Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[C:10]([C:28]2[O:32][C:31]([C:33]3[CH:38]=[CH:37][C:36]([CH2:39][N:40](C)[C:41](=O)OC(C)(C)C)=[CH:35][CH:34]=3)=[N:30][N:29]=2)=[N:11][C:12]([N:15]2[CH2:27][CH2:26][C:17]3([CH2:21][CH2:20][N:19]([C:22](=[O:25])[CH2:23][CH3:24])[CH2:18]3)[CH2:16]2)=[CH:13][N:14]=1)=O)(C)(C)C.Cl>O1CCOCC1>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([N:15]2[CH2:27][CH2:26][C:17]3([CH2:18][N:19]([C:22](=[O:25])[CH2:23][CH3:24])[CH2:20][CH2:21]3)[CH2:16]2)=[N:11][C:10]=1[C:28]1[O:32][C:31]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][NH:40][CH3:41])=[CH:35][CH:34]=2)=[N:30][N:29]=1
Reactant: CCC(=O)N1CCC2(CCN(c3cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c4nnc(-c5ccc(CN(C)C(=O)OC(C)(C)C)cc5)o4)n3)C2)C1
Agent: Cl
Solvent: C1COCCO1
Product: CCC(=O)N1CCC2(CCN(c3cnc(N)c(-c4nnc(-c5ccc(CNC)cc5)o4)n3)C2)C1
Reaction time: 0.67 h

Procedure:
A solution of tert-butyl N-[[4-[5-[3-[bis(tert-butoxycarbonyl)amino]-6-(3-propanoyl-3,7-diazaspiro[4.4]nonan-7-yl)pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (129 mg, 0.17 mmol) in dioxane (0.3 mL) was treated with a solution of hydrogen chloride (423 μL of 4 M, 1.7 mmol) in dioxane and the reaction mixture was allowed to stir for 40 minutes. The solvents were removed under reduced pressure and the residue was dissolved in DMF (1 mL) and purified by reverse phase HPLC using (10-99% ACN/H2O (5 mM HCl modifier)) to yield 1-(7-(5-amino-6-(5-(4-((methylamino)methyl)phenyl)-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-2,7-diazaspiro[4.4]nonan-2-yl)propan-1-one. 1H NMR (400 MHz, DMSO-d6) d 9.44 (s, 2H), 8.13 (dd, J=8.3, 2.4 Hz, 2H), 7.91 (t, J=4.5 Hz, 1H), 7.81 (d, J=7.5 Hz, 2H), 4.26-4.20 (m, 2H), 3.58 (dt, J=13.6, 6.8 Hz, 3H), 3.51-3.29 (m, 5H), 2.57 (t, J=5.3 Hz, 3H), 2.24 (dt, J=15.1, 7.5 Hz, 2H), 1.94 (ddt, J=32.7, 13.2, 6.6 Hz, 4H), 0.99 (dd, J=16.5, 7.5 Hz, 3H). LC/MS m/z 463.5 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][NH:8][C:9]2[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=2)[C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][C:19](=[O:23])[NH:20]3)=[CH:16][CH:15]=2)=[O:13])=[CH:5][C:4]([CH3:27])=[N:3]1.[CH:28](OCC)=[O:29].[O-]CC.[Na+].Cl>C(O)C>[CH3:1][N:2]1[C:6]([CH2:7][NH:8][C:9]2[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=2)[C:12]([C:14]2[CH:22]=[C:21]3[C:17]([C:18](=[CH:28][OH:29])[C:19](=[O:23])[NH:20]3)=[CH:16][CH:15]=2)=[O:13])=[CH:5][C:4]([CH3:27])=[N:3]1
Reactant: CCOC=O
Reactant: Cc1cc(CNc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)n(C)n1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(CNc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Temperature: 78 °C
Yield: 42 %

Procedure:
6-{3-[(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-amino]-benzoyl}-1,3-dihydro-indol-2-one (0.100 g, 0.278 mmol) and ethyl formate (0.066 mL, 0.834 mmol) were dissolved in anhydrous ethanol (0.600 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (0.519 mL, 1.39 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. The reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a tan precipitate. The suspension was filtered yielding 6-{3-[(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-amino]-benzoyl}-3-hydroxymethylene-1,3-dihydro-indol-2-one as an orange solid in 42% yield (0.045 g, 0.117 mmol). (prepared below, 0.021 g, 0.056 mmol)
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([OH:12])=O)[CH2:3]2.S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[ClH:15].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([Cl:1])=[O:12])[CH2:3]2
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1CN2CCC1CC2
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)C1CN2CCC1CC2

Procedure:
500 mg (2.61 mmol) of 3-quinuclidinecarboxylic acid hydrochloride (Orlek et al., J. Med. Chem. 1991, 34, 2726) are boiled together with 1.9 ml (26.09 mmol) of thionyl choride under reflux for 2 h. The reaction mixture is freed of thionyl chloride under reduced pressure. 20 ml portions of toluene are twice added and evaporated to dryness. The product obtained in this way is reacted further without further purification.
Reaction SMILES: [O:1]([CH2:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:23]=[N:24][CH:25]=[C:26]([CH:30]=2)[C:27]([NH2:29])=O)[N:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[O:1]([CH2:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:23]=[N:24][CH:25]=[C:26]([CH:30]=2)[C:27]#[N:29])[N:18]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1cncc(-c2noc(C3CCCCN3C(=O)COc3ccccc3)n2)c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1cncc(-c2noc([C@H]3CCCCN3C(=O)COc3ccccc3)n2)c1

Procedure:
0.15 mmol of 5-{5-[1-(2-Phenoxy-acetyl)-piperidin-2-yl]-[1,2,4]oxadiazol-3-yl}-nicotinamide are treated with trifluoracetic anhydride at room temperature over night. The reaction was quenched with aqueous NaHCO3 and product extracted with ethylacetate twice. The organic layers were washed with water/NaCl, combined, dried over Na2SO4 and the solvent evaporated. The product was purified via preparative HPLC.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:18]1[N:23]=[CH:22][C:21]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=3[CH3:39])[CH2:28][CH2:27]2)=[O:25])=[CH:20][CH:19]=1>>[CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[N:11]1[C:18]1[N:23]=[CH:22][C:21]([C:24]([N:26]2[CH2:27][CH2:28][N:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=3[CH3:39])[CH2:30][CH2:31]2)=[O:25])=[CH:20][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Reactant: O=S1(=O)CC[C@@H](COCc2ccccc2)N1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4[C@H](COCc5ccccc5)CCS4(=O)=O)nc3)CC2)c(C)c1
Yield: 61.4 %

Procedure:
Using (S)-3-benzyloxymethylisothiazolidine 1,1-dioxide (536 mg) described in Preparation Example 1 and (6-bromopyridin-3-yl) [4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (831 mg) described in Preparation Example 115 and by the reaction and treatment in the same manner as in Example 4, the title compound (729 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([CH3:10])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.Br[CH2:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]#[N:21])=[O:14]>>[CH3:10][C:5]12[CH2:8][CH2:9][C:2]([NH:1][CH2:12][C:13]([N:15]3[CH2:19][CH2:18][CH2:17][C@H:16]3[C:20]#[N:21])=[O:14])([CH2:7][CH2:6]1)[CH2:3][CH2:4]2
Reactant: CC12CCC(N)(CC1)CC2
Reactant: N#C[C@@H]1CCCN1C(=O)CBr
Product: CC12CCC(NCC(=O)N3CCC[C@H]3C#N)(CC1)CC2
Yield: 60.2 %

Procedure:
Using 4-amino-1-methylbicyclo[2,2,2]octane (75.0 mg) and (2S)-1-(2-bromoacetyl)pyrrolidine-2-carbonitrile (110 mg), the same procedure was followed as in Example 1 to obtain (2S)-1-[[N-(4-methylbicyclo[2,2,2]oct-1-yl)amino]acetyl]pyrrolidine-2-carbonitrile (84.0 mg).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=O.Cl.[C:12]([O:16][NH2:17])([CH3:15])([CH3:14])[CH3:13]>CO.C(OCC)(=O)C>[C:12]([O:16][N:17]=[CH:4][C:3]1[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:2]=1[Br:1])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)ON
Reactant: O=Cc1cc(O)ccc1Br
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)ON=Cc1cc(O)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
To the solution of 2-bromo-5-hydroxy-benzaldehyde (402 mg, 2 mmol) in methanol (10 ml) is added O-tert-butyl-hydroxylamine hydrochloride (125 mg, 10 mmol). The mixture is stirred at room temperature overnight. The resulting mixture is diluted with ethyl acetate, washed with brine, dried over MgSO4, and evaporated to afford the titled compound (360 mg) as colorless oil.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:9]([NH:14][C:15](=[O:40])[C:16]2[CH:21]=[C:20]([CH2:22][C:23]3[C:24](=[O:35])[C:25]([O:33][CH3:34])=[C:26]([O:31][CH3:32])[C:27](=[O:30])[C:28]=3[CH3:29])[CH:19]=[CH:18][C:17]=2[O:36][C:37](=[O:39])[CH3:38])=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:7])(C)(C)C>C(O)=O>[OH:7][C:6]([C:8]1[C:9]([NH:14][C:15](=[O:40])[C:16]2[CH:21]=[C:20]([CH2:22][C:23]3[C:24](=[O:35])[C:25]([O:33][CH3:34])=[C:26]([O:31][CH3:32])[C:27](=[O:30])[C:28]=3[CH3:29])[CH:19]=[CH:18][C:17]=2[O:36][C:37](=[O:39])[CH3:38])=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:5]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ncccc3C(=O)OC(C)(C)C)c2)=C(C)C1=O
Solvent: O=CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ncccc3C(=O)O)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.4 %

Procedure:
N-(3-tert-Butoxycarbonylpyridin-2-yl)-5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide (0.140 g, 0.254 mmol) was dissolved in formic acid (2.0 ml) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was concentrated and the obtained residue was purified by silica gel chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.110 g, 0.222 mmol, 87%).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].C(N(CC)CC)C.[C:20](Cl)([Cl:22])=[O:21]>C1COCC1.C1(C)C=CC=CC=1>[Cl:22][C:20]([O:8][C:7]1[C:2]([F:1])=[C:3]([F:12])[C:4]([F:11])=[C:5]([F:10])[C:6]=1[F:9])=[O:21]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(Cl)Oc1c(F)c(F)c(F)c(F)c1F
Reaction time: 2 h
Yield: 74.7 %

Procedure:
Pentafluorophenol (30 g; 163 mmol) and triethylamine (20 g, 200 mmol) were combined in 200 ml dry THF, and then added dropwise to a stirring solution of phosgene (20 g; 200 mmol) in 100 ml of toluene at 0° C. After 2 hours, the solution was filtered and evaporated to give the crude product as an oil, which was recrystallized from hexane to obtain 30 g (75%) pure pentafluorophenyl chloroformate.
Reaction SMILES: [SH:1][C:2]1[N:7]=[N:6][C:5]([C:8](=[S:10])[NH2:9])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1>CN(C=O)C>[F:26][C:25]([F:27])([F:28])[C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[O:18][CH2:17][CH2:16][CH2:15][CH2:14][S:1][C:2]1[N:7]=[N:6][C:5]([C:8](=[S:10])[NH2:9])=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cccc(OCCCCCl)c1
Reactant: NC(=S)c1ccc(S)nn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=S)c1ccc(SCCCCOc2cccc(C(F)(F)F)c2)nn1
Temperature: 25 °C
Yield: 47.1 %

Procedure:
A mixture of intermediate 11 (0.017 mol) in DMF (80 ml) was stirred at room temperature. Sodium hydride (50%, 0.02 mol) was added portionwise. The mixture was stirred for 30 minutes. A mixture of 1-(4-chlorobutoxy)-3-(trifluoromethyl)-benzene (0.02 mol) in DMF (20 ml) was added dropwise. The mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was stirred in DIPE (100 ml), filtered off and dried, yielding 3.1 g (47%) of 6-[[4-[3-(trifluoromethyl)-phenoxy]butyl]thio]-3-pyridazinecarbothioamide (intermediate 12).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[Cl-:8].[K+].[Pt+2:10].[Cl-:11].[Cl-]>O>[Pt+2:10].[Cl:8][C@H:3]1[C@@H:2]([NH2:1])[CH2:7][CH2:6][CH2:5][N:4]1[Cl:11]
Reactant: NC1CCCNC1
Reactant: [Cl-]
Agent: [Pt+2]
Agent: [K+]
Solvent: O
Product: N[C@H]1CCCN(Cl)[C@H]1Cl
Temperature: 25 °C
Reaction time: 40 h
Yield: 69.6 %

Procedure:
To a solution of (3RS)-3-aminopiperidine (1.7 g) in water (1000 ml) is added platinum (II) potassium chloride (7.2 g) and the mixture is stirred at room temperature for 40 hours. The precipitated solid is removed by filtration, and the filtrate is concentrated under reduced pressure. To the residue is added a small amount of water, and the resulting crystals are separated by filtration and washed with water and acetone to give cis-dichloro-(3RS)-3-aminopiperidine platinum (II) (4.3 g) as pale yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:31]#[N:32])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH:25]([O:28][CH3:29])[CH2:26][CH3:27])[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:30])[CH:9]=2)[CH:7]=1.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:31]#[N:32])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH:25]([O:28][CH3:29])[CH2:26][CH3:27])[C:17]([OH:19])=[O:18])[C:10](=[O:30])[CH:9]=2)[CH:7]=1
Reactant: CCC(CC(C(=O)OC(C)(C)C)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O)OC
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O)OC

Procedure:
668 mg (1.45 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-methoxyhexanoate (mixture of racemic diastereomers) were hydrolysed with trifluoroacetic acid according to General Method 6A. Yield: 623 mg (purity 94%, quant.)
Reaction SMILES: [CH2:1]([C:3]1([CH2:16][C:17]([OH:19])=O)[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([C:3]1([CH2:16][CH2:17][OH:19])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][C:13]([CH:1]([CH3:3])[CH3:2])=[CH:12][C:11]=3[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:2]
Reactant: CCC1(CC(=O)O)OCCc2c1[nH]c1ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1(CCO)OCCc2c1[nH]c1c(-c3ccccc3)cc(C(C)C)cc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 107 %

Procedure:
To solution of (1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid (0.52 g, 2.0 mmol) in tetrahydrofuran (10 mL) was added lithium aluminum hydride (0.114 g, 3.0 mmol) in several small portions. The mixture was stirred at room temperature for 6 hours. It was quenched with ethyl acetate carefully and washed with water. The organic layer was dried over magnesium sulfate and evaporated to dryness. Flash chromatography on silica gel provided 0.389 g (79%) of the title compound as an oil. 1H NMR (500 MHz, CDCl3) δ 7.82 (br, 1H), 7.52 (d, 1H), 7.34 (d, 1H), 7.18 (td, 1H), 7.13 (td, 1H), 4.07 (m, 1H), 4.01 (m, 1H), 3.70 (m, 1H), 3.64 (m, 1H), 2.89 (m, 1H), 2.77 (dt, 1H), 2.71 (br, 1H), 2.20 (m, 1H), 2.05 (m, 1H), 2.00 (m, 1H), 1.90 (m, 1H), 0.94 (t, 3H); ESI (+) MS m/e=246 (MH+), ESI (−) MS m/e=244 (MH−).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C1(S([N:19]2[C:23]3=[N:24][CH:25]=[CH:26][CH:27]=[C:22]3[C:21]([C:28]3[CH:33]=[CH:32][N:31]=[C:30](Cl)[N:29]=3)=[CH:20]2)(=O)=O)C=CC=CC=1>>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:30]1[N:29]=[C:28]([C:21]2[C:22]3[C:23](=[N:24][CH:25]=[CH:26][CH:27]=3)[NH:19][CH:20]=2)[CH:33]=[CH:32][N:31]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Reactant: Cc1cccc(C)c1N
Product: Cc1cccc(C)c1Nc1nccc(-c2c[nH]c3ncccc23)n1
Yield: 40 %

Procedure:
Using the procedure of example 1, 2,6-dimethylaniline (98 mg) was reacted with compound 1f (100 mg) to provide compound 35 (34 mg, 40%). 1H NMR (400 MHz, CD3OD) δ 8.40 (d, J=8.0 Hz, 1H), 8.21 (d, J=4.8 Hz, 1H), 8.19 (s, 1H), 8.17 (d, J=5.2 Hz, 1H), 7.50 (d, J=7.2 Hz, 1H), 7.35 (d, J=7.2 Hz, 1H), 7.14 (d, J=5.2 Hz, 2H), 7.03 (t, J=5.2 Hz, 1H), 2.36 (s, 6H). MS (ESI) m/z: 316 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Al+3].[Cl-:10].[Cl-].[Cl-].C1(SC2C=CC=CC=2)C=CC=CC=1.ClCl>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:10][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: [Cl-]
Agent: Cc1ccc(O)cc1
Agent: ClCl
Agent: [Al+3]
Product: Cc1ccc(O)c(Cl)c1
Yield: 93.2 %

Procedure:
100 parts by weight of 4-methylphenol were melted at ~35° C. and stirred. To this were added 1.5 parts by weight of AlCl3 and 0.95 part by weight of diphenyl sulphide. 74.6 parts by weight of gaseous chlorine were introduced uniformly in the course of 6 h, initially at 30°-31° C., later at 22°-25° C. After a short further stirring phase at approximately 25° C., 146.2 parts by weight of crude product were obtained of the GC composition 0.03% of 4-methylphenol and 93.20% of 2-chloro-4-methylphenol. Work-up by distillation produced 127.8 parts by weight of pure distillate having a GC content of 0.03% of 4-methylphenol, 99.92% of 2-chloro-4-methylphenol and 0.05% of unknown.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[CH:21]([C:23]2[CH:28]=[CH:27][C:26]([S:29][CH3:30])=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:24]=2)[OH:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:21]([C:23]2[CH:28]=[CH:27][C:26]([S:29][CH3:30])=[C:25]([C:31]([F:32])([F:33])[F:34])[CH:24]=2)=[O:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cnc2c(c1)cc(C(O)c1ccc(SC)c(C(F)(F)F)c1)n2S(=O)(=O)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1cnc2c(c1)cc(C(=O)c1ccc(SC)c(C(F)(F)F)c1)n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
To a 250 mL round bottomed flask charged with ((1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-methanol (5.08 g, 10 mmol) and dichloromethane (50 mL) was added Dess-Martin periodinane (10.65 g, 25 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 2 h before quenching with saturated aqueous sodium bicarbonate solution (100 mL). The mixture was extracted with ethyl acetate (250 mL), washed with saturated aqueous sodium bicarbonate solution (3×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to give (1-benzenesulfonyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-methanone as a light yellow solid (4.3 g, 85%) which was used for the next step without further purification: LC/MS m/e calcd for C23H18F3N2O4S2 [M+H]+ 507.06, observed 507.0.
Reaction SMILES: [CH:1](C1C=C(C=CC=1O)N)([CH3:3])[CH3:2].[OH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[CH:22]([CH3:24])[CH3:23])[NH:18][C:17](=[O:25])[C:16]2=[O:26].[CH:27]1[C:32]([NH:33][NH2:34])=[CH:31][CH:30]=[C:29]([S:35]([NH2:38])(=[O:37])=[O:36])[CH:28]=1.Cl>>[OH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[CH:22]([CH3:24])[CH3:23])[NH:18][C:17](=[O:25])[C:16]2=[O:26].[OH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH:1]([CH3:3])[CH3:2])[C:17](=[O:25])[C:16]2=[N:34][NH:33][C:32]1[CH:27]=[CH:28][C:29]([S:35]([NH2:38])(=[O:36])=[O:37])=[CH:30][CH:31]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: CC(C)c1cc(N)ccc1O
Agent: CC(C)c1cc2c(cc1O)C(=O)C(=O)N2
Agent: Cl
Product: CC(C)N1C(=O)C(=NNc2ccc(S(N)(=O)=O)cc2)c2cc(O)ccc21

Procedure:
5-Hydroxy-6-isopropyl-1H-indole-2,3-dione was prepared from 3-isopropyl-4-hydroxyaniline according to Procedure A: 1H NMR (DMSO-d6): δ 1.12 (d, J=6.8 Hz, 6H), 3.21 (septet, J=6.9 Hz, 1H), 6.62 (s, 1H), 6.82 (s, 1H), 9.51 (s, 1H), 10.61 (s, 1H); ESI−MS m/z 204 (M−H)−. The title compound was prepared from 5-hydroxy-6-isopropyl-1H-indole-2,3-dione and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G: mp>250° C.; 1H NMR (DMSO-d6): δ 1.12 (d, J=7.0 Hz, 6H), 3.21 (septet, J=6.8 Hz, 1H), 6.62 (s, 1H), 6.97 (s, 1H), 7.21 (s, 2H), 7.45 (d, J=8.9 Hz, 2H), 7.75 (d, J=8.7 Hz, 2H), 9.11 (s, 1H), 10.70 (s, 1H), 12.74 (s, 1H); ESI−MS m/z 373 (M−H)−. Anal. Calcd for C17H18N4O4S: C, 54.53; H, 4.85; N, 14.96; S, 8.56. Found: C, 54.37; H, 4.95; N, 14.84; S, 8.48.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[N:18][O:19][CH3:20])[C:15]([NH2:17])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1.Cl>[O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[N:18][O:19][CH3:20])[C:15]#[N:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON=C(C(N)=O)c1ccccc1Oc1ccccc1
Agent: Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: CON=C(C#N)c1ccccc1Oc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
2-(2-Phenoxyphenyl)-2-methoxyiminoacetamide (3.77 g) was dissolved in pyridine (5.53 g). The solution was cooled to 0° C. Trifluoroacetic anhydride (4.40 g) was added dropwise. The mixture was stirred for 2 hours at 0° C., and then diluted with dil. hydrochloric acid and extracted with ethyl acetate. The extract was dried and concentrated to leave a residue, which was purified by column chromatography on silica gel to obtain 2-(2-phenoxyphenyl)-2-methoxyiminoacetonitrile (3.41 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:26])[C:11]2[C:16]([CH3:17])=[CH:15][C:14]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][C:12]=2[O:24]C)=[CH:4][CH:3]=1.B(Br)(Br)Br.O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:26])[C:11]2[C:16]([CH3:17])=[CH:15][C:14]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[CH:13][C:12]=2[OH:24])=[CH:4][CH:3]=1
Reactant: COc1cc(N2CCOCC2)cc(C)c1C(=O)NCc1ccc(Cl)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cc1cc(N2CCOCC2)cc(O)c1C(=O)NCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To a solution of N-[(4-chlorophenyl)-methyl]-2-methoxy-6-methyl-4-morpholin-4-yl-benzamide (synthesized according to the methods described in sections a) to f) of example 10) (0.25 g, 0.67 mmol) in dichloromethane (10 ml) is added neat boron tribromide (0.095 ml, 1.0 mmol) at −78° C. The temperature is slowly raised to RT over a period of 30 min and stirred for 1 h at RT. The reaction mixture is poured onto cold water and extracted with dichloromethane (3×30 ml). The combined organic layers are washed with brine (30 ml), dried over sodium sulfate and evaporated to dryness. The crude material is purified by column chromatography (silica gel, 40% ethyl acetate/hexane) affording N-[(4-chlorophenyl)-methyl]-2-hydroxy-6-methyl-4-morpholin-4-yl-benzamide (0.11 g, 0.30 mmol, 45%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: CC(C)(C)N
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Solvent: C1CCOC1
Product: CC(C)(C)Nc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 109.8 %

Procedure:
To a solution of 4-bromo-1-fluoro-2-nitrobenzen (25 g, 0.1 mol) in THF (100 mL) is added t-butylamine (18 mL, 0.17 mol). The solution is heated at 60° C. for 16 hours. The solvent is removed in vacuum. The residue is suspended in methanol (20 mL). The precipitate is collected by filtration and washed with methanol to give (4-bromo-2-nitro-phenyl)-tert-butyl-amine as an orange solid (30 g, 97%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C@H:18]4[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[C@H:26]([OH:30])[CH:27]([CH3:29])[CH3:28])[CH2:20][CH2:19]4)[CH2:12][CH2:11]3)[C:4]=2[O:3][CH2:2]1.[CH3:32]I>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C@H:18]4[CH2:19][CH2:20][C@H:21]([NH:24][C:25](=[O:31])[C@H:26]([O:30][CH3:32])[CH:27]([CH3:29])[CH3:28])[CH2:22][CH2:23]4)[CH2:12][CH2:11]3)[C:4]=2[O:3][CH2:2]1
Reactant: CI
Reactant: CC(C)[C@@H](O)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Product: CO[C@@H](C(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1)C(C)C

Procedure:
The title compound, white solid (6 mg, 50.5%), MS (ISP) m/z=446.3 [(M+H)+], was prepared in accordance with the general method of example 62 from (R)-trans-N-{4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-2-hydroxy-3-methyl-butyramide (11.5 mg, 26.6 mmol) and methyl iodide.