Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.[I:10]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:9][C:4]1[N:3]=[C:2]([NH2:1])[C:7]([I:10])=[C:6]([Cl:8])[N:5]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1cc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(Cl)nc(Cl)c1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.9 %

Procedure:
1 g (6.1 mmol) of 4-amino-2,6-dichloropyrimidine were dissolved in 5 ml of DMF. To this solution was added 0.76 g (7.32 mmol) of N-Iodosuccinimide. The solution was stirred 18 h at room temperature and then poured onto 100 ml of cool water. The formed precipitate was filtered, washed with water and dried to yield 1.2 g (76%) of a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.Br[CH2:28][CH:29]1[CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:6]([O:8][CH2:28][CH:29]2[CH2:31][CH2:30]2)[CH:7]=1
Reactant: BrCC1CC1
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Product: Fc1cc2nc(-c3ccc(Cl)cc3OCC3CC3)n(CC3CCCCC3)c2cc1F

Procedure:
The title compound was prepared in analogy to Example 19, from 5-chloro-2-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-phenol (Example 19, intermediate a) and bromomethyl-cyclopropane (7051-34-5). Off-white powder (35%). MS (Turbo Spray): m/z=431.0 (M+H).
Reaction SMILES: [C:1]([S:5][CH:6]1[N:9]([CH:10]([C:24](=[O:30])[C:25]([CH3:29])([CH3:28])[CH2:26]Cl)[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C:8](=[O:31])[CH2:7]1)([CH3:4])([CH3:3])[CH3:2].[CH3:32][N:33]1[C:37]([SH:38])=[N:36][N:35]=[N:34]1>CN(C)C=O>[C:1]([S:5][CH:6]1[N:9]([CH:10]([C:24](=[O:30])[C:25]([CH3:29])([CH3:28])[CH2:26][S:38][C:37]2[N:33]([CH3:32])[N:34]=[N:35][N:36]=2)[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C:8](=[O:31])[CH2:7]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1nnnc1S
Reactant: CC(C)(C)SC1CC(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)C(C)(C)CCl
Solvent: CN(C)C=O
Product: Cn1nnnc1SCC(C)(C)C(=O)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1SC(C)(C)C

Procedure:
A mixture of 118 mg (0.25 mmol) of p-nitrobenzyl 2-(4-tert-butylthio-2-oxo-1-azetidinyl)-5-chloro-4,4-dimethyl-3-oxopentanoate and 82 mg (0.59 mmol) of the Na salt of 1-methyl-5-mercapto-1,2,3,4-tetrazole are stirred for 20 hours at room temperature in 0.2 ml of dimethylformamide. The reaction mixture is chromatographed directly on a chromatography column containing 6 g of silica gel using toluene:ethyl acetate (19:1), to give 60 mg of pure title compound as a non-crystalline solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:36]=1[O:37]C)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30]C)=[C:26]([O:32]C)[CH:25]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:32][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=1[OH:30])[CH2:23][CH:19]1[CH2:20][CH2:21][CH2:22][N:18]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][CH:7]1[CH2:6][C:5]1[CH:34]=[CH:35][C:36]([OH:37])=[C:3]([OH:2])[CH:4]=1
Reactant: COc1ccc(CC2CCCN2CCCCCCN2CCCC2Cc2ccc(OC)c(OC)c2)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Oc1ccc(CC2CCCN2CCCCCCN2CCCC2Cc2ccc(O)c(O)c2)cc1O
Temperature: -70 °C

Procedure:
1,6-bis[2-(3,4-dimethoxybenzyl)pyrrolidin-1-yl]hexane was dissolved in dry CH2Cl2 and cooled to -70° C. under inert atmosphere. BBr3 was added. The mixture was warmed to room temperature and CH3OH was added. The solvent was removed in vacuo to give 1,6-bis-[2-(3,4-dihydroxybenzyl)pyrrolidin-1-yl]hexane.
Reaction SMILES: Cl.[CH2:2]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:21])=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH:16]([CH3:20])[CH2:15]3)[CH:12]=2)[C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5]1)[CH3:3].C=O.[C:28](=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(O)=O>[CH3:20][CH:16]1[N:17]([CH3:28])[CH2:18][CH2:19][N:14]([C:11]2[CH:12]=[C:13]3[C:8]([C:7](=[O:22])[C:6]([C:23]([OH:25])=[O:24])=[CH:5][N:4]3[CH2:2][CH3:3])=[CH:9][C:10]=2[F:21])[CH2:15]1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(C)C3)cc21
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: Cl
Agent: [K+]
Solvent: O=CO
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)C(C)C3)cc21
Yield: 96.6 %

Procedure:
A mixture of 2.69 g of 1-ethyl-6-fluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxoquinoline-3-carboxylic acid hydrochloride, 5.4 ml 90% formic acid, 3.5 ml of 37% formalin and 0.70 g of potassium carbonate was heated for 5 hours under reflux. The reaction mixture was neutralized with 20% aqueous sodium hydroxide. The precipitate was filtered and recrystallized from a mixture of chloroform and methanol to give 1.70 g of the title compound as colorless needles, M.p. 244°-246° C.
Reaction SMILES: [CH2:1]([O:7][CH:8]1[NH:12][C:11](=[O:13])[CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[CH2:16]([N:12]1[CH:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:9][CH2:10][C:11]1=[O:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: CCCCCCOC1CCC(=O)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCCOC1CCC(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a mixture of 3.5 g of 5-(n-hexyloxy)-pyrrolidin-2-one, 1.58 g of potassium hydroxide hydrated to 85% and 0.35 g of tetra-n-butylammonium bromide in 50 cm3 of tetrahydrofuran, there is added, at 20° C. to 25° C. a solution of 3.23 g of benzyl bromide in 20 cm3 of tetrahydrofuran. After agitating for 1 hour at ambient temperature, filtering, evaporating to dryness and chromatographing the residue on silica (eluent: ethyl acetate--n-hexane, 1-2), 3.64 g of the expected product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([CH3:20])[CH:3]=1.[OH:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+]>O1CCOCC1.O.C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Rh].[Rh]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:25]2[CH:26]=[CH:27][C:22]([OH:21])=[CH:23][CH:24]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([CH3:20])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1/C=C/C(=O)c1ccc(=O)n(C)c1
Reactant: OB(O)c1ccc(O)cc1
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: O
Solvent: C1=CCCC=CCC1
Product: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(O)cc1

Procedure:
In analogy to example 203, step 1, 5-[(E)-3-(4-chloro-2-methyl-phenyl)-acryloyl]-1-methyl-1H-pyridin-2-one (example 323, step 3) was reacted with 4-hydroxyphenylboronic acid in the presence of chloro(1,5-cyclooctadiene)rhodium(I) dimer and sodium hydrogencarbonate in 1,4-dioxane and water at 60° C. to give the title compound as a colourless solid, MS (ESI−): m/z=380.1 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[C:57]([O:61][C:62](=[O:76])[CH2:63][C:64]1([C:69]2[CH:74]=[CH:73][C:72]([NH2:75])=[CH:71][CH:70]=2)[CH2:68][CH2:67][CH2:66][CH2:65]1)([CH3:60])([CH3:59])[CH3:58]>CN(C)C=O.CO.ClCCl>[C:57]([O:61][C:62](=[O:76])[CH2:63][C:64]1([C:69]2[CH:74]=[CH:73][C:72]([NH:75][C:21](=[O:23])[CH2:20][C:5]3[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:71][CH:70]=2)[CH2:68][CH2:67][CH2:66][CH2:65]1)([CH3:60])([CH3:58])[CH3:59]
Reactant: CC(C)(C)OC(=O)CC1(c2ccc(N)cc2)CCCC1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COc1cc(CC(=O)Nc2ccc(C3(CC(=O)OC(C)(C)C)CCCC3)cc2)ccc1NC(=O)Nc1ccccc1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A stirred solution of [3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetic acid (0.26 g, prepared as described in Example 52 of International Patent Application Publication No. WO 96/22966) in dry dimethylformamide (15 mL), under argon, was treated with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.32 g). This solution was stirred at room temperature for 10 minutes and then treated with diisopropylethylamine (0.28 ml) and a solution of [1-(4-amino-phenyl)-cyclopentyl]-acetic acid tert-butyl ester (0.21 g, Reference Example 5a) in dry dimethylformamide (5 mL). The resulting amber coloured solution was stirred at room temperature for 2 hours and then evaporated to low bulk. The residue was partitioned between water (containing 1 mL of 1M hydrochloric acid solution) and ethyl acetate. The organic phase was washed with water, then with brine, then dried over magnesium sulfate and then evaporated to yield a fawn solid which was subjected to flash chromatography on silica eluting with a mixture of dichloromethane and methanol (49:1, v/v) to give the title compound (0.30 g) as a pale yellow solid. MS(ES+): 594(M+Na)+; MS (ES−): 570 (M−H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:24](O)=[O:25])=[C:4]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1.[N:27]1([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:1][C:2]1[C:3]([C:24]([N:35]2[CH2:36][CH2:37][CH:32]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:33][CH2:34]2)=[O:25])=[C:4]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)[CH:7]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)cc(-c2cccnc2)c1C(=O)O
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)cc(-c2cccnc2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedures described in example 1, intermediate 11 E and in example 47, the title compound has been prepared by the following reaction sequence: i) 5-methyl-3-trifluoromethanesulfonyloxy-3′-trifluoromethyl-biphenyl-4-carboxylic acid methyl ester (intermediate 11 C) was reacted with pyridine-3-yl-boronic acid in DMF at 80° C. in the presence of potassium phosphate solution and tetrakis-(triphenylphosphine)-palladium to give 5-methyl-3-pyridin-3-yl-3′-trifluoromethyl-biphenyl-4-carboxylic acid methyl ester; ii) saponification of 5-methyl-3-pyridin-3-yl-3′-trifluoromethyl-biphenyl-4-carboxylic acid methyl ester gave 5-methyl-3-pyridin-3-yl-3′-trifluoromethyl-biphenyl-4-carboxylic acid; iii) transformation of 5-methyl-3-pyridin-3-yl-3′-trifluoromethyl-biphenyl-4-carboxylic acid into its acid chloride and reaction with 4-pyrrolidin-1-yl-piperidine gave the title compound as off-white amorphous solid. MS: 494.3 (MH+).
Reaction SMILES: [C:1]([O-:4])([O-])=[O:2].C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+].[F:19][C:20]1[CH:21]=[C:22]([CH:31]=[CH:32][C:33]=1[F:34])C(C1C=CC=CC=1)=O>FC(F)(F)C(O)=O>[F:19][C:20]1[CH:21]=[C:22]([CH:31]=[CH:32][C:33]=1[F:34])[C:1]([OH:4])=[O:2]
Reactant: O=C(c1ccccc1)c1ccc(F)c(F)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(F)c(F)c1
Temperature: 0 °C
Yield: 95.5 %

Procedure:
2.5 g of sodium percarbonate were added over 1 h to a solution of 2.2 g (10 mmol) of 3,4-difluorobenzophenone and 20 ml of trifluoroacetic acid (0° C.) and the temperature was then allowed to rise to 20° C. The mixture was stirred for 16 h at this temperature and 50 g of ice were then added. The mixture was subsequently extracted twice with dichloromethane and the organic phases were washed (NaHCO3) until the washings were neutral. The solvent was then removed. Working-up as described in Example 22 gave 1.2 g (7.6 mmol, 76%) of 3,4-difluorobenzoic acid, which can be obtained analytically pure from water (melting point 113°-120.5° C.).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].Cl.[NH2:24][OH:25].C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[N:24][OH:25])=[CH:17][CH:16]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: NO
Reactant: CS(=O)(=O)Oc1ccc(CCOc2ccc(C=O)cc2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)Oc1ccc(CCOc2ccc(C=NO)cc2)cc1
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 89.5 %

Procedure:
3.52 g (11 mmole) 4-[2-(4-formylphenoxy)ethyl]phenyl methanesulfonate was dissolved in 150 ml ethanol. 2.29 g (33 mmole) hydroxylamine hydrochloride and 3.6 g (44 mmole) sodium acetate in 30 ml water were added. The reaction mixture was stirred at 50° C. for 1 h 45 minutes. The solvent was evaporated in vacuo and water was added to give a white precipitate, which was filtered off and washed with hexane to give 3.3 g (yield 89%) of 4-{2-[4-(hydroxyiminomethyl)phenoxy]ethyl}phenyl methanesulfonate.
Reaction SMILES: [OH:1][C:2]1([C:6]2[NH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:29]=[CH:30][C:31]=3[CH3:32])[C:15]([N:17]3[CH2:20][CH:19]([C:21]4[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=4)[CH2:18]3)=[O:16])=[C:9]([CH3:11])[N:10]=2)[CH2:5][O:4][CH2:3]1.I[C:34]1N(COCC[Si](C)(C)C)C(C2(OC)COC2)=NC=1C.IC1N(COCC[Si](C)(C)C)C(C2(O)COC2)=NC=1C>>[CH3:34][O:1][C:2]1([C:6]2[NH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:29]=[CH:30][C:31]=3[CH3:32])[C:15]([N:17]3[CH2:18][CH:19]([C:21]4[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=4)[CH2:20]3)=[O:16])=[C:9]([CH3:11])[N:10]=2)[CH2:3][O:4][CH2:5]1
Reactant: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(C2(O)COC2)nc1C
Reactant: COC1(c2nc(C)c(I)n2COCC[Si](C)(C)C)COC1
Agent: Cc1nc(C2(O)COC2)n(COCC[Si](C)(C)C)c1I
Product: COC1(c2nc(C)c(-c3cc(C(=O)N4CC(c5ccc(C#N)cc5)C4)ccc3C)[nH]2)COC1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 192, except 5-iodo-2-(3-methoxyoxetan-3-yl)-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (compound 194.1) was used in place of 3-(5-iodo-4-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)oxetan-3-ol (compound 192.3). m/z (ES+) 443 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][C@H:5]([O:12]C(=O)C)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N+]=[N-].[C:16](OCC)(=[O:18])[CH3:17]>[Pd]>[C:16]([NH:1][CH2:4][C@H:5]([OH:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:18])[CH3:17]
Reactant: CCOC(=O)C[C@H](CN=[N+]=[N-])OC(C)=O
Reactant: CCOC(C)=O
Agent: [Pd]
Product: CCOC(=O)C[C@@H](O)CNC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
In a 200 ml autoclave were charged 4.50 g (20.9 mmol) of ethyl (R)-4-azido-3-acetoxybutyrate, 0.02 g of 5% Pd—C, and 5 ml of ethyl acetate, and the mixture was stirred at room temperature under a hydrogen pressure of 1000 KPa overnight. The catalyst was removed for concentration to give 3.20 g (81%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][CH3:23]>CCOCC.O>[NH2:1][C:2]1[C:7]([O:8][CH2:21][CH2:22][CH3:23])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCCBr
Reactant: Nc1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1cccnc1N
Temperature: 50 °C
Reaction time: 8 h
Yield: 24.1 %

Procedure:
A reaction flask was loaded with 2-amino-3-hydroxypyridine (12 g), dimethylformamide (75 ml), and potassium carbonate (18 g), and they were mixed. The temperature was raised to 50° C. To this mixture, 1-bromopropane (16.1 g) was dropwise added in 30 minutes. After stirring at 50° C. overnight, water and ether were added to the mixture, followed by stirring. The organic layer was collected from this, and washed with water, and then condensed to give 2-amino-3-propoxypyridine (4.0 g).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[CH:15][CH:14]=3)=[O:12])=[C:9]([CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[S:8][C:7]=2[CH:30]=1.[Cl-].[Al+3].[Cl-].[Cl-].C(S)C.Cl.C(=O)([O-])O.[Na+]>ClCCl.CO.C(Cl)(Cl)Cl.O.C1COCC1>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[CH:17][CH:18]=3)=[O:12])=[C:9]([CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[S:8][C:7]=2[CH:30]=1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN(C)C)cc3)c(C3CCCC3)sc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Al+3]
Solvent: ClC(Cl)Cl
Solvent: CCS
Solvent: CO
Product: CN(C)CCOc1ccc(C(=O)c2c(C3CCCC3)sc3cc(O)ccc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.1 %

Procedure:
35 mg of (6-methoxy-2-cyclopentylbenzo[b]thien-3yl)[4-[2-(dimethylamino)ethoxy]phenyl]methanone is dissolved in 5 mL of dichloromethane, 65 mg of aluminum chloride and 0.03 mL of ethanethiol are added, and this mixture is agitated for two hours at room temperature. 0.3 mL of THF, 0.075 mL of 20% hydrochloric acid, and 0.3 mL of water are added to the reaction mixture, after which a saturated aqueous solution of sodium hydrogencarbonate is added to render the solution alkaline, and the organic layer is extracted with ethyl acetate and dried with anhydrous magnesium sulfate. The solvent is distilled off, and the crude product thus obtained is refined by TLC (developing solvent was chloroform:methanol=19:1), which gives 21 mg of (6-hydroxy-2-cyclopentylbenzo[b]thien-3yl)[4-[2-(dimethylamino)ethoxy]phenyl]methanone.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.[CH3:34][O:35][C:36]1[C:41]([NH2:42])=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][N:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:39]4[CH:40]=[C:41]([NH2:42])[C:36]([O:35][CH3:34])=[N:37][CH:38]=4)[CH:3]=3)[N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:9]=2)[CH:12]=[N:13]1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ncc(-c2cnc3c(c2)c(-c2cnn(Cc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1N
Yield: 49.2 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of Step-i of example 9) (150 mg, 0.280 mmol) was coupled with 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (Intermediate 60) (86 mg, 0.34 mmol) using sodium carbonate (89 mg, 0.84 mmol) and Pd(PPh3)2Cl2 (10 mg, 0.014 mmol) in DME/water (10/1 mL) to afford 80 mg (49.2% yield) after purification by column (Silica gel 6/120) using 4/1/5 EtOAc/methanol/hexane as eluent.
Reaction SMILES: [CH:1]([C:4]1[N:9]=[C:8](O)[CH:7]=[C:6]([CH3:11])[N:5]=1)([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:14])=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:14][C:8]1[CH:7]=[C:6]([CH3:11])[N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)nc(C(C)C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)nc(C(C)C)n1
Temperature: 110 °C

Procedure:
76.1 g of 2-isopropyl-6-methyl-4-pyrimidinol [2814-20-2] (500 mmol) are dissolved in 300 ml of toluene at 90° C. 80.5 g of phosphorus oxychloride (525 mmol) are added dropwise thereto at from 90 to 103° C., and the reaction mixture is heated at 110° C. for 2 hours. After cooling to 20° C., the reaction mixture is adjusted to pH 8 using 4M sodium hydroxide solution, with cooling. The aqueous phase is separated off and extracted with 100 ml of toluene. The combined organic phases are washed three times with 100 ml of water each time and dried at RT under 2 mbar. 89.7 g (105%; contains toluene) are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([OH:12])([CH3:11])[CH3:10].[C:13]1(C)C=CC=C[CH:14]=1>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][CH:13]([CH3:14])[O:12][C:9]([CH3:10])([CH3:11])[C:3]=2[CH:4]=1
Reactant: Cc1ccccc1
Reactant: CC(C)(O)c1cc(Br)ccc1N
Product: CC1Nc2ccc(Br)cc2C(C)(C)O1
Reaction time: 0.17 h
Yield: 78 %

Procedure:
To a solution of 2-(2-amino-5-bromophenyl)propan-2-ol (27 g, 125 mmol) in anhydrous toluene was added at ambient temperature under a blanket of nitrogen acetylaldehyde (10.5 mL, 187 mmol). After 10 minutes, the mixture was passed through a pad of silica gel and filtrate was concentrated to yield 6-bromo-2,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazine as off-white solid (25 g, 78%): 1H-NMR (DMSO-d6) δ 7.22 (d, 1H, J=2.2 Hz), 7.08 (dd, 1H, J=8.6, 2.3 Hz), 6.51 (d, 1H, J=8.6 Hz), 6.36 (s, 1H), 4.72 (m, 1H), 1.45 (s, 3H), 1.40 (s, 3H), 1.25 (d, 3H, J=5.5 Hz).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:6]1[S:7][C:8]([CH:11]2[O:16]CC(C)(C)CO2)=[CH:9][CH:10]=1)[CH2:4][OH:5].C(N(CC)CC)C.C[Si](Cl)(C)C.[S:31]1[C:35]2[CH:36]=[C:37]([S:40](Cl)(=[O:42])=[O:41])[CH:38]=[CH:39][C:34]=2[N:33]=[CH:32]1.Cl>C(Cl)Cl.CO>[CH:11]([C:8]1[S:7][C:6]([C@H:3]([NH:2][S:40]([C:37]2[CH:38]=[CH:39][C:34]3[N:33]=[CH:32][S:31][C:35]=3[CH:36]=2)(=[O:41])=[O:42])[CH2:4][OH:5])=[CH:10][CH:9]=1)=[O:16]
Reactant: CC1(C)COC(c2ccc([C@H](N)CO)s2)OC1
Reactant: O=S(=O)(Cl)c1ccc2ncsc2c1
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=Cc1ccc([C@@H](CO)NS(=O)(=O)c2ccc3ncsc3c2)s1
Reaction time: 0.25 h

Procedure:
To a solution of (2R)-2-amino-2-[5-(5,5-dimethyl-1,3-dioxan-2-yl)thiophen-2-yl]ethanol hydrochloride (11.54 g, 39.3 mmol) in DCM (262 mL) at 0° C. was added slowly triethylamine (25 mL, 179 mmol). The mixture was stirred 15 minutes, after which TMSCl (5.52 mL, 43.2 mmol) was added. The mixture was stirred for 30 minutes at 0° C. and then 1,3-benzothiazole-6-sulfonyl chloride (9.64 g, 41.2 mmol) was added. The reaction mixture was allowed to reach room temperature overnight, and then 1N HCl (100 mL) and MeOH (50 mL) were added and the reaction mixture was stirred for 2 hours. The organic layer was separated and the aqueous layer was extracted 5 times with ethyl acetate (5×300 mL). The organic layers were combined and washed twice with a saturated solution of sodium bicarbonate (2×250 mL), then washed with brine (250 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was swished with ether to obtain the pure desired product.