Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:18]([OH:20])=O)[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[NH2:44][C@@H:45]([CH3:48])[CH2:46][OH:47].C(N(CC)C(C)C)(C)C>CCOC(C)=O.C(Cl)Cl>[OH:47][CH2:46][C@@H:45]([NH:44][C:18]([C:7]1[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[CH:8]=1)=[O:20])[CH3:48]
Reactant: C[C@H](N)CO
Reactant: COC(=O)c1cc(C(=O)O)cc(-c2ccc(C)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)N[C@@H](C)CO)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(methoxycarbonyl)-4′-methylbiphenyl-3-carboxylic acid (0.60 g, 2.2 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (470 mg, 2.4 mmol), 1-hydroxybenzotriazole hydrate (340 mg, 2.2 mmol), and CH2Cl2 (5 mL) were added (S)-2-aminopropan-1-ol (180 mg, 2.4 mmol) and N,N-diisopropylethylamine (0.58 mL, 3.3 mmol). The mixture was stirred at room temperature overnight, and then diluted with EtOAc, washed with aq. NaHCO3, brine, dried (Na2SO4), and concentrated. The residue was purified by silica gel column (0-80% EtOAc/hexane) to yield a white solid. LC-MS: 328.2 [M+1]+; 1H NMR (400 MHz, DMSO-d6): δ 8.48 (d, 1H, J=8.0 Hz), 8.40 (t, 1H, J=1.6 Hz), 8.37 (t, 1H, J=1.6 Hz), 8.28 (t, 1H, J=1.6 Hz), 7.69 (d, 2H, J=8.0 Hz), 7.34 (d, 2H, J=8.0 Hz), 4.78 (t, 1H, J=5.6 Hz), 4.07 (m, 1H), 3.92 (s, 3H), 3.49 (m, 1H), 3.38 (m, 1H), 2.37 (s, 3H), 1.16 (d, 3H, J=6.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23](Cl)[N:22]=3)=[O:20])=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29].C(O)=[O:33].O.C(=O)(O)[O-].[Na+]>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:33])[N:22]=3)=[O:20])=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:28]([F:29])([F:30])[F:31]
Reactant: O=CO
Reactant: O=C(c1cccc(Cl)n1)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(c1cccc(O)n1)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A 2 dram vial was charged with 4-chloro-N-[5-chloro-2-(6-chloro-pyridine-2-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (65 mg, 0.127 mmol), formic acid (2.0 mL) and water (0.50 mL). The heterogeneous solution was warmed to 110° C. and stirred overnight. The following day, the resultant mixture was neutralized with saturated aqueous sodium bicarbonate, diluted with EtOAc, and the organic layer washed with saturated sodium bicarbonate. The combined organics were dried with sodium sulfate, concentrated in vacuo, and purified via automated silica gel chromatography to afford the desired hydroxypyridine: MS (ES) (M+H)+ expected 492.0, found 491.9.
Reaction SMILES: [OH-:1].[Na+].CC(O)(C)CN[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]2[N:17]=[N:18][N:19]=[C:9]2[C:8]=1[N+:20]([O-:22])=[O:21]>O>[N+:20]([C:8]1[C:9]2[N:10]([N:17]=[N:18][N:19]=2)[C:11]2[C:16]([C:7]=1[OH:1])=[CH:15][CH:14]=[CH:13][CH:12]=2)([O-:22])=[O:21]
Reactant: CC(C)(O)CNc1c([N+](=O)[O-])c2nnnn2c2ccccc12
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1c(O)c2ccccc2n2nnnc12

Procedure:
Aqueous sodium hydroxide (30 g of 50%) was added to a suspension of 2-methyl-[(4-nitro-5-tetrazolo[1,5-a]quinolinyl)amino]-2-propanol (34.0 g, 0.1125 mole, Example 3) in water (500 mL), The mixture was heated on a steam bath and the solid dissolved rapidly. The solution was heated for about 30 minutes and then upon stirring a solid began to precipitate. The mixture was made acidic with 6N hydrochloric acid. The resulting solid was isolated by filtration; washed in succession with water, ethanol and ether; then dried under vacuum at 100° C. to provide 23.2 g of crude product as a pale yellow/green solid. A sample (3.2 g) was recrystallized initially from methanol/dichloromethane and then from toluene to provide 4-nitrotetrazolo[1,5-a]quinolin-5-ol. Analysis: Calculated for C9H5N5O3: %C, 46.76; %H, 2.18; %N, 30.29; Found: %C, 46.85; %H, 2.23; %N, 29.91.
Reaction SMILES: N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:25]I.[Br:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([N:36]2[CH2:40][CH2:39][CH2:38][C@H:37]2[CH2:41]O)=[O:35])=[CH:30][CH:29]=1>O1CCCC1.C(Cl)Cl.C(OCC)(=O)C>[Br:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([N:36]2[CH2:40][CH2:39][CH2:38][C@H:37]2[CH2:41][I:25])=[O:35])=[CH:30][CH:29]=1
Reactant: O=C(c1ccc(Br)cc1)N1CCC[C@H]1CO
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(c1ccc(Br)cc1)N1CCC[C@H]1CI
Reaction time: 3 h
Yield: 61.8 %

Procedure:
A solution of imidazole (310 mg, 4.5 mmol), 1.75 g (6.5 mmol) of triphenylphosphine, and 568 mg (2.2 mmol) of iodine in tetrahydrofuran (12 ml) was added under ice cooling to a solution of 504 mg (1.8 mmol) of (S)-(4-bromophenyl)(2-(hydroxymethyl)pyrrolidin-1-yl)methanone synthesized in step (i) of Reference Example 8 in methylene chloride (40 ml), and the mixture was stirred under ice cooling for 3 hr and then at room temperature for 4 hr. The reaction solution was diluted with 60 ml of ethyl acetate and was washed with an 8% aqueous sodium hydrogencarbonate solution. The aqueous layer was washed twice with 8 ml of ethyl acetate. The organic layers were combined and were washed with 25% brine. The organic layer was dried over anhydrous sodium sulfate and was filtered. The filtrate was concentrated under the reduced pressure, and the residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give 438 mg (yield 63%) of the title compound.
Reaction SMILES: [CH2:1]([C@H:5]1[C@H:9]([CH2:10][CH2:11]OS(C)(=O)=O)[O:8][C:7](=[O:17])[NH:6]1)[CH:2]([CH3:4])[CH3:3].[CH2:18]([SH:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[H-].[Na+].C(Cl)Cl>C1COCC1.[Cl-].[Na+].O>[CH2:1]([C@H:5]1[C@H:9]([CH2:10][CH2:11][S:26][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:8][C:7](=[O:17])[NH:6]1)[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)C[C@@H]1NC(=O)O[C@H]1CCOS(C)(=O)=O
Reactant: SCCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)C[C@@H]1NC(=O)O[C@H]1CCSCCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
To a 0° C. solution of 4(S)-isobutyl-5(S)-(2-mesyloxyethyl)-2-oxazolidinone (500 mg, 1.88 mmol) and phenethyl mercaptan (273 mg, 1.98 mmol) in THF (6 mL) was added NaH (95 mg, 1.98 mmol of a 50% dispersion) all at once. The reaction was stirred for 3 hours at room temperature and then distributed between methylene chloride and brine solution. The organic layer was washed with brine solution, dried over MgSO4 and evaporated. The residue was chromatographed on silica gel eluting with 65/35 hexane=ethyl acetate to give 570 mg (98%) of product as an oil.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[C:7]2([CH2:11][CH2:10][NH:9][CH2:8]2)[CH2:6]1)(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.[Cl:28][C:29]1[CH:38]=[CH:37][C:32]([CH:33]=[CH:34][CH2:35]Cl)=[CH:31][CH:30]=1>C(#N)C.C(OCC)(=O)C>[CH3:1][S:2]([N:5]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[C:7]2([CH2:11][CH2:10][N:9]([CH2:35]/[CH:34]=[CH:33]/[C:32]3[CH:37]=[CH:38][C:29]([Cl:28])=[CH:30][CH:31]=3)[CH2:8]2)[CH2:6]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)N1CC2(CCNC2)c2cc(Cl)ccc21
Reactant: ClCC=Cc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CS(=O)(=O)N1CC2(CCN(C/C=C/c3ccc(Cl)cc3)C2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 45.8 %

Procedure:
To a solution of 1-methanesulfonyl-5-chloro-spiro[indoline-3,3′-pyrrolidine] (725 mg) in acetonitrile (40 ml) were added diisopropylethylamine (0.66 ml) and 4-chloro-cinnamyl chloride (467 mg). The resulting solution was stirred at room temperature for 12 hours, diluted with ethyl acetate, washed with water, brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent cyclohexane:ethyl acetate 6:4) to afford 1-methanesulfonyl-5-chloro-1′-[trans-3-(4-chlorophenyl)allyl]spiro[indoline-3,3′-pyrrolidine] (500 mg) which was characterised by its mass and NMR spectra. MS (ES+) 437/439 (M+H+).
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH2:6]([N:13]([CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([OH:25])[CH:19]=1)=[O:17])[CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:26][C:27]([CH3:34])([CH2:31][CH2:32][CH3:33])[C:28](Cl)=[O:29]>CC(C)(CCC)C(O)=O>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH2:6]([N:13]([CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:28](=[O:29])[C:27]([CH3:34])([CH3:26])[CH2:31][CH2:32][CH3:33])=[C:20]([O:25][C:28](=[O:29])[C:27]([CH3:34])([CH3:26])[CH2:31][CH2:32][CH3:33])[CH:19]=1)=[O:17])[CH3:14])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCCC(C)(C)C(=O)Cl
Reactant: CN(CC(=O)c1ccc(O)c(O)c1)Cc1ccccc1
Agent: CCCC(C)(C)C(=O)O
Agent: CS(=O)(=O)O
Product: CCCC(C)(C)C(=O)Oc1ccc(C(=O)CN(C)Cc2ccccc2)cc1OC(=O)C(C)(C)CCC

Procedure:
Using a procedure similar to that described above in Example 3A, 3,4-dihydroxyphenyl N-benzyl-N-methylaminomethyl ketone methanesulfonate is reacted with two mole equivalents of 2,2-dimethylpentanoyl chloride in 2,2-dimethylpentanoic acid to yield 3,4-bis(2,2-dimethylpentanoyloxy)phenyl N-benzyl-N-methylaminomethyl ketone methanesulfonate as a white crystalline solid. This salt is debenzylated by catalytic hydrogenation in the presence of palladium-on-charcoal hydrogenation catalyst, in the same manner as the debenzylation procedure described above in Example 124, to yield 3,4-bis(2,2-dimethylpentanoyloxy)phenyl methylaminomethyl ketone methanesulfonate as a white crystalline solid. This salt is catalytically hydrogenated in anhydrous ethyl alcohol in the presence of 10 percent palladium-on-charcoal hydrogenation catalyst until one mole equivalent of hydrogen is absorbed. There is thus obtained 3,4-bis(2,2-dimethylpentanolyoxy)-alpha-(methylaminomethyl)benzyl alcohol methanesulfonate as a white crystalline solid.
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:30])[CH:13]([NH:17][CH:18]2[CH2:27][CH2:26][C:25]3[C:20](=[C:21]([F:29])[CH:22]=[C:23]([F:28])[CH:24]=3)[CH2:19]2)[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)([CH3:5])[CH:3]=O.[CH3:31][NH:32][CH3:33]>>[CH3:31][N:32]([CH3:33])[CH2:3][C:2]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:30])[CH:13]([NH:17][CH:18]2[CH2:27][CH2:26][C:25]3[C:20](=[C:21]([F:29])[CH:22]=[C:23]([F:28])[CH:24]=3)[CH2:19]2)[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)([CH3:1])[CH3:5]
Reactant: CNC
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)C=O)cn1
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)CN(C)C)cn1

Procedure:
2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid [1-(1,1-dimethyl-2-oxo-ethyl)-1H-imidazol-4-yl]-amide was reacted with dimethyl amine to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.5, 19.6, 26.2, 26.2, 26.3, 28.2, 28.3, 28.8, 29.6, 29.8, 36.6, 48.0, 52.3, 52.8, 58.9, 59.0, 60.3, 60.8, 70.0, 101.0, 104.6, 110.7, 131.2, 137.3, 159.8, 162.2, 172.4, 183.1, 183.9; MS m/z 448.4 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[Sn](CCCC)(CCCC)CCCC)(=[O:5])=[O:4].C1(C)C(C([O:33][C@@H:34]2[C@@H:38]([CH2:39][O:40]C(C3C(C)=CC=CC=3)=O)[O:37][C@@H:36]([N:50]3[C:54]4=[N:55][CH:56]=[CH:57][C:58](I)=[C:53]4[CH:52]=[CH:51]3)[CH2:35]2)=O)=CC=CC=1.[Cl-].[Li+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C@@H:36]1([N:50]2[C:54]3=[N:55][CH:56]=[CH:57][C:58]([C:7]4[N:6]([S:3]([N:2]([CH3:1])[CH3:24])(=[O:4])=[O:5])[CH:10]=[CH:9][N:8]=4)=[C:53]3[CH:52]=[CH:51]2)[O:37][C@H:38]([CH2:39][OH:40])[C@@H:34]([OH:33])[CH2:35]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccn1S(=O)(=O)N(C)C
Reactant: Cc1ccccc1C(=O)OC[C@H]1O[C@@H](n2ccc3c(I)ccnc32)C[C@@H]1OC(=O)c1ccccc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: CN(C)S(=O)(=O)n1ccnc1-c1ccnc2c1ccn2[C@H]1C[C@H](O)[C@@H](CO)O1
Temperature: 120 °C
Reaction time: 4 h
Yield: 53.5 %

Procedure:
N-Dimethylaminosulfonyl-2-(tributylstannyl)imidazole (930 mg, 2.0 mmol) was added to a solution of 1-[2-deoxy-3,5-di-O-(toluoyl)-β-D-ribofuranosyl]-4-iodo-pyrrolo[2,3-b]pyridine (596 mg, 1.0 mmol), lithium chloride (42 mg, 1.0 mmol), and tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol) in dioxane (10 mL), followed by stirring at 120° C. for 4 hr. The reaction solution was concentrated and was then purified with a silica gel column, and methanolic ammonia (30 mL) was added thereto. The resulting mixture was stirred at room temperature for 24 hr. The reaction solution was concentrated and purified with a silica gel column and then with HPLC to yield 218 mg (54%, second stage yield) of 1-(2-deoxy-β-D-ribofuranosyl)-4-(N-dimethylaminosulfonyl-2-imidazolyl)-pyrrolo[2,3-b]pyridine. 1-(2-Deoxy-β-D-ribofuranosyl)-4-(N-dimethylaminosulfonyl-2-imidazolyl)-pyrrolo[2,3-b]pyridine (200 mg, 0.49 mmol) was dissolved in 80% acetic acid, followed by stirring at 60° C. for 3 hr. The reaction solution was concentrated, and aqueous ammonia was added thereto for further concentration. Subsequently, 1-(2-deoxy-β-D-ribofuranosyl)-4-(2-imidazolyl)-pyrrolo[2,3-b]pyridine (dDia: 109 mg, 74%) was obtained through purification by HPLC.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1.[C:30]([O:34][C:35](=[O:54])[CH2:36][S@:37]([CH2:39][CH:40]([NH:45][C:46]1[C:51]([F:52])=[CH:50][N:49]=[C:48](Cl)[N:47]=1)[C:41]([CH3:44])([CH3:43])[CH3:42])=[O:38])([CH3:33])([CH3:32])[CH3:31].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:52][C:51]1[C:46]([NH:45][CH:40]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:39][S@@:37]([CH2:36][C:35]([O:34][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:54])=[O:38])=[N:47][C:48]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)[N:8]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:21])=[O:22])[CH:9]=2)=[N:49][CH:50]=1
Reactant: CC(C)(C)OC(=O)C[S@@](=O)CC(Nc1nc(Cl)ncc1F)C(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(F)cnc32)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC(C[S@](=O)CC(=O)OC(C)(C)C)C(C)(C)C)n3)c3cc(F)cnc32)cc1
Temperature: 115 °C

Procedure:
A solution of 5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 7a, (0.66 g, 1.58 mmol), tert-butyl((S)-2(2-chloro-5-fluoropyrimidin-4-ylamino)-3,3-dimethylbutylsulfinyl)ethanoate, 175a, (0.50 g, 1.27 mmol) and K3PO4 (0.65 g, 3.05 mmol) in 2-methyl THF (10 mL) and water (2 mL) was degassed under a stream of nitrogen for 30 minutes. X-Phos (0.04 g, 0.08 mmol) and Pd2(dba)3(0.02 g, 0.02 mmol) were added and the reaction mixture was heated at 115° C. in a pressure vial for 4 hours. The reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The residue was dissolved in EtOAc (50 mL) and washed with water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0-60% EtOAc/Hexanes gradient) to afford 450 mg of the desired product as a white foamy solid: LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=3.91 minutes (M+H) 648.40.
Reaction SMILES: C1(N2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)C=CC=CC=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.[CH3:49][C:50]1[CH:56]=[CH:55][C:54]([CH3:57])=[CH:53][C:51]=1[NH2:52]>C(O)(=O)C>[CH3:49][C:50]1[CH:56]=[CH:55][C:54]([CH3:57])=[CH:53][C:51]=1[N:52]1[C:12](=[O:13])[C:11]2[S:14][CH:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]=2[N:9]=[CH:8]1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: Cc1ccc(C)c(N)c1
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: Cc1ccc(C)c(-n2cnc3c(-c4ccccc4)csc3c2=O)c1
Yield: 44 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (45.6 mg, 0.20 mmol), triethyl orthoformate (0.40 ml), 2,5-dimethylaniline (44.8 mg, 0.37 mmol), and acetic acid (0.05 ml) were used to give 28.8 mg (0.087 mmol, 44% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Br:18]Br>C(O)C>[Br:18][CH2:14][C:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:16]=[CH:17][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)=[O:15]
Reactant: BrBr
Reactant: CC(=O)c1ccc(Oc2ccc(F)cc2)cc1
Solvent: CCO
Product: O=C(CBr)c1ccc(Oc2ccc(F)cc2)cc1
Reaction time: 2 h

Procedure:
A solution of 1-[4-(4-fluorophenoxy)phenyl]ethanone (17.7 g, 0.077 mol) in 220 ml of ethanol is cooled down to approximately 0° C. Bromine (4.8 ml, 0.096 mol) is added dropwise with a syringe. The temperature is allowed to return to ambient temperature, followed by stirring for 2 hours. After evaporation of the solvent then stirring for 10 hours in isopentane, the residue is filtered on frit and dried under a vacuum chamber bell jar. A beige-coloured powder is obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([O:24][CH3:25])[CH:16]=1.O>CN(C)C=O>[CH3:25][O:24][C:17]1[CH:16]=[C:15]([N:1]2[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]2)[CH:20]=[CH:19][C:18]=1[N+:21]([O-:23])=[O:22]
Reactant: OC1CCNCC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(N2CCC(O)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.1 %

Procedure:
To a suspension of piperidin-4-ol (2.79 g, 28 mmol) and potassium carbonate (3.88 g, 28 mmol) in N,N-dimethylformamide (40 mL), 4-Fluoro-2-methoxy-1-nitro-benzene (4.0 g, 23 mmol) is added and stirred at room temperature for 24 hours. The mixture is poured into water and the precipitate is collected by a filtration. The resulting solid is dried in vacuo at 50° C. to afford 1-(3-methoxy-4-nitro-phenyl)-piperidin-4-ol (5.23 g) as yellow solids in 89% yield.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH2:24][C:25]#[N:26])=[CH:4][CH:3]=1.[CH2:27](I)[CH3:28].CC(C)([O-])C.[K+]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([CH2:27][CH3:28])[C:25]#[N:26])=[CH:4][CH:3]=1
Reactant: CCI
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(CC#N)c23)c(C)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC(C#N)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
To a solution of [9-chloro-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]acetonitrile (176.0 mg, 0.478 mmol) in tetrahydrofuran (4.5 mL) was added ethyl iodide (57.3 μL, 0.717 mmol) and potassium tert-butoxide (75.8 mg, 0.574 mmol) at 0° C., The reaction mixture was stirred at 0° C. for 1 hr under nitrogen atmosphere. The mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-60% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless powder (154.3 mg, 0.390 mmol, 82%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[N:3]=1.[F:16][C:17]1[CH:18]=[C:19]([C@H:25]2[CH2:29][CH2:28][CH2:27][NH:26]2)[C:20]([O:23][CH3:24])=[N:21][CH:22]=1.CCN(C(C)C)C(C)C.C(O)CCC>CCOC(C)=O>[F:16][C:17]1[CH:18]=[C:19]([C@H:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]3[N:3]=2)[C:20]([O:23][CH3:24])=[N:21][CH:22]=1
Reactant: CCOC(=O)c1cnn2ccc(Cl)nc12
Reactant: COc1ncc(F)cc1[C@H]1CCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3OC)nc12
Temperature: 90 °C
Yield: 56.3 %

Procedure:
A mixture of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (0.75 g, 3.32 mmol), (R)-5-fluoro-2-methoxy-3-(pyrrolidin-2-yl)pyridine (Preparation A, 0.984 g, 3.66 mmol), DIEA (2.32 mL, 13.3 mmol) and n-butanol (1.11 mL) was sealed in a pressure tube and heated at 90° C. for 48 hours. The reaction mixture was diluted with EtOAc and washed with water, brine and sat NaHCO3. The organic layer was dried (MgSO4), filtered and concentrated to afford a dark orange oil. The crude material was purified by silica column chromatography eluting with 50-80% EtOAc/hexanes to afford (R)-ethyl 5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (0.72 g, 56.2% yield) as a yellow foamy solid. MS (apci) m/z=386.0 (M+H).
Reaction SMILES: [N:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][C:28]=1[O:36][CH3:37].CN(C)C=O>O>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][C:28]=3[O:36][CH3:37])[CH2:3][CH2:2]2)=[N:8]1
Reactant: c1ccc2c(N3CCNCC3)n[nH]c2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)=O)ccc1OCCCN1CCN(c2n[nH]c3ccccc23)CC1
Reaction time: 5 h
Yield: 85.7 %

Procedure:
A mixture of 3-(1-piperazinyl)-1H-indazole (4.0 g, 20 mmol), K2CO3 (3.0 g, 22 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3 g, 22 mmol), a few crystals of KI, and dimethylformamide (60 ml) was stirred at 90 C. for 5 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The extract was washed (brine), dried (MgSO4), and the solvent was concentrated to afford a white solid, which was triturated with diethyl ether and collected to yield 7.0 g of product. Two recrystallizations from absolute ethyl alcohol yielded 5.3 g (64%) of analytically pure 1-[4-[3-[4-(1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-ethanone, m.p.=155°-157° C.