Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl[C:10]1[S:11][C:12]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:13]=2[N:14]=1>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]2[S:11][C:12]3[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: Clc1ccc2nc(Cl)sc2c1
Product: Clc1ccc2nc(Nc3ccc(Br)cc3)sc2c1
Temperature: 25 °C
Yield: 100 %

Procedure:
Solid 4-Bromoaniline (1.00 g, 5.81 mmol) and 2,6-dichlorobenzothiazole (1.18 g, 5.81 mmol) were heated at 140° C. for 3 days in a flask equipped with an air condenser (fusion occurred within a few minutes to give a clear liquid which solidified over the course of 3 days). The reaction mixture was allowed to cooled to ambient temperature to give N-(4-bromophenyl)-N-(6-chloro-1,3-benzothiazol-2-yl)amine (1.97 g, 5.81 mmol): RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 14.65 min.
Reaction SMILES: C([O:9][CH2:10][CH:11]([CH2:35][CH:36]([O:38][C:39](=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH3:37])[CH2:12][O:13][C:14](=[O:34])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=O)C1C=CC=CC=1.[OH-].[Na+].C(OCC)(=O)C>CO.O1CCCC1>[C:39]([O:38][CH:36]([CH3:37])[CH2:35][CH:11]([CH2:12][O:13][C:14](=[O:34])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:10][OH:9])(=[O:46])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(COC(=O)c1ccccc1)CC(C)OC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CO)CC(C)OC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
To an ice cooled solution of 2.879 g (4.51 mM) of 2-(2-benzoyloxypropan-1-yl)-3-octadecylcarbamoyloxypropyl benzoate m6 in 25 ml of methanol and 25 ml of tetrahydrofuran, is added 4.51 ml (9.02 mM) of 2N aqueous sodium hydroxide and the mixture is stirred at 0° C. for 2 hours. The mixture is poured into ice-water and the product is isolated by ethyl acetate extraction. The ethyl acetate layer is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated. Purification of the product by column silica gel chromatography using n-hexane-ethyl acetate (2:1) as an eluent gives 1.72 g (71.4% yield) of the titled compound m7.
Reaction SMILES: O[Li].O.[Br:4][C:5]1[O:6][C:7]([C:14]([O:16]CC)=[O:15])=[C:8]([C:10]([F:13])([F:12])[F:11])[N:9]=1.Cl>C1COCC1.O.CCOC(C)=O.O>[Br:4][C:5]1[O:6][C:7]([C:14]([OH:16])=[O:15])=[C:8]([C:10]([F:12])([F:11])[F:13])[N:9]=1
Reactant: CCOC(=O)c1oc(Br)nc1C(F)(F)F
Agent: Cl
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1oc(Br)nc1C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
LiOH.H2O (0.64 g, 15.25 mmol) was added to a solution of ethyl 2-bromo-4-trifluoromethyloxazole-5-carboxylate (A-2) (3.50 g, 12.2 mmol) in THF/H2O (20/5 mL) at 0° C. followed by stirring for 3 h at 0° C. The reaction mixture was diluted with EtOAc/H2O (25/25 mL) and neutralized with 1 M HCl (16 mL) at 0° C. The organic phase was separated, dried over MgSO4, filtered, and concentrated. The product was dried in vacuo to yield 2-bromo-4-trifluoromethyloxazole-5-carboxylic acid (A-38) as a white solid (2.80 g, 88% yield).
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][CH2:7][C:8]([NH:17][C:18]([C:20]1[N:24]2[CH:25]=[CH:26][CH:27]=[C:28]([O:29][CH2:30][C:31]3[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=3[F:38])[C:23]2=[N:22][C:21]=1[CH3:39])=[O:19])([C:10]1[N:11]=[N:12][N:13]([CH2:15][CH3:16])[N:14]=1)[CH3:9])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.C(OCC)(=O)C>C1COCC1>[F:37][C:36]1[CH:35]=[CH:34][CH:33]=[C:32]([F:38])[C:31]=1[CH2:30][O:29][C:28]1[C:23]2[N:24]([C:20]([C:18]([NH:17][C:8]([C:10]3[N:11]=[N:12][N:13]([CH2:15][CH3:16])[N:14]=3)([CH3:9])[CH2:7][OH:6])=[O:19])=[C:21]([CH3:39])[N:22]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: CCn1nnc(C(C)(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)NC(=O)c2c(C)nc3c(OCc4c(F)cccc4F)cccn23)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCn1nnc(C(C)(CO)NC(=O)c2c(C)nc3c(OCc4c(F)cccc4F)cccn23)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
To a solution of 137 mg of N-[1-{[tert-butyl (diphenyl)silyl]oxy}-2-(2-ethyl-2H-tetrazol-5-yl)propan-2-yl]-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide in 3 ml of THF was added 0.3 ml of a 1 M tetrabutylammonium fluoride/THF solution, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography. To the obtained crude product was added ethyl acetate, and the insoluble materials were collected by filtration, washed with diisopropyl ether, and dried under reduced pressure to obtain 75 mg of 8-[(2,6-difluorobenzyl)oxy]-N-[2-(2-ethyl-2H-tetrazol-5-yl)-1-hydroxypropan-2-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=1)[CH3:2].[C:15]([O:19][C:20]([N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH2:32][CH2:33][O:34][C:35]3[CH:36]=[C:37]4[C:41](=[CH:42][CH:43]=3)[NH:40][CH:39]=[CH:38]4)[N:30]=2)[CH2:25][CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH2:32][CH2:33][O:34][C:35]3[CH:36]=[C:37]4[C:41](=[CH:42][CH:43]=3)[N:40]([C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=3)=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[O:14])[CH:39]=[CH:38]4)[N:30]=2)[CH2:25][CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)C#Cc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Product: CCOC(=O)C=C(c1cccc(Cl)c1)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Yield: 90 %

Procedure:
The title compound was synthesized from (3-chloro-phenyl)-propynoic acid ethyl ester and 7-[2-(1H-Indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure described in Example 16, step (d1), in 90% yield as an E/Z isomeric mixture. 1H NMR (CDCl3) [E/Z mixture] δ 7.36–7.24 (m, 2H), 7.14–7.6.70 (m, 8H), 6.56 (s, 0.5H), 6.48 (m, 0.5H), 6.21 (s, 0.5H), 6.14 (s, 0.5H), 4.37 (m, 2H), 4.12 (q, 2H, J=6.8 Hz), 3.76 (m, 2H), 3.20 (t, 2H, J=6.8 Hz), 2.73 (t, 2H, J=6.8 Hz), 1.92 (m, 2H), 1.52 (s, 9H), 1.26 (t, 3H, J=7.2 Hz). Mass Spectrum (LCMS, ESI) calculated for C29H29ClN3O3 502.2 (M-Boc+1); found 502.4.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:31][N:30]([C:32]3[N:36]([CH3:37])[N:35]=[C:34]([CH:38]([CH3:40])[CH3:39])[CH:33]=3)[CH2:29][CH2:28][C:4]=2[N:5]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10]([CH3:27])=[CH:11][N:12]3[S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:7]=1.[Cl:41]N1C(=O)CCC1=O>CC#N.C(OCC)C.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[C:3]2[CH2:31][N:30]([C:32]3[N:36]([CH3:37])[N:35]=[C:34]([CH:38]([CH3:40])[CH3:39])[C:33]=3[Cl:41])[CH2:29][CH2:28][C:4]=2[N:5]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10]([CH3:27])=[CH:11][N:12]3[S:17]([C:20]2[CH:21]=[CH:22][C:23]([CH3:24])=[CH:25][CH:26]=2)(=[O:18])=[O:19])[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc(Cl)c5c(n4)CCN(c4cc(C(C)C)nn4C)C5)cccc32)cc1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc(Cl)c5c(n4)CCN(c4c(Cl)c(C(C)C)nn4C)C5)cccc32)cc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a solution of 4-chloro-6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (90 mg, 0.156 mmol) in MeCN (2.0 mL) at 0° C. was added N-chlorosuccinimide (21 mg, 0.156 mmol). The reaction was permitted to stir for 2.5 h at 0° C., and then was diluted with diethyl ether and saturated aqueous sodium bicarbonate. The layers were separated and the organic layer was washed once with brine, dried over MgSO4, filtered and concentrated to furnish 4-chloro-6-(4-chloro-3-isopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine without the need for further purification. MS (ESI+) m/z 609.2 (M+H)+.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.ClC(Cl)(O[C:20](=[O:26])OC(Cl)(Cl)Cl)Cl.[NH2:28][C:29]1[N:34]=[C:33]([C:35]2[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[C:37]([F:43])[CH:36]=2)[CH:32]=[C:31]([N:44]2[CH2:49][CH2:48][CH2:47][C@@H:46]([NH2:50])[CH2:45]2)[N:30]=1>C(Cl)Cl>[CH:1]1([O:6][C:20](=[O:26])[NH:50][C@@H:46]2[CH2:47][CH2:48][CH2:49][N:44]([C:31]3[CH:32]=[C:33]([C:35]4[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[C:37]([F:43])[CH:36]=4)[N:34]=[C:29]([NH2:28])[N:30]=3)[CH2:45]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@@H](N)C3)nc(N)n2)cc1F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1ccc(-c2cc(N3CCC[C@@H](NC(=O)OC4CCCC4)C3)nc(N)n2)cc1F
Reaction time: 1 h

Procedure:
A premixed solution of cyclopentanol (33.5 mg, 0.389 mmol) and Hunig's base (57 uL) in CH2Cl2 (1 mL) was slowly added to a solution of triphosgene (38.5 mg, 0.130 mmol) in CH2Cl2 (1 mL), and the resulting solution was stirred for 1 hour. A premixed solution of 4-{2-amino-6-[(3R)-3-amino-1-piperidinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (125 mg, 0.324 mmol) and Hunig's base (226 uL) in CH2Cl2 (5 mL) was added, and the reaction mixture was stirred at room temperature overnight. The reaction was concentrated, then loaded on a Biotage SNAP 10 g column and purified with a gradient of 0 to 55% EtOAc in Hexane over 25 min. LC-MS (ES) m/z=425 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.Br[CH2:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=1/[CH:31]=[CH:32]/[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].O>C1COCC1>[CH2:1]([N:8]([C@@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])[C@@H:31]1[C:25]2[C:24](=[CH:29][C:28]([CH3:30])=[CH:27][CH:26]=2)[CH2:23][C@H:32]1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](NCc1ccccc1)c1ccccc1
Reactant: Cc1ccc(/C=C/C(=O)OC(C)(C)C)c(CBr)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2c(c1)C[C@@H](C(=O)OC(C)(C)C)[C@@H]2N(Cc1ccccc1)[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.5 ml of (1R)—N-benzyl-1-phenylethanamine in 40 ml of THF was added 4.35 ml of n-butyllithium (1.62 M hexane solution) at −78° C., followed by stirring for 30 minutes. At the same temperature, a solution of 1.00 g of tert-butyl (2E)-3-[2-(bromomethyl)-4-methylphenyl]acrylate in 5 ml of THF was added thereto, followed by stirring for 1.5 hours. To the reaction mixture was added water, followed by warming to room temperature. The solvent was evaporated under reduced pressure and ethyl acetate was then added thereto to carry out a layer separation operation. The organic layer was washed with a 1 M aqueous citric acid solution, water, and saturated brine in this order, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1.17 g of tert-butyl (1S,2R)-1-{benzyl[(1R)-1-phenylethyl]amino}-5-methylindane-2-carboxylate. Further, the present Preparation Example is in accordance with the method described in a reference (Synlett, 1999, No. 12, 1919-1920 by D. A. Price).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.[CH3:34][NH2:35]>O>[CH3:34][NH:35][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: Oc1ccc2ccccc2c1
Reactant: CN
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Product: CNc1ccc2ccccc2c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
288 parts of β-naphthol, 3 parts of triphenyl phosphite and 80 parts of methylamine gas are heated for 10 hours under pressure at 200° C in a pressure autoclave. The pressure is 40 atmospheres. When the two-phase mixture has cooled, water is added, the batch is stirred for 30 minutes at 70° C and the lower oily phase is separated off and distilled. 305 parts of N-methyl-β-naphthylamine, boiling at 165° - 166° C/12 mm Hg, are obtained. This corresponds to a yield of 97% of theory.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[B-](F)(F)(F)F.C1C=CN=CC=1.C1C=CN=CC=1.[IH2+:29].FC(F)(F)S(O)(=O)=O>ClCCl>[I:29][C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]=[CH:8]2
Reactant: Oc1ccc2cnccc2c1
Reactant: [IH2+]
Agent: F[B-](F)(F)F
Agent: O=S(=O)(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: Oc1ccc2cnccc2c1I
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
Under argon atmosphere 1.77 g (12.2 mmol) of compound 7 were added to a solution of 5.0 g (13.5 mmol) bis(pyridin)iodonium tetrafluoroborate in 100 mL of dry dichloromethane. A solution of 2.4 mL (4 g, 26.8 mmol) trifluoromethane sulfonic acid in 20 mL dry dichloromethane was added dropwise at 0° C. and the mixture was stirred for 3 hours at room temperature. The solvents were removed by distillation and the remainder was treated with aqueous NaHCO3 solution. The precipitate was filtered, washed with water and dried to yield 3.2 g (97%) of compound 10 as a beige solid.
Reaction SMILES: CO[C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([S:16][CH3:17])[C:4]=1C(O)=O.FC(F)(F)C1C=CC=CC=1[C:22]([OH:24])=[O:23].CSSC>>[CH3:17][S:16][C:8]1[CH:4]=[CH:3][CH:11]=[C:10]([C:12]([F:13])([F:14])[F:15])[C:9]=1[C:22]([OH:24])=[O:23]
Reactant: O=C(O)c1ccccc1C(F)(F)F
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)O
Solvent: CSSC
Product: CSc1cccc(C(F)(F)F)c1C(=O)O

Procedure:
The title compound, white solid, MS: m/e=235.0 [(M−H)−], was prepared in accordance with the general method of intermediate A from 2-(trifluoromethyl)benzoic acid and dimethyl disulfide.
Reaction SMILES: [N+:1]([C:4]1[N:8]2[N:9]=[C:10]([SH:13])[CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([CH2:25][OH:26])[C:20]=1[CH3:27].C(N(CC)CC)C.O>CN(C)C=O>[CH3:27][C:20]1[C:21]([CH2:25][OH:26])=[N:22][CH:23]=[CH:24][C:19]=1[O:18][CH2:17][CH2:16][CH2:15][S:13][C:10]1[CH:11]=[CH:12][C:7]2[N:8]([C:4]([N+:1]([O-:3])=[O:2])=[CH:5][N:6]=2)[N:9]=1
Reactant: Cc1c(OCCCCl)ccnc1CO
Reactant: O=[N+]([O-])c1cnc2ccc(S)nn12
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(OCCCSc2ccc3ncc([N+](=O)[O-])n3n2)ccnc1CO
Temperature: 25 °C
Yield: 69.5 %

Procedure:
570 mg (2.9 mmol) of 3-nitroimidazo[1,2-b]pyridazine-6-thiol, 500 mg (2.3 mmol) of [4-(3-chloropropoxy)-3-methylpyridin-2-yl]methanol and 0.4 ml (2.9 mmol) of triethylamine in 10 ml of dimethylformamide are heated to 100° C for 1 h under a nitrogen atmosphere. After cooling to room temperature, water (100 ml) is added and the mixture is extracted with 3×50 ml of ethyl acetate. The residual oil is crystallized from methanol. 600 mg (69%) of the title compound are isolated as a pale beige solid. M.p. 135-136° C.
Reaction SMILES: [N+](C1C=CC(N2CCNCC2)=CC=1)([O-])=O.[N+:16]([C:19]1[CH:20]=[C:21]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[CH:23][CH:24]=1)([O-])=O.CS(C1N=CC2=CC=C([C:43]3C=CC=[CH:45][C:44]=3[O:49]C)N2N=1)=O.[Cl:51][C:52]1[CH:53]=[C:54]([C:58]2[N:66]3[C:61]([CH:62]=[N:63][C:64](S(C)=O)=[N:65]3)=[CH:60][CH:59]=2)[CH:55]=[CH:56][CH:57]=1>>[Cl:51][C:52]1[CH:53]=[C:54]([C:58]2[N:66]3[C:61]([CH:62]=[N:63][C:64]([NH:16][C:19]4[CH:20]=[C:21]([N:25]5[CH2:30][CH2:29][N:28]([CH2:43][C@H:44]([OH:49])[CH3:45])[CH2:27][CH2:26]5)[CH:22]=[CH:23][CH:24]=4)=[N:65]3)=[CH:60][CH:59]=2)[CH:55]=[CH:56][CH:57]=1
Reactant: O=[N+]([O-])c1cccc(N2CCNCC2)c1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: CS(=O)c1ncc2ccc(-c3cccc(Cl)c3)n2n1
Agent: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Product: C[C@@H](O)CN1CCN(c2cccc(Nc3ncc4ccc(-c5cccc(Cl)c5)n4n3)c2)CC1

Procedure:
The compound was prepared in an analogous fashion to Example 73 replacing 1-(4-Nitro-phenyl)-piperazine with 1-(3-Nitro-phenyl)-piperazine and 2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine with 7-(3-Chloro-phenyl)-2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazine to afford 22.28 mg of (R)-1-(4-{3-[7-(3-Chloro-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperazin-1-yl)-propan-2-ol as a lyophilized powder. (M+H)=463.12. 1H NMR (400 MHz, DMSO, d6) δ 9.52 (m, 1H), 9.41 (s, 1H), 8.39 (m, 1H), 8.06 (d, 1H, J=7.68 Hz), 7.50 (m, 3H), 7.25 (m, 2H), 7.18 (m, 1H), 6.97 (d, 1H, J=4.76 Hz), 6.67 (d, 1H, J=8.00 Hz), 4.11 (m, 2H), 3.66 (m, 2H), 3.53 (m, 2H), 3.14 (m, 3H), 3.03 (m, 2H), 1.15 (d, 3H, J=6.16 Hz).
Reaction SMILES: [C:1]([O:7]CC)(=O)[CH2:2][C:3]([CH3:5])=O.C(=O)(O)O.[F:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH2:24])=[NH:23])=[CH:17][CH:16]=1.CN(C)C=O>C(OCC)C>[CH3:5][C:3]1[N:23]=[C:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)[N:24]=[C:1]([OH:7])[CH:2]=1
Reactant: N=C(N)Nc1ccc(F)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: O=C(O)O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(Nc2ccc(F)cc2)n1
Temperature: 25 °C
Yield: 30.2 %

Procedure:
A mixture solution of ethyl acetoacetate(3.8 ml, 30.3 mmol), 4-fluorophenylguanidine carbonate(5 g, 26.3 mmol), and dimethylformamide(5 ml) was refluxed for 2 hours and cooled to a room temperature. Ethyl ether was added to the reaction mixture and the resulting solid was filtered, washed with ethyl ether, and concentrated under a reduced pressure to give 1.74 g of the titled compound. (Yield 30%)
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]([Cl:13])=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1.[C:14]([O-])(=[O:16])[CH3:15].[Na+].C(OC(=O)C)(=O)C.N>O.C(O)(=O)C>[C:14]([N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:12]([Cl:13])[C:3]([Cl:2])=[CH:4][CH:5]=2)[CH2:10]1)(=[O:16])[CH3:15]
Reactant: Clc1ccc2c(c1Cl)CNCC2
Reactant: CC(=O)[O-]
Agent: Cl
Agent: N
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)N1CCc2ccc(Cl)c(Cl)c2C1

Procedure:
7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.001 mole) was treated with sodium acetate (0.001 mole), acetic anhydride (0.00125 mole), and 2 ml. of acetic acid and the mixture was heated at 95° C. for 15 minutes. The mixture was cooled, dilutes with water, made alkaline with aqueous ammonia and extracted with chloroform. Concentration of the extract and recrystallization of the residue from isopropanol gave 2-acetyl-7,8-dichloro-1,2,3,4-tetrahydroisoquinoline, m.p. 99.5°-100° C.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH2:8]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:23]([N:22]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:1](=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: O=C1CCC(=O)O1
Reactant: CCCCCCCCCCCCCCNCCCCCCCCCCCCCC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCN(CCCCCCCCCCCCCC)C(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.8 %

Procedure:
12.65 mmol of succinic anhydride (1.266 g), 12.65 mmol of 4-dimethylaminopyridine (1.546 g) and 10.75 mmol of ditetradecylamine (4.407 g) were successively added to 125 ml of dichloromethane in a round-bottomed flask. The reaction mixture was stirred for 18 hours at room temperature. Once the reaction was complete, the mixture was extracted with dichloromethane and hydrochloric acid (1N). The organic phase was then washed with brine and dried over magnesium sulfate, filtered and then concentrated to give 4.21 g of product (3) (yield: 66%).
Reaction SMILES: FC(F)(F)C1C=C2C(=CC=1)[N:8](CC1C=CC=C(F)C=1)C(C(O)=O)=C2.[CH:25]1([N:31]=[C:32]=[N:33][CH:34]2[CH2:39][CH2:38]CC[CH2:35]2)[CH2:30][CH2:29][CH2:28]CC1.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[CH3:35][C:34]1[N:33]=[C:32]2[CH:28]=[C:29]([NH2:8])[CH:30]=[CH:25][N:31]2[C:39]=1[CH3:38]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)c1cc2cc(C(F)(F)F)ccc2n1Cc1cccc(F)c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2cc(N)ccn2c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 150.3 %

Procedure:
To a solution, stirred at 20° C. under an inert atmosphere, of 1 g (2.96 mmol) of 5-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylic acid (WO 2006/072736) in 70 mL of DMF are added 0.74 g (3.56 mmol) of dicyclohexylcarbodiimide (DCC) and 0.48 g (3.56 mmol) of 1-hydroxybenzotriazole hydrate (HOBT). The reaction mixture is stirred at room temperature for 30 minutes. 0.7 g (4.45 mmol) of 2,3-dimethylimidazo[1,2-a]pyrid-7-ylamine, obtained according to the protocol described in step 14.4, and 100 mg of dimethylaminopyridine (DMAP) are then added to the reaction mixture. After stirring for 12 hours at 50° C., the reaction mixture is concentrated to dryness. The residue obtained is taken up in a mixture of 50 mL of water and 50 mL of ethyl acetate. The phases are separated by settling and the aqueous phase is extracted with 200 mL of ethyl acetate. The combined organic phases are dried over sodium sulfate and then concentrated under reduced pressure. The product is isolated after successive purifications by chromatography on a column of silica, eluting with a mixture of dichloromethane and methanol. 50 mg of the expected product are thus obtained.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH:15]1([C:18](Cl)=[O:19])[CH2:17][CH2:16]1>ClCCl>[CH:15]1([C:18]([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)=[O:19])[CH2:17][CH2:16]1
Reactant: OC1CCNCC1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C1CC1)N1CCC(O)CC1
Yield: 95.6 %

Procedure:
20 g of 4-hydroxypiperidine was dissolved in 400 ml of dichloromethane, to which 24 g of triethylamine was added. At -60° C., 100 ml of a dichloromethane solution containing 20.7 g of cyclopropanecarbonyl chloride was further added. After completion of the reaction, the reaction solution was extracted with chloroform under salting-out conditions and dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by the use of silica gel column chromatography (elution solvent: dichloroethane), thereby obtaining 32 g of the intended compound (yield 96%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([CH3:11])[N:8](S(C3C=CC(Br)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[OH-].[Na+].O.CCOC(C)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([CH3:11])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1cc2cc(Br)cnc2n1S(=O)(=O)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc2cc(Br)cnc2[nH]1
Yield: 50.2 %

Procedure:
To a suspension of 5-bromo-1-(4-bromophenylsulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridine (B-7-5) (4 g, 11.4 mmol) in THF (20 mL) was added aq. NaOH (20 mL) at room temperature. The mixture was heated to reflux overnight. LC-MS showed the reaction was complete. Water (100 mL) and EtOAc (50 mL×3) were added into the mixture. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated to give crude mixture which was purified via prep. HPLC to afford 5-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine (B-7-6) (1.2 g, 50.2%) as a white solid.