Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:13][CH2:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)=[O:16])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].[C:24]([O:28][C:29](=[O:32])[CH2:30]Br)([CH3:27])([CH3:26])[CH3:25]>CN(C=O)C>[C:24]([O:28][C:29]([CH2:30][O:23][C:19]1[CH:18]=[C:17]([C:15](=[O:16])[CH2:14][CH2:13][C:7]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([O:4][CH3:3])[CH:6]=2)[CH:22]=[CH:21][CH:20]=1)=[O:32])([CH3:27])([CH3:26])[CH3:25]
Reactant: COc1ccc(CCC(=O)c2cccc(O)c2)cc1OC
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CCC(=O)c2cccc(OCC(=O)OC(C)(C)C)c2)cc1OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 8228.3 %

Procedure:
A 60% mineral oil suspension of NaH (279 mg, 6.98 mmol) in anhydrous DMF (10 mL) was cooled to 0° C. in an ice bath and solid 3-(3,4-Dimethoxyphenyl)-1-(3-hydroxyphenyl)propan-1-one (7) (2 g, 6.98 mmol) added in one portion. The resulting yellow solution was stirred for 5 min after which time tert-butylbromoacetate (1.18 mL, 7.33 mmol) was added. Stirring was continued at 0° C. for 15 min after which time the reaction mixture was warmed to room temperature and partitioned between diethyl ether (50 mL) and water (50 mL). The organic layer was washed with a saturated NaCl solution (2×50 mL), dried over MgSO4, filtered, evaporated, and flash chromatographed (silica gel, 30% EtOAc/hexanes) to afford 230 g (82%) of a clear colorless oil: IR (neat) 2980, 1750, 1685, 1590, 1515, 1260, 1155 cm−1; 1H NMR (CDCl3, 300 MHz) 7.59 (d, J=7.7 Hz, 1H), 7.49 (s, 1H), 7.39 (app t, J=8.0 Hz, 1H), 7.14 (dd, J=8.2, 2.6 Hz, 1H), 6.81-6.79 (m, 3H), 4.58 (s, 2H), 3.89 (s, 3H), 3.88 (s, 3H), 3.28 (t, J=7.3 Hz, 2H), 3.02 (t, J=7.8 Hz, 2H), 1.51 (s, 9H); 13C NMR (CDCl3, 75 MHz) 199.2, 168.0, 158.6, 149.3, 147.8, 138.7, 134.2, 130.1, 121.8, 120.6, 113.5, 112.2, 111.8, 108.1, 83.0, 66.1, 56.2, 41.1, 30.2, 28.4.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([O:8][C:9]2[CH:10]=[C:11]([CH3:25])[C:12]3[CH:16]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:15][B:14]([OH:23])[C:13]=3[CH:24]=2)=[N:5][N:4]=1)#[N:2].Cl.[NH2:27][OH:28].C(N(CC)CC)C>CO>[OH:23][B:14]1[C:13]2[CH:24]=[C:9]([O:8][C:6]3[S:7][C:3]([C:1](=[NH:2])[NH:27][OH:28])=[N:4][N:5]=3)[CH:10]=[C:11]([CH3:25])[C:12]=2[CH:16]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:15]1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(C#N)s3)cc(C)c21
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(C(=N)NO)s3)cc(C)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a solution of ethyl 2-(6-(5-cyano-1,3,4-thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (1.63 g, 4.54 mmol, 1 eq.) and hydroxylamine hydrochloride (0.79 g, 11.35 mmol, 2.5 eq.) in methanol was added triethylamine (2.22 ml, 15.88 mmol, 3.5 eq.). After stirring at room temperature for one hour, the reaction mixture was evaporated under reduced pressure. The residue was dissolved in EtOAc and then washed with water. The organic layers were collected, dried with Na2SO4 and evaporated to give the crude product (1.73 g, yield 97.2%). The crude was used in subsequent steps without further purification.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH3:24][NH:25][CH3:26]>C(O)(C)C.O>[CH3:24][N:25]([CH3:26])[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1
Reactant: CNC
Reactant: C[Si](C)(C)CCOCn1cnc2c(-c3ccco3)nc(Cl)nc21
Solvent: CC(C)O
Solvent: O
Product: CN(C)c1nc(-c2ccco2)c2ncn(COCC[Si](C)(C)C)c2n1
Yield: 86 %

Procedure:
A solution of 2-chloro-6-(2-furyl)-9-(2-trimethylsilylethoxymethyl)-9H-purine (488 mg, 1.4 mmol) in isopropanol (5 mL) was treated with 40% dimethylamine in water (1 mL), refluxed for 2 h, concentrated in vacuo and purified by chromatography [SiO2; EtOAc Heptane, (1:1)] to give the title compound (431 mg, 86%) as a white solid.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(O)C.[Cl:24][C:25]1[CH:26]=[C:27]([C@H:32]2[C@@H:38]([CH:39]=O)[O:37][CH2:36][CH2:35][N:34]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:33]2)[CH:28]=[CH:29][C:30]=1[Cl:31].C[Si](C=[N+]=[N-])(C)C>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[Cl:24][C:25]1[CH:26]=[C:27]([C@H:32]2[C@@H:38]([CH:39]=[CH2:1])[O:37][CH2:36][CH2:35][N:34]([C:41]([O:43][C:44]([CH3:46])([CH3:47])[CH3:45])=[O:42])[CH2:33]2)[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](C=O)[C@H](c2ccc(Cl)c(Cl)c2)C1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Rh]
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [Cl-]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: C=C[C@H]1OCCN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.3 %

Procedure:
To a solution of chlorotris(triphenylphosphine)rhodium (I) (0.12 g) and triphenylphosphine (1.5 g) in tetrahydrofuran (5 ml) was added 2-propanol (0.44 ml), and tert-butyl (6R,7S)-6-(3,4-dichlorophenyl)-7-formyl-1,4-oxazepane-4-carboxylate (2.0 g) was added. To the reaction mixture was added trimethylsilyldiazomethane (2 M diethyl ether solution, 5.2 ml), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (1.1 g).
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:21][CH2:20][C@@H:19]([NH2:22])[CH2:18]2)=[CH:13][CH:12]=1)([O-:10])=[O:9].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:21][CH2:20][C@@H:19]([NH:22][C:3](=[O:5])[CH3:2])[CH2:18]2)=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: O=C(O)C(F)(F)F
Reactant: N[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)N[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1
Yield: 84.2 %

Procedure:
(3R)-1-(4-Nitrophenyl)pyrrolidin-3-amine trifluoroacetate salt (Method 41; 0.96 g, 3 mmol) and sodium acetate (0.245 g, 3 mmol) in acetic acid (10 ml) were reacted with acetic anhydride (0.57 ml, 6 mmol) for 18 hours at room temperature. After filtration and washing with ether gave the title compound as a yellow solid (0.63 g, 84%). NMR: 1.79 (s, 3H), 1.85-1.98 (m, 1H), 2.09-2.23 (m, 1H), 3.19-3.30 (m, 1H), 3.39-3.52 (m, 2H), 3.55-3.67 (m, 1H), 4.30-4.43 (m, 1H), 6.60 (d, 2H), 8.04 (d, 2H), 8.15 (d, 1H); m/z 250.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[CH2:10][O:11][CH2:12][C:8]=2[S:7][C:6]1=[NH:13])[CH2:2][CH2:3][CH3:4].[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:24][CH3:25])=[C:19]([CH:23]=1)[C:20](O)=[O:21].ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:5]1[C:9]2[CH2:10][O:11][CH2:12][C:8]=2[S:7]/[C:6]/1=[N:13]\[C:20](=[O:21])[C:19]1[CH:23]=[C:15]([Cl:14])[CH:16]=[CH:17][C:18]=1[O:24][CH3:25])[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(Cl)cc1C(=O)O
Reactant: CCCCn1c2c(sc1=N)COC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCn1c2c(s/c1=N\C(=O)c1cc(Cl)ccc1OC)COC2
Temperature: 80 °C
Reaction time: 2 h
Yield: 29.2 %

Procedure:
To a solution of Example 17A (220 mg, 0.56 mmol) in tetrahydrofuran (10 mL) were added 5-chloro-2-methoxybenzoic acid (114 mg, 0.61 mmol, Aldrich), 1-hydroxybenzotriazole (93 mg, 0.61 mmol, Aldrich), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (117 mg, 0.61 mmol) and triethylamine (0.23 mL, 1.7 mmol, Aldrich). The reaction mixture was stirred at 80° C. for 2 h, then cooled and quenched with saturated NaHCO3 (10 mL). The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280 ™ (SiO2, 0-100% EtOAc in hexanes) to afford 60 mg (30%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.92 (t, J=7.3 Hz, 3H), 1.33 (t, 2H), 1.74 (t, 2H), 3.80 (s, 3H), 4.10 (t, J=7.3 Hz, 2H), 4.87-5.08 (m, J=1.7 Hz, 4H), 7.13 (d, J=8.8 Hz, 1H), 7.47 (dd, J=8.8, 3.1 Hz, 1H), 7.75 (d, J=3.1 Hz, 1H); MS (ESI+) m/z 367 (M+H)+; Anal. Calculated C17H19ClN2O3S: C, 55.66; H, 5.22; N, 7.64. Found: C, 55.46; H, 5.03; N, 7.74.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([C@@H:42]2[CH2:47][CH2:46][C@H:45]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:44][CH2:43]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2.C(O)(C(F)(F)F)=O>>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([C@@H:42]4[CH2:43][CH2:44][C@H:45]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:46][CH2:47]4)=[C:35]4[C:39]=3[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[C:14]([O:28][CH3:29])[CH:15]=1)([O:22][CH2:23][CH3:24])=[O:25])[CH3:21]
Reactant: CCOC(=O)[C@H]1CC[C@@H](c2ccc(N)c3c2CN(C)C3=O)CC1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H]1CC[C@@H](c2ccc(Nc3nc(Nc4ccc(CP(=O)(OCC)OCC)cc4OC)ncc3C(F)(F)F)c3c2CN(C)C3=O)CC1
Yield: 38.8 %

Procedure:
A solution of diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (119.5 mg, 0.26 mmol) and ethyl cis-4-(7-amino-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)cyclohexanecarboxylate (100 mg, 0.32 mmol) in TFE (2.39 mL, 32.8 mmol) was treated with TFA (90.1 mg, 0.790 mmol) and irradiated on the microwave at 105° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure to a solid. The material was purified on a CombiFlash®Rf 4X Organic Purification System [24 g RediSep® Normal-phase GOLD Silica Flash Column, dry loaded, elution gradient: 0→5% MeOH in 1:1 DCM/EtOAc] to afford 74 mg (38%) of the desired product. 1H NMR (400 MHz, MeOD) δ ppm 8.46 (br. s., 1H), 8.35 (s, 1H), 7.89 (d, J=8.08 Hz, 1H), 7.26 (d, J=8.84 Hz, 1H), 7.08 (t, J=2.02 Hz, 1H), 6.94 (dt, 1H), 4.52 (s, 2H), 4.26 (q, J=7.07 Hz, 2H), 4.11 (quin, J=7.26 Hz, 4H), 3.92 (s, 3H), 3.36 (br. s., 1H), 3.30 (br. s., 1H), 3.20 (s, 3H), 2.79 (br. s., 1H), 2.68 (br. s., 1H), 2.28-2.33 (m, 2H), 2.30 (d, J=6.82 Hz, 2H), 1.77 (d, J=5.81 Hz, 6H), 1.27-1.37 (m, 9H). MS (ES+): m/z=734.23 [MH+]. HPLC: tR=1.77 min (UPLC TOF, polar—3 min).
Reaction SMILES: C([O:3][C:4](=[O:14])[C:5]([C:7]1[S:8][CH:9]=[C:10]([Cl:13])[C:11]=1[Cl:12])=[O:6])C.Cl>CC(C)=O.O>[Cl:12][C:11]1[C:10]([Cl:13])=[CH:9][S:8][C:7]=1[C:5](=[O:6])[C:4]([OH:14])=[O:3]
Reactant: CCOC(=O)C(=O)c1scc(Cl)c1Cl
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)C(=O)c1scc(Cl)c1Cl
Temperature: 25 °C
Yield: 22.8 %

Procedure:
A solution of yield (3,4-dichlorothiophen-2-yl)-oxo-acetic acid ethyl ester (0.42 g, 1.66 mmol) in acetone (10 ml), water (2 ml), and conc. HCl (10 ml) was stirred under reflux for 1 hour. The reaction mixture was allowed to cool to ambient temperature then was concentrated in vacuo to provide a crude oil. The crude oil was purified by preparative HPLC to provide pure (3,4-dichlorothiophen-2-yl)-oxo-acetic acid as a yellow solid (85 mg, 38%). MS (M−H)−: 222.80; 1H NMR (300 MHz, DMSO-d6) δ8.38 (1H, s). 13C NMR (75 MHz, CDCl3) δ173.14, 159.44, 136.57, 133.43, 128.97, 125.20.
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:20])=[C:5]([O:10][CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[C:6]([CH3:9])=[N:7][CH:8]=1)=O.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1C=CC=CC=1>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([CH2:11][O:10][C:5]2[C:4]([CH3:20])=[C:3]([CH2:1][NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]4[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=4)=[CH:26][CH:27]=3)[CH:8]=[N:7][C:6]=2[CH3:9])=[CH:13][CH:14]=1)#[N:17]
Reactant: N#Cc1ccc(-c2ccc(N)cc2)cc1
Reactant: Cc1ncc(C=O)c(C)c1OCc1ccc(C#N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: Cc1ncc(CNc2ccc(-c3ccc(C#N)cc3)cc2)c(C)c1OCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.9 %

Procedure:
A mixture of 4-(5-formyl-2,4-dimethyl-pyridin-3-yloxymethyl)-benzonitrile (23) (0.40 g, 1.5 mmol), 4-amino-4′-cyanobiphenyl (0.35 g, 1.8 mmol) and p-toluenesulfonic acid monohydrate (0.08 g, 0.45 mmol) was heated at 100° C. in benzene (15 mL) under nitrogen atmosphere with a Dean-Stark condenser for 18 hours. The solvent mixture was then evaporated and the crude product dissolved in methyl alcohol (20 mL), and to the solution was added sodium borohydride (0.56 g, 15 mmol). The reaction mixture was stirred at room temperature for 2 hours, quenched with saturated aqueous sodium bicarbonate, extracted with ethyl acetate and then back washed with water. The combined organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The crude product was purified by column chromatography on silica gel using a gradient mixture of ethyl acetate:hexane (0:1 to 1:1) as eluant to give 4′-{[5-(4-cyano-benzyloxy)-4,6-dimethyl-pyridin-3-ylmethyl]-amino}-biphenyl-4-carbonitrile (24) (266 mg, 40% overall yield for two steps).
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.B([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]=1[F:27])(O)O>>[Cl:12][C:11]1[C:2]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]=2[F:27])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([O:13][CH3:14])=[CH:6][CH:5]=2
Reactant: COc1ccc2nc(Cl)c(Cl)cc2c1
Reactant: O=C(O)c1ccc(B(O)O)c(F)c1
Product: COc1ccc2nc(-c3ccc(C(=O)O)cc3F)c(Cl)cc2c1

Procedure:
Scheme 3: starting from 2,3-dichloro-6-methoxyquinoline (Intermediate 4) and 4-borono-3-fluorobenzoic acid. An aqueous/EtOAc workup was performed followed by purification by silica gel column (PE/EtOAc=1/1) to give the desired product.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:26]=[CH:25][C:20]([O:21][CH2:22][C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([CH3:27])=[C:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:29]=[N+:30]=[N-:31].[Na+].[NH4+].[Cl-]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:18]=[CH:19][C:20]([O:21][CH2:22][C:23]4[NH:31][N:30]=[N:29][N:24]=4)=[CH:25][CH:26]=3)=[CH:14][CH:15]=2)[C:10]([CH3:27])=[C:9]1[CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C)n(Cc2ccccc2)c2ccc(-c3ccc(OCC#N)cc3)cc12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(C)n(Cc2ccccc2)c2ccc(-c3ccc(OCc4nnn[nH]4)cc3)cc12

Procedure:
The desired product was prepared using a procedure similar to step 6 of example 3. Thus, [4-(1-benzyl-2,3-dimethyl-1H-indol-5-yl)-phenoxy]-acetonitrile (0.202 g, 0.551 mmol) was reacted with NaN3 (0.179 g, 2.756 mmol) and NH4Cl (0.147 g, 2.756 mmol) in DMF (5 ml) to give the product (0.176 g, 0.430 mmol, 78%) as a yellow solid, dec. 229-232° C.
Reaction SMILES: [CH:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:7][CH:8]([CH2:11][CH3:12])[CH:9]=O>>[CH:1](=[O:6])[CH:2]=[CH:3][CH2:4][CH2:5][CH2:12][CH2:11][CH:8]([CH3:9])[CH3:7]
Reactant: CCCCC=O
Reactant: CCC(C)C=O
Product: CC(C)CCCCC=CC=O

Procedure:
This example describes the process of the invention for the co-aldol condensation of n-pentanal and 2-methylbutanal (2-MBA) to give an isodecenal consisting of the isomers 2-propyl-4-methylhexenal (1+2) and 2-propylheptenal (1+1). 400 kg/h of catalyst were passed through the reactor (as described in Example 3) at a temperature of 110° C. at the autogenous pressure of the reactants.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C[Al](C)C.[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([C:21](=[NH:22])[NH:9][C:8]2[CH:10]=[CH:11][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:19][CH:18]=1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: Cc1ccc(C#N)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline (10 mmol) in toluene (100 mL), trimethylaluminum (2M solution in toluene, 15 mmol) is added over 15 minutes. The reaction mixture is warmed to room temperature and stirred for 2.5 hours. A solution of 4-methylbenzonitrile (20 mmol) in toluene (50 mL) is added over 10 minutes and the reaction mixture is heated to 80°-85° C. After 20 hours, the reaction mixture is cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue is washed with a mixture of methylene chloride/methanol (2/1). The combined filtrates are concentrated in vacuo and the resulting yellowish solid is stirred with a mixture of hexane/ether (2/1, 1000 mL). The intermediate is filtered and washed with more of hexane/ether (2/1). The pale yellow solid 4-methyl-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide is used in the next reaction without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:24][CH:25]([O:31][CH:32]([CH3:34])C)[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:13]=[CH:14][C:15]=1[O:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:41]=[CH:40][C:39](OB(O)O)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:24][C:25]([O:31][CH2:32][CH2:34][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)([C:39]2[CH:40]=[CH:41][C:36]([F:35])=[CH:37][CH:38]=2)[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:13]=[CH:14][C:15]=1[O:16][S:17]([C:20]([F:22])([F:23])[F:21])(=[O:18])=[O:19])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: OB(O)Oc1ccc(F)cc1
Reactant: CCOC(=O)C(Cc1ccc(OS(=O)(=O)C(F)(F)F)c(CNC(=O)OC(C)(C)C)c1)OC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1ccc(OS(=O)(=O)C(F)(F)F)c(CNC(=O)OC(C)(C)C)c1)(OCCCc1ccccc1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 119.6 %

Procedure:
329 mg of ethyl 3-(3-[(tertiary butoxycarbonyl)amino]methyl-4-[(trifluoromethyl)sulfonyl]oxyphenyl)-2-isopropoxypropionate was dissolved in 4 ml toluene. 110 mg of 4-fluorophenylboric acid, 74 mg of tetrakistriphenyl phosphine palladium and 440 mg of potassium carbonate were added, followed by stirring overnight at 100° C. in a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate, filtered through Celite and the filtrate was evaporated. The residue was purified by silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (6:1), 262 mg of ethyl 3-(3-[(tertiary butoxycarbonyl)amino]methyl-4-[(trifluoromethyl)sulfonyl]oxyphenyl)-2-(4-fluorophenyl)phenylpropoxypropionate was obtained.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(COC)OC.C(O)C>[C:10]1([C:2]2[S:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)c1csc(Br)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: CCO
Product: O=C(O)c1csc(-c2ccccc2)c1

Procedure:
5-Bromo-thiophene-3-carboxylic acid (2.07 g, 10 mmol) was dissolved in dimethoxyethane (15 mL) and ethanol (15 mL). Phenyl boronic acid (14 mmol), [1,1′-bis(diphenylphosphino)ferrocine]dichloropalladium (II) (0.5 mmol) and caesium carbonate (14 mmol) were added and the reaction mixture refluxed under nitrogen overnight. The solvent was evaporated under vacuum, and the residue dissolved in ethyl acetate. The organic solution was washed with 1 N hydrochloric acid, dried over magnesium sulfate, filtered and the solvent evaporated. The residue was dissolved in hot ethyl acetate, filtered and the solvent evaporated to give the title compound as a pale brown solid. LCMS m/z 203.20 [M−H]− R.T.=3.23 min (Analytical Method 5).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12](=[O:14])[CH3:13])[CH:6]=[CH:5]2.[F:15][C:16]([Si](C)(C)C)([F:18])[F:17].Cl>[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([OH:14])([CH3:13])[C:16]([F:18])([F:17])[F:15])[CH:6]=[CH:5]2
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(=O)c1ccc2cc(Br)ccc2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CN(C)C=O
Product: CC(O)(c1ccc2cc(Br)ccc2n1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 105.1 %

Procedure:
A DMF (5 ml) solution of 1-(6-bromoquinolin-2-yl)ethanone (129 mg, 0.52 mmol), (trifluoromethyl)trimethylsilane (220 mg, 1.55 mmol) and tetrabutylammonium fluoride (13.5 mg, 0.052 mmol) was stirred at 100° C. for 2 hours. Then the mixture was cooled to room temperature and 1N-hydrochloride aqueous solution (2 ml) was added. After 4 hours, the mixture was quenched with saturated sodium bicarbonate aqueous solution, and the product was extracted with ethyl acetate which was dried over sodium sulfate. Then, filtration, evaporation and purification through silica gel column chromatography, eluting with hexane/ethyl acetate (4:1), furnished the title compound (175 mg, quant.) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.81 (3H, s), 6.51 (1H, s), 7.64 (1H, d, J=8.1 Hz), 7.66-7.89 (1H, m), 8.00-8.12 (2H, m), 8.21 (1H, d, J=8.8 Hz). MS (ESI): m/z 320, 322 (M+H)+.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][C:34]3[S:35][CH:36]=[CH:37][N:38]=3)[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([C:24]2[N:23]=[C:22]([S:33]([C:34]3[S:35][CH:36]=[CH:37][N:38]=3)=[O:9])[NH:21][C:20]=2[C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=2)=[CH:30][CH:29]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(-c2nc(Sc3nccs3)[nH]c2-c2ccc(OC)cc2)cc1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3nccs3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is added dropwise to a solution of 3.95 g of 4,5-bis(4-methoxyphenyl)-2-(2-thiazolylthio)imidazole in 100 ml of dichloromethane. The solution is stirred for 3 hours at room temperature, washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is chromatographed on 150 g of silica gel with acetone/hexane 2:3, thus obtaining 3.28 g of 4,5-bis(4-methoxyphenyl)-2-(2-thiazolylsulfinyl)imidazole as an amorphous foam.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[C:18](=[O:19])[CH:17]=[C:16]2[C:7](=[N:8][C:9]3[C:14]([S:15]2)=[CH:13][C:12]([O:20][CH3:21])=[CH:11][CH:10]=3)[CH:6]=1.CO>C(O)(=O)C>[Br:1][C:17]1[C:18](=[O:19])[C:5]([O:4][CH3:3])=[CH:6][C:7]2[C:16]=1[S:15][C:14]1[C:9](=[CH:10][CH:11]=[C:12]([O:20][CH3:21])[CH:13]=1)[N:8]=2
Reactant: BrBr
Reactant: COc1ccc2nc3cc(OC)c(=O)cc-3sc2c1
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc2nc3cc(OC)c(=O)c(Br)c-3sc2c1
Reaction time: 2 h
Yield: 96.8 %

Procedure:
A solution of bromine (280 g) in acetic acid (2.8 l) was added over a period of 30 minutes to a suspension of 2,7-dimethoxy-3H-phenothiazin-3-one (250 g) (Step 3) in acetic acid (7.5 l) and the mixture was stirred for 2 hours. Methanol (12 l) was added over a period of 30 minutes to the reacting mixture and the black suspension was stirred until it became an orange suspension. Then, the precipitate was filtered, washed with methanol and air-dried to afford the desired compound (312 g), m.p. 260°-261° C.