Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)C=CC=CC=1.[CH:34]([C@H:36]1[N:40]([CH3:41])[C:39](=[O:42])[CH2:38][C@H:37]1[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=O.O>C1(C)C=CC=CC=1>[CH3:41][N:40]1[C@H:36]([CH:34]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[C@H:37]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:38][C:39]1=[O:42]
Reactant: Clc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CN1C(=O)C[C@@H](c2ccccc2)[C@H]1C=O
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Product: CN1C(=O)C[C@@H](c2ccccc2)[C@H]1C=Cc1cccc(Cl)c1
Reaction time: 0.25 h

Procedure:
32.8 g (77 mmol) of n-butyllithium (15% in hexane) were added dropwise under nitrogen with ice cooling to 36.0 g (77 mmol) of triphenyl-m-chlorobenzylphosphonium bromide in 150 ml of toluene in the course of 20 minutes, and the orange suspension was subsequently stirred for 15 minutes. 15.6 g (77 mmol) of cis-5-formyl-1-methyl-4- phenylpyrrolidin-2-one (German Laid-Open Application DOS 3,537,075 and 3,632,589; J. Org. Chem. 52 (1987), 4352) in 120 ml of toluene were then added dropwise and stirred in at room temperature for 3 hours (color change toward pale yellow). 200 ml of H2O were then added, the mixture was acidified with dilute HCL and filtered with suction, the phases were separated, the aqueous phase was extracted twice more with toluene, and the combined organic phases were washed with H2O, dried and concentrated. The crude product was taken up in 100 ml of methyl t-butyl ether and filtered with suction and cooling to remove precipitated triphenylphosphine oxide. The filtrate was concentrated and purified by column chromatography (silica gel, eluent: 98/2 methylene chloride/methanol); yield: 16.1 g (67%). Judging by a 1H-NMR spectrum, the styryl side chain is 90% in the trans configuration and 10% in the cis configuration.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[N:9][CH:8]=[C:7]2[C:14](OC)=[O:15].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>CCOCC.[OH-].[Na+]>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[N:9][CH:8]=[C:7]2[CH2:14][OH:15]
Reactant: COC(=O)c1cncc2ccc(OC)cc12
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: COc1ccc2cncc(CO)c2c1
Temperature: 25 °C

Procedure:
The compound obtained in Step A (0.395 g; 0.0015 mol), in the form of a base, is dissolved in 200 ml of ether. Lithium aluminium hydride (0.14 g; 0.004 mol) is then progressively added while cooling the flask in ice. The reaction mixture is stirred at ambient temperature for one week. A minimum of 30% sodium hydroxide solution (a few drops) is added to the reaction mixture to form the precipitates of lithium and aluminium hydroxides. The precipitates are then filtered off and washed with ethyl acetate. The organic phase is dried over magnesium sulphate, filtered and evaporated under reduced pressure. The oil obtained is taken up in ether saturated with HCl(g). The precipitate formed is suction-filtered off and recrystallised from acetonitrile to yield the title product in the form of a white solid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14]C)=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O1CCCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nccc(Br)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2nccc(Br)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
Methyl 4-bromo-6-quinolinecarboxylate (6.00 g) was dissolved in methanol (60 ml) and tetrahydrofuran (40 ml). A 1N aqueous sodium hydroxide solution (30 ml) was added to the solution while stiring at room temperature and the mixture was stirred at room temperature for 3 hr. A 1N aqueous sodium hydroxide solution (20 ml) was added and the mixture was heated under reflux for 2 hr. The reaction mixture was adjusted to pH 4 with 1N hydrochloric acid. The resulting solid was collected by filtration and washed with water and ether to give 4-bromo-6-quinolinecarboxylic acid (4.65 g) as a white powder.
Reaction SMILES: ClC1C(OC2CCC(=O)CC2)=CC(F)=C(C=1)C(O)=O.[CH:20]1([C:23]2[C:24]([O:33][CH:34]3[CH2:41][CH2:40][C:37]4([CH2:39][CH2:38]4)[CH2:36][CH2:35]3)=[CH:25][C:26]([F:32])=[C:27]([CH:31]=2)[C:28](O)=[O:29])[CH2:22][CH2:21]1.[CH3:42][S:43]([NH2:46])(=[O:45])=[O:44]>CO>[CH:20]1([C:23]2[C:24]([O:33][CH:34]3[CH2:41][CH2:40][C:37]4([CH2:39][CH2:38]4)[CH2:36][CH2:35]3)=[CH:25][C:26]([F:32])=[C:27]([CH:31]=2)[C:28]([NH:46][S:43]([CH3:42])(=[O:45])=[O:44])=[O:29])[CH2:22][CH2:21]1
Reactant: O=C(O)c1cc(C2CC2)c(OC2CCC3(CC2)CC3)cc1F
Reactant: CS(N)(=O)=O
Agent: O=C1CCC(Oc2cc(F)c(C(=O)O)cc2Cl)CC1
Solvent: CO
Product: CS(=O)(=O)NC(=O)c1cc(C2CC2)c(OC2CCC3(CC2)CC3)cc1F

Procedure:
Following the procedure as described in Example 357 Step 4 and making non-critical variations to replace 5-chloro-2-fluoro-4-((4-oxocyclohexyl)oxy)benzoic acid with 5-cyclopropyl-2-fluoro-4-(spiro[2.5]octan-6-yloxy)benzoic acid and methanol with methanesulfonamide, the title compound was obtained as a colorless solid (0.121 g, 53% yield): 1H NMR (300 MHz, CDCl3) δ8.69 (d, J=16.2 Hz, 1H), 7.55 (d, J=9.2 Hz, 1H), 6.58 (d, J=14.8 Hz, 1H), 4.49-4.42 (m, 1H), 3.39 (s, 3H), 2.11-1.77 (m, 5H), 1.54-1.21 (m, 4H), 0.96-0.89 (m, 2H), 0.67-0.61 (m, 2H), 0.34-0.27 (m, 4H); MS (ES−) m/z 380.20 (M−1).
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][CH2:8][NH:9][C:10](=[O:28])[CH2:11][NH:12][C:13](=[O:27])[CH2:14][CH2:15][CH2:16][C:17]1[N:26]=[C:25]2[C:20]([CH2:21][CH2:22][CH2:23][NH:24]2)=[CH:19][CH:18]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:24]1[C:25]2[C:20](=[CH:19][CH:18]=[C:17]([CH2:16][CH2:15][CH2:14][C:13]([NH:12][CH2:11][C:10]([NH:9][CH2:8][CH2:7][C:6]([OH:29])=[O:5])=[O:28])=[O:27])[N:26]=2)[CH2:21][CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)CCNC(=O)CNC(=O)CCCc1ccc2c(n1)NCCC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCNC(=O)CNC(=O)CCCc1ccc2c(n1)NCCC2
Temperature: 25 °C

Procedure:
Ester 19-9 (69 mg, 0.17 mmol) was dissolved in 1 mL CH2Cl2 at 0° C., 1 mL TFA was added, and the reaction was warmed to ambient temperature for 6 hr. After concentrating and azeotroping with toluene, flash chromatography (silica, 7:20:1:1 EtOAc/EtOH/H2O/NH4OH) provided 19-10 as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:13]2[C:9]([S:10][CH:11]=[C:12]2[CH3:14])=[N:8][CH:7]=1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:14][C:12]1[N:13]2[C:6]([CH2:4][OH:3])=[CH:7][N:8]=[C:9]2[S:10][CH:11]=1
Reactant: CCOC(=O)c1cnc2scc(C)n12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1csc2ncc(CO)n12
Yield: 76.2 %

Procedure:
A solution of 3-Methylimidazo[2,1-b]thiazole-5-carboxylic acid ethyl ester (Formula C-4) (1.93 g, 9.2 mmol) in dry THF (20 ml) at 0° was treated with LiAlH4 (12.3 mmols, 0.47 gms) and reacted at 25° for 2 hours. The reaction was quenched by serial additions of 2% aqueous.. THF (24 mL), 15% NAOH (0.47 mL), and 2% aqueous THF (1.5 mL). The suspension was filtered and the filtrate was concentrated to a white solid (1.48 gm). The solid was recrystallized from isopropanol to yield pure 3-Methylimidazo[2,1-b]thiazole-5-Methanol (FIG. C-5) (1.18 g), m.p. 161-162°.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=3[CH:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)O)[CH:8]=2)[N:3]=1.[ClH:33].S(Cl)([Cl:36])=O>C(Cl)Cl.CC(O)C>[ClH:36].[Cl:33][CH:25]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:18]=1[C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH2:1])[C:11]([N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)=[CH:10]2
Reactant: Cc1cccc(C(O)c2ccccc2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: Cc1cccc(C(Cl)c2ccccc2)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylphenyl)(phenyl)methanol (0.155 g, 0.364 mmol) in DCM was treated with 0.4 mL of 5N HCl in iPrOH. The mixture was concentrated in vacuo and azeotroped 3× with DCM. The resulting yellow solid was treated again with DCM (1.21 mL) and thionyl chloride (0.80 mL, 10.93 mmol) was added dropwise, and the reaction mixture was stirred for 30 min at ambient temperature for 1 h and concentrated in vacuo. The residue was azeotroped 2× with DCM and dried under vacuum to afford crude 6-(2-(chloro(phenyl)methyl)-6-methylphenyl)-3-morpholinoquinolin-2-amine hydrochloride which was used without further purification.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:28])[N:11]([CH3:27])[CH:12]=[C:13]([C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[C:17]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:19][CH:20]=[C:15]([C:13]2[CH:14]=[C:9]([OH:8])[C:10](=[O:28])[N:11]([CH3:27])[CH:12]=2)[CH:16]=1
Reactant: Cn1cc(-c2cccc(-c3ccccc3)c2)cc(OCc2ccccc2)c1=O
Agent: [Pd]
Solvent: CO
Product: Cn1cc(-c2cccc(-c3ccccc3)c2)cc(O)c1=O
Yield: 9.7 %

Procedure:
A solution of 3-(benzyloxy)-5-(biphenyl-3-yl)-1-methylpyridin-2(1H)-one (34 mg, 0.093 mmol) in MeOH (5 mL) was hydrogenated under atmospheric H2 in the presence of 5% Pd/C (15 mg) for 21 h. Filtered and concentrated. Purification by preparative HPLC (5-65% CH3CN/H2O over 20 min, 0.05% added TFA) afforded 2.5 mg (10%) of 5-Biphenyl-3-yl-3-hydroxy-1-methylpyridin-2(1H)-one as a white solid. 1H NMR (500 MHz, CDCl3): δ 7.63-7.60 (m, 3H), 7.56 (d, J=7.8 Hz, 1H), 7.52-7.43 (m, 3H), 7.41-7.36 (m, 2H), 7.25-7.06 (br, 2H), 3.72 (s, 3H). High resolution mass spec (FT/ICR) cale (M+H)+=278.1165 found 278.1176.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[CH2:10][CH:9]=[CH:8][CH2:7][C:6]=2[C:5]([CH3:13])([CH3:12])[CH2:4][CH2:3]1.P([O-])([O-])(O)=[O:16].[Na+].[Na+].C(OO)(C)(C)C>ClCCCl.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo]>[O:16]1[CH:8]2[CH:9]1[CH2:10][C:11]1[C:2]([CH3:14])([CH3:1])[CH2:3][CH2:4][C:5]([CH3:13])([CH3:12])[C:6]=1[CH2:7]2
Reactant: CC1(C)CCC(C)(C)C2=C1CC=CC2
Reactant: O=P([O-])([O-])O
Agent: [Mo]
Agent: CC(C)(C)OO
Agent: [C-]#[O+]
Solvent: ClCCCl
Product: CC1(C)CCC(C)(C)C2=C1CC1OC1C2

Procedure:
35 g of a hydrocarbon mixture containing (according to GC) 43% of 1,1,4,4-tetramethyl-1,2,3,4,5,8-hexahydronaphthalene (IIh) are dissolved in 140 ml of 1,2-dichloroethane and treated in accordance with method C described in Example 1 with 0.304 g of molybdenum hexacarbonyl, 0.1148 g of disodium hydrogen phosphate and 65 ml of 2.85 molar tert.butyl hydroperoxide solution. After working-up, 30 g of crude product are obtained. 10 g thereof are chromatographed on 600 g of silica gel Merck (0.04-0.063 mm) (elution agent: 2-3% ether/hexane). 1.9 g of 6,7-epoxy-1,1,4,4-tetramethyl-1,2,3,4,5,6,7,8-octahydro-naphthalene are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13](=[O:29])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.[F-].[Cs+].B1(B2OCC(C)(C)CO2)OCC(C)(C)CO1.Br[C:57]1[C:62]([F:63])=[CH:61][C:60]([F:64])=[CH:59][C:58]=1[F:65]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)=[CH:16][CH:15]=1)=[O:29])=[C:8]([C:61]1[C:62]([F:63])=[CH:57][C:58]([F:65])=[CH:59][C:60]=1[F:64])[CH:7]=[CH:6]2
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: Fc1cc(F)c(Br)c(F)c1
Agent: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3c(F)cc(F)cc3F)ccc2c1
Temperature: 90 °C
Yield: 69.5 %

Procedure:
Alternatively, combine trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (1.93 g, 3.60 mmol), cesium fluoride (5.0 g, 33 mmol), bis(neopentyl glycolato)diboron (1.0 g, 4.4 mmol), bis(tricyclohexylphosphine)palladium (0.50 g, 0.75 mmol) and acetonitrile (50 mL). Heat the mixture to 90° C. for 20 minutes to obtain a dark-colored solution. Add 2-bromo-1,3,5-trifluoro-benzene (5 g, 23.7 mmol) and heat at 90° C. for 2 hours. Add bis(tricyclohexylphosphine)palladium (0.50 g, 0.75 mmol) and 2-bromo-1,3,5-trifluoro-benzene (5.0 g, 23 mmol) and heat at 90° C. for 4 hours. Cool to room temperature and filter through a pad of celite and evaporate the solvent. Purify the residue over silica gel, eluting the material with methanol in dichloromethane (0 to 5%), to give 1.30 g (67%) of title compound: mass spectrum (ion spray) m/z=520.2 (M+H).
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:28][CH2:29][OH:30]>C(#N)C>[F:1][C:2]1[C:7]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:9])=[O:10])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:15]1[CH2:20][CH2:19][N:18]([CH2:28][CH2:29][OH:30])[CH2:17][CH2:16]1
Reactant: O=S(=O)(c1cccc(C2CCNCC2)c1F)C(F)(F)F
Reactant: OCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=S(=O)(c1cccc(C2CCN(CCO)CC2)c1F)C(F)(F)F

Procedure:
Preparation according to Example 1: 4-{2-fluoro-3-[(trifluoromethyl)sulfonyl]phenyl}-piperidine (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and 2-iodoethanol (0.01 g). MS m/z (rel. intensity, 70 eV) 355 (M+, 1), 325 (15), 324 (bp), 191 (36), 133 (12).
Reaction SMILES: [CH:1]1([C:10]([OH:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Br:13]Br.Cl>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:13][C:7]1[CH:8]=[C:9]2[C:4]([CH2:3][CH2:2][CH:1]2[C:10]([OH:12])=[O:11])=[CH:5][CH:6]=1
Reactant: BrBr
Reactant: O=C(O)C1CCc2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)C1CCc2ccc(Br)cc21
Reaction time: 3 h

Procedure:
By following the procedure of Tetsuya, et al. referenced in part A, the 6-bromo compound can be obtained. For example, to a stirred, ice-cooled mixture of 8.1 g (50 mmol) indane-1-carboxylic acid and 8.1 g of FeCl3 in 300 ml of CCl4 is added dropwise a solution of 8.8 g of Br2 in 100 ml methylene chloride over a 1 hour period. The mixture is stirred for 3 hours under cooling and then for 1.5 hours at room temperature. The mixture is poured into 500 ml of dilute HCl and extracted with CHCl3. The extract is washed with water, dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue is crystallized from hexane to give 6-bromo-indane-1-carboxylic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:18]([NH:20][C@H:21]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)[CH3:22])=[O:19])[CH:11]=[CH:10]2)=[CH:4][CH:3]=1.N1CCCCC1.[CH2:38]([OH:40])[CH3:39]>>[CH2:38]([O:40][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:18]([NH:20][C@H:21]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)[CH3:22])=[O:19])[CH:11]=[CH:10]2)=[CH:4][CH:3]=1)[CH3:39]
Reactant: C[C@H](NC(=O)c1cccc2ccn(Cc3ccc(Cl)nc3)c12)c1ccc(C(=O)O)cc1
Reactant: CCO
Solvent: C1CCNCC1
Product: CCOc1ccc(Cn2ccc3cccc(C(=O)N[C@@H](C)c4ccc(C(=O)O)cc4)c32)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-{(1S)-1-[({1-[(6-chloropyridin-3-yl)methyl]-1H-indol-7-yl}carbonyl)amino]ethyl}benzoic acid (95 mg) were added ethanol (2.0 mL) and piperidine (65 μL), followed by stirring at room temperature overnight. After concentration under reduced pressure, DMSO (1.0 mL), piperidine (65 μL), and potassium tert-butoxide (61 mg) were added thereto, followed by stirring at 80° C. for 2 hours. To the reaction mixture was added a 10% aqueous citric acid solution (10 mL), followed by extraction with ethyl acetate. The obtained organic layer was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=99/1-95/5) to obtain 4-{(1S)-1-[({1-[(6-ethoxypyridin-3-yl)methyl]-1H-indol-7-yl}carbonyl)amino]ethyl}benzoic acid (9.0 mg).
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[NH:3][C:2]=1[C:10]1[C:18]2[N:17]3[CH:19]=[CH:20][CH:21]=[C:16]3[C:15](=[N:22]O)[C:14]=2[CH:13]=[CH:12][CH:11]=1.C(O)C.O>C(O)(=O)C.[Zn]>[N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[NH:3][C:2]=1[C:10]1[C:18]2[N:17]3[CH:19]=[CH:20][CH:21]=[C:16]3[CH:15]([NH2:22])[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: ON=C1c2cccc(-c3nc4ccncc4[nH]3)c2-n2cccc21
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: NC1c2cccc(-c3nc4ccncc4[nH]3)c2-n2cccc21
Temperature: 25 °C
Yield: 26.7 %

Procedure:
In a 100 ml round-bottomed flask, a mixture of 200 mg of 5-(3H-imidazo[4,5-c]pyridin-2-yl)pyrrolo[1,2-a]indol-9-one oxime obtained according to the preceding stage, in 5 ml of glacial acetic acid, 5 ml of ethanol and 5 ml of water, is stirred at ambient temperature. 43 mg of powdered zinc are added and the stirring is maintained at ambient temperature for 2 hours. The reaction medium is filtered through clarcel, washing being carried out with methanol. The filtrate is evaporated to dryness under vacuum and the residue is chromatographed on silica gel (15-40 μm), elution being carried out with a mixture of dichloromethane and 5N ammoniacal methanol (95/5 v/v). 51 mg of 5-(3H-imidazo[4,5-c]pyridin-2-yl)-9H-pyrrolo[1,2-a]indol-9-ylamine are obtained in the form of a solid, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][N:22]1[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[N:23]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:27]([C:24]3[CH:25]=[CH:26][N:22]([CH3:21])[N:23]=3)=[O:28])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: Cn1ccc(C(=O)O)n1
Product: Cn1ccc(C(=O)Nc2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 1-methyl-1H-Pyrazole-3-carboxylic acid as starting materials, MS (LC/MS): 411.0 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=2)[CH:3]=1.C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.C[C:49]([N:51](C)C)=O>FC(F)(F)C([O-])=O.[Pd+2].FC(F)(F)C([O-])=O.[Zn].[C-]#N.[Zn+2].[C-]#N>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][NH:9][C:4]2[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([C:49]#[N:51])[CH:3]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(CNc2cc(Cl)nc(C)n2)cc1
Reactant: CC(=O)N(C)C
Agent: [Pd+2]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Agent: O=C([O-])C(F)(F)F
Product: Cc1nc(C#N)cc(NCc2ccc(O)cc2)n1
Temperature: 95 °C

Procedure:
6-chloro-N-(4-methoxybenzyl)-2-methylpyrimidin-4-amine (500 mg, 01.90 mmol) from Step 1 from this example, palladium (II) trifluoroacetate (27.1 mg, 0.082 mmol), zinc dust (23.6 mg, 0.36 mmol), rac-2-(di-t-butylphosphino)-1,1-binaphthyl (66.5 mg, 0.17 mmol), zinc cyanide (125 mg, 1.1 mmol) was added dimethylacetamide (10 mL) in a flask (flame-dried) and evacuated and back-filled with N2 (3×). The reaction was heated to 95° C. for 30 min, cooled to room temperature. Water (20 mL) was added, extracted with ethyl acetate (20 mL), second wash with brine (20 mL). The organic phase was dried by magnesium sulfate and filtered through silica gel pad (1 inch deep), concentrated and purified by column chromatography through a 40 gram RediSep Rf™ silica gel cartridge eluting with 18% ethyl acetate/hexanes to give the title compounds as a pale yellow oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[N:2]1.[Cl:10][S:11](O)(=[O:13])=[O:12]>>[S:1]1[C:5]2[C:6]([S:11]([Cl:10])(=[O:13])=[O:12])=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[N:2]1
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc2sncc2c1
Product: O=S(=O)(Cl)c1cccc2cnsc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.6 %

Procedure:
Benzo[d]isothiazole 24B (1 g, 7.45 mmol) was added dropwise to chlorosulfonic acid (5.5 mmol) at 0° C. After the addition was complete, the mixture was stirred at room temperature for 0.5 h and then heated at 105° C. and stirred overnight. The resulting mixture was cooled to −10° C. and quenched by pouring on crushed ice slowly. The resulting mixture was extracted with EtOAc (100 mL×2). The combined organic phase was washed with brine, dried over anhy. Na2SO4 and concentrated in vacuo. Column chromatography (15% PE/EtOAc) afforded 200 mg of title compound. 1H NMR (CHLOROFORM-d) δ: 9.68 (s, 1H), 8.66 (d, J=1.9 Hz, 1H), 8.10 (d, J=9.4 Hz, 1H), 7.99 (dd, J=9.4, 2.1 Hz, 1H).
Reaction SMILES: [C:1]([O:32]C)(=[O:31])[CH2:2][CH2:3][C:4]([O:6][CH2:7][C:8]([CH3:30])([CH3:29])[O:9][C:10]1[CH:11]=[CH:12][C:13]2[C:14]3[C:22]([CH2:23][CH2:24][C:25]=2[CH:26]=1)=[C:21]1[C:17]([C:18]([CH3:28])([CH3:27])[CH2:19][CH2:20]1)=[CH:16][CH:15]=3)=[O:5].[I-].[Li+].Cl>N1C=CC=CC=1>[C:4]([O:6][CH2:7][C:8]([CH3:30])([CH3:29])[O:9][C:10]1[CH:11]=[CH:12][C:13]2[C:14]3[C:22]([CH2:23][CH2:24][C:25]=2[CH:26]=1)=[C:21]1[C:17]([C:18]([CH3:28])([CH3:27])[CH2:19][CH2:20]1)=[CH:16][CH:15]=3)(=[O:5])[CH2:3][CH2:2][C:1]([OH:32])=[O:31]
Reactant: COC(=O)CCC(=O)OCC(C)(C)Oc1ccc2c(c1)CCc1c-2ccc2c1CCC2(C)C
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CC(C)(COC(=O)CCC(=O)O)Oc1ccc2c(c1)CCc1c-2ccc2c1CCC2(C)C

Procedure:
A mixture of 7 parts of methyl 2,2-dimethyl-2-[(7,15,16,17-tetrahydro-17,17-dimethyl-6H-cyclopenta[a]phenanthren-3-yl)oxy]ethyl butanedioate and 24 parts of lithium iodide in 700 parts of pyridine is heated at the boiling point under reflux for 3 days, then cooled and thereupon poured into 1000 parts of approximately 4% hydrochloric acid. The resultant mixture is extracted with dichloromethane. The dichloromethane extract is consecutively washed with 4% hydrochloric acid and water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. The residue is crystallized from a mixture of ether and hexane to give 2,2-dimethyl-2-[(7,15,16,17-tetrahydro-17,17-dimethyl-6H-cyclopenta[a]phenanthren-3-yl)oxy]ethyl hydrogen butanedioate melting at 118°-120°. The product has the formula ##STR10##
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[NH:17][CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O1CCOCC1>>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:25])[NH:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(NC(=O)NCCC(=O)OCC)cc1
Solvent: C1COCCO1
Product: CCCCCCCCc1ccc(NC(=O)NCCC(=O)O)cc1
Temperature: 25 °C
Yield: 65.5 %

Procedure:
To a solution of the product of Step A (0.05 g; 0.143 mmol) in dioxane (1 ml) 2N KOH (0.36 ml; 0.72 mmol) was added and the mixture was refluxed for 15 min, cooled to room temperature and evaporated to dryness under reduced pressure. The residue was diluted to 2 ml with H2O and filtered. The filtrate was acidified to pH ˜4 with citric acid. The solid formed was filtered off, washed with H2O (3×2 ml), dried in vacuo to give the title compound (0.03 g; 65%), as a colourless solid. 1H-NMR (CD3OD+CDCl3) 7.16 (d, 2H, J=8.4 Hz); 7.0 (d, 2H, J=8.4 Hz); 4.21 (s, CD3OH); 3.4 (t, 2H, J=6.7 Hz); 2.73 (m, 4H); 2.5-2.44 (m, 4H); 1.5 (m, 2H); 1.2 (m, 10H); 0.81 (m, 3H).