Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Br:15]N1C(=O)CCC1=O>ClCCl>[Br:15][C:7]1[CH:8]=[C:9]([O:10][C:11]([F:12])([F:13])[F:14])[C:2]([OH:1])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: O=Cc1cccc(OC(F)(F)F)c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: O=Cc1cc(Br)cc(OC(F)(F)F)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
2-hydroxy-3-trifluoromethoxybenzaldehyde (10.38 g) was dissolved in dichloromethane (100 mL), and N-bromosuccinimide (9.41 g) was added to the solution, and then the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 10% sodium thiosulfate and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (14.27 g) as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]([OH:16])[CH2:11]C(NN)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[N:18]([O-])=O.[Na+].C([O:25][CH2:26]C)(=O)C>O>[C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[O:16][C:26](=[O:25])[NH:18][CH2:11]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(C)=O
Reactant: O=N[O-]
Reactant: CC(C)(C)OC(=O)NC[C@H](O)CC(=O)NN
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)NC[C@@H]1CNC(=O)O1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 52 %

Procedure:
10 ml of water was added to 2.00 g (8.57 mmol) of (R)-4-t-butoxycarbonylamino-3-hydroxybutanohydrazide (optical purity: >99.9%e.e.), and the mixture was cooled to 0° C. A 0.89 g (8.57 mmol) of 35% HCl was added thereto dropwise over 10 min, and then an aqueous solution of 0.59 g (8.57 mmol) of sodium nitrite dissolved in 2.0 ml of water was further added thereto dropwise slowly. After the reaction mixture was stirred for 1 hour at that temperature, the thus prepared reaction mixture was added to 10 ml of warm water (50° C.) dropwise over 1 hour. After the addition, the mixture was further stirred for 1 hour, cooled to room temperature, and then extracted thrice with a 20 ml portion of ethyl acetate. The extracted ethyl acetate was then concentrated to give 1.06 g of a crude product. The crude product was subjected to column chromatography (ethyl acetate) to obtain 0.96 g (52%) of the title compound. Melting point: 115.5° C. Optical purity: >99.9%e.e.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][CH2:12]3)[NH:7][C:6]=2[CH:5]=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.C(B(CC)[C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)C.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(COC)OC>[N:36]1[CH:37]=[CH:38][CH:39]=[C:34]([C:2]2[C:10]3[N:9]=[C:8]([N:11]4[CH2:12][CH2:13][N:14]([C:17]5[C:22]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:20]=[CH:19][N:18]=5)[CH2:15][CH2:16]4)[NH:7][C:6]=3[CH:5]=[C:4]([C:27]([F:30])([F:28])[F:29])[CH:3]=2)[CH:35]=1
Reactant: CCB(CC)c1cccnc1
Reactant: FC(F)(F)c1cc(Br)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: FC(F)(F)c1cc(-c2cccnc2)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1
Reaction time: 0.67 h

Procedure:
A mixture of 4-bromo-6-trifluoromethyl-2-[4-(3-trifluoromethylpyridin-2-yl)piperazin-1-yl]-1H-benzoimidazole (99 mg, 0.2 mmol, Example 7), diethyl(3-pyridyl)borane (37 mg, 0.25 mmol, Aldrich), Pd(PPh3)4 (23 mg, 0.02 mmol, Aldrich), Na2CO3 (32 mg, 0.3 mmol) and dimethoxyethane (1 mL) was subjected to microwave irradiation at 200° C. with stirring for 40 min. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 60% EtOAc/hexane, to give the title compound as a yellow amorphous solid. MS (ESI, pos. ion) m/z: 493 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C(O[C:13](=O)[CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])C.[CH2:27]([O:29][C:30](=[O:35])/[CH:31]=[C:32](\[NH2:34])/[CH3:33])[CH3:28]>C(O)C>[CH2:27]([O:29][C:30]([C:31]1[CH:6]([C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:31]([C:30]([O:29][CH2:27][CH3:28])=[O:35])=[C:32]([CH3:33])[NH:34][C:13]=1[CH2:14][N:15]1[C:16](=[O:25])[C:17]2=[CH:24][CH:23]=[CH:22][CH:21]=[C:18]2[C:19]1=[O:20])=[O:35])[CH3:28]
Reactant: O=Cc1ccc(F)cc1
Reactant: CCOC(=O)/C=C(/C)N
Reactant: CCOC(=O)CN1C(=O)c2ccccc2C1=O
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(CN2C(=O)c3ccccc3C2=O)=C(C(=O)OCC)C1c1ccc(F)cc1
Yield: 80 %

Procedure:
12.4 g of 4-fluorobenzaldehyde, 31 g of phthalimidoacetic acid ethyl ester and 13 g of β-aminocrotonic acid ethyl ester in 100 ccs of ethanol are heated to the boil under reflux for 2×24 hours, the mixture is allowed to cool, whilst stirring, and, after filtering, yellow crystals of melting point 144°-145° C. (ethanol) are obtained, yield: 80%.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:7]=1[C:8](Cl)=[O:9].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH3:28])[CH:21]=[C:22]([O:26]C)[C:23]=1[O:24][CH3:25]>ClCCl>[Cl:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:7]=1[C:8]([C:21]1[C:20]([CH3:28])=[CH:19][C:18]([O:17][CH3:16])=[C:23]([O:24][CH3:25])[C:22]=1[OH:26])=[O:9]
Reactant: COc1cc(C)cc(OC)c1OC
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)c(O)c1OC
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Aluminum chloride (14.67 g, 0.1 mol), 2,6-dichlorobenzoyl chloride (20.95 g, 0.1 mol) and a solution of 3,4,5-trimethoxytoluene (18.22 g, 0.1 mol) in dichloromethane (50 ml), are slowly and consecutively added to dichloromethane stirred at 0° C., stirred for 1 h at ice bath temperatures and for 16 h at room temperature, and poured into ice. The organic layer is separated, washed with dilute hydrochloric acid and water, dried, and, after addition of silica gel (100 g), concentrated in vacuo. A flash chromatography column is packed with silica gel (400 g) and the charged silica gel is layered on top of that. Elution with petrol ether/ethyl acetate (90/10, 1 l; 80/20, 1 l; 50/50, 1 l ) yields 2,6-dichloro-3',4'-dimethoxy-2'-hydroxy-6'-methylbenzophenone, 10.35 g, (30% y), mp. 161° C.
Reaction SMILES: C(O)C.Cl.[CH:5]1([C:8]2[CH:9]=[C:10]([C:50]([O:52]CC)=[O:51])[C:11](=[O:49])[N:12]3[C:17]=2[C:16]([O:18][CH3:19])=[C:15]([C:20]2[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=2)[CH:25]([CH3:29])[N:24](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:23]4)[CH:14]=[CH:13]3)[CH2:7][CH2:6]1>C1COCC1>[CH:5]1([C:8]2[CH:9]=[C:10]([C:50]([OH:52])=[O:51])[C:11](=[O:49])[N:12]3[C:17]=2[C:16]([O:18][CH3:19])=[C:15]([C:20]2[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=2)[CH:25]([CH3:29])[NH:24][CH2:23]4)[CH:14]=[CH:13]3)[CH2:7][CH2:6]1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(OC)c(-c3ccc4c(c3)CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C4C)ccn2c1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: COc1c(-c2ccc3c(c2)CNC3C)ccn2c(=O)c(C(=O)O)cc(C3CC3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
6.0 ml ethanol, 2.0 ml of THF and 1.0 ml of 1N hydrochloric acid were added to 248.0 mg of ethyl 1-cyclopropyl-9-methoxy-8-(1-methyl-2-tritylisoindoline-5-yl)-4-oxo-4H-quinolizine-3-carboxylate (XIV) and the resulting mixture was stirred at a room temperature for 30 minutes. The solvent was distilled off under reduced pressure and water was added to the resulting residue, which was washed with ethyl acetate, and thereafter, the resulting water layer was concentrated under reduced pressure. 10 ml of water, 5 ml of ethanol and 3 ml of 1N sodium hydroxide were added to the residue and the resulting mixture was stirred at 50° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and thereafter, dissolved in 4 ml of water and neutralized with 1N hydrochloric acid. The precipitated crystal was separated by filtering to obtain 99.1 mg of 1-cyclopropyl-9-methoxy-8-(1-methylisoindoline-5-yl)-4-oxo-4H-quinolizine-3-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1.C(OCC)C>CN(C)C=O>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C:12]3([S:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)(=[O:10])=[O:11])[S:16][C:15](=[O:17])[NH:14][C:13]3=[O:18])=[CH:22][CH:23]=2)=[CH:28][CH:29]=1
Reactant: Clc1ccc(-c2ccc(CBr)cc2)cc1
Reactant: COc1ccc(S(=O)(=O)C2SC(=O)NC2=O)cc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)C2(Cc3ccc(-c4ccc(Cl)cc4)cc3)SC(=O)NC2=O)cc1

Procedure:
Prepared analogously to Example 9 from from 5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione and 4′-bromomethyl-4-chlorobiphenyl in N,N-dimethylformamide. Trituration with diethyl ether provided an off-white solid. 1H NMR: δ 7.99 (s, 1H), 7.93 (dm, J=9.0 Hz, 2H), 7.45-7.49 (m, 4H), 7.38-7.41 (m, 2H), 7.23-7.26 (m, 2H), 7.06 (dm, J=9.0 Hz, 2H), 3.97, (A of AB, J=13.7 Hz, 1H), 3.92 (s, 3H), 3.39 (B of AB, J=13.7 Hz, 1H). MS (m/e): 486.0 & 488.0 (M−H)−Cl isotopes. Anal: Calc for C23H18ClNO5S2.C3H7NO: 55.66% C, 4.49% H, 4.99% N; Found: 55.57% C, 4.41% H, 4.85% N. MP: 197-200° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[CH:7][CH2:8][C:9]2([CH3:13])[CH3:12])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:26]([O:28]CC)=[CH2:27])CCC.Cl.C(OCC)(=O)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][C:9]1([CH3:13])[C:10]2[CH:11]=[C:2]([C:26](=[O:28])[CH3:27])[CH:3]=[CH:4][C:5]=2[C:6]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[CH:7][CH2:8]1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1ccc(C2=CCC(C)(C)c3cc(Br)ccc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)C(C)(C)CC=C2c1ccc(C)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 94.9 %

Procedure:
A solution of 7-bromo-1,1-dimethyl-4-p-tolyl-1,2-dihydro-naphthalene (Compound 4, 295 mg, 0.90 mmol) in 5 ml of THF was first degassed by bubbling with argon for 30 min. Tributyl(1-ethoxyvinyl)tin (650 mg, 1.80 mmol) and PdCl2(PPh3)2 (63 mg, 0.09 mmol) were added. After stirring at 80° C. for 18 h, the mixture was cooled to room temperature and 3 mL of 10% HCl was added. The mixture was then stirred for another 30 min before extraction with ethyl acetate (3×10 mL). The combined organic layer was washed with brine (1×10 mL), dried (MgSO4) and concentrated at reduced pressure. Purification by flash chromatography (80:20 hexane/ethyl acetate) afforded the title compound (248 mg, 95% yield) as a colorless oil:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][N:7]1[S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.CCCCCC>C1COCC1>[C:17]1([CH3:20])[CH:16]=[CH:15][C:14]([S:11]([N:7]2[CH2:8][CH2:9][CH2:10][CH:6]2[CH2:5][CH2:4][CH2:3][OH:2])(=[O:12])=[O:13])=[CH:19][CH:18]=1
Reactant: COC(=O)CCC1CCCN1S(=O)(=O)c1ccc(C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)N2CCCC2CCCO)cc1

Procedure:
Reduction of (RS)-3-[1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionic acid methyl ester with lithium aluminum hydride (1.5 eq.) in THF at RT, aqueous work-up and crystallization from diethyl ether/hexane yielded (RS)-3-[1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propanol, colorless oil, MS: m/e=284.2 (M+H+).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][CH:9]=[CH2:10].[CH2:11]([O:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([OH:22])[CH:16]=1)[CH3:12]>CC(C)=O>[CH2:11]([O:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH2:10][CH:9]=[CH2:8])[CH:16]=1)[CH3:12]
Reactant: C=CCBr
Reactant: CCOC(=O)c1ccc(Cl)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(C(=O)OCC)ccc1Cl
Temperature: 25 °C

Procedure:
K2CO3 (78.5 mmol) and 3-bromo-1-propen (52.3 mmol) are added to a solution of 4-chloro-3-hydroxy-benzoic acid ethyl ester (26.2 mmol) in acetone (50 mL). The mixture is heated to reflux for 16 h and cooled to RT. The solvents are removed in vacuo to give the desired product which is used without further purification. LC-MS: tR=1.05 min; [M+H]+=240.9.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[NH2:5][C:6]1[N:11]=[C:10]([CH2:12][O:13][CH2:14][CH3:15])[NH:9][C:8](=[O:16])[CH:7]=1.[OH-].[Na+].S(=O)(=O)(O)O>O>[NH2:5][C:6]1[N:11]=[C:10]([CH2:12][O:13][CH2:14][CH3:15])[NH:9][C:8](=[O:16])[C:7]=1[N:1]=[O:3]
Reactant: O=N[O-]
Reactant: CCOCc1nc(N)cc(=O)[nH]1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOCc1nc(N)c(N=O)c(=O)[nH]1

Procedure:
17.7 g (0.256 mole) of sodium nitrite are added to a solution of 39.5 g (0.233 mole) of 6-amino-2-(ethoxymethyl)-4(3H)-pyrimidinone in 336 ml (0.336 mole) of 1N sodium hydroxide. A solution of 17.9 ml (0.320 mole) of 96% sulphuric acid diluted in 179 ml of water is then added dropwise at between 0° and 5° C. The precipitate formed is isolated by filtration immediately after completion of the addition. The solid obtained is washed with cold water and then with ethyl ether. After drying, it is used in the next step without further purification. Yld: 46.2 g (quantitative), m.p. 163°-165° C. An analytical sample was obtained by recrystallization from methanol. M.p. 166°-167° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:38]=[CH:37][CH:36]=[CH:35][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19]([NH:21][CH2:22][C:23]3[CH:24]=[C:25]([CH:30]=[C:31]([O:33][CH3:34])[CH:32]=3)[C:26]([O:28]C)=[O:27])=[O:20])=[CH:15][N:14]=2)[CH2:8]1)[CH3:2].O[Li].O>C1COCC1.O>[CH2:1]([O:3][C:4]1[CH:38]=[CH:37][CH:36]=[CH:35][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:14]=[CH:15][C:16]([C:19]([NH:21][CH2:22][C:23]3[CH:24]=[C:25]([CH:30]=[C:31]([O:33][CH3:34])[CH:32]=3)[C:26]([OH:28])=[O:27])=[O:20])=[CH:17][N:18]=2)[CH2:8]1)[CH3:2]
Reactant: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)NCc3cc(OC)cc(C(=O)OC)c3)cn2)C1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)NCc3cc(OC)cc(C(=O)O)c3)cn2)C1
Reaction time: 18 h
Yield: 71.8 %

Procedure:
To a solution of methyl (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-5-methoxybenzoate (60 mg, 0.11 mmol) in THF:H2O (1:1, 5 mL) at 20-25° C. was added LiOH.H2O (15 mg, 0.34 mmol). The mixture was stirred for 18 hours, and then was concentrated under reduced pressure. The resulting residue was diluted with water (5 mL) and washed with ethyl acetate (3 times with 5 mL). The aqueous layer was acidified to pH 2 with 1N HCl (5 mL), and then was extracted with ethyl acetate (3 times with 5 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to afford (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-5-methoxybenzoic acid (40 mg, 72%). 1H NMR (300 MHz, DMSO-d6) δ 8.91 (m, 1H), 8.78 (s, 2H), 7.49 (s, 1H), 7.34 (s, 1H), 7.02 (m, 2H), 6.89 (m, 3H), 4.45 (d, 2H), 4.32 (m, 1H), 4.20 (d, 1H), 3.91 (m, 5H), 3.78 (s, 3H), 2.05 (m, 1H), 1.85 (m, 2H), 1.52 (m, 1H), 1.21 (t, 3H). MS (ES+) 507.1 (M+H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([CH3:12])[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1.Br[C:14]([CH3:19])([CH3:18])[C:15](Br)=[O:16].Cl>C(Cl)Cl>[CH3:18][CH:14]1[CH2:19][C:9]2[C:10](=[C:5]([CH3:12])[CH:6]=[C:7]([CH3:11])[CH:8]=2)[C:15]1=[O:16]
Reactant: Cc1cccc(C)c1
Reactant: CC(C)(Br)C(=O)Br
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(C)c2c(c1)CC(C)C2=O
Yield: 93 %

Procedure:
107 g (810 mmol) of AlCl3 are slowly added to a solution of 34.4 g (324 mmol) of m-xylene (99% pure) and 74 g (324 mmol) of 2-bromoisobutyryl bromide (98% pure) in 600 ml of analytical grade methylene chloride via a solids metering funnel at room temperature, while stirring vigorously, whereupon vigorous evolution of gas started. The mixture was stirred at room temperature for 15 hours, poured onto ice-water, which was acidified with 25 ml of concentrated HCl, and extracted several times with ether. The combined organic phases were washed first with a saturated NaHCO3 solution and then with a saturated NaCl solution and dried with magnesium sulfate. The oil which remained after the solvent had been stripped off under reduced pressure was distilled over a short distillation bridge. 52.4 g of the indanone 1 passed over at 81°-90° C./0.1-0.2 mbar in the form of a colorless oil which crystallized at room temperature. The yield was 93%.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH:8]2[CH2:14][NH:13][CH:12]([CH3:15])[CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[CH3:18].[I:19][C:20]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:21]=1[C:22](O)=[O:23].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH:8]2[CH2:14][N:13]([C:22](=[O:23])[C:21]3[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:20]=3[I:19])[CH:12]([CH3:15])[CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[CH3:18]
Reactant: Cc1cc(OCC2CCCC(C)NC2)ccc1F
Reactant: Cc1ccc(I)c(C(=O)O)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(I)c(C(=O)N2CC(COc3ccc(F)c(C)c3)CCCC2C)c1
Temperature: 23 °C
Reaction time: 16 h

Procedure:
A solution of 6-[(4-fluoro-3-methylphenoxy)methyl]-2-methylazepane (2-7, 120 mg, 0.48 mmol, 1.0 equiv) in DMF (5 mL) was treated with 2-iodo-5-methylbenzoic acid (140 mg, 0.52 mmol, 1.1 equiv), EDC (110 mg, 0.57 mmol, 1.2 equiv), HOBT (88 mg, 0.57 mmol, 1.2 equiv) and triethylamine (0.20 mL, 140 mg, 1.4 mmol, 3.0 equiv) and the resulting mixture was stirred at 23° C. for 16 hours. The mixture was filtered and purified by reverse phase liquid chromatography (Sunfire C18 OBD 5 um, 20×150 mm column; 0-100% CH3CN/H2O gradient w/0.10% TFA present) to yield 6-[(4-fluoro-3-methylphenoxy)methyl]-1-(2-iodo-5-methylbenzoyl)-2-methylazepane (3-1). δ 7.87 (m, 1H), 7.10 (m, 6H), 6.43 (m, 1H), 4.79-1.04 (m, 19H). LRMS m/z (M+H) 496.2 found, 496.1 required.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[O:11]=[S:12]1(=[O:29])[CH2:17][CH2:16][N:15]2[CH2:18][CH2:19][CH2:20][C@@H:21]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[C:14]2=[N:13]1.C(N(CC)CC)C>CN(C=O)C.C(O[Cu]OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:28][C:25]1[CH:24]=[CH:23][C:22]([C@H:21]2[C:14]3=[N:13][S:12](=[O:29])(=[O:11])[CH2:17][CH2:16][N:15]3[CH2:18][CH2:19][CH2:20]2)=[CH:27][CH:26]=1
Reactant: O=S1(=O)CCN2CCC[C@@H](c3ccc(O)cc3)C2=N1
Reactant: OB(O)c1cccc(Cl)c1
Agent: CC(=O)O[Cu]OC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S1(=O)CCN2CCC[C@@H](c3ccc(Oc4cccc(Cl)c4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.4 %

Procedure:
A mixture of (3-chlorophenyl)boronic acid (167 mg), 4-[(9S)-2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl]phenol (100 mg), diacetoxycopper (130 mg), triethylamine (0.248 ml), and powdered 4A MS (1.50 g) in DMF (10 mL) was stirred at room temperature overnight. The mixture was added with NH silica gel, concentrated in vacuo, and purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (34.0 mg) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:47])[CH2:25][C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[C:37]([CH2:38][O:39]C3CCCCO3)=[CH:36][N:35]=[N:34]2)[CH:28]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:39][CH2:38][C:37]1[N:33]([C:29]2[CH:28]=[C:27]([C:26]3[CH2:25][C:24](=[O:47])[NH:23][C:9]4[CH:10]=[C:11]([C:19]([F:22])([F:20])[F:21])[C:12]([N:14]5[CH2:18][CH2:17][CH2:16][CH2:15]5)=[CH:13][C:8]=4[N:7]=3)[CH:32]=[CH:31][CH:30]=2)[N:34]=[N:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-n3nncc3CO)c2)=Nc2cc(N3CCCC3)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from (RS)-[2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionylamino)-5-pyrrolidin-1-yl-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example M37) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (33 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[C:17]([C:19]2[CH:27]=[CH:26][C:25]([NH:28][C:29]([O:31][CH3:32])=[O:30])=[CH:24][C:20]=2[C:21]([OH:23])=O)[CH:16]=[CH:15][N:14]=1)[CH2:10][CH:11]=[CH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:33]([NH2:36])[CH:34]=[CH2:35].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[C:17]([C:19]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:30])[O:31][CH3:32])=[CH:24][C:20]=2[C:21](=[O:23])[NH:36][CH2:33][CH:34]=[CH2:35])[CH:16]=[CH:15][N:14]=1)[CH2:10][CH:11]=[CH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)c1cc(-c2ccc(NC(=O)OC)cc2C(=O)O)ccn1
Reactant: C=CCN
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCNC(=O)c1cc(NC(=O)OC)ccc1-c1ccnc([C@H](CC=C)NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.7 %

Procedure:
To a solution of 24D (0.06 g, 0.136 mmol), prop-2-en-1-amine (9.31 mg, 0.163 mmol), EDC (0.052 g, 0.272 mmol) and HOBT (0.042 g, 0.272 mmol) in DMF (1 mL) was added TEA (0.057 mL, 0.408 mmol). The reaction was stirred at rt for 18 h. The reaction was diluted with EtOAc, washed with water, brine, dried over Na2SO4, filtered, and concentrated. Purification by normal phase chromatography provided 24E (0.056 g, 86%) as a white solid. MS (ESI) m/z: 481.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1.[N+:17]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][N:24]=[CH:23]2)([O-:19])=[O:18]>>[Cl:9][C:10]1[CH:16]=[CH:15][C:13]([NH:14][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:24]3[CH:23]=[C:22]4[C:26]([CH:27]=[CH:28][C:20]([N+:17]([O-:19])=[O:18])=[CH:21]4)=[N:25]3)[N:7]=2)=[CH:12][CH:11]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: Nc1ccc(Cl)cc1
Product: O=[N+]([O-])c1ccc2nn(-c3nccc(Nc4ccc(Cl)cc4)n3)cc2c1

Procedure:
Was prepared according to Method A from 2,4-dichloropyrimidine, 4-chloroaniline and 5-nitroindazole. LC-ESI-HRMS of [M+H]+ shows 367.0692 Da. Calc. 367.071027 Da, dev. −5 ppm.