Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16]CC2C=CC=CC=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[C].[Pd].C(O)C>[C:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Oc1ccc(OCc2ccccc2)cc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(Oc1ccc(O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.6 %

Procedure:
A reaction vessel was charged with 38 g of 4-benzyloxyphenyl benzoate and 500 ml of ethanol, and the air in the vessel was replaced with nitrogen. Then, 1.0 g of 10% palladium carbon was added thereto, and the nitrogen in the vessel was replaced with hydrogen, followed by vigorous stirring at room temperature for 24 hours. The hydrogen in the vessel was replaced with nitrogen, after which the reaction mixture was filtered though celite, and the filtrate was concentrated, which afforded 24.5 g of 4-hydroxyphenyl benzoate (94% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26]([O:28]CC)=O)[C:5]2[C:6](=O)[CH:7]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:8]([C:12]3[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=3)[NH:9][C:10]=2[CH:11]=1.O.[NH2:32][NH2:33]>CO>[F:1][C:2]1[CH:11]=[C:10]2[NH:9][CH:8]([C:12]3[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=3)[CH:7]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:6]3=[N:32][NH:33][C:26](=[O:28])[C:4]([CH:3]=1)=[C:5]23
Reactant: NN
Reactant: CCOC(=O)c1cc(F)cc2c1C(=O)C(c1ccc(F)cc1)C(c1nccn1C)N2
Solvent: CO
Solvent: O
Product: Cn1ccnc1C1Nc2cc(F)cc3c(=O)[nH]nc(c23)C1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 14 %

Procedure:
A mixture of ethyl 7-fluoro-3-(4-fluorophenyl)-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (200 mg, 0.486 mmol) in 85% hydrazine monohydrate (1 mL) and methanol (5 mL) was stirred at room temperature for 4 h. The resulting mixture was filtered and washed by water (20 mL) and methanol (5 mL) to obtain a white solid, which was then dried in vacuum at 50° C. to obtain the title compound (25.4 mg, yield 14%). LC-MS (ESI) m/z: 380 (M+1)+; 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.56 (s, 3H), 4.52-4.53 (d, J=6.8 Hz, 1H), 5.02-5.04 (m, 1H), 6.73 (s, 1H), 6.82-6.85 (m, 1H), 6.99-7.09 (m, 4H), 7.18-7.22 (m, 2H), 7.69 (s, 1H), 12.34 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11](Cl)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][NH2:17]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:16][NH2:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: Clc1cc(OCc2ccccc2)ccn1
Solvent: c1ccncc1
Product: NNc1cc(OCc2ccccc2)ccn1

Procedure:
To a solution of 4-(benzyloxy)-2-chloropyridine (4.89 g, 22.30 mmol) in pyridine (120 mL) was added hydrazine (45 mL, 22.30 mmol). After heating to reflux for 18 hours, the mixture was concentrated to provide the crude product, which was used without further purification.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([CH3:28])([CH3:27])[CH2:21][NH:22][C:23]2=[O:26])=[CH:18][CH:17]=1.[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1.C(O)(=O)C>ClCCl>[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([CH3:28])([CH3:27])[CH2:21][NH:22][C:23]3=[O:26])=[CH:18][CH:17]=2)=[CH:32][CH:31]=1
Reactant: CC1(C)CNC(=O)c2cc(N)ccc21
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC1(C)CNC(=O)c2cc(NCc3ccc(Cl)cc3)ccc21
Reaction time: 8 h
Yield: 38.7 %

Procedure:
Sodium triacetoxyborohydride (800 mg, 3.79 mmol) was added to a stirred solution of 7-amino-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one (220 mg, 1.15 mmol), 4-chlorobenzaldehyde (324 mg, 2.31 mmol) and acetic acid (69 μl, 1.15 mmol) in anhydrous dichloromethane (10 ml) at room temperature. The reaction was stirred overnight and quenched with the addition of water. The organic phase was separated, washed with brine, then dried (MgSO4) and evaporated in vacuo. The resulting residue was purified by flash column chromatography (20% ethyl acetate in dichloromethane) to afford the title compound as a light brown solid (140 mg, 39%). HPLC retention time 4.40 min. Mass spectrum (ES+) m/z 315 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[CH3:11].[Cl:12][CH2:13][C:14]([CH2:16]Cl)=O.S(=O)(=O)(O)O>>[Cl:12][CH2:13][C:14]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([F:1])=[C:3]([CH3:11])[CH:4]=2)[O:7][CH:16]=1
Reactant: O=C(CCl)CCl
Reactant: Cc1cc(C(N)=O)ccc1F
Agent: O=S(=O)(O)O
Product: Cc1cc(-c2nc(CCl)co2)ccc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2.00 g (12.80 mmol) of 4-fluoro-3-methylbenzamide and 1.79 g (14.08 mmol) of 1,3-dichloroacetone are stirred at 130° C. for 2 days. A melt is formed. The mixture is then cooled to RT, 3.0 ml of conc. sulfuric acid are added carefully at this temperature and the mixture is stirred for 15 min. The resulting suspension is poured into 20 ml of ice-water and stirred at RT overnight. The precipitate formed is filtered off and dried at 40° C. in a vacuum drying cabinet overnight.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([NH2:22])[N:15]=1)[N:7]=3.O1CCCCC1[O:31][CH2:32][CH2:33][N:34]1[CH:38]=[C:37]([Sn](CCCC)(CCCC)CCCC)[N:36]=[CH:35]1>>[NH2:22][C:16]1[N:15]=[C:14]([C:8]2[N:7]=[C:6]3[C:5]4[CH:23]=[CH:24][C:2]([C:37]5[N:36]=[CH:35][N:34]([CH2:33][CH2:32][OH:31])[CH:38]=5)=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][N:10]3[CH:9]=2)[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=1
Reactant: CC(C)n1nc(N)nc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(CCOC2CCCCO2)cn1
Product: CC(C)n1nc(N)nc1-c1cn2c(n1)-c1ccc(-c3cn(CCO)cn3)cc1OCC2

Procedure:
5-(8-Bromo-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-ylamine was reacted with 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(tributylstannyl)-1H-imidazole to give 229 after THP-removal with aqueous HCl purification by reverse phase HPLC (49 mg). LCMS: 421.2
Reaction SMILES: OC(CO)CN(CC(O)CO)CCCN.OC(CO)CN(CC(O)CO)CCCN(CC(O)CO)CCCN.[C:40]1([CH2:46][CH2:47][CH:48]([NH:57][CH2:58][CH2:59][CH2:60][N:61]([CH2:76][CH:77]([OH:80])[CH2:78][OH:79])[CH2:62][CH2:63][CH2:64][N:65](CC(O)CO)CC(O)CO)[CH2:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[C:40]1([CH2:46][CH2:47][CH:48]([NH:57][CH2:58][CH2:59][CH2:60][N:61]([CH2:76][CH:77]([OH:80])[CH2:78][OH:79])[CH2:62][CH2:63][CH2:64][NH2:65])[CH2:49][CH2:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: OCC(O)CN(CCCNC(CCc1ccccc1)CCc1ccccc1)CCCN(CC(O)CO)CC(O)CO
Agent: NCCCN(CC(O)CO)CC(O)CO
Agent: NCCCN(CCCN(CC(O)CO)CC(O)CO)CC(O)CO
Product: NCCCN(CCCNC(CCc1ccccc1)CCc1ccccc1)CC(O)CO

Procedure:
In a like manner and using analogous quantities, but employing N,N-di-(2,3-dihydroxypropyl)trimethylenediamine and 1,1,5-tri-(2,3-dihydroxypropyl)-1,5,9-triazanonane instead of 3,3'-(2,3-dihydroxypropylimino)bispropylamine there are prepared respectively N-[1,5-di-(phenyl)-3-pentyl]-N'-di-(2,3-dihydroxypropyl)trimethylenediamine, and 1-[1,5-di-(phenyl)-3-pentyl]-5-(2,3-dihydroxypropyl)-9,9-di-(2,3-dihydroxypropyl)-1,5,9-triazanonane.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:38])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34](I)=[CH:33][N:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.[C:44](=O)([O-:46])[O-:45].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C@@:12]2([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10][C@@H:9]([C:28]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([C:44]([OH:46])=[O:45])=[CH:33][N:32]=3)=[O:29])[C@@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:38])=[C:16]([F:22])[CH:17]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(I)cn2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: O=C([O-])[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)cn2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 70 °C
Reaction time: 3 h

Procedure:
In a 50 ml pressure tube, (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-(5-iodopyridin-2-yl)-5-neopentylpyrrolidine-2-carboxamide (87 mg, 130 μmol, Eq: 1.00) was combined with DMF (3.48 ml) and water (174 μl). Potassium carbonate (35.9 mg, 260 μmol, Eq: 2) was added. The mixture was bubbled with nitrogen and then palladium (II) acetate (3.48 mg, 15.5 μmol, Eq: 0.119) was added. The tube was subjected to CO atmosphere at 40 PSI and stirred for 3 hours at 70° C.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[N:11]([CH2:15][CH:16](OS(C)(=O)=O)[C:17]3[CH:22]=[N:21][CH:20]=[CH:19][N:18]=3)[C:10]3[CH2:9][CH2:8][N:7]4[CH2:28][CH2:29][CH2:30][CH:6]4[C:5]=3[C:4]=2[CH:3]=1.[N-:31]=[N+:32]=[N-:33].[Na+]>CN(C=O)C>[N:31]([CH:16]([C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1)[CH2:15][N:11]1[C:10]2[CH2:9][CH2:8][N:7]3[CH2:28][CH2:29][CH2:30][CH:6]3[C:5]=2[C:4]2[CH:3]=[C:2]([CH3:1])[CH:14]=[CH:13][C:12]1=2)=[N+:32]=[N-:33]
Reactant: Cc1ccc2c(c1)c1c(n2CC(OS(C)(=O)=O)c2cnccn2)CCN2CCCC12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(N=[N+]=[N-])c2cnccn2)CCN2CCCC12
Temperature: 90 °C
Yield: 24.7 %

Procedure:
Methanesulfonicacid 2-(9-methyl-1,2,3,4,5,10c-hexahydro-3a,6-diaza-cyclopenta[c]fluoren-6-yl)-1-pyrazin-2-yl-ethyl ester (280 mg, 0.65 mmol) was dissolved in 3 mL DMF, sodium azide (64 mg, 0.98 mmol) was added and heated at 90° C. for 1 h. The reaction mixture was monitored by LCMS. After consumption of starting material, the reaction mixture was cooled to RT, diluted with water (3 mL) and concentrated to obtain the crude product, which was purified by reverse phase chromatography to obtain 60 mg of 6-(2-azido-2-pyrazin-2-yl-ethyl)-9-methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6-diaza-cyclopenta[c]fluorene. 1H NMR (CDCl3, freebase) δ (ppm): 8.65 (d, 1H), 8.60 (s, 1H), 8.50 (s, 1H), 7.8 (d, 1H), 7.22 (d, 1H), 7.09 (t, 1H), 5.1 (m, 1H), 4.8 (m, 1H), 4.6 (dd, 1H), 4.3 (m, 1H), 3.45 (m, 3H), 2.97 (m, 2H), 2.84 (m, 2H), 2.6 (m, 1H), 2.45 (d, 3H), 2.2 (m, 1H), 1.9 m (1′H). Separation by chiral HPLC provided enantiomers II-261a-b.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:11](Cl)(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1[Cl:10])([O-:3])=[O:2].ClCCl.[CH2:18]([NH2:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(N(CC)CC)C>[CH2:18]([NH:34][S:11]([C:6]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:13])=[O:12])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: CCCCCCCCCCCCCCCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCNS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Yield: 88 %

Procedure:
800 g of 3-nitro-4-chlorobenzenesulfonyl chloride and 1,000 ml of dichloromethane were mixed, and thereto was added dropwise a dichloromethane solution containing 600 g of hexadecylamine and 251 ml of triethylamine. After the completion of the reaction, the solvent used was distilled away under reduced pressure, and the residue was dissolved under heating in 3,000 ml of ethanol. Upon gradual cooling, crystals separated out. These crystals were filtered off, and dried. Yield: 1,020 g, Percent yield: 88%, Melting point: 91°-93° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:21][CH3:22])[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)=[O:10])=[C:4]([F:23])[CH:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][NH:11][C:9](=[O:10])[CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:29]3[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)=[CH:3][C:4]=2[F:23])[O:21][CH3:22])=[CH:14][CH:15]=1)#[N:20]
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(Br)cc1F
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc(C(OC)C(=O)NCc3ccc(C#N)cc3)c(F)c2)cc1

Procedure:
In analogy to example 57.1, (RS)-2-(4-bromo-2-fluoro-phenyl)-N-(4-cyano-benzyl)-2-methoxy-acetamide (example 41.2) was reacted with 4-methoxyphenylboronic acid to give (RS)-N-(4-cyano-benzyl)-2-(3-fluoro-4′-methoxy-biphenyl-4-yl)-2-methoxy-acetamide. Off-white solid.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:9]([CH:10]=[O:11])=[CH:8][CH:7]=[C:6]([Cl:12])[N:5]=1>CO>[Cl:3][C:4]1[C:9]([CH2:10][OH:11])=[CH:8][CH:7]=[C:6]([Cl:12])[N:5]=1
Reactant: O=Cc1ccc(Cl)nc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(Cl)nc1Cl
Reaction time: 0.5 h

Procedure:
Sodium borohydride (125 mg, 4.49 mmol) was added to 2,6-dichloro-pyridine-3-carbaldehyde (0.62 g, 3.5 mmol) in 20 mL of methanol at 0° C. After 30 minutes, the mixture was quenched with NaHCO3 (20 mL) and water (20 mL) and extracted with EtOAc (2×20 mL). The combined extracts were dried and concentrated under vacuum to afford 72a: LC-MS178.0 (MH+)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][C:17](=O)[CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.N1C(C)=CC=CC=1C.Cl.[CH2:36]([O:43][NH2:44])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C1COCC1>[CH2:36]([O:43]/[N:44]=[C:17](\[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)/[CH2:16][N:6]1[C:7]2[CH:8]=[CH:9][C:10]([Br:15])=[CH:11][C:12]=2[C:13]2[C:5]1=[CH:4][CH:3]=[C:2]([Br:1])[CH:14]=2)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(COc1ccccc1)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)c1cc(Br)ccc1n2C/C(COc1ccccc1)=N/OCc1ccccc1
Reaction time: 12 h
Yield: 93.4 %

Procedure:
To a solution of the product of Step 1 (17.7 mg, 0.0374 mmol, 1.0 equiv) in THF (400 μL) were added 2,6-lutidine (4.4 μL, 0.0374 mmol, 1.0 equiv), O-benzylhydroxylamine hydrochloride (14.3 mg, 0.0898 mmol, 2.4 equiv) and 4A molecular sieves (15.8 mg). The mixture was stirred for 12 h until TLC indicated complete consumption of starting material. The reaction mixture was quenched with saturated NaHCO3 and extracted 3 times with dichloromethane. The combined organic extracts were dried with MgSO4 and concentrated to give crude product. It was further purified by silica gel chromatography (5-10% EtOAc/Hex) to afford 20.2 mg white solid as product, yield 93.4%. 1H NMR (CDCl3, 400 MHz) δ=4.68 (s, 2H) 5.00 (s, 2H) 5.14 (s, 2H) 6.72 (d, J=8.2 Hz, 2H) 6.94 (t, J=7.3 Hz, 1H) 7.47-7.16 (m, 11H) 8.06 (s, 2H)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][NH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[Br:28]N1C(=O)CCC1=O>C1COCC1.C1CCCCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[C:16]([Br:28])=[CH:17][NH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3[nH]ccc23)CC1
Reactant: O=C1CCC(=O)N1Br
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3[nH]cc(Br)c23)CC1
Temperature: -70 °C
Reaction time: 0.08 h

Procedure:
To an ice-cooled solution of 0.4 g (1.32 mmole) 4-(1H-indol-4-yl)-piperazine-1-carboxylic acid tert-butyl ester in 10 mL THF was added 0.83 mL (1.65 mmole) 2M n-butyl lithium in cyclohexane. The reaction mixture was stirred for 5 min and then cooled to −70° C. A solution of 0.26 g (1.44 mmole) N-bromosuccinimide in 6 mL THF was added and the mixture was stirred at 0° C. for 0.5 hr. The mixture was diluted with 10 mL water and extracted with 25 mL ether. The organic phase was washed with 5 mL water, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was subjected to column chromatography over silica gel eluting with hexane/chloroform/ethyl acetate (50:48:2) to afford) 4-(3-bromo-1H-indol-4-yl)-piperazine-1-carboxylic acid tert-butyl ester as a foam, 0.46 g. Nmr (deuteriochloroform) ppm δ: 1.50 (s 9H), 3.08 (m, 4H), 3.71 (m, 4H), 6.72 (dd, 1H), 7.14 (m, 3H), 8.42 (brs, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:27])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([CH3:26])([CH3:25])[C:20]([O:22]CC)=[O:21])[CH2:9][CH2:8][CH2:7]1)=[O:5])C.O>>[C:4]([C:6]1([CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:27])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([CH3:25])([CH3:26])[C:20]([OH:22])=[O:21])[CH2:7][CH2:8][CH2:9]1)([OH:5])=[O:3]
Reactant: CCOC(=O)C(C)(C)CCCCC(=O)CCCCC1(C(=O)OCC)CCC1
Solvent: O
Product: CC(C)(CCCCC(=O)CCCCC1(C(=O)O)CCC1)C(=O)O

Procedure:
Compound 107e was prepared likewise Method D starting from 106e (8.83 g, >90% pure by 1H NMR, 20.8 mmol) and LiiO.H2O (2.91 and 1.94 g after 18 h, 69.4 and 46.2 mmol) to give, after recrystallized from iPr2O/heptane, 7e (5.19 g, 76%) as a white solid. mp=53-55° C. 1H NMR: δ 10.80 (br s, 2H), 2.50-2.35 (m, 2H), 2.39 (t, J=7.2 Hz, 4H), 1.98-1.74 (m, 6H), 1.65-1.49 (m, 6H), 1.31-1.11 (m, 4H), 1.18 (s, 6H). 13C NMR: δ 210.6, 184.3, 183.4, 47.6, 42.7, 42.6, 42.2, 40.5, 37.8, 30.1 (2×), 25.1 (2×), 24.8, 24.7, 24.2, 24.1, 15.7.
Reaction SMILES: ClC(Cl)C.[NH2:5][N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C([C@@H]1COC(=O)N1[C:25](=[O:47])[C@H:26]([CH2:30][C:31]1[C:36]([Cl:37])=[CH:35][C:34]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:33][C:32]=1[Cl:46])[CH2:27][CH:28]=O)C1C=CC=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:39]([O:38][C:34]1[CH:33]=[C:32]([Cl:46])[C:31]([CH2:30][C@@H:26]2[CH2:27][CH2:28][N:5]([N:6]3[CH2:11][CH2:10][O:9][CH2:8][CH2:7]3)[C:25]2=[O:47])=[C:36]([Cl:37])[CH:35]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: NN1CCOCC1
Reactant: O=CC[C@@H](Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: O=C1[C@H](Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1N1CCOCC1
Yield: 8 %

Procedure:
Stir a mixture of dichloroethane (25 mL), N-aminomorpholine (0.204 g, 2 mmol), (R)-4-((R)-4-benzyl-2-oxo-oxazolidin-3-yl)-3-(4-benzyloxy-2,6-dichloro-benzyl)-4-oxo-butyraldehyde (1.064 g, 2 mmol) and sodium triacetoxyborohydride (1.266 g, 6 mmol) at room temperature for 12 hours. Bring the reaction to 60° C. and stir for 3 hours. Cool the reaction, dilute with dichloromethane, and wash with water. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify on silica with a 50 to 75% ethyl acetate in hexanes gradient to afford 0.07 g (80%) of the titled product. MS (m/z): 435 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:23])=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[C:11]([CH3:21])=[C:12]([CH:17]=[CH:18][C:19]=1[CH3:20])[C:13]([O:15][CH3:16])=[O:14])=[O:8].[C:24]([Si:28]([CH3:38])([CH3:37])[O:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]1)([CH3:27])([CH3:26])[CH3:25].C([O-])([O-])=O.[Cs+].[Cs+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:28]([O:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][N:33]([C:2]2[CH:3]=[CH:4][C:5]([F:23])=[C:6]([CH:22]=2)[C:7]([NH:9][C:10]2[C:11]([CH3:21])=[C:12]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:13]([O:15][CH3:16])=[O:14])=[O:8])[CH2:32]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:38])[CH3:37]
Reactant: CC(C)(C)[Si](C)(C)OCC1CCCNC1
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2cc(Br)ccc2F)c1C
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCCC(CO[Si](C)(C)C(C)(C)C)C3)ccc2F)c1C
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of methyl 3-[(5-bromo-2-fluoro-benzoyl)amino]-2,4-dimethyl-benzoate (0.7 g, 1.84 mmol), tert-butyl-dimethyl-(3-piperidylmethoxy)silane (2.53 g, 11.03 mmol, see preparation 14) and Cs2CO3 (1.81 g, 5.50 mmol) in 1,4-dioxane (15 ml) is added Pd2(dba)3 (0.168 g, 0.184 mol) followed by S-Phos (0.075 g, 0.184 mol). The reaction mixture is purged with nitrogen for 5 minutes and then heated at 120° C. After 6 hours, the reaction mixture is concentrated under reduced pressure and residue is carried forward without further purification.
Reaction SMILES: [CH3:1][C:2](=C)[CH2:3][CH2:4]O.CC(C)=CC=O.CCCC.[C:17]1(=[O:23])[O:22][C:20](=[O:21])[CH:19]=[CH:18]1>>[C:20]1(=[O:21])[O:22][C:17](=[O:23])[C:18]2=[CH:1][CH:2]=[CH:3][CH:4]=[C:19]12
Reactant: O=C1C=CC(=O)O1
Reactant: C=C(C)CCO
Agent: CC(C)=CC=O
Solvent: CCCC
Product: O=C1OC(=O)c2ccccc21

Procedure:
Examples of reactions which can be carried out particularly expediently in the reactors according to the invention are, without this listing being exhaustive: dehydrogenations, for example, of cyclohexylidene-aniline to give diphenylamine and of cyclohexenyl-cyclohexanone to give o-phenylphenol; hydrogenations, for example, of nitrobenzene to give aniline and of phenol to give cyclohexanone; oxidative alcohol dehydrogenations, for example, of 3-methyl-3-buten-1-ol to give 3-methyl-2-buten-1-al; selective oxidations of hydrocarbons, for example, of n-butane to give maleic anhydride, of oxylene to give phthalic anhydride and of propene to give acrolein or acrylic acid and alkylations and halogenations.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]([OH:15])=O)[C:8](=[O:20])[C:7]3=[CH:21][NH:22][C:5]([C:6]=23)=[N:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C:26]#[N:27].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C)C1C=CN=CC=1.CN(C=O)C>[Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([C:16]([CH3:17])([CH3:19])[CH3:18])[C:13]([NH:27][CH2:26][CH2:25][C:24]#[N:23])=[O:15])[C:8](=[O:20])[C:7]3=[CH:21][NH:22][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: N#CCCN
Reactant: CC(C)(C)[C@H](C(=O)O)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)[C@H](C(=O)NCCC#N)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Yield: 53.5 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3,3-dimethylbutanoic acid (5 mg, 0.016 mmol). DMF (0.5 mL), 3-aminopropanenitrile (1.089 mg, 0.016 mmol), HOBt (3.57 mg, 0.023 mmol), EDC (4.47 mg, 0.023 mmol) and N,N-dimethylpyridin-4-amine (1.898 mg, 0.016 mmol) were added and the solution was stirred at 25° C. for 4 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 20-50%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a yellow oil (3.2 mg, 55.1%). 1H NMR (500 MHz, CD3OD) δ 1.19 (s, 9 H) 2.63-2.72 (m, 2 H) 3.38-3.53 (m, 2 H) 4.89 (br. s., 1 H) 5.29 (d, J=19.04 Hz, 1 H) 5.41 (d, J=19.00 Hz, 2 H) 7.85 (s, 1 H) 8.24 (s, 1 H) 8.55 (d, J=4.88 Hz, 1 H). [M+H] calc'd for C18H20ClN5O2, 374; found, 374.5.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:16]([O-:18])=[O:17])[C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.O.[C:24](OCC)(=O)C>CO>[C:1]([C:5]1[CH:6]=[C:7]([N+:16]([O-:18])=[O:17])[C:8]([O:14][CH3:15])=[C:9]([CH:13]=1)[C:10]([O:12][CH3:24])=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(C)=O
Reactant: COc1c(C(=O)O)cc(C(C)(C)C)cc1[N+](=O)[O-]
Solvent: O
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(C(C)(C)C)cc([N+](=O)[O-])c1OC
Temperature: 0 °C

Procedure:
5.4 g 5-tert-butyl-2-methoxy-3-nitro-benzoic acid are dissolved in 50 ml of methanol, cooled to 0° C. and combined dropwise with 2.32 ml of thionyl chloride. After the addition has ended the mixture is heated for 12 hours to 60° C. Then the solvents are eliminated in vacuo, the residue is divided between water and ethyl acetate and the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are dried on magnesium sulphate and the solvent is eliminated in vacuo. The residue thus obtained is chromatographed on silica gel (cyclohexane/ethyl acetate (98:2 to 60:40).