Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH2:1].[Na].Cl[CH2:4][CH2:5][CH2:6][Si:7]([O:12][CH3:13])([O:10][CH3:11])[O:8][CH3:9].[SiH4]>CN(C)C=O>[SH:1][CH2:4][CH2:5][CH2:6][Si:7]([O:12][CH3:13])([O:10][CH3:11])[O:8][CH3:9]
Reactant: CO[Si](CCCCl)(OC)OC
Reactant: S
Agent: [Na]
Agent: [SiH4]
Solvent: CN(C)C=O
Product: CO[Si](CCCS)(OC)OC
Temperature: 110 °C
Yield: 84 %

Procedure:
566 g (10.1 mols) of sodium hydrogen sulfide together with 2,400 g of dimethylformamide were introduced into the apparatus described in Example 1. While stirring, 2,000 g (10.1 mols) of 3-chloropropyltrimethoxysilane were added to the contents of the flask over a period of 60 minutes, whereby the temperature of the contents of the flask rose to about 100° C. By application of additional heat the temperature was increased to 110° C. and maintained at this level. Samples of the reaction mixture were taken at intervals of 15 minutes and gas-chromatographically analyzed. After the elapse of 75 minutes of reaction time only traces of the provided silane compound could be detected in the reaction mixture. The distillative work-up of the raw reaction mixture gave a yield of 84% of 3-mercaptopropyltrimethoxysilane.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]([NH:15][CH:16]([CH:24]([OH:49])[CH2:25][CH:26]([NH:34][C:35]([O:37][CH2:38][CH2:39][CH2:40][O:41][Si](C(C)(C)C)(C)C)=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])(C(C)(C)C)(C)C>CO.C[Si](Cl)(C)C>[OH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]([NH:15][C@H:16]([C@@H:24]([OH:49])[CH2:25][C@@H:26]([NH:34][C:35]([O:37][CH2:38][CH2:39][CH2:40][OH:41])=[O:36])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14]
Reactant: CC(C)(C)[Si](C)(C)OCCCOC(=O)NC(Cc1ccccc1)CC(O)C(Cc1ccccc1)NC(=O)OCCCO[Si](C)(C)C(C)(C)C
Agent: C[Si](C)(C)Cl
Solvent: CO
Product: O=C(N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCCCO)OCCCO
Reaction time: 2.25 h
Yield: 19.6 %

Procedure:
A 0.170 g (0.237 mmol) of the compound from Example 337B above was dissolved in 2 mL of methanol to which 30 μL of trimethylsilyl chloride was added and stirred for 2.25 hours. The solvent was removed and the crude product chromatographed on silica gel, eluting with 2% and 5% methanol in methylene chloride. The solvent was removed and the product dried to afford 22.7 mg of the title compound. MS M/Z (DCI/NH3): 489 (M+H), 506 (M+NH4). Proton NMR (DMSO): δ 1.45 (t, 2H), 1.60 (m, 4H), 2.55-2.75 (4H) 3.40 (m, 2H), 3.55 (br, 1H), 3 74-3.96 (8H), 4.44 (t, 2H), 4.62 (d, 1H), 6.63 (d, 1H), 6.89 (d, 1H.), 7.07-7.27 (10H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[N:3]=1.[C:25]([NH2:28])(=[O:27])[CH3:26]>[Cu]>[Cl:22][C:20]1[CH:19]=[CH:18][C:17]([O:23][CH3:24])=[C:16]([C:4]2[N:3]=[C:2]([NH:28][C:25](=[O:27])[CH3:26])[CH:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=3)[CH:5]=2)[CH:21]=1
Reactant: COc1ccc(Cl)cc1-c1cc(Nc2ccc(C)cc2)cc(Cl)n1
Reactant: CC(N)=O
Agent: [Cu]
Product: COc1ccc(Cl)cc1-c1cc(Nc2ccc(C)cc2)cc(NC(C)=O)n1
Temperature: 180 °C
Yield: 23.5 %

Procedure:
A mixture of [2-chloro-6-(5-chloro-2-methoxy-phenyl)-pyridin-4-yl]-p-tolyl-amine (60 mg, 0.167 mmol) prepared according to Example 1, copper powder (100 mg, 1.54 mmol) and acetamide (2.0 g, 33.9 mmol) was heated at 180° C. for 3 hours. The mixture was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:1 followed by 3:2) to provide title compound (15 mg, 23% yield). 1H NMR (acetone-d6) δ 2.19 (s, 3H, CH3), 2.32 (s, 3H, CH3), 3.91 (s, 3H, CH3), 7.12 (d, 1H, J=8.8 Hz, Ar), 7.19–7.25 (m, 4H, Ar), 7.35 (dd, 1H, J=8.8 Hz, J=2.8 Hz, Ar), 7.47–7.48 (m, 1H, Ar), 7.86 (s, 1H, NH), 7.89 (d, 1H, J=2.8 Hz, Ar), 8.05 (s, 1H, NH).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]4[S:26][N:25]=[CH:24][N:23]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][N:9]=2)=[C:4]([O:27][CH3:28])[CH:3]=1.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[F:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[C:17]4[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]5[S:26][N:25]=[CH:24][N:23]=5)(=[O:20])=[O:19])=[CH:15][CH:16]=4)[N:11]=[CH:10][N:9]=3)=[C:4]([O:27][CH3:28])[CH:3]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: COc1cc(Cl)ccc1-c1ncnc2cc(S(=O)(=O)Nc3ncns3)ccc12
Reactant: OB(O)c1cccc(F)c1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1cc(-c2cccc(F)c2)ccc1-c1ncnc2cc(S(=O)(=O)Nc3ncns3)ccc12

Procedure:
A vial was charged with 4-(4-chloro-2-methoxyphenyl)-N-(1,2,4-thiadiazol-5-yl)quinazoline-7-sulfonamide (Example 524; 0.050 g, 0.115 mmol), (3-fluorophenyl)boronic acid (0.032 g, 0.230 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (2.365 mg, 5.76 μmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii) dichloromethane (4.36 mg, 5.76 μmol), and potassium phosphate (0.073 g, 0.346 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (0.524 ml) and Water (0.052 ml) were added in sequence. The vial was sealed and microwaved at 80° C. for three hours. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 12 g, gradient elution 0-10% MeOH:DCM) to afford 4-(3′-fluoro-3-methoxy-[1,1′-biphenyl]-4-yl)-N-(1,2,4-thiadiazol-5-yl)quinazoline-7-sulfonamide as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=9.47 (s, 1H), 8.39 (d, J=1.7 Hz, 1H), 8.34 (s, 1H), 8.00-7.97 (m, 1H), 7.91-7.87 (m, 1H), 7.75-7.72 (m, 1H), 7.72-7.68 (m, 2H), 7.61-7.49 (m, 4H), 7.31-7.23 (m, 1H), 3.81 (s, 3H). m/z (ESI) 494.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:3]=1[CH2:4][O:5]/[N:6]=[C:7](/[C:13](=[O:15])[CH3:14])\[C:8]([O:10][CH2:11][CH3:12])=[O:9].[Br:21]Br>>[Br:21][CH2:14][C:13](=[O:15])/[C:7](=[N:6]/[O:5][CH2:4][C:3]1[C:2]([Cl:1])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:20])/[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)/C(=N\OCc1c(Cl)cccc1Cl)C(C)=O
Reactant: BrBr
Product: CCOC(=O)/C(=N\OCc1c(Cl)cccc1Cl)C(=O)CBr

Procedure:
Ethyl (Z)-2-(2,6-dichlorobenzyloxyimino)-3-oxobutyrate (5.8 g) was reacted with bromine (0.94 ml) as described in Example 4c to give the title compound (7.2 g), δH (CDCl3) 1.31 (3H, t), 4.35 (2H, s), 4.45 (2H, q), 5.73 (2H, s), and 7.43 (3H, m).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4].C(O)(=[O:28])C>OO>[CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:24])(=[O:25])[NH2:23])[C:14]=1[S:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:28])[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CC(=O)O
Reactant: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Sc1ccccc1
Agent: OO
Product: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1S(=O)c1ccccc1

Procedure:
To a suspension of 3-n-butylamino-4-phenylthio-5-sulphamyl-benzoic acid (0.5 g) in acetic acid (5 ml), perhydrol (2.5 ml of 30% hydrogen peroxide in water) was added while stirring. The reaction mixture was stirred for an additional 24 hours at 30°C, after which the 3-n-butylamino-4-phenylsulphinyl-5-sulphamyl-benzoic acid was collected by suction and washed with aqueous acetic acid. After recrystallization from aqueous ethanol, the compound was obtained with a melting point of 203°-204°C (decomp.).
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([N:13]2[CH2:17][CH2:16][CH:15]([NH:18]C(=O)OC(C)(C)C)[CH2:14]2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].[NH:26]([C:28](OCC)=[O:29])[NH2:27]>CN1C(=O)CCC1.CO>[NH2:18][CH:15]1[CH2:16][CH2:17][N:13]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:12]=[C:3]([C:1]3[NH:2][C:28](=[O:29])[NH:26][N:27]=3)[N:4]=2)[CH2:14]1
Reactant: CCOC(=O)NN
Reactant: CC(C)(C)OC(=O)NC1CCN(c2nc(C#N)cc3ccccc23)C1
Solvent: CO
Solvent: CN1CCCC1=O
Product: NC1CCN(c2nc(-c3n[nH]c(=O)[nH]3)cc3ccccc23)C1
Temperature: 175 °C
Yield: 17 %

Procedure:
To a crude reaction mixture containing tert-butyl (1-(3-cyanoisoquinolin-1-yl)pyrrolidin-3-yl)carbamate (786 mg) was added ethyl hydrazinecarboxylate (242 mg, 2.323 mmol) in NMP (5 mL). The resulting suspension was heated at 175° C. overnight and was subsequently cooled, diluted with MeOH, and filtered. The crude product was purified using mass-triggered HPLC eluting with a gradient of 20-45% ACN in water (acid mode). The product-containing fractions were concentrated to give the title compound (117 mg, 17.0% over 2 steps). ESI-MS m/z [M+H]+ 297.5.
Reaction SMILES: [CH3:1]OS(OC)(=O)=O.[C:8]1(=[O:21])[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10][NH:9]1.[OH-].[Na+]>CC(C)=O>[CH3:1][N:13]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[C:20]2[C:8](=[O:21])[NH:9][CH2:10][CH2:11][C:12]1=2
Reactant: COS(=O)(=O)OC
Reactant: O=C1NCCc2[nH]c3ccccc3c21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cn1c2c(c3ccccc31)C(=O)NCC2

Procedure:
Dimethylsulphate (2.28 ml) was added over 5 min to a stirred mixture of 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one (3 g), acetone (12 ml) and 20% w/v aqueous sodium hydroxide (9 ml) at ca. 50°. The mixture was heated at reflux for 10 min. Further sodium hydroxide (6 ml) was added and the mixture was heated at reflux for 5 min. On cooling a solid crystallised. Water (10 ml) was added and the mixture was filtered. The solid was washed with water (2×20 ml), and dried in vacuo 45° to give the title compound (3.16 g). The t.l.c. data for this material were consistent with those obtained for the product of Example 1.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[Cl:16][C:17]1[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([C:24](O)=[O:25])[CH:18]=1>>[CH3:1][N:2]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[C:24]([C:19]1[CH:18]=[C:17]([Cl:16])[CH:22]=[C:21]([CH3:23])[N:20]=1)=[O:25]
Reactant: Cc1cc(Cl)cc(C(=O)O)n1
Reactant: CNc1cnccc1-c1ccccc1C
Product: Cc1cc(Cl)cc(C(=O)N(C)c2cnccc2-c2ccccc2C)n1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 4-chloro-6-methylpyridine-2-carboxylic acid (CAS RN 30235-19-9). Colorless solid (35%). MS (ESI): m/z=352.12 [M+H]+.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[C:11]([NH:12][CH2:13][C:4]2=[CH:3][CH:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.C(N(C(C)C)C(C)C)C.[Cl:23][C:24]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:25]=1[O:26][C:27]1[C:32]([C:33](N2C3C(=CC=CC=3)NCC2)=[O:34])=[CH:31][CH:30]=[CH:29][N:28]=1>C(O)C.[Pd]>[Cl:23][C:24]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:25]=1[O:26][C:27]1[C:32]([C:33]([N:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]3[CH2:1][CH2:2][CH2:3][CH:4]3[CH2:13]2)=[O:34])=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: O=C(c1cccnc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Reactant: c1ccc2c(c1)NCc1cccn1-2
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=C(c1cccnc1Oc1cc(Cl)ccc1Cl)N1CC2CCCN2c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.4 %

Procedure:
To a solution of 4,5-dihydro-pyrrolo[1,2-α]quinoxaline (30.6 mg, 0.18 mmol, 1.2 equiv; [CAS RN 56721-86-9]) in ethanol (5 mL) was added palladium on carbon (3.2 mg, 0.003 mmol, 0.02 equiv; 10% Pd/C; [CAS RN 7440-05-3]) and the reaction mixture stirred under an atmosphere of hydrogen (3 bar) at rt for 4 h. The reaction mixture was concentrated under reduced pressure, filtered over Celite® and the remaining residue redissolved in anhydrous DMF (1 mL). To this solution was added N-ethyldiisopropylamine (64 mg, 86 μL, 0.50 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and 2-(2,5-dichloro-phenoxy)-nicotinoylchloride (45.4 mg, 0.15 mmol, 1.0 equiv; prepared according to Example 122) and the reaction mixture stirred at rt over night. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 21.4 mg (32%) of the title compound. MS (ISP): 440.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1.C([Li])CCC.[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl>O1CCCC1>[C:13]([CH2:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1)([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:19]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cn1nnnc1S
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)Cn1nnnc1S
Reaction time: 0.67 h
Yield: 80.1 %

Procedure:
A solution of 1-methyl-1H-tetrazole-5-thiol (23 g) in dry tetrahydrofuran (80 ml) was added over 20 minutes with stirring under dry nitrogen atmosphere to a n-butyllithium (250 ml, 15% in hexane) solution in dry tetrahydrofuran (250 ml) precooled to -15° to -10° C. After stirring at the same temperature for 40 minutes, the mixture was cooled to -60°±5° C. and thereto was added dropwise a solution of diethyl oxalate (28.95 g) in dry tetrahydrofuran (80 ml) over 30 min. The reaction mixture was stirred at -60°±5° C. for 1.5 hours. 10% Aqueous hydrochloric acid (72 ml) was added with stirring and the separated aqueous layer (pH 7.5) was adjusted to pH 2.5 with 10% hydrochloric acid and extracted with ethyl acetate (200 ml×3). The combined extracts were dried over magnesium sulfate and evaporated to give oily residue of 1-ethoxalylmethyl-1H-tetrazole-5-thiol (34.3 g).
Reaction SMILES: [O:1]=[C:2]1[CH2:22][C:5]2[C:6]([C:19]([OH:21])=[O:20])=[N:7][N:8]([S:9]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)(=[O:11])=[O:10])[C:4]=2[CH2:3]1.O[N:24]1[C:28](=[O:29])[CH2:27][CH2:26][C:25]1=[O:30].C(Cl)CCl>C(Cl)Cl>[O:30]=[C:25]1[CH2:26][CH2:27][C:28](=[O:29])[N:24]1[O:20][C:19]([C:6]1[C:5]2[CH2:22][C:2](=[O:1])[CH2:3][C:4]=2[N:8]([S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)(=[O:11])=[O:10])[N:7]=1)=[O:21]
Reactant: O=C1CCC(=O)N1O
Reactant: Cc1ccc(S(=O)(=O)n2nc(C(=O)O)c3c2CC(=O)C3)cc1
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)n2nc(C(=O)ON3C(=O)CCC3=O)c3c2CC(=O)C3)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the intermediate from step C above, (320 mg, 1.0 mmol) in CH2Cl2(20 mL) was added N-hydroxy succinimide (230 mg, 2.0 mmol) followed by EDC (384 mg, 2.0 mmol). After stirring at room temperature for 18 hours, the reaction mixture was concentrated in vacuo. The residue was diluted with ethyl acetate (20 mL), washed with saturated NaHCO3, solution and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. A yellow solid was obtained.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:17][C:9]2[O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:8]=2[C:7]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[K+].[Br-]>>[C:25]1([C:7]2[C:8]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[O:10][C:9]=3[CH:17]=[C:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:6]=2[O:5][CH2:4][C:3]([OH:31])=[O:2])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)COc1c(-c2ccccc2)cc2oc3ccccc3c2c1-c1ccccc1
Agent: [Br-]
Agent: [K+]
Product: O=C(O)COc1c(-c2ccccc2)cc2oc3ccccc3c2c1-c1ccccc1

Procedure:
The tide compound was prepared as a white solid (0.091 g, 88%) from (1,3-diphenyl-dibenzofuran-2-yloxy)acetic acid methyl ester using a procedure similar to step 2 of Example 36, mp>120° C. (decomp.); 1H NMR (DMSO-d6) δ 3.66 (s, 2H), 6.80 (d, J=7.5 Hz, 1H), 7.09-7.15 (m, 1H), 7.33-7.39 (m, 1H), 7.39-7.47 (m, 3H), 7.48-7.56 (m, 5H), 7.68 (d, J=8.1 Hz, 1H), 7.70-7.74 (m, 3H); IR (KBr) 3420, 3070, 2950, 2910, 1730, 1610, 1500, 1465, 1455, 1405, 1330, 1310, 1240, 1220, 1175, 1155, 1070, 750, and 700 cm−1; mass spectrum [EI], m/z 394 (M)+; Anal. Calcd. for C26H18O4.1.25H2O: C, 74.90; H, 4.96; N, 0.00, Found: C, 75.07; H, 4.89; N, 0.06.
Reaction SMILES: COC1C=C(OC)C=CC=1[CH2:5][NH:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[NH:15][C:16]1[N:21]=[C:20]([NH:22][C@H:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([F:33])[CH:31]=3)[O:26][CH2:25][CH2:24]2)[C:19]([NH2:34])=[CH:18][N:17]=1.O.[C:42]1(C)C=CC(S(O)(=O)=O)=CC=1.C(OC)(OC)OC>CO>[F:33][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[O:26][CH2:25][CH2:24][C@H:23]2[N:22]1[CH:42]=[N:34][C:19]2[C:20]1=[N:21][C:16]([N:15]1[C:8]3[CH:9]=[C:10]([C:11]#[N:12])[CH:13]=[CH:14][C:7]=3[N:6]=[CH:5]1)=[N:17][CH:18]=2
Reactant: COc1ccc(CNc2ccc(C#N)cc2Nc2ncc(N)c(N[C@@H]3CCOc4ccc(F)cc43)n2)c(OC)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(OC)OC
Solvent: CO
Product: N#Cc1ccc2ncn(-c3ncc4ncn([C@@H]5CCOc6ccc(F)cc65)c4n3)c2c1
Reaction time: 0.08 h

Procedure:
To a microwave vial was added the above amine, a catalytic amount of para-toluene sulfonic acid monohydrate, trimethyl orthoformate (0.5 mL) and MeOH (1 mL). The vial was capped and heated in an Emrys™ Optimizer microwave at 150.degree C. for 5 minutes. The mixture was concentrated in vacuo, and purified by RP HPLC to yield 4.6 mg of the titled product as the TFA salt, NMR CDCl3 1H δ 9.5 (br s, 1H), 9.3 (s, 1H), 9.0 (s, 1H), 8.2 (br s, 1H), 8.0 (d, 1H), 7.7 (d, 1H), 7.1-7.0 (m, 2H), 6.6 (dd, 1H), 6.0 (t, 1H), 4.4 (m, 1H), 4.3 (m, 1H), 2.7 (m, 2H); 19F δ −121, −76 ppm; MH+=412.
Reaction SMILES: [C:1]([O:5][C:6](/[C:8](/[CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:9]/[C:10]1([C:15](O)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.S(Cl)(Cl)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:45][C@@H:46]1[CH2:51][CH2:50][C@H:49]([C:52]([O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[O:53])[CH2:48][CH2:47]1.C(N(CC)CC)C>C(OCC)(=O)C.CN(C)C=O.O>[C:1]([O:5][C:6](/[C:8](/[CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:9]/[C:10]1([C:15]([NH:45][C@@H:46]2[CH2:51][CH2:50][C@H:49]([C:52]([O:54][CH2:55][C:56]3[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=3)=[O:53])[CH2:48][CH2:47]2)=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCOC/C(=C\C1(C(=O)O)CCCC1)C(=O)OC(C)(C)C
Reactant: N[C@H]1CC[C@@H](C(=O)OCc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COCCOC/C(=C\C1(C(=O)N[C@H]2CC[C@@H](C(=O)OCc3ccccc3)CC2)CCCC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 93.9 %

Procedure:
To a solution of (E)-1-[2-(tert-butoxycarbonyl)-3-(2-methoxyethoxy)prop-1-enyl]-1-cyclopentanecarboxylic acid (1.0 g, 3.04 mmol) in ethyl acetate (10.6 mL) under a nitrogen atmosphere at room temperature was added dimethylformamide (1 drop), pyridine (0.49 mL, 6.08 mmol) and thionyl chloride (0.28 mL, 3.95 mmol) and the mixture stirred at room temperature for 40 minutes. Benzyl cis-4-amino-1-cyclohexanecarboxylate p-toluenesulphonate (1.29 g, 3.19 mmol) was added at room temperature followed by triethylamine (1.27 mL, 9.12 mmol) and the mixture stirred at room temperature for 3 hours. The reaction mixture was diluted with distilled water (50 mL) and ethyl acetate (50 mL) and the layers separated. The ethyl acetate layer was washed with distilled water (2×50 mL), 1.0M aqueous hydrochloric acid solution (50 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give a brown oil (1.552 g). The crude product was purified by chromatography on silica by elution with hexane/ethyl acetate (1:1) to give, after combination and evaporation of appropriate fractions, the title compound as an oil (1.07 g, 65%).
Reaction SMILES: [H][H].[C]=O.[CH3:5][CH:6]=[CH:7][CH2:8][CH2:9][CH3:10].[CH:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]C>[Rh].O>[CH3:5][CH:6]=[CH:7][CH2:8][CH2:9][CH3:10].[CH2:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: [H][H]
Reactant: CCCCCCC=O
Agent: [Rh]
Agent: CC=CCCC
Agent: [C]=O
Solvent: O
Product: C=CCCCC
Temperature: 100 °C
Reaction time: 3 h

Procedure:
20 parts by volume of the rhodium catalyst solution prepared as described in Example B are mixed with 800 parts by volume of polyethylene glycol 400 having a water content of 2% and are introduced into an autoclave whose gas space is then filled with an equimolar mixture of hydrogen and carbon monoxide under a total pressure of 80 bar. The solution is heated while stirring to 100° C., this temperature is held for another three hours while continuing to stir and while maintaining the pressure of 80 bar and 800 parts by volume of 2-hexene are then added while maintaining these reaction conditions, the reaction mixture is stirred for another two hours at 100° C. and 80 bar and, after cooling and venting the autoclave, the reaction mixture obtained is transferred to a phase separator in which the aldehyde phase having a heptanal content of 96% is separated off. As a result of the partial isomerization of 2-hexene to 1-hexene, this gives a mixture of 1-heptanal and 2-heptanal in a mixing ratio of 0.83. The yield of heptanal mixture is 96% of theory.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[CH:2]1.[NH:17]1[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:18]1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][CH:13]([N:17]3[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=4)=[O:23])[CH2:18]3)[CH2:12][CH2:11]2)=[CH:2]1
Reactant: O=C1CCC(c2c[nH]c3ccccc23)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3c[nH]c4ccccc34)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(1H-indol-3-yl)-cyclohexanone (prepared following the procedure described in EP 345808 A119891213) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=3)[CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:54][C:55]([F:64])([F:63])[C:56]1[CH:57]=[C:58]([CH:60]=[CH:61][CH:62]=1)[NH2:59]>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH:59][C:58]4[CH:60]=[CH:61][CH:62]=[C:56]([C:55]([F:54])([F:63])[F:64])[CH:57]=4)=[O:18])=[CH:14][CH:13]=3)[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Nc1ncc2c(n1)CCN(c1ccc(C(=O)O)cc1)C2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc2c(n1)CCN(c1ccc(C(=O)Nc3cccc(C(F)(F)F)c3)cc1)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 7.3 %

Procedure:
A mixture of 4-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (27 mg, 0.10 mmol), N,N-diisopropylethylamine (0.087 mL, 0.50 mmol), and HBTU (42 mg, 0.11 mmol) in 1.0 mL DMF was stirred at room temperature for 10 minutes. Then 3-(trifluoromethyl)aniline (0.025 mL, 0.20 mmol) was added and the reaction heated at 55° C. for 18 hours and then 90° C. for 2 hours. The reaction mixture was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with dilute aqueous HCl, aqueous Na2CO3 solution, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid was chromatographed eluting with CHCl3, then gradient 2% to 5% MeOH/CHCl3 to give the title compound as a brownish-tan solid (3 mg, 8%). 1H NMR (CDCl3) δ: 8.15 (s, 1H), 7.93 (s, 1H), 7.80-7.89 (m, 4H), 7.44-7.51 (m, 1H), 7.35-7.40 (m, 1H), 6.94-7.00 (m, 2H), 5.00 (br. s., 2H), 4.39 (s, 2H), 3.73 (t, J=6.0 Hz, 2H), 2.94 (t, J=6.0 Hz, 2H)