Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:22].C(N(S(F)(F)[F:29])CC)C>C(Cl)Cl>[F:29][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:22]
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1O
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: O=C1Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1F
Temperature: 0 °C
Yield: 83.5 %

Procedure:
A well stirred suspension of 3.6 g (0.012 mole) of 1,3-dihydro-3-hydroxy-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one in 200 ml methylene chloride was cooled to -70°, and 5 ml (0.04 mole) of diethylaminosulfur trifluoride was added dropwise. The reaction mixture was allowed to warm slowly to -10°, at which temperature all of the solid went into solution. The reaction mixture was poured into 400 ml of ice water, and the organic layer was separated, washed with water, dried (MgSO4) and evaporated to dryness under reduced pressure. The residue was recrystallized from benzene-heptane to give 3.0 g (83%) of 3-fluoro-1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one as colorless crystals: mp 174°-175° (dec.); 1H nmr (DMSO-d6) δ 5.90 ppm (d, J=57 Hz, 1H), 7.3-7.7 ppm (m, 6H), 8.07 ppm (d, J=2.5 Hz, 1H) and 8.45 ppm (d, d, J=9.0, 2.5 Hz, 1H); 19F nmr (DMSO-d6) δ -161.4 ppm (d, J=57 Hz).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]\[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][N:16]=1)[C:10]([O:12]C)=[O:11])=O.O.[NH2:19]N>C(O)C>[NH:2]1[CH:3]=[CH:4][C:5]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][N:16]=2)[C:10]([OH:12])=[O:11])=[N:19]1
Reactant: COC(=O)c1ccnc(C(=O)/C=C\N(C)C)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccnc(-c2cc[nH]n2)c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 46.5 %

Procedure:
To a 2 L three-necked flask was added (Z)-methyl 2-(3-(dimethylamino)acryloyl)isonicotinate (0.894 mol), hydrazine hydrate (48.8 g), anhydrous ethanol (1 L). The suspension was stirred at 20° C. overnight. The solvent was removed in vacuo. The residue was taken up in concentrated hydrochloric acid (600 mL) and heated to reflux for 2 hours. The mixture was cooled to ambient temperature. The resultant precipitate was filtered, washed with water, ethanol and acetone and dried to give 78.6 g of the title compound as a brown solid. 1HNMR (DMSO-d6/D2O) δ ppm 8.80 (d, 1H), 8.50 (s, 1H), 7.91 (d, 1H), 7.87 (dd, 1H), 7.15 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:23])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Br:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:27][CH2:28][O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:23])[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Br:22])[CH2:27][CH2:28][O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2Br)CC1
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N(CCOC2CCCCO2)c2ccccc2Br)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-(2-Bromo-phenylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 2.60 mmol) was dissolved in dry N,N-dimethylformamide (10.0 mL). To the reaction mixture was then added at 0° C. sodium hydride (60% in mineral oil, 127.3 mg, 3.18 mmol) under nitrogen atmosphere and the reaction mixture was stirred at 0° C. for one hour. To the reaction mixture was then added at 0° C., 2-(2-bromo-ethoxy)-tetrahydro-pyran (0.6 g, 2.86 mmol). The reaction mixture was stirred at 0° C. for one hour, then at room temperature under nitrogen atmosphere for 18 hours. The reaction mixture was then partitioned with water-ice and methylene chloride. The organic layer was washed with brine, dried with Na2SO4, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (25% ethyl acetate/hexanes) to yield the title compound as a gum.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[C:22]([F:23])=[CH:21][C:15]3[NH:16][C:17](=[O:20])[CH2:18][O:19][C:14]=3[CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].C([O-])([O-])=O.[K+].[K+].[CH2:30](Br)[C:31]#[CH:32]>CS(C)=O.O>[Cl:1][C:2]1[C:3]([C:12]2[C:22]([F:23])=[CH:21][C:15]3[N:16]([CH2:32][C:31]#[CH:30])[C:17](=[O:20])[CH2:18][O:19][C:14]=3[CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:9])([F:8])[F:10]
Reactant: C#CCBr
Reactant: Cn1nc(-c2cc3c(cc2F)NC(=O)CO3)c(Cl)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C#CCN1C(=O)COc2cc(-c3nn(C)c(C(F)(F)F)c3Cl)c(F)cc21
Temperature: 45 °C
Reaction time: 16 h
Yield: 90.4 %

Procedure:
At 25° C., 2.7g (7.7 mmole) the product of step A, 1.1g (8.0 mmole) K2CO3 and 0.9 mL (8.0 mmole) 80% propargyl bromide were slurried in 25 mL DMSO. The mixture was stirred at 45° C. for 16 hours. The mixture was cooled, diluted with 100 mL cold water and extracted four times with ethyl acetate. The ethyl acetate extracts were washed with brine, dried over anhydrous MgSO4 and stripped in vacuo. The residue was purified chromatographically using methylene chloride as the eluent to give 2.7 g (90%) of 7-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-6-fluoro-4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-one as a white solid, mp 184° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[NH:7]1[CH:11]=[CH:10][C:9]([C:12]([OH:14])=O)=[CH:8]1.[NH:15]1[CH2:18][CH2:17][CH2:16]1>CN(C)C=O.ClCCl>[N:15]1([C:12]([C:9]2[CH:10]=[CH:11][NH:7][CH:8]=2)=[O:14])[CH2:18][CH2:17][CH2:16]1
Reactant: O=C(O)c1cc[nH]c1
Reactant: C1CNC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(c1cc[nH]c1)N1CCC1
Temperature: 2.5 °C
Reaction time: 15 h
Yield: 39.3 %

Procedure:
Oxalyl chloride (0.13 mL, 1.5 mmol) was added to a mixture of 1H-pyrrole-3-carboxylic acid (0.111 g, 1.00 mmol) and 1 drop of N,N-dimethylformamide in 5 mL of dichloromethane. The mixture was stirred for 15 h, then concentrated, then redissolved in 5 mL of dichloromethane and cooled to 0-5° C. Azetidine (0.21 mL, 2.5 mmol) was added, and the mixture was stirred for 1 h at 0-5° C. then absorbed onto silica gel and concentrated. Column chromatography (2->10% MeOH/CH2Cl2) afforded 0.059 g (39%) of azetidin-1-yl-(1H-pyrrol-3-yl)-methanone as an off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[N:13]=[C:14]([CH3:16])[S:15][C:8]=2[C:7]=1[OH:17])=[O:5])[CH3:2].C([Sn](CCCC)(CCCC)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)CCC>>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]2[N:13]=[C:14]([CH3:16])[S:15][C:8]=2[C:7]=1[OH:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2nc(C)sc2c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Product: CCOC(=O)c1nc(-c2ccccc2)c2nc(C)sc2c1O

Procedure:
The title compound was prepared from 4-Bromo-7-hydroxy-2-methyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester and tributylphenyl tin under conditions analogous to the experimental procedure found in example 169(a). MS (ESI+): m/z 315.1 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:18])[NH:8][N:9]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:11]=1)=O)C.O.[NH2:20][NH2:21]>C(O)C>[O:18]=[C:7]1[C:6]([C:4]([NH:20][NH2:21])=[O:3])=[CH:11][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:9][NH:8]1
Reactant: NN
Reactant: CCOC(=O)c1cc(-c2ccncc2)n[nH]c1=O
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cc(-c2ccncc2)n[nH]c1=O
Temperature: 25 °C

Procedure:
10 g of 3-oxo-6-pyridin-4-yl-2,3-dihydro-pyridazine-4-carboxylic acid ethyl ester are dissolved in 150 ml of ethanol, 4.2 ml of hydrazine hydrate is added and the mixture is refluxed for 5 hours. After cooling to room temperature, the solid is collected by filtration and dried in vacuo at 40° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.C([O-])=O.[Na+].C(O)=O>CO.[Pd]>[CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=CO
Product: Cc1nccn1-c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.8 %

Procedure:
A mixture of 54.0 g of 2-methyl-1-(p-nitrophenyl)imidazole, 2.87 g of palladium black, 36 7 g of sodium formate and 47.4 ml of formic acid in 1100 ml of methyl alcohol is stirred at room temperature for 18 hours under a hydrogen atmosphere. The mixture is filtered and the filtrate evaporated to a residue. The residue is partitioned between saturated potassium bicarbonate and chloroform. The organic layer is dried and passed through a pad of hydrous magnesium silicate. The filtrate is evaporated to a residue which is crystallized from ether:ethanol to give 34.9 g of the desired product as a solid, m.p. 108°-110° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:17][C:18]1[C:23]([NH:24][C:25]([O:27]C(C)(C)C)=O)=[CH:22][N:21]=[C:20]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:19]=1)C(OC)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[O:27]=[C:25]1[CH:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:17][C:18]2[C:23](=[CH:22][N:21]=[C:20]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:19]=2)[NH:24]1
Reactant: COC(=O)C(Cc1cc(-c2ccccc2)ncc1NC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1Cc2cc(-c3ccccc3)ncc2NC1=O)OCc1ccccc1
Yield: 64.9 %

Procedure:
A solution of 3E (980 mg, 1.94 mmol) in TFA (2 mL) and CH2Cl2 (2 mL) was stirred at RT for 2 h. After this time, no starting material was detected by LC-MS. The reaction was concentrated under reduced pressure. The resulting residue was diluted with EtOAc (30 mL) and washed with saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc (30 mL×3). The combined organic layers were washed with saturated NaCl, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel (40 g) column chromatography eluting with a gradient of EtOAc (30-100%) in hexane to give the title compound as a white solid (470 mg, 65%). LC/MS (method A): retention time=2.72 min, (M+H)+=374.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:7][Si:8]([CH3:23])([CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH:14]1[CH2:16][O:15]1>C(O)C>[CH3:23][Si:8]([CH3:7])([CH2:17][CH2:18][Si:19]([CH3:20])([CH3:22])[CH3:21])[CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH:14]([OH:15])[CH2:16][N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: C[Si](C)(C)CC[Si](C)(C)CCCOCC1CO1
Solvent: CCO
Product: C[Si](C)(C)CC[Si](C)(C)CCCOCC(O)CN1CCNCC1
Temperature: 70 °C

Procedure:
piperazine (3.14 g; 36.4 mMol) and 40 mL of ethanol were charged to a 100 mL RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 70° C. 2-{3-[Dimethyl-(2-trimethylsilanyl-ethyl)-silanyl]-propoxymethyl}-oxirane 8 (2 g; 7.28 mMol) mixed with 10 g ethanol was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 70° C. for an additional 4 hours. Ethanol was stripped off on the rotovap. The mixture was distilled under vacuum to remove impurities. Excess piperazine was removed by sublimation.
Reaction SMILES: [CH2:1]([CH:7]([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:8][C:9]1[S:13][C:12]([C:14]2[C:25]3[S:24][CH:23]=[CH:22][C:21]=3[C:20]([C:26]3[S:27][C:28]([CH2:31][CH:32]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:29][CH:30]=3)=[C:19]3[C:15]=2[CH:16]=[CH:17][S:18]3)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C1COCC1.C([Li])CCC.[CH3:65][Sn:66](Cl)([CH3:68])[CH3:67]>CCCCCC>[CH2:41]([CH:32]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:31][C:28]1[S:27][C:26]([C:20]2[C:19]3[S:18][C:17]([Sn:66]([CH3:68])([CH3:67])[CH3:65])=[CH:16][C:15]=3[C:14]([C:12]3[S:13][C:9]([CH2:8][CH:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])=[CH:10][CH:11]=3)=[C:25]3[C:21]=2[CH:22]=[C:23]([Sn:66]([CH3:68])([CH3:67])[CH3:65])[S:24]3)=[CH:30][CH:29]=1)[CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CCCCCCCCC(CCCCCC)Cc1ccc(-c2c3ccsc3c(-c3ccc(CC(CCCCCC)CCCCCCCC)s3)c3ccsc23)s1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCC(CCCCCC)Cc1ccc(-c2c3cc([Sn](C)(C)C)sc3c(-c3ccc(CC(CCCCCC)CCCCCCCC)s3)c3cc([Sn](C)(C)C)sc23)s1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
4,8-Bis-[5-(2-hexyl-decyl)-thiophen-2-yl]-1,5-dithia-s-indacene (2.06 g, 2.56 mmol) was added into a 200-mL flask. The system was vacuumed and backfilled with argon 3 times before 80 mL of anhydrous THF was injected. n-Butyl lithium (2.5 M in hexane, 2.3 mL, 5.6 mmol) was added after the mixture was cooled to −78° C. The mixture was stirred at −78° C. for 30 minutes and then at room temperature for one more hour. The system was cooled down to −78° C. again before trimethyltin chloride (0.5 g, 2.5 mmol) was added in portions. Stirring was continued overnight at room temperature. Hexane (200 mL) was added and the organic layer was washed with 150 mL of water. The aqueous layer was extracted with 100 mL of hexane twice. The combined organic layer was dried over anhydrous Na2SO4. Removal of the solvent under vacuum yielded a yellow liquid (2.2 g, 76.0% yield) as the final product after drying in vacuo overnight. 1H NMR (CDCl3, 500 MHz): δ 7.57 (s, 2H), δ 7.21 (d, 2H, J=3.0 Hz), δ 6.78 (d, 2H, J=3.5 Hz), δ 2.76 (d, 4H, J=6.5 Hz), δ 1.62 (s, 2H), δ 1.26˜1.19 (m, 48H), δ 0.76 (m, 12H), δ 0.29 (m, 18H).
Reaction SMILES: [C:1]1(C2C=CC=CC=2)[CH:6]=[CH:5][C:4]([C:7]2[CH:8]([O:14][CH3:15])[O:9][CH:10]([O:12][CH3:13])[CH:11]=2)=[CH:3][CH:2]=1.C1(C2C=COC=2)C=CC=CC=1>>[CH3:15][O:14][CH:8]1[C:7]([C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)=[CH:11][CH:10]([O:12][CH3:13])[O:9]1
Reactant: COC1C=C(c2ccc(-c3ccccc3)cc2)C(OC)O1
Agent: c1ccc(-c2ccoc2)cc1
Product: COC1C=C(c2ccccc2)C(OC)O1
Yield: 82 %

Procedure:
According to the procedure described in Example 1(a) for the preparation of 3-biphenyl-4-yl-2,5-dihydro-2,5-dimethoxyfuran, 3-phenylfuran (see Pridgen, L. N.; Jones, S. S. J. Org. Chem. 1982, 47, 1590-1592 and Yang, Y.; Wong, H. N. C. Tetrahedron 1994, 32, 9583-9608; 848 mg, 5.89 mmol) provided 1.00 g (82%) of 2,5-dihydro-2,5-dimethoxy-3-phenylfuran as a yellow oil, which was an approximately 80:20 mixture of diastereomers by 1H NMR and used without further purification. 1H NMR (CDCl3): δ 7.64-7.52 (m, 2H), 7.44-7.30 (m, 3H), 6.36-6.30 (m, 0.9H, major+minor isomer), 6.28 (dd, 0.1H, minor isomer, J=1.2, 3.7 Hz), 6.04-6.00 (m, 0.9H, major+minor isomer), 5.70 (d, 0.8H, major isomer, J=1.2 Hz), 3.52 (s, 2.2H, major isomer), 3.46 (s, 0.60H, minor isomer), 3.43 (s, 2.2H, major isomer), 3.40 (s, 0.60H, minor isomer); Anal. Calculated for C12H14O3.0.04 Br2: C, 67.78; H, 6.64. Found: C, 67.79; H, 6.45.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[C:9]1([CH2:17][OH:18])[C:10](CO)=[CH:11][CH:12]=[CH:13][CH:14]=1.C[C:20](C)=[O:21]>CS(O)(=O)=O.O>[CH:5]1[C:6]([OH:7])=[CH:1][CH:2]=[C:3]([CH3:8])[CH:4]=1.[OH:18][CH2:17][C:9]1[CH:14]=[CH:13][C:12]([CH2:20][OH:21])=[CH:11][CH:10]=1
Reactant: OCc1ccccc1CO
Reactant: CC(C)=O
Agent: CS(=O)(=O)O
Agent: Cc1ccc(O)cc1
Solvent: O
Product: OCc1ccc(CO)cc1
Temperature: 95 °C

Procedure:
38.4 g (0.36 mol) of p-cresol and 35.0 g (0.25 mol) of xylene-α,α'-diol were dissolved under heating, then 0.15 g of methanesulfonic acid was added thereto at 90-100° C. and the mixture was stirred and reacted at the same temperature for 2 hours. After cooling, 100 ml of acetone was poured into and dissolved in the reaction solution and then the solution was poured into 2,000 ml of water, stirred and then allowed to stand, after which the supernatant was decanted and the residue was dissolved in 100 ml of acetone, poured into 2,000 ml of water and stirred. The solution was allowed to stand, the supernatant was decanted and the residue was evaporated to dryness under reduced pressure to give 65.0 g of p-cresol/1,4-dihydroxymethylbenzene polycondensate as faintly yellow-tinted powdery crystals. Mw≈6,700; Mw/Mn=3.50 (GPC with polystyrene calibration).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].[NH:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:24][C@H:13]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=4[CH2:24][C@H:13]23)=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: Nc1ccc(C(=O)O)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Nc1ccc(C(=O)N2CCC[C@@H]3c4ccccc4C[C@@H]32)cc1F
Yield: 62 %

Procedure:
The title compound is prepared from 4-amino-3-fluoro-benzoic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 62% of theory; LC (method 4): tR=1.91 min; Mass spectrum (ESI+): m/z=311 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:13].[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1B(O)O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:23]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=2[F:13])[CH:24]=1
Reactant: CCS(=O)(=O)c1ccc(Br)c(F)c1
Reactant: OB(O)c1cc(Cl)ccc1OCc1ccccc1
Product: CCS(=O)(=O)c1ccc(-c2cc(Cl)ccc2OCc2ccccc2)c(F)c1

Procedure:
The subtitle compound was prepared by the method of example 1 step (ii) using the product from step (ii) and the product from example 16 step (ii). Yield 0.55 g
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N+:5]([O-])=[C:4]([CH3:10])[CH:3]=1.[C:11]([O:14]C(=O)C)(=[O:13])[CH3:12]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH2:10][O:14][C:11](=[O:13])[CH3:12])[CH:3]=1
Reactant: Cc1cc(Cl)cc(C)[n+]1[O-]
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCc1cc(Cl)cc(C)n1
Reaction time: 8 h

Procedure:
4.0 g (25.4 mmol) of 4-chloro-2,6-dimethylpyridine-1-oxide was dissolved in 12 ml of acetic anhydride. The resultant solution was gradually heated to raise the temperature to the reflux temperature, and the solution was then stirred overnight at the same temperature. The reacted solution was then condensed under reduced pressure to obtain a crude product of acetic 4-chloro-6-methyl-2-pyridinylmethyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:15][C@@:7]3([OH:20])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:21]([O:24][CH2:25]CO)([CH3:23])[CH3:22]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][CH2:19][CH2:25][O:24][CH:21]([CH3:23])[CH3:22])=[O:17])[CH2:15][C@@:7]3([OH:20])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OCCO
Reactant: COC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Solvent: Cc1ccccc1
Product: CC(C)OCCOC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1

Procedure:
To methyl (2S,3aR,9bR)-6-chloro-9b-hydroxy-5-methyl-1,2,3,3a-,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate (Preparation 118, 0.20 g, 0.67 mmol) was added toluene (10 ml) titanium (IV) ethoxide (0.07 ml) and 2-isopropoxy ethanol. The reactants were stirred together and then heated under reflux for 1 h, before concentrating in vacuo. The crude residue was purified using a Sep Pak cartridge eluting with hexane and then hexane:ethyl acetate (50:50). Further purification by preparative HPLC was performed using a Magellan column 212×150 mm, flow rate 20 ml/min, eluting with a gradient of water:acetonitrile (55:45 to 90:10) over 8 min to yield the title compound (63.9 mg).
Reaction SMILES: COC1C=C2C(=CC=1)NN=C2C(NCC1CCN(CC2SC=C(C(OC)=O)N=2)CC1)=O.[Br:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[NH:38][N:37]=[C:36]2[C:42]([OH:44])=O.[NH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:49][CH2:48]1>>[Br:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[NH:38][N:37]=[C:36]2[C:42]([NH:45][CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:49][CH2:48]1)=[O:44]
Reactant: O=C(O)c1n[nH]c2ccc(Br)cc12
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: COC(=O)c1csc(CN2CCC(CNC(=O)c3n[nH]c4ccc(OC)cc34)CC2)n1
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)c2n[nH]c3ccc(Br)cc23)CC1

Procedure:
Tert-butyl 4-({[(5-bromo-1H-indazol-3-yl)carbonyl]amino}methyl)piperidine-1-carboxylate 11a was prepared, according to the procedure described for compound 7, from 5-bromo-1H-indazole-3-carboxylic acid and tert-butyl 4-(aminomethyl)piperidine-1-carboxylate. Yield: 40.6 g, 87%
Reaction SMILES: C([O:3][C:4]([C:6]1([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:11][CH2:10][N:9](OCCC2C=CC=CC=2)[CH2:8][CH2:7]1)=[O:5])C.[CH2:32]1[CH2:36][O:35][CH2:34][CH2:33]1.CO>[OH-].[Na+]>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([S:21]([C:6]2([C:4]([OH:3])=[O:5])[CH2:7][CH2:8][N:9]([CH2:32][CH2:36][O:35][C:34]3[CH:33]=[CH:8][CH:7]=[CH:6][CH:4]=3)[CH2:10][CH2:11]2)(=[O:22])=[O:23])=[CH:29][CH:28]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(OCCc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(CCOc3ccccc3)CC2)cc1

Procedure:
4-(4-methoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethoxy)-piperidine-4-carboxylic acid ethyl ester (5.0 g, 11.1 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.0 g (63%); off white powder; mp 235° C.; MS: 420.5 (M+H)+.
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:18][N:17]=[C:16]([CH2:19]OS(C)(=O)=O)[CH:15]=3)=[CH:10][CH:9]=2)[O:6][C:5]([CH3:26])([CH3:25])[N:4]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].[CH3:34][S:35]([O-:37])=[O:36].[Na+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[O:18][N:17]=[C:16]([CH2:19][S:35]([CH3:34])(=[O:37])=[O:36])[CH:15]=3)=[CH:12][CH:13]=2)[O:6][C:5]([CH3:25])([CH3:26])[N:4]1[C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28]
Reactant: CS(=O)[O-]
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cc(COS(C)(=O)=O)no3)cc2)OC1(C)C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cc(CS(C)(=O)=O)no3)cc2)OC1(C)C
Yield: 77.5 %

Procedure:
(4S,5R)-tert-butyl 4-(fluoromethyl)-2,2-dimethyl-5-(4-(3-((methylsulfonyloxy)methyl)isoxazol-5-yl)phenyl)oxazolidine-3-carboxylate (200 mg, 0.413 mmol), sodium methanesulfinate (100 mg, 0.83 mmol), and 18-crown-6 (23 mg, 0.08 mmol) in acetonitrile (8 mL) are stirred at room temperature for 16 hours then the mixture is concentrated and purified by column chromatography on silica gel eluting with a gradient of ethyl acetate/heptane to afford the title compound (150 mg). m/z (Cl) 469 [M+H].