Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8](C(OC(C)(C)C)=O)[C:9](=[O:40])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([CH3:36])=[CH:34][C:33]([CH:37]3[CH2:39][CH2:38]3)=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])=O)(C)(C)C.O1CCCC1.CN>>[CH:37]1([C:33]2[CH:34]=[C:35]([CH3:36])[C:30]([N:27]3[CH2:28][CH2:29][N:24]([C:22]([C:11]4[CH:12]=[CH:13][C:14]([N:16]5[CH2:20][CH2:19][CH2:18][C:17]5=[O:21])=[CH:15][C:10]=4[C:9]([NH:8][CH3:6])=[O:40])=[O:23])[CH2:25][CH2:26]3)=[N:31][CH:32]=2)[CH2:39][CH2:38]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCC3=O)cc2C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC1
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)c1cc(N2CCCC2=O)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Yield: 36.1 %

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-oxopyrrolidin-1-yl)benzamide (70 mg) described in Example 814 and 2 mol/L methylamine tetrahydrofuran solution (216 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (18 mg) was obtained.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O.Cl.[NH2:21][CH:22]1[CH2:27][CH:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[CH2:25][N:24]([C:38]([N:40]2[CH2:49][CH2:48][C:43]3([O:47][CH2:46][CH2:45][O:44]3)[CH2:42][CH2:41]2)=[O:39])[CH2:23]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:10][C:11]1[CH:12]=[C:13]([C:14]([NH:21][CH:22]2[CH2:27][CH:26]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][CH:29]=3)[CH2:25][N:24]([C:38]([N:40]3[CH2:41][CH2:42][C:43]4([O:47][CH2:46][CH2:45][O:44]4)[CH2:48][CH2:49]3)=[O:39])[CH2:23]2)=[O:16])[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC3(CC2)OCCO3)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC3(CC2)OCCO3)C1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.59 ml (3.38 mmol) of N,N′-diisopropylethylamine and 248 mg (1.58 mmol) of 3-chlorobenzoic acid were added to a solution of the compound from Example 62A (500 mg, 1.06 mmol) in N,N′-dimethylformamide (18 ml). After addition of 522 mg (1.37 mmol) of HATU, the mixture was stirred at RT overnight. The reaction mixture was purified directly by preparative HPLC(RP18 column; acetonitrile/water gradient). Yield: 414 mg (67% of theory)
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Br:9][C:10]1[C:11]([CH3:17])=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13]>C(#N)C>[Br:9][C:10]1[C:11]([CH3:17])=[C:12]([C:14]([Cl:1])=[CH:15][CH:16]=1)[NH2:13]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1c(N)cccc1Br
Solvent: CC#N
Product: Cc1c(Br)ccc(Cl)c1N
Temperature: 60 °C
Reaction time: 7 h

Procedure:
At RT, 8.61 g (64.5 mmol) of N-chlorosuccinimide were added to a solution of 12.0 g (64.5 mmol) of 3-bromo-2-methylaniline in 150 ml of acetonitrile. The reaction mixture was stirred at 60° C. for 7 h and, after cooling, concentrated under reduced pressure. The residue was taken up in dichloromethane, and the mixture was washed successively with sat. sodium bicarbonate solution and sat. sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The crude product gave, after chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 40:1 to 20:1), 3.78 g of the target product (26.6% of theory).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[N:5][NH:6][C:7]=1[N:8]=[CH:9][N:10](C)C)#[N:2].Cl.[Cl:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)N>C(O)C>[Cl:24][C:25]1[CH:31]=[C:30]([NH:2][C:1]2[N:10]=[CH:9][N:8]=[C:7]3[NH:6][N:5]=[C:4]([NH:13][CH2:14][C:15]4[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[C:3]=23)[CH:29]=[CH:27][CH:26]=1
Reactant: COc1ccc(CNc2n[nH]c(N=CN(C)C)c2C#N)cc1
Reactant: Nc1cccc(Cl)c1
Agent: Cl
Solvent: CCO
Product: COc1ccc(CNc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Temperature: 5 °C

Procedure:
A mixture of 4.475 g (15 mmol) of 4-cyano-5-(dimethylamino-methyleneamino)-3-(4-methoxy-benzylamino)-pyrazole, 2.83 g (17.25 mmol) of 3-chloro-aniline hydrochloride and 80 ml of ethanol is heated under reflux for 16 hours. Cooling to approx. 5° C., filtering and washing the filter residue with diethyl ether yield the title compound; m.p. 222-223° C.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][N:20]([CH2:28][C:29]([F:32])([F:31])[F:30])[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][N:22]=1>>[CH3:19][N:20]([CH2:28][C:29]([F:32])([F:30])[F:31])[C:21]1[N:22]=[CH:23][C:24]([NH:27][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:25][CH:26]=1
Reactant: CN(CC(F)(F)F)c1ccc(N)cn1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: CN(CC(F)(F)F)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 16 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {6-[methyl-(2,2,2-trifluoro-ethyl)-amino]-pyridin-3-yl}-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N2-methyl-N2-(2,2,2-trifluoro-ethyl)-pyridine-2,5-diamine. LCMS calcd for C19H14F6N4O2 (m/e) 444, obsd 445 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][C:8]([N+:14]([O-])=O)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]([C:17](=[O:22])[CH2:18][N:19]([CH3:21])[CH3:20])[CH2:4][CH2:3]1.CO.[H][H]>C(OCC)(=O)C.O.[Pd]>[CH3:21][N:19]([CH2:18][C:17]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([O:12][CH3:13])=[C:8]([NH2:14])[CH:7]=2)[C:2]([CH3:23])([CH3:1])[CH2:3][CH2:4]1)=[O:22])[CH3:20]
Reactant: [H][H]
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CN(C)C)CCC2(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COc1cc2c(cc1N)N(C(=O)CN(C)C)CCC2(C)C
Yield: 88.9 %

Procedure:
{2-[4,4-dimethyl-6-(methyloxy)-7-nitro-3,4-dihydro-1(2H)-quinolinyl]-2-oxoethyl}dimethylamine (assumed 2.8 mmol) was dissolved in a mixture of ethyl acetate (50 mL) and water (5 mL) and transferred to a Fischer Porter apparatus. 10% Palladium on carbon (500 mg, Aldrich) was added followed by methanol (5 mL) and the mixture stirred under 60 psi hydrogen pressure for 2 h. The pressure was released, the reaction vessel evacuated, and back-filled with nitrogen twice. The mixture was filtered through celite and the filtrate was concentrated to provide 1-[(dimethylamino)acetyl]-4,4-dimethyl-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinamine (724 mg, 2.49 mmol, 89% over three steps). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (s, 6 H), 1.62-1.68 (m, 2 H), 2.20 (s, 6 H), 3.17 (s, 2 H), 3.62-3.69 (m, 2 H), 3.75 (s, 3 H), 4.58 (bs, 2 H), 6.56-6.94 (s at 6.71 on top of a very broad singlet caused by amide rotomers, 2 H); ESIMS (M+H)+=292.
Reaction SMILES: C(O[C:5](=O)[CH3:6])(=O)C.S(=O)(=O)(O)O.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1>>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([C:5]2([CH3:6])[CH2:18][CH2:19][CH2:14][CH2:15][CH2:16]2)[CH:15]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC1(c2cc(Br)ccc2O)CCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.6 %

Procedure:
There are then slowly added 10.8 ml (117 mmoles) of acetic anhydride and the reaction mixture is stirred at ambient temperature for 18 hours. 2.7 ml (50 mmoles) of concentrated sulfuric acid are then added and in small portions 17.3 g (100 mmoles) of 4-bromophenol. The reaction mixture is stirred at ambient temperature for 24 hours, evaporated to dryness and taken up in 200 ml of water. The pH is adjusted to 7 with sodium bicarbonate and extracted with ethylether. The organic phase is decanted, dried over magnesium sulfate and evaporated. The residue is purified by chromatography on a silica column by using as the eluant a 40/60 mixture of dichloromethane and hexane. The solvents are evaporated and 8.97 g (33% yield) of 4-bromo-2-(l-methylcyclohexyl) phenol in the form of a yellowish oil are obtained.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].Cl[C:7]1(Cl)[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8]1.C(OCC)(=O)C>C1C=CC=CC=1>[CH3:1][S:2]([N:5]=[C:7]1[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8]1)(=[O:4])=[O:3]
Reactant: ClC1(Cl)Oc2ccccc2O1
Reactant: CS(N)(=O)=O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CS(=O)(=O)N=c1oc2ccccc2o1
Temperature: 25 °C
Yield: 83.2 %

Procedure:
53.4 g of methanesulfonamide and 89.4 g of 2,2-dichloro-1,3-benzodioxole were heated under reflux with 400 ml of anhydrous ethyl acetate for 7 hours. After cooling, the solvent was removed by distillation under reduced pressure. To the residue thus obtained was added 200 ml of benzene, and the mixture was refluxed for 10 minutes and then cooled slowly to room temperature with stirring. The crystals deposited were collected by filtration and washed with benzene, water and 2-propanol in this order to obtain 83 g (yield: 83%) of 2-methanesulfonylimino-1,3-benzodioxole.
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=[CH:10][CH:11]=1)#[N:2]>CO.[Pd]>[NH2:2][CH2:1][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2C#N)c1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)Cc1cccc(Oc2ccccc2CN)c1

Procedure:
8 g of the ethyl 3-(2-cyanophenoxy)phenylacetate obtained are dissolved in 200 ml of methanol and hydrogenated in the presence of 3.5 g of a Pd-C 5% catalyst. After the reaction has ended, the catalyst is filtered off. After customary working up, ethyl 3-(2-aminomethylphenoxy)-phenylacetate is obtained as an oil.
Reaction SMILES: N1(S(C2C=CC([C:14]3[CH:15]=[C:16]4[N:22]=[C:21]([CH2:23][CH2:24][CH:25]5[NH:31][C:30](=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26]5)[NH:20][C:17]4=[N:18][CH:19]=3)=CC=2)(=O)=O)CCC1.Br[C:34]1[CH:39]=[CH:38][C:37]([S:40]([NH:43][C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][C:45]=2[F:51])(=[O:42])=[O:41])=[CH:36][CH:35]=1.BrC1C=C2N=C(CCC3NC(=O)CCCC3)NC2=NC=1>>[F:51][C:45]1[CH:46]=[C:47]([CH3:50])[CH:48]=[CH:49][C:44]=1[NH:43][S:40]([C:37]1[CH:38]=[CH:39][C:34]([C:14]2[CH:15]=[C:16]3[N:22]=[C:21]([CH2:23][CH2:24][CH:25]4[CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:32])[NH:31]4)[NH:20][C:17]3=[N:18][CH:19]=2)=[CH:35][CH:36]=1)(=[O:42])=[O:41]
Reactant: O=C1CCCCC(CCc2nc3cc(-c4ccc(S(=O)(=O)N5CCC5)cc4)cnc3[nH]2)N1
Reactant: Cc1ccc(NS(=O)(=O)c2ccc(Br)cc2)c(F)c1
Agent: O=C1CCCCC(CCc2nc3cc(Br)cnc3[nH]2)N1
Product: Cc1ccc(NS(=O)(=O)c2ccc(-c3cnc4[nH]c(CCC5CCCCC(=O)N5)nc4c3)cc2)c(F)c1

Procedure:
The title compound is synthesized as described for 7-(2-{6-[4-(azetidine-1-sulfonyl)-phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}-ethyl)-azepan-2-one (compound B6) from 472 mg of 4-bromo-N-(2-fluoro-4-methyl-phenyl)-benzenesulfonamide (compound C5) and 300 mg of 7-[2-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)-ethyl]-azepan-2-one (compound C1). Purification by chromatography on flash silica gel (eluent gradient: dichloromethane/5-20 vol. % ethanol) yields 185 mg of the title compound as a waxy solid. ESI-MS: 522.2 (MH+). TLC: Rf=0.26 (dichloromethane/ethanol 10:1 parts by volume).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]1.[H-].[Na+].[CH3:16]I.[Cl-].[NH4+]>CN(C=O)C>[CH3:16][N:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[C:4]2[C:9]([CH:8]=[CH:7][CH:6]=[CH:5]2)=[N:1]1
Reactant: CI
Reactant: COC(=O)c1n[nH]c2ccccc12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1c2ccccc2nn1C
Temperature: 0 °C
Yield: 40.4 %

Procedure:
Methyl indazole-3-carboxylate (3.71 g, 21.1 mmol) was dissolved in DMF (40 ml). To the resulting solution was added sodium hydride (60% in oil, 1.01 g, 25.3 mmol) in portions under stirring at 0° C. The reaction mixture was stirred at the same temperature for 30 minutes. Methyl iodide (1.57 ml, 25.3 mmol) was added to the mixture. The resulting mixture was stirred at the same temperature for 30 minutes. A saturated aqueous solution of ammonium chloride was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane-ethyl acetate (3:1, v/v) eluate fractions, methyl 2-methylindazole-3-carboxylate (1.62 g, 26%) was obtained as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[S:6]/[C:5](=[N:7]\C(=O)OC(C)(C)C)/[N:4]([CH3:15])[C:3]=1[CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23](=[O:40])[CH2:24][CH2:25][S:26]([C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([Cl:39])[CH:35]=3)[CH:30]=2)(=[O:28])=[O:27])[CH2:19][CH2:18]1>FC(F)(F)C(O)=O>[Br:1][C:2]1[S:6][C:5](=[NH:7])[N:4]([CH3:15])[C:3]=1[CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23](=[O:40])[CH2:24][CH2:25][S:26]([C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([Cl:39])[CH:35]=3)[CH:30]=2)(=[O:27])=[O:28])[CH2:19][CH2:18]1
Reactant: Cn1c(CN2CCN(C(=O)CCS(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)c(Br)s/c1=N\C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(CN2CCN(C(=O)CCS(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)c(Br)sc1=N
Yield: 6.9 %

Procedure:
tert-Butyl ((2Z)-5-bromo-4-((4-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)carbamate (1.2 g) obtained in Example 30c) was dissolved in trifluoroacetic acid (10 mL), and the mixture was mixed at room temperature for 1 hour. The solvent was distilled off, and the residue was poured into an aqueous potassium carbonate solution. The mixture was extracted with a mixed solution of chloroform-methanol, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified with a basic silica gel column to give the title compound (0.07 g) as a pale brown powder.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]([F:15])([F:14])[F:13])=[C:7]([CH:10]=1)[C:8]#[N:9].S(Cl)([Cl:18])=O.O>C1(C)C=CC=CC=1>[Cl:18][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]([F:15])([F:14])[F:13])=[C:7]([CH:10]=1)[C:8]#[N:9]
Reactant: N#Cc1cc(CO)ccc1OC(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1cc(CCl)ccc1OC(F)(F)F
Temperature: 75 °C
Yield: 73.7 %

Procedure:
5-(Hydroxymethyl)-2-(trifluoromethoxy)benzonitrile (0.150 g, 0.691 mmol) was taken up in toluene (2 mL) and thionyl chloride (0.303 mL, 4.14 mmol) was added. The mixture was heated at 75° C. for 15 min. Water was added and the mixture was extracted with hexanes (2×75 mL). The organics were treated with aqueous NaHCO3. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated to give the title compound as a colorless oil (120 mg). LCMS m/z=236.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ ppm 1.98 (s, 1H), 4.52 (s, 2H), 7.32-7.34 (m, 1H), 7.59-7.62 (m, 1H), 7.68 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:32])[CH:21]=3)[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)C.Cl.O1CCOCC1>[ClH:32].[ClH:32].[Cl:32][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([NH:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[N:24]=[C:23]2[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc(-c3ccccc3F)c3cc(Cl)ccc3n2)CC1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: Fc1ccccc1-c1nc(NC2CCNCC2)nc2ccc(Cl)cc12

Procedure:
A solution of 4-[6-chloro-4-(2-fluoro-phenyl)-quinazolin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (0.66 g, 1.44 mmol) in ethanol (5 mL) and 4 M HCl in dioxane (20 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 356.9 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([Li])CCC.[CH2:21]([O:28][C:29]([N:31]1[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>O1CCCC1.CCCCCC.C(OCC)(=O)C>[CH2:21]([O:28][C:29]([N:31]1[CH2:36][CH2:35][C:34]([OH:37])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:33][CH2:32]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Brc1ccccc1OCc1ccccc1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCC(O)(c2ccccc2OCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 51.5 %

Procedure:
A solution of benzyl 2-bromophenyl ether (3.5 g) in 50 mL of anhydrous tetrahydrofuran was cooled to -78° C. and treated with 5.3 mL of 2.5M n-butyl lithium solution in hexane followed by a solution of 1-benzyloxycarbonyl-4-oxopiperidine (3.1 g) in 3 mL of anhydrous tetrahydrofuran. After stirring at -78° C. for 1 hour the reaction mixture was warmed to 0° C., stirred for 2 hours and then allowed to warm to room temperature. Addition of water, extraction with ethyl acetate, drying the organic layer over magnesium sulfate and evaporation afforded the crude product. This material was purified by chromatography: elution with hexane:isopropanol (9:1) afforded the named compound (2.86 g) as a solid; MS: 418; NMR: 2.0 (br, 4), 3.3-3.4 (br, 2), 3.9-4.1 (s, 3), 5.1 (two s, 4), 6.9-7.0 (m, 2), 7.2-7.3 (m, 2), 7.3-7.4 (m, 10).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12])=[CH:5]2.[CH:19]12[CH2:24][CH:23]1[CH2:22][N:21]([CH2:25][CH2:26][CH2:27]O)[CH2:20]2>>[CH:19]12[CH2:24][CH:23]1[CH2:22][N:21]([CH2:25][CH2:26][CH2:27][O:1][C:2]1[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[O:12])=[CH:5]3)[CH2:20]2
Reactant: OCCCN1CC2CC2C1
Reactant: O=C(c1cc2cc(O)ccc2[nH]1)N1CCOCC1
Product: O=C(c1cc2cc(OCCCN3CC4CC4C3)ccc2[nH]1)N1CCOCC1

Procedure:
In analogy to the procedure described for the synthesis of example 1, step 1, the title compound was synthesized from (5-hydroxy-1H-indol-2-yl)-morpholin-4-yl-methanone (example 5, step 3) and 3-(3-aza-bicyclo[3.1.0]hex-3-yl)-propan-1-ol (example 5, step 2). The title product was obtained in 49% yield as white solid. MS (m/e): 370.5 (MH+, 100%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:16][C:17](=[O:19])[CH3:18])[CH:7]=[C:8]([S:10]([F:15])([F:14])([F:13])([F:12])[F:11])[CH:9]=1)(=[O:3])[CH3:2].[Br-:20].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.S(=O)(=O)(O)O>CO.C1COCC1>[Br:20][CH2:2][C:1]([C:4]1[CH:5]=[C:6]([NH:16][C:17](=[O:19])[CH3:18])[CH:7]=[C:8]([S:10]([F:11])([F:12])([F:13])([F:14])[F:15])[CH:9]=1)=[O:3]
Reactant: CC(=O)Nc1cc(C(C)=O)cc(S(F)(F)(F)(F)F)c1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)Nc1cc(C(=O)CBr)cc(S(F)(F)(F)(F)F)c1
Temperature: 40 °C
Yield: 76.5 %

Procedure:
N-[3-Acetyl-5-(pentafluorosulfanyl)phenyl]acetamide (859 mg) was dissolved in a mixture of methanol (10 ml) and THF (10 ml) and phenyltrimethylammonium tribromide (1.065 g) was added in portions while stirring. After stirring at RT for 2 h, the mixture was heated to 40° C. for a further 3 h. After cooling, the reaction mixture was added to 2 N sulfuric acid and the aqueous phase was extracted 3 times with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated. The crude product was purified using silica gel with ethyl acetate/heptane as the eluent. 480 mg of the desired compound were obtained.
Reaction SMILES: Br[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[O:5].[C:11]12[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=1[S:18][C:17]1[C:16](=[O:24])[NH:15][N:14]=[CH:13][C:12]2=1.C([O-])([O-])=O.[K+].[K+].COC1C2C(=C3C(=CC=2)C(OC)=CC=N3)N=CC=1>O1CCOCC1.[Cu]I>[Cl:10][C:6]1[CH:7]=[CH:8][N:9]=[C:2]([N:15]2[C:16](=[O:24])[C:17]3[S:18][C:19]4[CH2:20][CH2:21][CH2:22][CH2:23][C:11]=4[C:12]=3[CH:13]=[N:14]2)[C:3]=1[CH:4]=[O:5]
Reactant: O=c1[nH]ncc2c3c(sc12)CCCC3
Reactant: O=Cc1c(Cl)ccnc1Br
Agent: [Cu]I
Agent: COc1ccnc2c1ccc1c(OC)ccnc12
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=Cc1c(Cl)ccnc1-n1ncc2c3c(sc2c1=O)CCCC3
Temperature: 80 °C
Reaction time: 16 h
Yield: 34.3 %

Procedure:
To a suspension of 2-bromo-4-chloronicotinaldehyde 103a (641 mg, 2.9 mmol) and 8-thia-4,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3-trien-6-one 191d (400 mg, 1.94 mmol) in dioxane (20 mL) was added K2CO3 (536 mg, 3.88 mmol), CuI (369 mg, 1.94 mmol), and 4,7-dimethoxy-1,10-phenanthroline (471 mg, 1.96 mmol). After bubbling nitrogen through the resulting solution for 30 min, the mixture was stirred at 80° C. for 16 h. It was allowed to cool to room temperature and added into H2O (100 mL). The aqueous layer was separated and extracted with ethyl acetate (2×200 mL). The combined organic layer was washed with brine (100 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified on flash column eluting with PE:EA (5:1) to afford 124a (230 mg, 34%). LCMS: [M+H]+ 346
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].ClCCl.[CH3:11][NH:12][CH2:13][C:14]([O:16][CH:17]1[CH2:23][CH2:22][CH2:21][N:20]([C:24](=[O:42])[C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:40])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH3:39])=[CH:27][C:26]=2[CH3:41])[C:19]2[CH:43]=[CH:44][C:45]([Cl:47])=[CH:46][C:18]1=2)=[O:15].CN1CCOCC1>C(OCC)(=O)C>[Cl:7][CH:5]([O:4][C:2]([CH2:11][NH:12][CH2:13][C:14]([O:16][CH:17]1[CH2:23][CH2:22][CH2:21][N:20]([C:24](=[O:42])[C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:40])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH3:39])=[CH:27][C:26]=2[CH3:41])[C:19]2[CH:43]=[CH:44][C:45]([Cl:47])=[CH:46][C:18]1=2)=[O:15])=[O:3])[CH3:6]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CNCC(=O)OC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2C)c2ccc(Cl)cc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OC(=O)CNCC(=O)OC(C)Cl)c3cc(Cl)ccc32)c(C)c1
Yield: 89.1 %

Procedure:
1-Chloroethyl chloroformate (0.12 ml, 1.2 mmol) was added dropwise to a dichloromethane (10 ml) solution of 7-chloro-1-[2-methyl-4-(2-methylbenzamido)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl methylaminoacetate (0.60 g, 1.2 mmol), and the mixture was cooled with ice. Then N-methylmorpholine (0.15 ml, 1.4 mmol) was gradually added dropwise thereto. After the resultant mixture was stirred at room temperature for 1 hour, the reaction mixture was diluted with ethyl acetate, washed with water and an aqueous saturated sodium chloride solution, dried over sodium sulfate. After filtration and concentration, the residue was purified by silica gel chromatography (n-hexane:ethyl acetate) to obtain 0.67 g (93%) of 7-chloro-1-[2-methyl-4-(2-methylbenzamido)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl [(1-chloroethoxycarbonyl)methylamino]acetate as amorphous.