Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[C:6](=[CH:10][CH:11]=1)[C:7](O)=[O:8].C(OC(=O)C)(=O)C>CC(O)=O>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]2[C:6](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:13][C:12]2=[O:14]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C(=O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2cc(C(F)(F)F)ccc21

Procedure:
25.0 g of 4-trifluoromethyl-phthalic acid were dissolved in 50 ml of HOAc and 15.1 ml of acetic anhydride added. The mixture was refluxed for 6 h. The solvent was then removed in vacuo. The residue was treated three times with 50 ml of toluene each followed by the removal of the solvent in vacuo. Yield 23.1 g of a colorless oil (Rf (CH2Cl2)=0.60).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[NH:8])=[CH:5][CH:4]=1.[CH3:12][CH:13]([CH3:22])[C:14](=O)[CH2:15][C:16](OCC)=[O:17].CC(C)([O-])C.[K+]>C(O)C>[Cl:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]2[N:9]=[C:16]([OH:17])[CH:15]=[C:14]([CH:13]([CH3:22])[CH3:12])[N:8]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: N=C(N)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CC(C)c1cc(O)nc(-c2ccc(Cl)cc2)n1
Temperature: 25 °C

Procedure:
A mixture of 19.1 g of 4-chlorobenzamidine hydrochloride, 15.8 g of ethyl 4-methyl-3-oxopentanoate, 11.2 g of potassium tert-butoxide and 200 ml of ethanol was heated under reflux for 2 hours. After cooling to room temperature, the solid was filtered off with suction, washed with water and with a little ethanol and dried at 40° C. in vacuo. Yield: 12.5 g. M.p.: 164° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]1([N:13]2[C:17]3[N:18]=[C:19]([NH2:22])[N:20]=[CH:21][C:16]=3[C:15]3[CH:23]=[CH:24][N:25]=[CH:26][C:14]2=3)[CH2:12][CH2:11][CH2:10][CH2:9]1.Cl[C:28]1[N:33]=[CH:32][C:31]([CH2:34][N:35]2[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH2:36]2)=[CH:30][CH:29]=1>>[CH:8]1([N:13]2[C:17]3[N:18]=[C:19]([NH:22][C:28]4[CH:29]=[CH:30][C:31]([CH2:34][N:35]5[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]5)=[CH:32][N:33]=4)[N:20]=[CH:21][C:16]=3[C:15]3[CH:23]=[CH:24][N:25]=[CH:26][C:14]2=3)[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Cl)nc2)CC1
Reactant: Nc1ncc2c3ccncc3n(C3CCCC3)c2n1
Solvent: O=C(O)C(F)(F)F
Product: c1cc2c3cnc(Nc4ccc(CN5CCNCC5)cn4)nc3n(C3CCCC3)c2cn1

Procedure:
Compound 338 was prepared as an off-white solid (TFA salt) from compound 4 and compound 339 using chemistry similar to that described in example 200. 1H NMR (500 MHz, CD3OD) δ ppm 9.68 (1 H, s), 9.35 (1 H, s), 8.68 (2 H, q, J=6.3 Hz), 8.43 (1 H, d, J=1.5 Hz), 8.26 (1 H, dd, J=8.9, 2.1 Hz), 7.88 (1 H, d, J=8.8 Hz), 5.48 (1 H, quin, J=8.7 Hz), 3.78 (2 H, s), 3.27-3.30 (4 H, m), 2.83 (4 H, br. s.), 2.48-2.59 (2 H, m), 2.15-2.31 (4 H, m), 1.83-1.97 (2 H, m). LCMS-ESI (POS), M/Z, M+1: Found 429.2.
Reaction SMILES: [CH3:1][N:2]([CH3:49])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:46][CH3:47])=[C:12]([NH:15][C:16]3[N:17]=[C:18]([NH:35][C:36]4[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:37]=4[C:38]([NH2:40])=[O:39])[C:19]4[CH:24]=[CH:23][N:22](S(C5C=CC(C)=CC=5)(=O)=O)[C:20]=4[N:21]=3)[CH:13]=2)[CH2:8][C@H:7]1[CH3:48])=[O:5].[OH-].[Na+].[Na+].[Cl-]>O1CCOCC1.CCOC(C)=O>[CH3:1][N:2]([CH3:49])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:46][CH3:47])=[C:12]([NH:15][C:16]3[NH:21][C:20]4=[N:22][CH:23]=[CH:24][C:19]4=[C:18]([NH:35][C:36]4[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:37]=4[C:38]([NH2:40])=[O:39])[N:17]=3)[CH:13]=2)[CH2:8][C@H:7]1[CH3:48])=[O:5]
Reactant: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n1)N(C(=O)CN(C)C)[C@H](C)C2
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccnc-3[nH]1)N(C(=O)CN(C)C)[C@H](C)C2
Temperature: 25 °C
Yield: 75 %

Procedure:
A solution of 2-({2-{[(2R)-1-(N,N-dimethylglycyl)-2-methyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide (246 mg, 0.358 mmol) in dioxane (10 mL) and a 2M aqueous NaOH solution (2 mL) was heated at 80° C. for 5 h. The resulting mixture was allowed to cool to rt, diluted with EtOAc (50 mL) and a saturated NaCl solution (10 mL). The organic layer was concentrated onto Celite and purified by silica gel chromatography using 1-10% MeOH (containing 0.2% NH3)/CH2Cl2 to afford 2-[(2-{[(2R)-1-(N,N-dimethylglycyl)-2-methyl-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluorobenzamide as a yellow solid (143 mg, 75%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26 (d, J=5.49 Hz, 3H), 2.27 (s, 6H), 2.60 (d, J=15.57 Hz, 1H), 3.08 (d, J=14.28 Hz, 1H), 3.26-3.48 (m, 2H), 3.80 (s, 3H), 4.71-4.86 (m, 1H), 6.24 (dd, J=3.11, 1.65 Hz, 1H), 6.89 (t, J=9.25 Hz, 1H), 6.98 (s, 2H), 7.23-7.43 (m, 1H), 7.56 (s, 1H), 8.03 (s, 1H), 8.11 (s, 1H), 8.49 (d, J=8.24 Hz, 1H), 8.63 (s, 1H), 10.53 (s, 1H), 11.33 (s, 1H); ESIMS (M+H)+=533.36; Optical rotation +14.4 (1 mg/mL MeOH, rt).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@H:5]1[O:10][C:9]2[CH:11]=[C:12]3[C:17](=[CH:18][C:8]=2[NH:7][C:6]1=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13]3.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl.C(N(CC)CC)C>[S:21]([O:1][CH2:2][CH2:3][CH2:4][C@@H:5]1[O:10][C:9]2[CH:11]=[C:12]3[C:17](=[CH:18][C:8]=2[NH:7][C:6]1=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13]3)([CH3:20])(=[O:23])=[O:22]
Reactant: O=C1Nc2cc3c(cc2O[C@H]1CCCO)CCCC3
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCC[C@@H]1Oc2cc3c(cc2NC1=O)CCCC3
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 79.7 %

Procedure:
To a stirred , ice-cooled suspension of (S)-6,7,8,9-tetrahydro-2-(3-hydroxypropyl)-2H-naphtho[2,3-b][1,4] oxazin-3(4H)-one (1.15 g) in a mixture of dichloromethane (40 ml) and triethylamine (0.45 g), was added dropwise methanesulfonyl chloride (1.01 g). The whole was stirred at 0° C. for 1.5 hour, washed with water and dried over magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography on silica gel (60 g) with ethyl acetate-hexane (3:2, v/v). The resulting crystals were recrystallized from methanol to yield (S)-6,7,8,9-tetrahydro-2-(3-mesyloxypropyl)-2H-naphto[2,3-b][1,4]oxazin-3(4H)-one as colorless needles (1.19 g, 79.7%), m.p. 153°-154° C. [α]D26 +4.8° (c=0.8, CHCl3).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:9](=[O:23])[N:10]([CH2:12][C:13]3[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=3)[N:11]=2)[CH:5]=[N:6][C:7]=1Cl.[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:7]2[N:6]=[CH:5][N:4]3[C:9](=[O:23])[N:10]([CH2:12][C:13]4[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=4)[N:11]=[C:3]3[C:2]=2[C:28]2[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=2)=[CH:27][CH:26]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2c(Br)c(Cl)ncn12
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: Cc1ccccc1
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)ncn12
Temperature: 100 °C
Yield: 9.8 %

Procedure:
To a solution of 8-bromo-7-chloro-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (81.3 mg, 0.20 mmol) in toluene (3 mL) at room temperature under argon was added 4-chlorophenylboronic acid (46.8 mg, 0.30 mmol), tetrakis(triphenylphosphine)palladium (46 mg, 0.040 mmol), and aqueous Na2CO3 solution (2.0 M, 0.20 mL, 0.40 mmol). The resulting suspension was stirred and heated at 100° C. under argon for 22 h. Analysis by HPLC/MS indicated that starting material had been consumed. After the reaction mixture was cooled to room temperature, water (10 mL) and EtOAc (15 mL) were added. The layers were separated. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluted with ethyl acetate-hexanes to obtain the title compound (7.6 mg) as an off-white solid. HPLC/MS: retention time=4.10 min, [M+H]30 =516.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](Cl)=[O:13])([O:7][CH3:8])=[O:6].[CH2:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH3:19]>ClCCl>[CH2:18]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[C:24]([CH:25]=1)[C:12]([C:11]1[CH:15]=[CH:16][CH:17]=[C:9]([C:5]([O:7][CH3:8])=[O:6])[CH:10]=1)=[O:13])[CH3:19]
Reactant: CCc1ccc(OC)cc1
Reactant: COC(=O)c1cccc(C(=O)Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCc1ccc(OC)c(C(=O)c2cccc(C(=O)OC)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Aluminium chloride (39.9 g, 0.3 mole) was stirred in dichloromethane (133 ml) and treated with 3-carbomethoxybenzoyl chloride (59.5 g, 0.3 mole) (ice-bath cooling), over 0.5 hours.4-Ethylanisole (40.8 g, 0.3 mole) in dichloromethane (70 ml) was added to the stirred, cooled mixture, which was then stirred at room temperature overnight. The reaction mixture was processed as in Example 15 to leave 5-ethyl-2-methoxy-3'-carbomethoxybenzophenone. The latter was heated in 55% aqueous hydrogen bromide (500 ml) at 110°-120° C. for 5 hours. The mixture was evaporated to dryness to leave 5-ethyl-2-hydroxy-3'-carboxybenzophenone, which was characterised by having the correct C, H and N microanalysis. The latter carboxylic acid was then refluxed overnight in methanol (500 ml) containing concentrated sulphuric acid (5 ml), poured into water (1 L) and extracted with ether. The combined ethereal extracts were washed with saturated NaHCO3 solution, dried (MgSO4), filtered and evaporated to leave the desired ester, which gave a satisfactory microanalysis.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:24][C:25]1[C:26]([CH3:31])=[N:27][CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:24][C:25]4[C:26]([CH3:31])=[N:27][CH:28]=[CH:29][CH:30]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: Cc1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ncccc1Oc1ncnc2c1cnn2C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Yield: 88.7 %

Procedure:
A mixture of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 3.00 g, 8.9 mmol), 3-hydroxy-2-methylpyridine (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 1.26 g, 12 mmol), and potassium carbonate (1.59 g, 11.5 mmol) in dimethylformamide (30 mL) was heated at 100° C. overnight. The solvent was evaporated under high vacuum. Water (50 mL) and dichloromethane (50 mL) were added. The layers were separated and the organic layer was washed twice with water and then evaporated to dryness to give 4-[4-(2-methyl-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (3.24 g, 89%). A sample of this material (500 mg) was purified by silica gel column chromatography, eluting with 0-75% ethyl acetate/hexanes, to give 4-[4-(2-methyl-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (381 mg, 10%) as a white powder. 1H NMR (300 MHz, CDCl3) δ 1.49 (s, 9H), 1.97-2.06 (m, 2H), 2.20-2.34 (m, 2H), 2.47 (s, 3H), 2.91-3.05 (m, 2H), 4.26-4.39 (m, 2H), 4.91-5.03 (m, 1H), 7.27-7.29 (m, 1H), 7.50-7.55 (m, 1H), 8.07 (s, 1H), 8.48-8.51 (m, 2H). Mass spectrum MH+=411. HRMS Calcd. For C21H27N6O3 (MH+): 411.2139. Found: 411.2137.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[C:4]([NH:6][C:7]([O:9]C1C=CC([N+]([O-])=O)=CC=1)=O)=[O:5].[Br:24][C:25]1[CH:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=1>>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[C:4]([NH:6][C:7]([NH:31][C:28]1[CH:27]=[CH:26][C:25]([Br:24])=[CH:30][N:29]=1)=[O:9])=[O:5]
Reactant: O=C(NC(=O)c1c(F)cccc1Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(Br)cn1
Product: O=C(NC(=O)c1c(F)cccc1Cl)Nc1ccc(Br)cn1

Procedure:
To a solution of 2-chloro-6-fluorobenzamidocarboxylic acid, 4-nitrophenyl ester, in an inert organic solvent is added 5-bromo-2-aminopyridine. The reaction mixture is stirred at an elevated temperature for a period of time, and is then evaporated to dryness under vacuum. The product named in the heading above, identical to the product of Example 2, is isolated and purified by recrystallization.
Reaction SMILES: [CH2:1]([P:16](=[O:29])([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[P:2](=[O:15])([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C=O.[CH2:32](NCC)C>CO>[C:1]([P:2](=[O:15])([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])([P:16](=[O:29])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH2:32]
Reactant: CCCCCOP(=O)(CP(=O)(OCCCCC)OCCCCC)OCCCCC
Reactant: CCNCC
Agent: C=O
Solvent: CO
Product: C=C(P(=O)(OCCCCC)OCCCCC)P(=O)(OCCCCC)OCCCCC
Yield: 68.3 %

Procedure:
20.20 g (44.0 mmol) of tetra-n-pentyl methylenebisphosphonate, 6.61 g (220.0 mmol) of paraformaldehyde and 3.22 g (64.0 mmol) of diethylamine are combined with the same reactants and the same conditions as described above in Example I. This mixture is then refluxed for 48 hours. After the methanol is eliminated as described above in Example I. 14.08 g of tetra-n-pentyl ethenylidenebisphosphonate is produced as a clear liquid.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][N:25]1[C:30]2=[C:31]([C:35](O)=[O:36])[CH:32]=[CH:33][CH:34]=[C:29]2[O:28][CH2:27][CH2:26]1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:35]([C:31]2[CH:32]=[CH:33][CH:34]=[C:29]3[O:28][CH2:27][CH2:26][N:25]([CH3:24])[C:30]=23)=[O:36])=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: CN1CCOc2cccc(C(=O)O)c21
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3c2N(C)CCO3)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 4-Methyl-3,4-dihydro-2H-benzo[1,4]oxazine-5-carboxylic acid. LC-MS (basic): tR=0.89 min; [M+H]+=503.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:3][CH:2]=1.[CH3:18][N:19]([CH3:32])[C:20]1([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1.FC(F)(F)S(O)(=O)=O>ClCCl>[CH3:18][N:19]([CH3:32])[C:20]1([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[CH2:25][CH2:24][C:23]([C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)([C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:22][CH2:21]1
Reactant: c1ccc2c(CCc3ccncc3)c[nH]c2c1
Reactant: CN(C)C1(c2cccs2)CCC(=O)CC1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C1(c2cccs2)CCC(c2[nH]c3ccccc3c2CCc2ccncc2)(c2[nH]c3ccccc3c2CCc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
3-(2-pyridin-4-ylethyl)-1H-indole (667 mg, 3 mmol, synthesis cf. WO2008009415, indole unit Ind-14) together with 4-(dimethylamino)-4-(thiophen-2-yl)cyclohexanone (671 mg, 3 mmol, synthesis cf. WO2008009415, ketone unit Ket-12) was dissolved in abs. dichloromethane (45 ml) and mixed with trifluoromethane sulphonic acid (0.660 ml, 7.43 mmol). The batch was stirred for 64 h at RT, and a brown oil separated out. For work up the reaction solution was mixed with 1N NaOH (30 ml) and methanol (10 ml). The mixture was stirred a further 60 min. After separation of the phases the aqueous phase was extracted with dichloromethane (3×10 ml). The combined organic extracts were dried over Na2SO4 and then concentrated to low volume. The raw product obtained (1.33 g) was purified by column chromatography [silica gel 60 (100 g); ethyl acetate/methanol 10:1, (1650 ml), ethyl acetate/methanol (5:1, (600 ml)].
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]1=[O:7].[CH2:8]1[O:10][CH:9]1[CH2:11]O.[H-].[Na+]>CN(C=O)C.[Cl-].[Na+].O>[O:10]1[CH2:8][CH:9]1[CH2:11][O:7][C:2]1[N:1]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=c1nccc[nH]1
Reactant: OCC1CO1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1cnc(OCC2CO2)nc1
Yield: 30 %

Procedure:
A solution of 2 (1H)-pyrimidinone (0.61 g, 4 mmol) and glycidol (0.30 g, 4 mmol) in DMF (10 mL) was added dropwise to a stirred suspension of NaH (0.14 g, 6 mmol) in DMF (5 mL). The reaction mixture is stirred at r. t. until the reagents disappeared (TLC). The reaction mixture is taken up with brine and extracted with EtOAc (3×20 mL). The organic phases are separated, dried over Na2SO4 and evaporated under reduced pressure. The crude residue was chromatographed (Petroleum ether/AcOEt, 1:1, as eluent) to afford pure compound in 30% yield. 1H NMR (CDCl3): δ 2.60-2.70 (m, 2H), 3.16 (m, 1H), 3.89-4.04 (m, 2H), 4.17-4.28 (m, 1H), 4.50-4.65 (m, 1H), 7.00 (t, 1H, J=7.4 Hz), 8.56 (d, 2H, J=4.9 Hz).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:36])([F:35])[C:8]1[CH:9]=[C:10]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:11]([N:13]1[CH2:17][C@@:16]([CH2:25][CH2:26][OH:27])([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[O:15][CH2:14]1)=[O:12].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][S:2]([O:27][CH2:26][CH2:25][C@:16]1([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[O:15][CH2:14][N:13]([C:11](=[O:12])[C:10]2[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=[C:8]([C:7]([F:35])([F:6])[F:36])[CH:9]=2)[CH2:17]1)(=[O:4])=[O:3]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CO[C@](CCO)(c2ccc(F)cc2)C1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC[C@@]1(c2ccc(F)cc2)CN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CO1
Reaction time: 1 h
Yield: 90.4 %

Procedure:
Methanesulfonyl chloride (26 mL, 0.336 mol) was added dropwise to a solution of the compound (102.11 g, 0.226 mol) obtained in Example 1c, triethylamine (63 mL, 0.452 mol) and 4-(dimethylamino)pyridine (2.76 g, 0.0273 mol) in dichloromethane (1000 mL) under ice cooling, and the mixture was stirred under ice cooling for 1 hour. The reaction mixture was washed with water and saturated sodium chloride solution, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-n-hexane, 30%→50%) to give the title compound (108.21 g; yield, 90%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]([F:30])([F:29])[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]=[C:27]=[O:28]>>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:27]([NH:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][C:18]([F:17])([F:29])[F:30])=[O:28])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C=Nc1ccccc1OC(F)(F)F
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Product: COc1ccc(NC(=O)Nc2ccccc2OC(F)(F)F)cc1-c1c(Cl)cnn1C
Yield: 3 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 2-trifluoromethoxyphenyl isocyanate in a similar manner as described in Example 1.53, providing 1.5 mg (3%) of Compound 34: LCMS m/z (%)=440 (M+H37Cl, 14), 438 (M+H35Cl, 14). 1H NMR (400 MHz, acetone-d6) δ: 8.19 (s, 1H), 7.90 (s, 1H), 7.43 (d, J=4 Hz, 1H), 7.25 (s, 1H), 7.04 (t, J=12 Hz, 2H), 6.99 (dd, J1=8 Hz, H2=2 Hz, 1H), 6.75 (d, J=4 Hz, 1H), 6.72 (d, J=4 Hz, 1H), 6.66 (d, J=2 Hz, 1H), 3.63 (s, 3H), 3.45 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:30])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:15]=2)[N:10]([C:26](=[O:28])[CH3:27])[C@@H:9]([CH3:29])[CH2:8]1)[CH3:3].Br[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][C:40]([O:42][CH2:43][C:44]2C=CC=CC=2)=[O:41])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.C1(C)C=CC=CC=1.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:26]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:32]3[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:34][CH:33]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5]([O:4][CH:2]([CH3:3])[CH3:1])=[O:30])[CH2:8][C@@H:9]1[CH3:29])(=[O:28])[CH3:27]
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: O=C(CCc1ccc(Br)cc1)OCc1ccccc1
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)CCc1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cc1
Temperature: 100 °C
Yield: 35 %

Procedure:
A mixture of 1-methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 52) (100 mg, 0.240 mmol), phenylmethyl 3-(4-bromophenyl)propanoate (92 mg, 0.288 mmol), potassium carbonate (100 mg, 0.721 mmol) and tetrakis(triphenylphosphine)palladium(0) (13.88 mg, 0.012 mmol) in ethanol (2.5 mL) and toluene (2.500 mL) was degassed for 15 min under house vacuum and quenched several times with nitrogen, and then was heated at 100° C. for 1 h before being cooled to room temperature and partitioned between AcOEt (35 mL) and water (20 mL). The layers were separated and the aqueous phase was extracted with AcOEt (15 mL). The combined organic phases were washed with brine (15 mL), dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 40 to 70% AcOEt in Hexanes) gave a residue which was further purified by MDAP (modifier: formic acid) to give ethyl 3-{4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]phenyl}propanoate (39.7 mg, 0.085 mmol, 35%) as a white solid.