C@@H](NC)C(=O)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(C#CC#CC2CC2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 115.1 %

Procedure:
HATU (1.1 g) and DIPEA (1.0 mL) were added to a DMF (4.0 mL) solution of 4-(4-cyclopropylbuta-1,3-diyn-1-yl)benzoic acid (0.42 g) as obtained in Example 6-(2), whereafter the mixture was stirred for 2.5 hours at room temperature. Then, N,N2,O-trimethyl-3-oxoserinamide hydrochloride (Intermediate 5-2, 0.59 g) was added, and the mixture was stirred for 40 minutes at 70 to 80° C. The reaction mixture was cooled to room temperature, and ethyl acetate and water were added to isolate the organic layer. The extract was washed sequentially with water and brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered out, and then the solvent was distilled off under reduced pressure to obtain 1-(4-cyclopropylbuta-1,3-diyn-1-yl)-4-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}benzene (brown oil) (0.81 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:18]2[CH2:21][C:20]([F:23])([F:22])[CH2:19]2)=[C:4]([C@H:10]([OH:17])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]>C(Cl)Cl>[Br:1][C:2]1[C:3]([N:18]2[CH2:19][C:20]([F:23])([F:22])[CH2:21]2)=[C:4]([C@H:10]([O:17][C:4]([CH3:10])([CH3:5])[CH3:3])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(C)c([C@H](O)C(=O)OC(C)C)c(N2CC(F)(F)C2)c1Br
Solvent: ClCCl
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CC(F)(F)C2)c1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
The isobutylene gas was bubbled into a nitrogen purged, cooled (0° C.) solution of (S)-isopropyl 2-(5-bromo-4-(3,3-difluoroazetidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (175 mg, 0.45 mmol) and 0.05 mL of 70% HClO4 in DCM (5 mL) for 20 min. The reaction mixture was allowed to warm to rt and stirred for 18 h in a pressure sealed vessel, diluted with DCM, washed with 1M Na2CO3 solution, and dried over MgSO4. The crude product was charged (DCM) to a 24 g ISCO silica gel cartridge and gradient elution (5-35% EtOAc/hexanes) using an Isolera chromatography gave (S)-isopropyl 2-(5-bromo-4-(3,3-difluoroazetidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate 88 mg (44%). 1H NMR (400 MHz, DMSO-d6) δ 5.72 (s, 1H), 5.10-5.03 (m, 1H), 4.80-4.72 (m, 2H), 4.59-4.15 (m, 2H), 2.62 (s, 3H), 2.48 (s, 3H), 1.38 (d, J=6.1 Hz, 3H), 1.20 (s, 9H), 1.19 (d, J=6.1 Hz, 3H). UPLC (M+H)=451.3.
Reaction SMILES: [H-].[Na+].P(=O)([O-])O[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1.[F:24][CH2:25][CH2:26][O:27][C:28]1[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[CH:33]=[CH:32][C:29]=1[CH:30]=O.C(Cl)Cl.CO>C1COCC1>[N+:36]([C:34]1[CH:33]=[CH:32][C:29](/[CH:30]=[CH:5]/[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]4[CH:21]=3)=[CH:8][CH:7]=2)=[C:28]([O:27][CH2:26][CH2:25][F:24])[CH:35]=1)([O-:38])=[O:37]
Reactant: Cc1ccc2nc(-c3ccc(CO[PH](=O)[O-])cc3)cn2c1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1OCCF
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc2nc(-c3ccc(/C=C/c4ccc([N+](=O)[O-])cc4OCCF)cc3)cn2c1
Yield: 74.6 %

Procedure:
Prepared as described in the Alkene Formation section using sodium hydride (60% dispersion in mineral oil, 27 mg, 0.67 mmol), diethyl[4-(6-methylimidazo[1,2-a]pyridin-2-yl)benzyl phosphonate (200 mg, 0.559 mmol) and 2-(2-fluoroethoxy)-4-nitrobenzaldehyde (119 mg, 0.559 mmol) in dry THF (15 ml) to give the title compound (174 mg, 74%) as an orange solid after work-up and flash chromatography (50:1 DCM/MeOH).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[C:18]3[C:13](=[C:14]([NH2:19])[CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([C:20]([F:23])([F:22])[F:21])[N:10]=2)[CH2:4][CH2:3]1.[Cl:25][C:26]1[C:31]([C:32](O)=[O:33])=[C:30]([F:35])[C:29]([CH2:36][NH:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:28][CH:27]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:25][C:26]1[C:31]([C:32]([NH:19][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[N:12]=[C:11]([C:20]([F:23])([F:21])[F:22])[N:10]=[C:9]3[NH:8][CH:5]2[CH2:4][CH2:3][C:2]([CH3:24])([CH3:1])[CH2:7][CH2:6]2)=[O:33])=[C:30]([F:35])[C:29]([CH2:36][NH:37][C:38](=[O:43])[C:39]([CH3:41])([CH3:40])[CH3:42])=[CH:28][CH:27]=1
Reactant: CC1(C)CCC(Nc2nc(C(F)(F)F)nc3c(N)cccc23)CC1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)CCC(Nc2nc(C(F)(F)F)nc3c(NC(=O)c4c(Cl)ccc(CNC(=O)C(C)(C)C)c4F)cccc23)CC1
Yield: 19.5 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(4,4-dimethylcyclohexyl)-2-(trifluoromethyl)quinazoline-4,8-diamine (Intermediate-26, 100 mg, 0.295 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 127 mg, 0.443 mmol), oxalyl chloride (84 mg, 0.66 mmol), DMF (1 drop) and DIPEA (115 mg, 0.89 mmol) in CH2Cl2 (3 mL) to afford 35 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.30 (s, 1H), 8.67-8.65 (d, J=7.2 Hz, 1H), 8.59-8.56 (d, J=8.1 Hz, 1H), 8.22-8.16 (m, 2H), 7.74-7.68 (t, J=8.4 Hz, 1H), 7.45-7.33 (m, 2H), 4.32-4.30 (d, J=5.4 Hz, 2H), 4.14 (m, 1H), 1.76-1.66 (m, 4H), 1.43-1.24 (m, 4H), 1.14 (s, 9H), 0.99 (s, 3H), 0.95 (s, 3H); MS (m/z): 608.38 (M+H)+.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]([C:24](=[O:26])[CH3:25])[CH:21]=[CH:22][CH:23]=3)=[CH:14][C:12]=2[CH:13]=1.[CH3:27][Mg]Br.CCOCC>O1CCCC1>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]([C:24]([OH:26])([CH3:27])[CH3:25])[CH:21]=[CH:22][CH:23]=3)=[CH:14][C:12]=2[CH:13]=1
Reactant: CC(=O)c1cccc(-c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@@H]1CCCN1CCc1cc2cc(-c3cccc(C(C)(C)O)c3)ccc2o1
Reaction time: 8 h

Procedure:
The product from Example 136C (87 mg, 0.25 mmol) was dissolved into tetrahydrofuran (5 mL), treated with 3 M methylmagnesium bromide in ether (0.3 mL, 0.9 mmol), stirred overnight, quenched with 0.5 M aqueous dipotassium hydrogen phosphate, and diluted with EtOAc and a little CH2Cl2. The resulting emulsion was sonicated, and the aqueous phase was separated and extracted with EtOAc. The combined organic phases were washed consecutively with 0.5 M aqueous dipotassium hydrogen phosphate and brine, dried (Na2SO4), concentrated, and chromatographed on silica with a gradient of 2 to 10% MeOH/20% MeCN/CH2Cl2 followed by 10% MeOH/CH2Cl2 to provide the title compound as an orange resin (˜33% yield). 1HNMR (300 MHz, CD3OD) δ 1.20 (d, 3 H), 1.42-1.58 (m, 1 H), 1.58 (s, 6 H), 1.76-1.90 (m, 2 H), 1.96-2.12 (m, 1 H), 2.3-2.7 (m, 3 H), 2.97-3.13 (m, 2 H), 3.22-3.4 (m, 2 H), 6.62 (s, 1 H), 7.38 (dd, 1 H), 7.40-7.46 (m, 2 H), 7.46-7.48 (m, 2 H), 7.72 (dd, 1 H), 7.76 (dd, 1 H).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].C([O-])(=O)C.[Pb+4:17].[CH3:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([O:27][CH3:28])[C:21]=1B(O)O>C(Cl)(Cl)Cl.ClCCl>[C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].[CH3:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([O:27][CH3:28])[C:21]=1[Pb+3:17]
Reactant: COc1cc(C)cc(OC)c1B(O)O
Reactant: [Pb+4]
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C)cc(OC)c1[Pb+3]
Temperature: 40 °C
Reaction time: 1.25 h
Yield: 90 %

Procedure:
45.4 g of lead tetraacetate and 3.2 g of mercuric acetate are suspended in 150 ml of anhydrous chloroform and the mixture is heated to 40° C. under an argon atmosphere. A solution of 20 g of 2,6-dimethoxy-4-methylphenylboronic acid (prepared above) in 100 ml of chloroform is added dropwise to the reaction mixture at 40° C. The reaction mixture is left for 75 minutes at 40° C. and is then left to return to room temperature while stirring well. The reaction mixture is stirred at room temperature for 18 hours and is then diluted with 800 ml of dichloromethane. The solution is filtered over a bed of celite and the solvent is then evaporated to dryness in order to obtain yellow crystals of 2,6-dimethoxy-4-methylphenyllead triacetate, M.p.=172° C., Yield: 90%.
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[C:5]([Br:11])=[CH:4][CH:3]=1.[CH2:12]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC([O-])(C)C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C.C1(C)C=CC=CC=1>[Br:11][C:5]1[C:6]2[C:10](=[N:9][S:8][N:7]=2)[C:2]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:3][CH:4]=1
Reactant: CCCCCCNCCCCCC
Reactant: Brc1ccc(Br)c2nsnc12
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCCCCN(CCCCCC)c1ccc(Br)c2nsnc12
Temperature: 160 °C
Reaction time: 0.25 h

Procedure:
4,7-Dibromobenzo[c][1,2,5]thiadiazole (0.500 g, 1.70×10−3 mol), N,N-dihexylamine (0.50 ml, 2.1×10−3 mol), Pd2dba3 (45 mg, 4.9×10−5 mol), 2-(di-t-butylphosphino)biphenyl (30 mg, 1.0×10−4 mol), NaOt-Bu (0.242 g, 2.5×10−3 mol), toluene (4.0 ml) and DMF (0.40 ml) were added to a reaction vial. The reaction mixture was stirred at 160° C. for 15 min under microwave irradiation. After the reaction mixture was filtered and the solvent was evaporated, the residue was chromatographed on silica gel with 1:1 hexane:CH2Cl2. Yield=0.271 g (40% based on 0.500 g of 4,7-dibromobenzo[c][1,2,5]thiadiazole). 1H NMR (250 MHz, CDCl3): δ 7.59 (d, 1H, J=8.4 Hz, Ph-H), 6.31 (d, 1H, J=8.5 Hz, Ph-H), 3.68 (t, 4H, J=7.7 Hz, —NCH2), 1.51-1.75 (m, 4H, —NCH2CH2—), 1.20-1.44 (m, 12H, —CH2—), 0.89 (t, 6H, J=6.7 Hz, —CH3). CI MS m/z: 398.125 ((M+H)+) (calcd 398.127).
Reaction SMILES: [ClH:1].C([N:5]1[CH2:10][CH2:9][C:8]2[S:11][C:12]([C:15]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:16])=[C:13]([NH2:14])[C:7]=2[CH2:6]1)(=O)C>C(O)CCC>[ClH:1].[NH2:14][C:13]1[C:7]2[CH2:6][NH:5][CH2:10][CH2:9][C:8]=2[S:11][C:12]=1[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:16]
Reactant: CCCCOC(=O)c1sc2c(c1N)CN(C(C)=O)CC2
Agent: Cl
Solvent: CCCCO
Product: CCCCOC(=O)c1sc2c(c1N)CNCC2
Yield: 64 %

Procedure:
40 ml of n-butanol and then 5.1 ml of concentrated hydrochloric acid were added to 2.96 g of n-butyl 5-acetyl-3-amino-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (Compound No. 18) obtained in Example 2. The resultant mixture was heated in a steam bath for 2 hours. The solvent was distilled off. 20° ml of acetonitrile was added to the reaction mixture and the crystals thus formed were taken by filtration to obtain 1.86 g (64%) of n-butyl 3-amino-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate hydrochloride.
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[C@H:3]([NH:7][CH3:8])[C:4]([OH:6])=[O:5].[OH-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:19]([O:21][CH3:22])=[O:20]>>[CH3:22][O:21][C:19]([N:7]([CH3:8])[C@@H:3]([CH:2]([CH3:9])[CH3:1])[C:4]([OH:6])=[O:5])=[O:20]
Reactant: COC(=O)Cl
Reactant: CN[C@H](C(=O)O)C(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)N(C)[C@H](C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
(2S)-3-Methyl-2-methylamino-butanoic acid (5 g, 38.12 mmol) is added to a stirring solution of sodium hydroxide (76.2 mL of 1 M, 76.24 mmol). After complete dissolution, sodium carbonate (2.1 g, 19.82 mmol) is added followed by methyl chloroformate (3.18 mL, 41.17 mmol) at 0° C. over 40 minutes. The reaction mixture is stirred at rt for 4 hours, and then washed with diethyl ether (2×75 ml). The aqueous layer is cooled to 0° C., acidified to pH 1-2 and extracted with CH2Cl2. The organic phase is dried over MgSO4, filtered and concentrated to dryness to give the title compound (2S)-2-[methoxycarbonyl(methyl)amino]-3-methyl-butanoic acid (5.12 g, 71%) as a clear oil.
Reaction SMILES: [CH3:1][Si:2]([CH3:42])([CH2:21][CH2:22][C:23]([F:41])([F:40])[C:24]([F:39])([F:38])[C:25]([F:37])([F:36])[C:26]([F:35])([F:34])[C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[CH:18][C:17]([OH:20])=[CH:16][N:15]=2)=[CH:10][CH:9]=1.[CH2:43]([CH:47]1[CH2:51][C:50](=[O:52])[O:49][CH:48]1[CH2:53]OS(C1C=CC(C)=CC=1)(=O)=O)[CH:44]([CH3:46])[CH3:45].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:42][Si:2]([CH3:1])([CH2:21][CH2:22][C:23]([F:41])([F:40])[C:24]([F:38])([F:39])[C:25]([F:36])([F:37])[C:26]([F:34])([F:35])[C:27]([F:32])([F:33])[C:28]([F:29])([F:30])[F:31])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[CH:16][C:17]([O:20][CH2:53][CH:48]3[O:49][C:50](=[O:52])[CH2:51][CH:47]3[CH2:43][CH:44]([CH3:46])[CH3:45])=[CH:18][N:19]=2)=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2OC(=O)CC2CC(C)C)cc1
Reactant: C[Si](C)(CCCCOc1ccc(-c2ncc(O)cn2)cc1)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)CC1CC(=O)OC1COc1cnc(-c2ccc(OCCCC[Si](C)(C)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of compound 47 (0.162 g, 0.250 mmol), toluene-4-sulfonic acid 3-isobutyl-5-oxo-tetrahydro-furan-2-ylmethyl ester (0.0815 g, 0.250 mmol) and cesium carbonate (0.098 g, 0.300 mmol) in DMF 5.0 ml) was stirred at room temperature for 24 h. The reaction mixture was washed with water and the organic layer extracted into ethyl acetate/hexane (3×20 ml, 1:1). The combine extracts were washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residues were purified by column chromatography [silica gel, hexane/ethyl acetate (9:1)] to yield a colorless solid, which was recrystallized from acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:29]1[C:33]([S:34](Cl)(=[O:36])=[O:35])=[N:32][CH:31]=[N:30]1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10](=[O:13])[N:11]([S:34]([C:33]3[NH:29][N:30]=[CH:31][N:32]=3)(=[O:36])=[O:35])[N:12]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(Cn2c(-c3ccc(Cl)cc3)n[nH]c2=O)cc1
Reactant: O=S(=O)(Cl)c1ncn[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1ccc(Cn2c(-c3ccc(Cl)cc3)nn(S(=O)(=O)c3ncn[nH]3)c2=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
529 mg (1.68 mmol) of 5-(4-chlorophenyl)-4-(4-methoxybenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one [preparation according to WO 2007/134862 Example 55A] were dissolved in 10 ml of acetonitrile, and 1.09 g (3.35 mmol) of cesium carbonate and 281 mg (1.68 mmol) of 1H-1,2,4-triazole-5-sulfonyl chloride, dissolved in 5 ml of acetonitrile, were added successively. The reaction mixture was stirred at RT for 90 min. For work-up, 10 g of silica gel were added and the solvent was removed under reduced pressure. The crude product, adsorbed on silica gel, was purified by chromatography on silica gel (mobile phase: first ethyl acetate, then dichloromethane/methanol 90:10→80:20). This gave 268 mg (32% of theory) of the target compound.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].N1C=CC=CC=1.[C:16](Cl)(=[O:18])[CH3:17]>ClCCl>[C:16]([O:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])(=[O:18])[CH3:17]
Reactant: Oc1cccc(F)c1F
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1cccc(F)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.1 %

Procedure:
To a solution of 2,3-difluorophenol (30.0 g, 231 mmol) and pyridine (18.6 mL, 231 mmol) in dichloromethane (230 mL) at 0° C. was carefully added acetyl chloride (16.4 mL, 231 mmol). The reaction was allowed to warm to ambient temperature and stirred for 16 h. The reaction mixture was then diluted with dichloromethane (100 mL), washed with 1N aqueous hydrochloric acid (2×50 mL) and brine (75 mL), and concentrated to produce 41.0 g (100%) of the title compound. MS (DCI/NH3) m/z 190 (M+NH4)+.