Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:25]=[CH:24][C:8]2[N:9]([CH3:23])[C:10]([NH:12][C:13]3[S:14][C:15]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:16]=4[N:17]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[Li+].[OH-]>>[F:22][C:19]1[CH:20]=[CH:21][C:15]2[S:14][C:13]([NH:12][C:10]3[N:9]([CH3:23])[C:8]4[CH:24]=[CH:25][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=4[N:11]=3)=[N:17][C:16]=2[CH:18]=1
Reactant: COC(=O)c1ccc2c(c1)nc(Nc1nc3cc(F)ccc3s1)n2C
Agent: [Li+]
Agent: [OH-]
Product: Cn1c(Nc2nc3cc(F)ccc3s2)nc2cc(C(=O)O)ccc21
Yield: 89.5 %

Procedure:
2-(5-Fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid (1.53 g) was prepared by following General Procedure E starting from 2-(5-fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid methyl ester (1.78 g), and LiOH (10.0 ml, 2.0 N solution in water). LC/MS: m/z 344.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:7][NH:8]2)([O-:3])=[O:2].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].Br[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>CC(C)=O>[C:33]([O:32][C:30](=[O:31])[CH2:29][N:8]1[C:9]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2)[CH:6]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:7]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)CCC1CNc2cccc([N+](=O)[O-])c21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCC1CN(CC(=O)OC(C)(C)C)c2cccc([N+](=O)[O-])c21
Temperature: 25 °C

Procedure:
To a solution of (±)-ethyl 3-(4-nitro-2,3-dihydro-1H-indol-3-yl)propanoate from Step A (980 mg, 3.71 mmol), sodium carbonate (590 mg, 5.56 mmol), and potassium iodide (123 mg, 0.74 mmol) in acetone (10 mL) was added tert-butyl bromoacetate (16.4 mL, 111 mmol). The mixture was heated at reflux for 18 h, then cooled to ambient temperature and concentrated in vacuo. The residue was partitioned between H2O (30 mL) and EtOAc (2×60 mL) and the organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 65:35, to give the title compound. MS: m/z=379 (M+1).
Reaction SMILES: [CH3:1][C:2]1([C:17]([O:19]C)=[O:18])[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.[Li+].[OH-]>C(O)C>[CH2:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][C:2]([CH3:1])([C:17]([OH:19])=[O:18])[CH2:3]1)=[O:8])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)C1(C)CCN(C(=O)OCc2ccccc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C(=O)O)CCN(C(=O)OCc2ccccc2)C1
Temperature: 78 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
1-Benzyl 3-methyl 3-methylpyrrolidine-1,3-dicarboxylate (2.72 g, 9.81 mmol) in ethanol (15 mL) was added to a 3M LiOH solution (14.7 mL, 29.4 mmol), and the reaction mixture was stirred at 78° C. (bath) for 1 hour. The ethanol was removed and, ether (30 mL) was added. The aqueous layer was separated and acidified with saturated potassium hydrogen sulfate to a pH of about 3 to about 4, extracted with ethyl acetate (50 mL), washed with brine and dried over sodium sulfate. After removal of the solvent, 1-(benzyloxycarbonyl)-3-methylpyrrolidine-3-carboxylic acid (2.56 g, 99% yield) was isolated as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([CH:19]=[C:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:27]=1.C(N(CC)CC)C>CS(C)=O.O>[Br:1][C:2]1[CH:18]=[C:17]([CH:16]=[C:4]([O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=2)[CH:3]=1)[CH:19]=[C:20]1[CH2:25][CH2:24][N:23]([C:33]([NH:32][C:28]2[N:27]=[N:26][CH:31]=[CH:30][CH:29]=2)=[O:34])[CH2:22][CH2:21]1
Reactant: O=C(Nc1cccnn1)Oc1ccccc1
Reactant: FC(F)(F)c1ccc(Oc2cc(Br)cc(C=C3CCNCC3)c2)nc1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cccnn1)N1CCC(=Cc2cc(Br)cc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Reaction time: 8 h
Yield: 66 %

Procedure:
2-(3-Bromo-5-(piperidin-4-ylidenemethyl)phenoxy)-5-(trifluoromethyl)pyridine (0.57 g, 1.379 mmol) and phenyl pyridazin-3-ylcarbamate (0.296 g, 1.38 mmol) were dissolved in DMSO (4 mL). Triethylamine (0.57 mL, 4.13 mmol) was added and the reaction was stirred overnight. The reaction mixture was diluted with water and extracted with ethyl acetate three times. The organic layer was washed with brine, dried over Na2SO4, and evaporated to dryness. The residue was purified by silica gel column chromatography (37% acetone in hexane) to give the title compound (0.486 g, 66%). 1H NMR (500 MHz, DMSO-d6): δ 8.78 (s, 1H), 8.45 (s, 1H), 8.27 (s, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.41 (dd, J=4.75 Hz, 1H), 7.24 (s, 1H), 7.20 (s, 1H), 7.04 (d, J=9 Hz, 1H), 6.94 (s, 1H), 6.35 (s, 1H), 3.69 (m, 2H), 3.60 (m, 2H), 2.58 (m, 2H), 2.17 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 165.16, 156.80, 153.50, 145.43, 140.30, 139.57, 136.97, 128.86, 128.09, 124.66, 123.35, 122.86, 122.49, 122.24, 121.98, 120.73, 111.67, 45.55, 44.52, 35.74, 29.29, 29.18; m/z (534.1, 536.1, M+ H+); HPLC: 99.0%.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:29])[C:11]([OH:28])([C:20]1[CH:25]=[CH:24][CH:23]=[C:22](OC)[CH:21]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14](OC)[CH:13]=1)[CH2:2]2.O[C:31](C1C=CC=C(OC)C=1)(C1C=CC=C(OC)C=1)C(O)=O.OC(C1C=CC=CC=1)(C1C=CC=CC=1C)C(O)=O>>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:29])[C:11]([OH:28])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:31])[CH2:2]2
Reactant: COc1cccc(C(O)(C(=O)O)c2cccc(OC)c2)c1
Reactant: COc1cccc(C(O)(C(=O)O[C@H]2CN3CCC2CC3)c2cccc(OC)c2)c1
Agent: Cc1ccccc1C(O)(C(=O)O)c1ccccc1
Product: Cc1ccccc1C(O)(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1

Procedure:
This compound is prepared by an analogous method to hydroxy-bis-(3-methoxy-phenyl)-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Intermediate K) by replacing hydroxy-bis-(3-methoxy-phenyl)-acetic acid (Intermediate J) with hydroxy-phenyl-o-tolyl-acetic acid (Intermediate M).
Reaction SMILES: [O:1]=[C:2]1[C:7](C(OCC)=O)=[CH:6][NH:5][N:4]2[CH:13]=[CH:14][CH:15]=[C:3]12.[Na+].[Cl-].O>CS(C)=O>[NH:5]1[CH:6]=[CH:7][C:2](=[O:1])[C:3]2=[CH:15][CH:14]=[CH:13][N:4]12
Reactant: CCOC(=O)c1c[nH]n2cccc2c1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=c1cc[nH]n2cccc12
Temperature: 150 °C
Yield: 67.1 %

Procedure:
A mixture of ethyl 4-oxo-1,4-dihydropyrrolo[1,2-b]pyridazine-3-carboxylate (206 mg, 1.0 mmol), NaCl (64 mg, 1.1 mmol), water (0.054 mL, 3.0 mmol) and DMSO (2 mL) was heated at 150° C. for 3 hours. At the end of the reaction DMSO was distilled off and the residue was purified by silica gel flash chromatography (eluted with 1–10% EtOAc/CH2Cl2) to give the title compound (90 mg, 67%) as a light yellow solid.
Reaction SMILES: C1(CCO[P:10]2[O:15][CH2:14][C:13]3([CH2:20][O:19][P:18](OCCC4C=CC=CC=4)[O:17][CH2:16]3)[CH2:12][O:11]2)C=CC=CC=1.C1(CCBr)C=CC=CC=1>>[CH2:20]1[C:13]2([CH2:12][O:11][PH:10][O:15][CH2:14]2)[CH2:16][O:17][PH:18][O:19]1
Reactant: c1ccc(CCOP2OCC3(CO2)COP(OCCc2ccccc2)OC3)cc1
Agent: BrCCc1ccccc1
Product: C1OPOCC12COPOC2
Temperature: 25 °C
Reaction time: 10 h
Yield: 184.8 %

Procedure:
436.4 g (1.0 mole) of 3,9-di(2-phenylethoxy)-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane and 370.1 g (2.0 moles) of 2-phenylethyl bromide were charged into a reactor equipped with a stirrer, thermometer and condenser, and dry nitrogen was let flow into the reactor under agitation at room temperature. Then, heating was started with an oil bath, and the reactor was kept at an oil bath temperature of 180° C. for 10 hours. The oil bath was then removed to cool the reactor to room temperature. After 2,000 ml of methanol was added to the obtained white solid reaction product and stirred to wash the product, a white powder was separated by filtration with a glass filter. The obtained white powder and 4,000 ml of methanol were put into a reactor equipped with a condenser and stirrer and refluxed for about 2 hours. After cooling to room temperature, the crystal was separated by filtration and washed with 2,000 ml of methanol. The obtained white powder was dried at 100 Pa and 120° C. for 8 hours to obtain 362.3 g of 2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane, 3,9-di(2-phenylethyl)-3,9-dioxide. It was confirmed by mass spectral analysis, 1Hand 31P nuclear magnetic resonance spectral analysis and elemental analysis that the product was bis-2,4,8,10-tetraoxa-3,9-diphosphaspiro[5.5]undecane, 3,9-di(2-phenylethyl)-3,9-dioxide. The yield rate was 83%, the HPLC purity was 99.3%, and the acid value was 0.41 mgKOH/g.
Reaction SMILES: [C:1]([O:4][C@H:5]([C:7]1[O:8][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][CH:18]=[C:17](Br)[C:16]=3[CH:21]=2)=[N:10][N:11]=1)[CH3:6])(=[O:3])[CH3:2].[CH3:22][S:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[C:1]([O:4][C@H:5]([C:7]1[O:8][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][CH:18]=[C:17]([C:27]4[CH:28]=[CH:29][C:24]([S:23][CH3:22])=[CH:25][CH:26]=4)[C:16]=3[CH:21]=2)=[N:10][N:11]=1)[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H](C)c1nnc(-c2ccc3occ(Br)c3c2)o1
Reactant: CSc1ccc(B(O)O)cc1
Product: CSc1ccc(-c2coc3ccc(-c4nnc([C@H](C)OC(C)=O)o4)cc23)cc1
Yield: 64 %

Procedure:
In the same manner as in Reference Example 19 and using (1S)-1-[5-(3-bromo-1-benzofuran-5-yl)-1,3,4-oxadiazol-2-yl]ethyl acetate instead of methyl 3-iodoimidazo[1,2-a]pyridine-6-carboxylate and [4-(methylthio)phenyl]boronic acid instead of (4-methoxyphenyl)boronic acid, the title compound (yield 64%) was obtained as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH3:8].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[N+](C1C=CC([O:28][C:29]([C:31]2[CH:32]=[CH:33][C:34]([O:45][CH3:46])=[C:35]3[O:39][C:38]([C:40]([CH:42]4[CH2:44][CH2:43]4)=[O:41])=[CH:37][C:36]=23)=O)=CC=1)([O-])=O.O>CN(C)C=O>[CH3:8][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[NH:1][C:29]([C:31]1[CH:32]=[CH:33][C:34]([O:45][CH3:46])=[C:35]2[O:39][C:38]([C:40]([CH:42]3[CH2:43][CH2:44]3)=[O:41])=[CH:37][C:36]=12)=[O:28]
Reactant: Cc1cnccc1N
Reactant: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cc(C(=O)C3CC3)oc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)Nc2ccncc2C)c2cc(C(=O)C3CC3)oc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.5 %

Procedure:
To a stirred solution of 4-amino-3-methylpyridine (160 mg) in dimethylformamide (10 ml) under an atmosphere of nitrogen was added sodium hexamethyldisilazide (1.0M solution in tetrahydrofuran, 1.5 ml). The reaction mixture was stirred at room temperature for 10 minutes. 2-Cyclopropanecarbonyl-7-methoxy-benzofuran-4-carboxylic acid 4-nitrophenyl ester (280 mg) was then added and stirring continued for 18 h. Water (10 ml) was added and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (150 ml), washed with water (3×50 ml) and washed with brine (50 ml). The combined aqueous layers were extracted with dichloromethane (2×50 ml), the organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography on silica eluting with 5% methanol in dichloromethane followed by trituration with diethyl ether afforded the title compound as an off-white solid (130 mg).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24]([NH2:25])[C@H:21]3[S:20][CH2:19][C:18]=2[S:27][CH:28]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[S:29][C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:54]([O:58][C:59]([NH:61][C:62]1[S:63][CH:64]=[C:65](/[C:67](=[N:71]/[O:72][C:73]([C:76]([O:78][C:79]([CH3:82])([CH3:81])[CH3:80])=[O:77])([CH3:75])[CH3:74])/[C:68](O)=[O:69])[N:66]=1)=[O:60])([CH3:57])([CH3:56])[CH3:55].CN1CCOCC1.P(Cl)(Cl)(OC1C=CC=CC=1)=O.Cl>ClCCl.O>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:26])[C@@H:24]([NH:25][C:68](=[O:69])/[C:67](/[C:65]4[N:66]=[C:62]([NH:61][C:59]([O:58][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:60])[S:63][CH:64]=4)=[N:71]\[O:72][C:73]([C:76]([O:78][C:79]([CH3:82])([CH3:81])[CH3:80])=[O:77])([CH3:74])[CH3:75])[C@H:21]3[S:20][CH2:19][C:18]=2[S:27][CH:28]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[S:29][C:30]2[N:31]=[N:32][NH:33][CH:34]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SC(Sc3c[nH]nn3)C(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)O)cs1
Agent: Cl
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(SC(Sc4c[nH]nn4)C(c4ccccc4)(c4ccccc4)c4ccccc4)CS[C@H]23)cs1
Temperature: -30 °C
Reaction time: 0.83 h
Yield: 69.2 %

Procedure:
To a solution of 7β-amino-3-(trityl-1,2,3-triazol-4-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (800 mg: 1.06 mMol.) and (Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-(1-t-butoxycarbonyl-1-methylethoxyimino)acetic acid (479 mg: 1.12 mMol.) in dichloromethane (8 ml) cooling at -30° C. are added N-methylmorpholine (0.27 ml) (2.46 mMol.) and phenyl dichlorophosphate (0.19 ml: 1.27 mMol.), and the mixture is stirred at -30° C. for 50 minutes. The reaction mixture is mixed with 10% hydrochloric acid (1 ml), diluted with water, and extracted with ethyl acetate. The extract is washed with brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel column chromatography (toluene: ethyl acetate=10:1 to 5:1) to give 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-(1-t-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-(trityl-1,2,3-triazol-4-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (855 mg) as yellow foam. Yield: 69%.
Reaction SMILES: C([CH2:3][C:4]1[N:8]2[CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])=[CH:14][C:13]=3[C:7]2=[N:6][C:5]=1[C:24]([NH2:26])=[O:25])#N.BrC1C=CC2OCCN3C(CCl)=C(C([O-])=O)N=C3C=2C=1.[Cl:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[OH:54]>>[Cl:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[O:54][CH2:3][C:4]1[N:8]2[CH2:9][CH2:10][O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])=[CH:14][C:13]=3[C:7]2=[N:6][C:5]=1[C:24]([NH2:26])=[O:25]
Reactant: Oc1ccccc1Cl
Reactant: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)c(CC#N)n1CCO2
Agent: O=C([O-])c1nc2n(c1CCl)CCOc1ccc(Br)cc1-2
Product: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)c(COc3ccccc3Cl)n1CCO2
Yield: 6 %

Procedure:
Prepared similarly to as described in the synthesis of 3-(cyanomethyl)-10-(3-hydroxy-3-methylbut-1-yn-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide starting from 10-bromo-3-(chloromethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylate replacing sodium cyanide with 2-chlorophenol to give the titled compound as an off-white solid (7 mg, 6%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([SH:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C@:11]([OH:17])([CH3:16])[C:12]([F:15])([F:14])[F:13].I[C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C[O-].[Na+]>CC(N(C)C)=O.[Cu]Cl>[Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:20]2[CH:25]=[CH:24][C:23]([S:26]([N:29]3[CH2:30][CH2:31][CH2:32][CH2:33]3)(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C@:11]([OH:17])([CH3:16])[C:12]([F:15])([F:13])[F:14]
Reactant: O=S(=O)(c1ccc(I)cc1)N1CCCC1
Reactant: C[C@@](O)(C(=O)Nc1ccc(S)cc1Cl)C(F)(F)F
Agent: Cl[Cu]
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: C[C@@](O)(C(=O)Nc1ccc(Sc2ccc(S(=O)(=O)N3CCCC3)cc2)cc1Cl)C(F)(F)F
Temperature: 150 °C
Reaction time: 4 h
Yield: 44.9 %

Procedure:
Copper(I) chloride (0.038 g) was added to a mixture of (R)-N-(2-chloro-4-mercaptophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 210) (0.21 g), N-(4-iodobenzenesulphonyl)pyrrolidine (0.258 g) and sodium methoxide (0.042 g) in DMA (5 ml). The mixture was heated at 150° C. with stirring for 4 hours then cooled and the DMA removed by evaporation. Ethyl acetate (20 ml) and water (20 ml) was added and the mixture was filtered. The aqueous layer was extracted with ethyl acetate (3×20 ml) and the organic layers were combined and dried. Volatile material was removed by evaporation and the residue was purified on a silica gel Mega Bond Elut column, eluting with methanol/DCM 0-10% to give the title compound (0.16 g) as a solid. NMR (CDCl3): 1.75 (s, 3H), 1.75-1.85 (m, 4H), 3.2-3.3 (m, 4H), 4.0 (s, 1H), 7.2-7.3 (m, 2H), 7.4-7.45 (m, 1H), 7.6 (s, 1H), 7.7 (d, 2H), 8.45 (d, 1H), 9.15 (s, 1H); MS (ESP−): 507.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]1(C)C=CC(S(O)(=O)=O)=CC=1>C(OC(OCC)OCC)C>[C:2]1([C:1]2[O:8][CH:11]=[N:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(OCC)OCC
Product: c1ccc(-c2nnco2)cc1
Temperature: 120 °C
Yield: 5695 %

Procedure:
A mixture of the benzoic hydrazide (22.5 g, 165 mmol), triethylorthoformate (150 mL) and p-toluenesulfonic acid (300 mg) was heated at 120° C. for 12 h. Excess triethylorthoformate was removed under vacuum and the residue was purified by silica gel column chromatography to produce 2-phenyl-[1,3,4]-oxadiazole (14.5 g).
Reaction SMILES: C[O:2][C:3](=[O:22])/[CH:4]=[CH:5]/[CH:6]=[C:7](/[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)\[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.[OH-].[Na+]>CO>[CH:16]1(/[C:7](/[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:6]/[CH:5]=[CH:4]/[C:3]([OH:22])=[O:2])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)/C=C/C=C(\c1ccc(OC)cc1)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C(=C\C=C\C(=O)O)C2CCCCC2)cc1
Yield: 70.6 %

Procedure:
As described in Example 99, (2E,4Z)-5-cyclohexyl-5-(4-methoxyphenyl)-2,4-pentadienoic acid methyl ester (5.2 g) was saponified in a refluxing mixture of methanol (20 mL) and 2N NaOH (20 mL). After 2.5 hours the crude product was isolated in the usual way crystallized from 2-propanol-hexane to give 3.5 g of (2E,4Z)-5-cyclohexyl-5-(4-methoxyphenyl]-2,4-pentadienoic acid, mp 185°-186° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C@@H:26]1[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]1[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].[CH3:40][O:41][C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][CH:50]=1)[N:47]([CH3:51])[N:46]=[C:45]2[C:52]1[N:53]=[C:54]2[C:60]([C:61](O)=[O:62])=[CH:59][N:58]([CH2:64][O:65][CH2:66][CH2:67][Si:68]([CH3:71])([CH3:70])[CH3:69])[C:55]2=[N:56][CH:57]=1>CN(C=O)C>[CH3:40][O:41][C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][CH:50]=1)[N:47]([CH3:51])[N:46]=[C:45]2[C:52]1[N:53]=[C:54]2[C:60]([C:61]([NH:25][C@@H:26]3[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]3[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:62])=[CH:59][N:58]([CH2:64][O:65][CH2:66][CH2:67][Si:68]([CH3:69])([CH3:71])[CH3:70])[C:55]2=[N:56][CH:57]=1
Reactant: COc1ccc2c(c1)c(-c1cnc3c(n1)c(C(=O)O)cn3COCC[Si](C)(C)C)nn2C
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cnc3c(n1)c(C(=O)N[C@@H]1CCOC[C@@H]1NC(=O)OC(C)(C)C)cn3COCC[Si](C)(C)C)nn2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
In a 16×100 mm screw cap test tube were added HATU (80.5 mg, 212 μmol.20) and tert-butyl (3R,4R)-4-aminotetrahydro-2H-pyran-3-ylcarbamate (prepared as described in WO2010/97248 A1, 2010; 38.1 mg, 176 μmol) then 2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (80 mg, 176 mmol) dissolved in DMF (2.00 mL) was added to give a light yellow solution which immediately formed a white precipitated. The reaction mixture stirred at 25° C. overnight, solvents evaporated and residue purified by chromatography (60 g column, 50 μm from Analogix, 0 to 5% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane to yield tert-butyl (3R,4R)-4-(2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)tetrahydro-2H-pyran-3-ylcarbamate (115 mg, 176 μmol, 100%) as a very light yellow solid. MS (M+Na)+=674 (>90% purity); 1H NMR (CDCl3) δ: 9.29 (s, 1H), 8.51 (d, J=9.1 Hz, 1H), 8.37 (s, 2H), 7.48 (d, J=9.1 Hz, 1H), 7.31 (dd, J=9.1, 3.0 Hz, 1H), 6.27 (d, J=10.2 Hz, 1H), 5.75 (s, 2H), 4.59-4.81 (m, 1H), 4.18-4.36 (m, 4H), 3.91-4.16 (m, 5H), 3.54-3.81 (m, 4H), 2.33 (qd, J=12.7, 4.9 Hz, 1H), 1.89 (d, J=13.2 Hz, 1H), 0.93-1.12 (m, 2H), 0.82 (s, 9H), 0.00 (s, 9H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]3[CH2:18][CH:19]([CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][N:26]([C:29]5[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][N:30]=5)[CH2:25][CH2:24]4)[O:20][C:15]4[C:16]3=[C:11]([CH:12]=[CH:13][CH:14]=4)[C:10]=2[CH3:36])=[CH:5][CH:4]=1.B(Br)(Br)Br.CO>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:17]3[CH2:18][CH:19]([CH2:21][CH2:22][N:23]4[CH2:24][CH2:25][N:26]([C:29]5[CH:34]=[C:33]([CH3:35])[CH:32]=[CH:31][N:30]=5)[CH2:27][CH2:28]4)[O:20][C:15]4[C:16]3=[C:11]([CH:12]=[CH:13][CH:14]=4)[C:10]=2[CH3:36])=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2c(C)c3cccc4c3n2CC(CCN2CCN(c3cc(C)ccn3)CC2)O4)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Cc1ccnc(N2CCN(CCC3Cn4c(-c5ccc(O)cc5)c(C)c5cccc(c54)O3)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.3 %

Procedure:
1.9 g of 2,3-dihydro-5-(4-methoxyphenyl)-6-methyl-2-[2-(4-(4-methylpyridin-2-yl)piperazin-1-yl)ethyl]pyrrolo[1,2,3-de]-1,4-benzoxazine (Preparation see Example 1) were dissolved in 5 ml of anhydrous dichloromethane under a nitrogen atmosphere. The solution was cooled to 0° to 5° C. and 1.5 g of boron tribromide were then added all at once. The reaction mixture was subsequently stirred for 3 hours at room temperature. The reaction mixture was then again cooled to 0° to 5° C. and 10 ml of methanol were added, and the reaction mixture was again stirred for half an hour at room temperature and then evaporated. The residue was dissolved in 20 ml of aqueous ammonia solution (pH=8/9) and the solution was extracted with dichloromethane. The extracts were dried, filtered and concentrated. The crude title compound remaining as a residue was purified by column chromatography using toluene/ethanol 95:5 and crystallized from isopropanol. 1.5 g of 2,3-dihydro-5-(4-hydroxyphenyl)-6-methyl-2-[2-(4-(4-methylpyridin-2-yl)piperazin-1-yl)ethyl]pyrrolo[1,2,3-de]-1,4-benzoxazine were obtained as a white powder having a melting point of 213° to 214° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=1)=[O:11].Br[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=1>>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=2)=[O:11])=[N:28][CH:29]=1
Reactant: Cc1ccc(-c2ccc(F)cn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Clc1ccc(Br)nc1
Product: Cc1ccc(-c2ccc(F)cn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(Cl)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(2-(5-fluoropyridin-2-yl)-5-methylphenyl)methanone and 2-bromo-5-chloropyridine. MS (ESI) 453 (M+H).