Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]1([N:17]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:18]([O:20][CH2:21][C:22]2([OH:41])[CH:28]([OH:29])[CH2:27][CH2:26][C:25]3[C:30]([O:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:31][CH:32]=[CH:33][C:24]=3[CH2:23]2)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCN(CC)CC>C(Cl)Cl.CCOC(C)=O>[C:42]1([N:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:18]([O:20][CH2:21][C:22]2([OH:41])[C:28](=[O:29])[CH2:27][CH2:26][C:25]3[C:30]([O:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:31][CH:32]=[CH:33][C:24]=3[CH2:23]2)=[O:19])[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: CCOC(=O)COc1cccc2c1CCC(O)C(O)(COC(=O)N(c1ccccc1)c1ccccc1)C2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)COc1cccc2c1CCC(=O)C(O)(COC(=O)N(c1ccccc1)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 65.1 %

Procedure:
To a solution of oxalyl chloride (0.052 ml) in CH2Cl2 (10 ml) was added a solution of DMSO (0.084 ml) in CH2Cl2 (0.5 ml) keeping the temperature below −55° C. The mixture was stirred for 20 minutes. After addition of a solution of ethyl {[(6RS,7RS)-6-(N,N-diphenylcarbamoyloxy)methyl-6,7-dihydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-1-yl]oxy}acetate (150 mg) in CH2Cl2 (3 ml) at the same temperature, the mixture was stirred for 30 minutes. After addition of Et3N (0.33 ml), the mixture was warmed to room temperature over 30 minutes. After stirring for 1 hour at the same temperature, the mixture was diluted with EtOAc, washed with 1N-hydrochloric acid, water, saturated sodium hydrogencarbonate solution, water, and then brine. It was dried over magnesium sulfate and then evaporated. The residue was purified by silica gel column chromatography (hexane-EtOAc 5:2) to give ethyl {[6-(N,N-diphenylcarbamoyloxy)methyl-6-hydroxy-7-oxo-6,7,8,9-tetrahydro-5H-benzocyclohepten-1-yl]oxy}acetate (97.2 mg) as a solid.
Reaction SMILES: C(N(CC)CC)C.[N:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][C:20]([SH:22])=[N:19][N:18]=3)=[CH:13][C:12]=12.Cl[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:33][CH3:34])=[C:29]([CH:32]=1)[C:30]#[N:31]>>[CH3:34][O:33][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][S:22][C:20]2[O:21][C:17]([C:14]3[CH:15]=[CH:16][N:11]4[N:10]=[CH:9][N:8]=[C:12]4[CH:13]=3)=[N:18][N:19]=2)=[CH:32][C:29]=1[C:30]#[N:31]
Reactant: Sc1nnc(-c2ccn3ncnc3c2)o1
Reactant: COc1ccc(CCl)cc1C#N
Solvent: CCN(CC)CC
Product: COc1ccc(CSc2nnc(-c3ccn4ncnc4c3)o2)cc1C#N
Yield: 56 %

Procedure:
In the same manner as in Example 1 and using 5-(1,2,4-triazolo[1,5-a]pyridin-7-yl)-1,3,4-oxadiazole-2-thiol triethylamine salt instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 5-(chloromethyl)-2-methoxybenzonitrile instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 56%) was obtained as pale-brown crystals.
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:13])[C:9]([OH:23])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:24][S:25]([N:28]1[CH2:34][CH2:33][S:32](=[O:36])(=[O:35])[NH:31][CH2:30][CH2:29]1)(=[O:27])=[O:26]>N1C=CC=CC=1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:12]([C:10]2[C:9]([OH:23])=[C:8]3[C:3]([CH:4]=[CH:5][CH:6]=[N:7]3)=[C:2]([N:31]3[CH2:30][CH2:29][N:28]([S:25]([CH3:24])(=[O:26])=[O:27])[CH2:34][CH2:33][S:32]3(=[O:36])=[O:35])[N:11]=2)=[O:13])=[CH:17][CH:18]=1
Reactant: O=C(NCc1ccc(F)cc1)c1nc(Br)c2cccnc2c1O
Reactant: CS(=O)(=O)N1CCNS(=O)(=O)CC1
Solvent: c1ccncc1
Product: CS(=O)(=O)N1CCN(c2nc(C(=O)NCc3ccc(F)cc3)c(O)c3ncccc23)S(=O)(=O)CC1
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-N-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide (0.147 g, 0.39 mmol), 5-(methylsulfonyl)-1,2,5-thiadiazepane 1,1-dioxide (0.081 g, 0.355 mmol) and Cu2O (0.056 g, 0.39 mmol) in pyridine (2.4 mL) were heated at reflux for 16 hr. The reaction was filtered and the solids washed with CHCl3 (100 mL). The filtrate was stirred for 1 hr with disodium ethylenediamine tetraacetate (0.2 g in water 10 mL) in the presence of air. The organic extracts were stirred for 1 hr with disodium ethylenediamine tetraacetate (0.2 g in water 10mL) in the presence of air. The organic extracts were dried (MgSO4) and the solvent evaporated in vacuo. The residue was purified by preparative HPLC (Gilson semi preparative HPLC system and a YMC Combiprep Pro Column (50×20 mm I.D., C18, S-5 um, 120A) eluting with 5-95% acetonitrile/water (0.1% TFA) at 15 ml/min) to afford the title compound after lyophilization.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([C:19]#[N:20])[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1.[C:28](C1C2C=CC=CC=2ONC1=O)#[N:29].CN>O1CCCC1>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]([NH:8][C:9]2[C:10]([C:11]([NH:29][CH3:28])=[O:13])=[CH:14][C:15]([C:19]#[N:20])=[CH:16][C:17]=2[CH3:18])=[O:12])[N:4]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1
Reactant: Cc1cc(C#N)cc2c(=O)oc(-c3cc(Cl)nn3-c3ncccc3Cl)nc12
Reactant: N#CC1C(=O)NOc2ccccc21
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)c1cc(C#N)cc(C)c1NC(=O)c1cc(Cl)nn1-c1ncccc1Cl
Reaction time: 0.08 h

Procedure:
To a solution of 2-[3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-cyano-8-methyl-4H-3,1-benzoxazin-4-one (e.g. the cyanobenzoxazinone product of Step F) (100 mg, 0.25 mmol) in tetrahydrofuran (5 mL) was added dropwise methylamine (2.0 M solution in THF, 0.5 mL, 1.0 mmol) and the reaction mixture was stirred for 5 minutes, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was purified by chromatography on silica gel to afford the title compound, a compound of the present invention, as a white solid (52 mg), which decomposed in the melting apparatus above 140° C.
Reaction SMILES: [C:1]([N:4]1[CH2:11][CH2:10][C:9](=[O:12])[NH:8][CH2:7][C:6]2[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:5]1=2)(=[O:3])[CH3:2].Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:35]([CH3:36])=[CH:34][CH:33]=[CH:32][C:27]=2[O:28][CH2:29][C:30]#[N:31])[C:22]([Cl:37])=[CH:21][N:20]=1>>[C:1]([N:4]1[CH2:11][CH2:10][C:9](=[O:12])[NH:8][CH2:7][C:6]2[CH:13]=[C:14]([NH:17][C:19]3[N:24]=[C:23]([NH:25][C:26]4[C:35]([CH3:36])=[CH:34][CH:33]=[CH:32][C:27]=4[O:28][CH2:29][C:30]#[N:31])[C:22]([Cl:37])=[CH:21][N:20]=3)[CH:15]=[CH:16][C:5]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(=O)NCc2cc(N)ccc21
Reactant: Cc1cccc(OCC#N)c1Nc1nc(Cl)ncc1Cl
Product: CC(=O)N1CCC(=O)NCc2cc(Nc3ncc(Cl)c(Nc4c(C)cccc4OCC#N)n3)ccc21

Procedure:
Title compound was prepared from 1-Acetyl-8-amino-2,3,5,6-tetrahydro-1H-benzo[b][1,5]diazocin-4-one and [2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-methyl-phenoxy]-acetonitrile in an analogous manner to Example 1221d. Product was isolated as a white solid (104 mg, 76%). MP: 210-214, LCMS 506.15 (M+H), HPLC purity 97%, 1H-NMR (DMSO-d6, 400 MHz) δ 9.65-9.63 (m, 1H), 8.83-8.85 (m, 1H), 8.15 (s, 1H), 7.6307.61 (m, 1H), 7.36-7.32 (m, 3H), 7.14 (d, J=8.5 Hz, 1H), 7.07 (d, J=7.7 Hz, 1H), 6.90 (d, J=8.6 Hz, 1H), 5.11 (s, 2H), 2.58-2.54 (m, 2H), 4.15-4.11 (m, 1H), 3.60-3.52 (m, 1H), 2.85-2.81 (m, 1H), 2.28-2.24 (m, 1H), 2.16 (s, 3H), 1.60 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]=[CH2:23])=[CH:18][C:17]=2[F:24])=[C:7]([F:14])[C:8]2[N:9]([CH:11]=[CH:12][N:13]=2)[CH:10]=1)=[O:4]>C(O)C.[Pd]>[CH3:1][O:2][C:3]([C:5]1[C:6]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][C:17]=2[F:24])=[C:7]([F:14])[C:8]2[N:9]([CH:11]=[CH:12][N:13]=2)[CH:10]=1)=[O:4]
Reactant: C=Cc1ccc(Nc2c(C(=O)OC)cn3ccnc3c2F)c(F)c1
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc(Nc2c(C(=O)OC)cn3ccnc3c2F)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.4 %

Procedure:
8-Fluoro-7-(2-fluoro-4-vinyl-phenylamino)-imidazo[1,2-a]pyridine -6-carboxylic acid methyl ester (165 mg, 0.50 mmol) was suspended in ethanol (5mL), added 10% Pd/C (267 mg, 0.25 mmol) and placed under an atmosphere of H2. The reaction mixture was stirred vigorously at room temperature for 16 hours. The reaction mixture was filtered through CELITE, washed with ethanol and tetrahydrofuran and the filtrate concentrated to a yellow oil. Purification of the crude product by flash column chromatography (gradient of dichloromethane to 20:1 dichloromethane/methanol) provided the desired product (110 mg, 66%) as a dark yellow solid. MS ESI (+) m/z 332 (M+1) detected.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Cl[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22].[OH-].[K+].Cl>O.[I-].[K+].C(O)C>[OH:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: OCCCCCCCCCCCl
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(OCCCCCCCCCCO)cc1
Reaction time: 18 h
Yield: 57.9 %

Procedure:
A mixture of 4-hydroxybenzoic acid (69.0 g, 0.5 mol), 10-chloro-1-decanol (106 g, 0.55 mol), potassium hydroxide (75 g, 1.15 mol), potassium iodide (0.1 g), and absolute ethanol (300 mL) was heated to reflux with mechanical stirring for 18 hours. The mixture was diluted with water (800 mL) and stirred 0.5 hours at room temperature. The mixture was acidified with 12N hydrochloric acid (125 mL) and the mixture stirred for 5 hours. The material was allowed to sit overnight and filtered. The solid was washed with water and air dried 4 days. The solid was recrystallized from tetrahydrofuran (300 mL) to give 4-(10-hydroxydecyloxy)benzoic acid (85.2 g, 58%): mp 115°-117° C.; NMR (CDCl3+d6 DMSO) 7.93(d, 2H), 6.85(d, 2H), 4.0(t, 2H), 3.52(t, 2H), 3.48(bs, 1H), 1.9-1.2(m, 16H).
Reaction SMILES: B(Br)(Br)Br.Cl.[N:6]12[CH2:13][CH2:12][CH:9]([CH2:10][CH2:11]1)[C@@H:8]([NH:14][C:15]([C:17]1[O:18][C:19]3[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32]C)=[CH:24][CH:23]=[CH:22][C:20]=3[CH:21]=1)=[O:16])[CH2:7]2.C(OCC)C.[OH-].[Na+]>ClCCl.O>[N:6]12[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13]1)[C@@H:8]([NH:14][C:15]([C:17]1[O:18][C:19]3[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[OH:32])=[CH:24][CH:23]=[CH:22][C:20]=3[CH:21]=1)=[O:16])[CH2:7]2
Reactant: COc1ccccc1-c1cccc2cc(C(=O)N[C@H]3CN4CCC3CC4)oc12
Agent: BrB(Br)Br
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3ccccc3O)c2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.42 ml of a 1 M boron tribromide solution in dichloromethane are added dropwise to a suspenion, cooled to −20° C., of 200 mg (0.48 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-(2-methoxyphenyl)-1-benzofuran-2-carboxamide hydrochloride (Example 102) in 8 ml of dichloromethane. After 2 h, the reaction is stopped by adding diethyl ether. The mixture is stirred at room temperature for 30 min and, after addition of water, neutralized with 1N sodium hydroxide solution. After extraction with ethyl acetate, the organic phases are combined and dried over sodium sulphate. Concentration and drying under high vacuum result in 125.9 mg (71.7% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([O:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:18])=[N:6][CH:7]=1.[C:27]1(=O)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C([BH3-])#N.[Na+].Cl>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:26])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([O:19][CH:20]2[CH2:21][CH2:22][N:23]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:24][CH2:25]2)=[O:18])=[N:6][CH:7]=1
Reactant: O=C1CCCCC1
Reactant: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)OC1CCNCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)OC1CCN(C2CCCCC2)CC1
Yield: 65.2 %

Procedure:
Using a similar procedure to that described in Example 9-C, N-(5-chloropyridin-2-yl)-2-[(piperidin-4-yloxycarbonyl)amino]benzamide (100 mg, 0.205 mmol), cyclohexanone (0.106 mL, 1.02 mmol), and sodium cyanoborohydride (51 mg, 0.82 mmol) yielded, after treatment with HCl, 33 mg (33%) of the title compound as a hydrochloride salt.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[CH2:9][CH2:8][C:7]2([CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)[CH2:6][CH2:5]1.Cl>C(O)C>[OH:15][CH:12]1[CH2:11][CH2:10][C:7]2([CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]2)[CH2:14][CH2:13]1
Reactant: O=C1CCC2(CC1)CCC(=O)CC2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C1CCC2(CC1)CCC(O)CC2
Reaction time: 1.5 h
Yield: 27.7 %

Procedure:
Sodium borohydride (0.400 g) was added in portions to a solution of 10.0 g of 3,9-dioxo-spiro[5.5]undecane (III) (Rice L. M. et al., J.Org.Chem., 1967, 32, 1966) in 80 ml of ethanol, under nitrogen atmosphere, at room temperature. After 1.5 hrs, 10.0 ml. of 1N hydrochloric acid were added and the resulting mixture was evaporated under reduced pressure. The crude residue, dissolved in 150 ml. of ethyl acetate, was washed with water to neutrality. The organic layer, dried over anhydrous sodium sulfate, was evaporated to dryness under reduced pressure to give a mixture of starting material, 3,9-dihydroxy- and 9-hydroxy-3-oxo-spiro[5.5]undecane. The components of the mixture were separated by flash chromatography (SiO2 ; ethyl acetate/n-hexane 70/30) and 2.80 g of 9-hydroxy-3-oxo-spiro[5.5]undecane were obtained as a white solid, mp 65°-67° C. TLC: Rf=0.32 (SiO2 plates, diethylether) 1H-NMR (300 MHz, CDCl3, ppm from TMS): 3.75 (1H, hept), 2.35 (4H, q), 1.25-1.95 (12H, m)
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[N:11]1[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(Cl)cc2Cl)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(N2CCCNCC2)c(Cl)c1
Yield: 96.6 %

Procedure:
To a solution of 4-(2,4-dichloro-phenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (0.13 g, 0.38 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL). The reaction was stirred until complete (as monitored by LC-MS) and the volatiles were removed in vacuo. The residue was partitioned between ethyl acetate (5 mL) and saturated aqueous sodium bicarbonate (5 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as a gum (0.09 g, 100%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CN(C)C>>[OH:1][CH2:2][C:3]1[CH:7]=[CH:6][N:5]([C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:4]=1
Reactant: OCc1cc[nH]n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)C
Product: OCc1ccn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 60 %

Procedure:
This compound was prepared from 3-(hydroxymethyl)-1 H-pyrazole, [J. Am. Chem. Soc, 71, 3996, (1949)], trityl chloride and trimethylamine using the method of Preparation 18, above. The crude product was purified by flash chromatography (gradient elution with hexane/ethyl acetate) to give a white solid (1.428 g, 60%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][CH:3]1[CH2:18][CH3:19].B(F)(F)F.[CH3:24]COCC>CO>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([O:17][CH3:24])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][CH:3]1[CH2:18][CH3:19]
Reactant: CCOCC
Reactant: CCC1Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Agent: FB(F)F
Solvent: CO
Product: CCC1Cc2cc(OCC(=O)OC)c(Cl)c(Cl)c2C1=O
Yield: 73 %

Procedure:
A solution of (1-oxo-2-ethyl-6,7-dichloro-5-indanyloxy)-acetic acid (138.5 g., 0.457 mole) in methanol (1.5 1.) and containing boron trifluoride etherate (325 g., 2.28 mole) is refluxed for 3/4 hour. The solvent is distilled at reduced pressure and the product which remains is filtered, washed with sodium bicarbonate and water and dried. The methyl (1-oxo-2-ethyl-6,7-dichloro-5-indanyloxy)acetate thus obtained (81 g., 73% yield) melts at 134°-137° C. after recrystallization from benzene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([N+:22]([O-])=O)[C:11]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH3:25]C(O)=O>[Zn]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[N:22]=[CH:25][N:14]([C:15]4[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=4)[C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: Nc1cccc(Nc2ncc(-c3ccc(F)cc3)cc2[N+](=O)[O-])c1
Agent: [Zn]
Product: Nc1cccc(-n2cnc3cc(-c4ccc(F)cc4)cnc32)c1
Temperature: 60 °C

Procedure:
Zinc dust (9.3 g, 142 mmol) was added to a stirred solution of N-[5-(4-fluoro-phenyl)-3-nitro-pyridin-2-yl]-benzene-1,3-diamine (2.3 g, 7.1 mmol) in AcOH (35 ml) at RT. After the exotherm had subsided the reaction was stirred and heated at 60° C. for 3 hours. The mixture was allowed to cool to RT then filtered through Celite—washing with AcOH (˜150 ml). The filtrate was evaporated and the residue was azeotroped with toluene (×2). The residue was taken up in trimethylorthoformate (50 ml) and then stirred and heated at reflux under N2 for 1 hour. After cooling to RT, the volatiles were removed in vacuo. The residue was taken up in EtOH (100 ml). c. HCl (4 ml) was added and the mixture was heated at reflux for 2 hours. After cooling, the mixture was concentrated to ˜4 ml and basified with saturated aqueous NaHCO3. The aqueous mixture was extracted with CH2Cl2 (×3). The combined extracts were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica (40→100% EtOAc/petrol) to give the title compound (0.86 g).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH:5]([CH3:16])[CH2:4]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:16][CH:5]1[CH2:4][CH:3]([CH2:2][NH2:1])[CH2:8][CH2:7][NH:6]1
Reactant: CC1CC(CN)CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CC(CN)CCN1

Procedure:
A mixture comprising tert-butyl 4-(aminomethyl)-2-methylpiperidine-1-carboxylate (2 g, 8.76 mmol) and trifluoroacetic acid (10 ml, 130 mmol) in DCM (29.2 ml) was stirred at room temperature for 1 hour. The resulting mixture was loaded on to an Isolute® SCX-2 10 g cartridge and washed with DCM. The product was eluted with 7M ammonia in MeOH and concentrated under reduced pressure. The crude material was suspended in EtOH and filtered. The filtrate was concentrated under pressure to afford the title compound which was used in the next step without further purification;
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[F:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)=[CH:10][CH:9]=1
Reactant: Brc1cccs1
Reactant: OB(O)c1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Fc1ccc(-c2cccs2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-bromothiophene (233.0 g, 1.43 mol), 4-fluorophenyl boronic acid (200.0 g, 1.43 mol), bis(triphenylphosphine)palladium(II) dichloride (10.0 g, 14.2 mmol) and aqueous Na2CO3 (454.5 g, 4.3 mol in 1.5 L of H2O) in 1,2-dimethoxyethane (2 L) was stirred at 75-80° C. (internal temperature) for 2 hours. The resulting mixture was cooled to room temperature and then stirred overnight. The solid was separated and discarded. The liquid was washed with water (2×500 mL). The combined aqueous layer was extracted with diethylether (2×500 mL). The combined organic layers were then dried over NaCl, concentrated and purified by flask distillation to yield the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([N:11]3[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18](=[O:20])[OH:19])[CH2:12]3)=[C:5]2[NH:4][C:3]1=[O:21].Br[CH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1>>[C:24]([O:20][C:18](=[O:19])[NH:17][C@@H:13]1[CH2:14][CH2:15][CH2:16][N:11]([C:10]2[CH:9]=[CH:8][N:7]=[C:6]3[N:2]([CH3:1])[C:3](=[O:21])[N:4]([CH2:23][C:24]4[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=4)[C:5]=23)[CH2:12]1)([CH3:31])([CH3:25])[CH3:23]
Reactant: Cn1c(=O)[nH]c2c(N3CCC[C@@H](NC(=O)O)C3)ccnc21
Reactant: N#Cc1ccc(CBr)cc1
Product: Cn1c(=O)n(Cc2ccc(C#N)cc2)c2c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)ccnc21
Yield: 126.1 %

Procedure:
The specific operation referred to the step (5) described in Example 1 for details. 347 mg (R)-1-(3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl)piperidin-3-yl carbamic acid ter.-butyl ester (1 mmol) and 235 mg 4-(bromomethyl)benzonitrile (1.2 mmol) were charged. A column chromatography was performed to afford 350 mg titled product with a yield of 75.6%.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:12]([NH2:14])=O>O>[I:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:12][N:14]=[C:4]2[OH:5]
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: NC=O
Solvent: O
Product: Oc1ncnc2ccc(I)cc12
Temperature: 190 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A mixture of 2-amino-5-iodobenzoic acid (125 g, 475 mmol) and formamide (200 mL) was heated to 190° C. for 2 hours. After cooling to room temperature, the reaction mixture was poured into water (500 mL) and stirred for 2 hours. The solids were filtered and dried under high vacuum to provide the product (108 g, 83%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][N:3]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O.O.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>[F:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][N:3]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COCOc1ccc(Cl)nc1
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: O
Solvent: CN(C)C=O
Product: COCOc1ccc(-c2cccc(F)c2)nc1
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
200 mg (1.0 eq) of the obtained 2-chloro-5-(methoxymethoxy)pyridine was dissolved in N,N-dimethylformamide/H2O=5:1 (16 mL), 193 mg (1.2 eq) of (3-fluorophenyl)boronic acid, 48 mg (3 mol %) of Pd(PPh3)4 and 586 mg (4.0 eq) of Na2CO3 were added. After reacting with microwave reactor at 120° C. for 30 minutes, N,N-dimethylformamide was removed by concentrating under reduced pressure. After extracting with ethyl acetate, the extract was treated with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (developing solvent, hexane:ethyl acetate=9:1) to obtain 220 mg of 2-(3-fluorophenyl)-5-(methoxymethoxy)pyridine.