Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=[C:3]([C:21](=[O:23])[CH3:22])[C:4]([C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:5])=O>C(O)(C(F)(F)F)=O.ClCCl>[O:23]=[C:21]([CH3:22])[CH2:3][C:4]([C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])=[O:5]
Reactant: CC(=O)C(=C=O)C(=O)[C@H]1CCCN1C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)CC(=O)[C@H]1CCCN1C(=O)OCc1ccccc1
Yield: 18 %

Procedure:
A solution of (2R)-benzyl 2-(2-(carbonyl)-3-oxobutanoyl)pyrrolidine-1-carboxylate in TFA (50 mL) and dichloromethane (50 mL) was stirred at room temperature for 1 hr and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexanes/ethyl acetate gradient, 10-100% EtOAc) to afford (R)-benzyl 2-(3-oxobutanoyl)pyrrolidine-1-carboxylate (2.1 g, 18% over two steps). LCMS: 6.9 min calculated: 289, found (MH+): 290.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([CH:19]2[CH2:21][CH2:20]2)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=[O:24].OO.[OH-].[Na+]>CCO.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]2[O:24][C@H:16]2[C:17]([CH:19]2[CH2:21][CH2:20]2)=[O:18])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(/C=C/c1ccc(OCc2ccccc2)cc1)C1CC1
Reactant: CC(C)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(C1CC1)[C@@H]1O[C@H]1c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
(2E)-3-[4-(Benzyloxy)phenyl]-1-cyclopropyl-2-propen-1-one (6.25 g) was suspended in EtOH (67.5 ml), acetone (22.5 ml) To this mixture was added hydrogen peroxide 30% aqueous solution (4.5 ml), and 3M NaOH (4.5 ml), and the mixture was stirred at ambient temperature for l day. The mixture was diluted with H2O. White precipitates were collected and washed with H2O, and air dried to give {(2R,3S)-3-[4-(benzyloxy)phenyl]-2-oxiranyl}(cyclopropyl)methanone (6.27 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.B([C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[C:18]([F:25])[CH:17]=1)(O)O>>[F:25][C:18]1[CH:17]=[C:16]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=3)[N:3]=2)[CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21]
Reactant: O=C(O)c1ccc(B(O)O)cc1F
Reactant: Oc1ccc2nc(Cl)ccc2c1
Product: O=C(O)c1ccc(-c2ccc3cc(O)ccc3n2)cc1F

Procedure:
Followed Scheme 3: Starting Materials: 2-chloroquinolin-6-ol (Intermediate 2) and 4-borono-2-fluorobenzoic acid. 1H NMR (CD3OD, 400 MHz): δ 8.54 (d, J=8.4 Hz, 1H), 8.20-8.06 (m, 3H), 8.06-7.96 (m, 2H), 7.55 (dd, J=9.2, 2.4 Hz, 1H), 7.32 (d, J=2.8 Hz, 1H). MS (ESI): m/z 283.6 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11](Cl)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][NH2:17]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:16][NH2:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc(OCc2ccccc2)ccn1
Reactant: NN
Solvent: c1ccncc1
Product: NNc1cc(OCc2ccccc2)ccn1

Procedure:
To a solution of 4-(benzyloxy)-2-chloropyridine (4.89 g, 22.30 mmol) in pyridine (120 mL) was added hydrazine (45 mL, 22.30 mmol). After heating to reflux for 18 hours, the mixture was concentrated to provide the crude product, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:24]=2)[CH:20]=1)[C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.Cl>[C:33]([O:32][C:30]([NH:29][C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][C:19]2[CH:18]=[C:13]([CH:12]=[C:11]([NH:10][C:6]3[C:5]([Cl:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:20]=2)[C:14]([O:16][CH3:17])=[O:15])[CH:28]=[CH:27][CH:26]=1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: COC(=O)c1cc(N)cc(CCc2cccc(NC(=O)OC(C)(C)C)c2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(CCc2cccc(NC(=O)OC(C)(C)C)c2)cc(Nc2nc(Cl)ncc2Cl)c1
Yield: 71.6 %

Procedure:
A solution of 2,4,5-trichloropyrimidine (0.371 mL, 3.24 mmol) and methyl 3-amino-5-(2-{3-[(tert-butoxycarbonyl)amino]phenyl}ethyl)benzoate (1.20 g, 3.24 mmol) in DMF (20 mL) and potassium carbonate (895 mg, 6.48 mmol) were stirred at 60° C. overnight. The reaction mixture was diluted with 1 N HCl and extracted with ethyl acetate three times. The combined organic solutions were dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography to yield the desired product (1.20 g, 72%). LCMS for C25H26Cl2N4O4Na (M+Na)+: m/z=539.3, 541.3.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([NH2:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:13][S:14]([CH2:17][CH2:18][O:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[N:23][N:24]2[C:29]1[CH:34]=[CH:33][N:32]=[C:31](S(CCC)(=O)=O)[N:30]=1)(=[O:16])=[O:15]>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:31]2[N:30]=[C:29]([N:24]3[C:25]4[C:21](=[C:20]([O:19][CH2:18][CH2:17][S:14]([CH3:13])(=[O:15])=[O:16])[CH:28]=[CH:27][CH:26]=4)[CH:22]=[N:23]3)[CH:34]=[CH:33][N:32]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCCS(=O)(=O)c1nccc(-n2ncc3c(OCCS(C)(=O)=O)cccc32)n1
Reactant: CCOC(=O)C1CCC(N)CC1
Product: CCOC(=O)C1CCC(Nc2nccc(-n3ncc4c(OCCS(C)(=O)=O)cccc43)n2)CC1

Procedure:
4-{4-[4-(2-Methanesulfonyl-ethoxy)-indazol-1-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid ethyl ester was prepared by reaction of 4-amino-cyclohexanecarboxylic acid ethyl ester with 4-(2-methanesulfonyl-ethoxy)-1-[2-(propane-1-sulfonyl)-pyrimidin-4-yl]-1H-indazole following generally the procedure of Example 5.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:7][CH:6]=[CH:5][N:4]=1.[F:21][C:22]([F:37])([F:36])[C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[N:31]=1)[C:26](O)=[O:27]>>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH2:16][C:17]([F:18])([F:20])[F:19])[C:26](=[O:27])[C:25]2[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[N:31]=[C:23]([C:22]([F:37])([F:21])[F:36])[CH:24]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1-c1ccncc1NCC(F)(F)F
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Product: COc1ncccc1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from (2-methoxy-[3,4′]bipyridinyl-3′-yl)-(2,2,2-trifluoro-ethyl)-amine (example 135, intermediate a) and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.) after a reaction time of 96 hours. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). Light yellow solid (41%). MS (ESI): m/z=525.10 [M+H]+.
Reaction SMILES: Cl.[NH2:2][OH:3].N1C=CC=CC=1.[CH:10]([C:12]1[S:16][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:13]=1)=O>CCO>[OH:3][N:2]=[CH:10][C:12]1[S:16][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:13]=1
Reactant: NO
Reactant: COC(=O)c1ccc(C=O)s1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: COC(=O)c1ccc(C=NO)s1
Temperature: 25 °C
Yield: 57.9 %

Procedure:
Hydroxylamine hydrochloride (420 mg, 6.1 mmol) and pyridine (0.5 mL) were added to a solution of methyl 5-formylthiophene-2-carboxylate (690 mg, 4.1 mmol) in EtOH (25 mL). The reaction mixture was refluxed for 3 h, cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in diethyl ether, the organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to get product methyl 5-((hydroxyimino)methyl)thiophene-2-carboxylate (440 mg, yield 60%), which was carried through without any further purification. 1H NMR (400 MHz, DMSO-d6) δ 12.5 (s, 1H), 7.98 (s, 1H), 7.78 (d, J=4.1 Hz, 1H), 7.51 (d, J=4.1 Hz, 1H), 3.82 (s, 3H). MS (ESI) m/z: Calculated for C7H7NO3S: 185.01. found: 186.0 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[F:8][C:9]1[CH:10]=[C:11](Br)[CH:12]=[C:13]([F:15])[CH:14]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[F:8][C:9]1[CH:10]=[C:11]([N:6]2[CH2:5][CH2:4][NH:3][C@@H:2]([CH3:1])[CH2:7]2)[CH:12]=[C:13]([F:15])[CH:14]=1
Reactant: C[C@H]1CNCCN1
Reactant: Fc1cc(F)cc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@H]1CN(c2cc(F)cc(F)c2)CCN1
Temperature: 100 °C
Reaction time: 24 h
Yield: 43.3 %

Procedure:
A mixture composed of 2.48 g of (S)-2-methylpiperazine, 3.97 g of 3,5-difluorobromobenzene, 2.76 g of sodium tert-butoxide, 326 mg of dichlorobis[(tri-ortho-tolyl)phosphine]palladium (II) (PdCl2[P(o-tolyl)3]2) and 100 ml of toluene was stirred at 100° C. for 24 hours in an atmosphere of nitrogen. After removal of the insoluble matter by filtration, the filtrate was washed with water and then with saturated brine. The organic layer was dried with anhydrous sodium sulfate and then concentrated under a reduced pressure, the residue was applied to a silica gel column chromatography (270 to 400 mesh, 100 g) and developed with a methanol-chloroform (6:94) mixed solvent, and then the fractions containing the compound of interest were concentrated to obtain 1.89 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][NH:12][C:13]3[CH:17]=[CH:16][NH:15][C:14]=3[C:18]([O:20]CC)=O)[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:23].C([N:32]=[C:33]=[S:34])(=O)C1C=CC=CC=1>C(Cl)Cl>[CH3:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][N:12]3[C:13]4[CH:17]=[CH:16][NH:15][C:14]=4[C:18](=[O:20])[NH:32][C:33]3=[S:34])[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:23]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CCOC(=O)c1[nH]ccc1NCc1nc2c(C)c(C)ccc2[nH]1
Solvent: ClCCl
Product: Cc1ccc2[nH]c(Cn3c(=S)[nH]c(=O)c4[nH]ccc43)nc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.6 %

Procedure:
Ethyl 3-{[(4,5-dimethyl-1H-benzimidazol-2-yl)methyl]amino}-1H-pyrrole-2-carboxylate (0.043 g, 0.14 mmol) was dissolved in CH2Cl2 (1.5 mL) and benzoyl isothiocyanate (0.026 g, 0.16 mmol) was added. After stirring at r.t. for 1 h the solvent was removed in vacuo. The residue was dissolved in ammonia (7N in methanol) and heated to 70° C. for 2 h in a sealed vessel. The solvent was removed in vacuo and the residue was purified by preparative HPLC, obtaining a white solid, 0.008 g (18%) of the title compound, as a tautomeric mixture (1:1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[S:14][CH:13]=[N:12][CH:11]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:18][C:19]2[N:20]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[S:22][CH:23]=2)[N:3]=1.[NH2:31][CH2:32][C@@H:33]([OH:36])[CH2:34][OH:35]>C1COCC1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:21]2[S:22][CH:23]=[C:19]([CH2:18][S:17][C:4]3[C:5]([C:15]#[N:16])=[C:6]([C:10]4[S:14][CH:13]=[N:12][CH:11]=4)[C:7]([C:8]#[N:9])=[C:2]([NH:31][CH2:32][C@@H:33]([OH:36])[CH2:34][OH:35])[N:3]=3)[N:20]=2)=[CH:25][CH:26]=1
Reactant: NC[C@@H](O)CO
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cncs1
Solvent: C1CCOC1
Product: N#Cc1c(NC[C@@H](O)CO)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cncs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
100 mg (0.206 mmol) of 2-chloro-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-4-(1,3-thiazol-5-yl)pyridine-3,5-dicarbonitrile, together with 38 mg (0.411 mmol) of (2R)-3-aminopropane-1,2-diol, were dissolved in 1.5 ml of THF. The mixture was stirred at room temperature for two hours, and the product was then purified by preparative HPLC (acetonitrile/water: 10:90→95:5, 0.1% TFA added). This gave 64 mg (58%/0 of theory) of the target compound.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:19])[NH:7][C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([CH2:4][NH:5][C:6](=[O:19])[NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:17][CH:18]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1ccc(NC(=O)NCC2CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(NCC1CC1)Nc1ccc(C(=O)O)cc1
Yield: 93.4 %

Procedure:
Ethyl 4-(3-(cyclopropylmethyl)ureido)benzoate (55.3 mmol, 14.5 g) was suspended in ethanol (400 ml) and 4M sodium hydroxide (332 mmol, 83 mL) added. The reaction was then refluxed until complete saponification was achieved. The ethanol was removed by evaporation and the reaction neutralised with concentrated hydrochloric acid. The white precipitate was collected and washed with water. The material was dried under vacuum to give the title compound (12.1 g)
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH:16]([C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=1O)=[O:17].C(N(CC)C(C)C)(C)C>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:25]1[CH:24]=[C:21]([C:22]#[N:23])[CH:20]=[CH:19][C:18]=1[CH:16]=[O:17])(=[O:5])=[O:4]
Reactant: N#Cc1ccc(C=O)c(O)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1ccc(C=O)c(OS(=O)(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.4 ml (14.27 mmol) of trifluoromethanesulfonic anhydride are added dropwise to a solution of 2 g (13.59 mmol) of 4-formyl-3-hydroxybenzonitrile and 2.5 ml (14.27 mmol) of N,N-diisopropyl-ethylamine in 37 ml of anhydrous dichloromethane at 0° C. under an argon atmosphere. The reaction mixture is stirred at RT for 1 h, then diluted with 70 ml of dichloromethane and washed successively with 1 M hydrochloric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic solution is dried over magnesium sulfate and concentrated. The residue is purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 7:1). 2.36 g (62% of theory) of the title compound are obtained as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[Cl:22][C:23]1[CH:28]=[C:27](I)[CH:26]=[CH:25][N:24]=1>C([Mg]Cl)(C)C.[Cl-].[Cl-].[Zn+2]>[Cl:22][C:23]1[CH:28]=[C:27]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:3]=2)[CH:26]=[CH:25][N:24]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(Br)n2)cc1
Reactant: Clc1cc(I)ccn1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(-c3ccnc(Cl)c3)n2)cc1

Procedure:
The title compound was prepared from 2-bromo-4-trifluoromethyl-6-(4-trifluoromethylphenyl)-pyridine (example A.19) (1.11 g, 3.0 mmol), commercially available 2-chloro-4-iodo-pyridine [CAS No. 153034-86-7] (740 mg, 3.1 mmol) and i-PrMgCl/ZnCl2 according to the general procedure IVc protocol a. Obtained as a white solid (0.601 g, 50%). MS (ISP) 403.3 [(M+H)+] and 405.2 [(M+2+H)+].
Reaction SMILES: Cl[C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:11]1([SH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[N+:8]([C:3]1[C:2]([S:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ncccc1Cl
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ncccc1Sc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70 %

Procedure:
3-chloro-2-nitropyridine (30.6 g, 193 mmol) was dissolved in DMSO (200 mL). Benzenethiol (20.7 mL, 203 mmol) was added followed by cesium carbonate (69.3 g, 212 mmol) and stirred at ambient temperature for 1.5 hours. The solution was diluted with water (750 mL) and the solids filtered. The crude material was recrystallized from EtOAc (400 mL) and with adding hexanes (1L) to give an A-crop of 23.5 g. The filtrate was concentrated and recrystallized from EtOAc/hexanes to give 7.87 g. The solids were dried on high vacuum to provide the title compound (31.38 g, 69.8% yield).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:8]=[N:9][N:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[N:11]2)=O.[CH:17]1([NH:20][C:21]([NH2:23])=[NH:22])[CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:17]1([NH:20][C:21]2[N:23]=[C:5]([C:7]3[CH:8]=[N:9][N:10]4[C:15]=3[CH:14]=[CH:13][CH:12]=[N:11]4)[CH:4]=[CH:3][N:22]=2)[CH2:19][CH2:18]1
Reactant: N=C(N)NC1CC1
Reactant: CN(C)/C=C/C(=O)c1cnn2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cnn2ncc(-c3ccnc(NC4CC4)n3)c2c1
Temperature: 165 °C
Yield: 75 %

Procedure:
To a solution of (2E)-3-(dimethylamino)-1-pyrazolo[1,5-b]pyridazin-3-yl-2-propen-1-one (43 mg, 0.20 mmol) in DMF (2 mL) was added N-cyclopropylguanidine.0.5H2SO4 (160 mg, 0.80 mmol) and potassium carbonate (110 mg, 0.80 mmol). The reaction was heated at an oil bath temperature of 165° C. for about 18 hours. The mixture was cooled to RT and the solvent was removed in vacuo. The residue was dissolved in chloroform and filtered. The filtrate was purified by flash column chromatography (0-10% gradient MeOH/CH2Cl2) to give the title compound as a yellow solid (38 mg, 75%). 1H-NMR (400 MHz, d6-DMSO) δ 9.13 (dd, 1H, J=9.0, 1.6 Hz), 8.77 (s, 1H), 8.53 (dd, 1H, J=4.4, 1.6 Hz), 8.24 (d, 1H, J=5.2 Hz), 7.38 (m, 1H), 7.10 (d, 1H, J=5.2 Hz), 2.72 (m, 1H), 0.71 (m, 2H), 0.47 (m, 2H); MS (ESI) (M+H)+ 253.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH2:13][CH2:14][CH2:15][CH3:16])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][N:18]([CH3:22])[C:19](Cl)=[O:20]>N1C=CC=CC=1>[CH2:13]([C:10]1[N:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:19]([N:18]([CH3:22])[CH3:17])=[O:20])[CH:3]=2)[O:12][N:11]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1noc(-c2cccc(N)c2)n1
Reactant: CN(C)C(=O)Cl
Solvent: c1ccncc1
Product: CCCCc1noc(-c2cccc(NC(=O)N(C)C)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8.0 g (0.037 mol) of 5-(3-aminophenyl)-3-butyl-1,2,4-oxadiazole were dissolved in 15 ml pyridine and were reacted with 3.4 ml (0.037 mol) of dimethylcarbamoylchloride. The reaction was complete after stirring for 8 hours at room temperature. The mass was then reacted with about 100 ml ice water resulting in precipitation of the reaction product. The reaction produce was removed by suction, subjected to drying at 50° C. in a vacuum and recrystallized from diisopropylether. There were obtained 8.3 g=77.5% of the theoretical value of 3-butyl-5-[3-(3,3-dimethylureido)-phenyl]-1,2,4-oxadiazole; m.p. 108° to 110° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:11][C@H:10]([C:20](O)=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[CH:14]1([C@H:12]2[CH2:11][C@@H:10]([CH2:20][OH:21])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13]2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C(=O)O)C[C@@H](C2CCCCC2)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](CO)C[C@H](C2CCCCC2)C1
Yield: 131.9 %

Procedure:
To the solution of cis-1-(tert-butoxycarbonyl)-5-cyclohexylpiperidine-3-carboxylic acid (400.9 mg) in THF (10 ml) was added 2 M solution of borane dimethylsulfide complex in THF (4.0 ml) at −15° C. under stirring. After stirring for 4 hours, The mixture was quenched by addition of MeOH. The resulting mixture was allowed to be room temperature and concentrated. To the residue was added saturated aqueous solution of NH4Cl and extracted with EtOAc. The extract was washed with brine, dried over MgSO4 and concentrated. The residue was purified with silica gel column chromatography (eluent: CHCl3/MeOH=99/1˜90/10) to give tert-butyl cis-3-cyclohexyl-5-(hydroxymethyl)piperidine-1-carboxylate (505.1 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([N:4]1[C:10]2[N:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][C:18](OS(C(F)(F)F)(=O)=O)=[N:19][C:5]1=2)[CH2:2][CH3:3].C([Sn](CCCC)(CCCC)[C:33]1[CH:34]=[N:35][NH:36][CH:37]=1)CCC>>[CH2:1]([N:4]1[C:10]2[N:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][C:18]([C:33]3[CH:34]=[N:35][NH:36][CH:37]=3)=[N:19][C:5]1=2)[CH2:2][CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn[nH]c1
Reactant: CCCN1c2nc(OS(=O)(=O)C(F)(F)F)ccc2NC(=O)c2cccnc21
Product: CCCN1c2nc(-c3cn[nH]c3)ccc2NC(=O)c2cccnc21

Procedure:
The title compound (mp 291°-292° C.) was prepared from 5,11-dihydro-11-n-propyl-2-trifluoromethanesulfonyloxy-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and 4-(tributylstannyl)pyrazole in a manner analogous to that described in Example 1.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH2:7]([C:11]1[N:12]([CH3:23])[C:13]2[C:18](C=1C(O)=O)=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:9][CH3:10]>C(Cl)Cl>[CH2:7]([C:11]1[N:12]([CH3:23])[C:13]2[C:14]([C:1]=1[C:2]([Cl:4])=[O:3])=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCc1c(C(=O)O)c2ccccc2n1C
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCCCc1c(C(=O)Cl)c2ccccc2n1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (5.89 mL, 66.1 mmol) was added under nitrogen to a solution of 2-butyl-1-methyl-1H-indole-3-carboxylic acid (3.06 g, 13.2 mmol), prepared in the previous step, in 100 mL of methylene chloride at room temperature. There was an immediate evolution of gas. After the addition the reaction was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. To remove excess oxalyl chloride the residue was dissolved in benzene and the solvent removed under reduced pressure to give 2-butyl-1-methyl-1H-indole-3-carbonyl chloride as a brown oil. The material was immediately used without additional purification.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH:2]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[N:29]1[C:21]([NH:18][C@H:16]([C:8]2[N:7]([C:3]3[CH:2]=[C:1]([CH3:19])[CH:6]=[CH:5][CH:4]=3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH3:17])=[C:22]2[C:26]([NH:25][CH:24]=[N:23]2)=[N:27][CH:28]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: Cc1cccc(-n2c([C@H](C)N)nc3cccnc32)c1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(-n2c([C@H](C)Nc3ncnc4[nH]cnc34)nc3cccnc32)c1
Temperature: 90 °C
Yield: 30.9 %

Procedure:
A mixture of (S)-1-(3-m-tolyl-3H-imidazo[4,5-b]pyridin-2-yl)ethylamine (420 mg, 1.66 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (550 mg, 2.33 mmol) and DIPEA (0.52 mL, 3.00 mmol) in n-butanol (3 mL) was heated at 90° C. in a sealed vial for 16 h. After cooling to RT, the crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge and washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) to afford 177 as a white solid (190 mg, 31%). LCMS (Method K): RT 2.84 min [M+H]+ 371.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.90 (1H, s), 8.33-7.77 (5H, m), 7.45-7.14 (5H, m), 5.56 (1H, br), 2.25 (3H, s), 1.58 (3H, d, J=6.81 Hz). Broad signals due to presence of rotamers/tautomers
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1.[BH4-].[Na+].C(O)(=O)C>C1COCC1>[OH:1][CH:2]1[CH2:3][CH2:4][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:7][CH2:6]2)[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CCC(O)CC2)CC1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
tert-Butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (1.5 g) was dissolved in THF (7.5 ml) and cooled to −5° C. NaBH4 (0.212 g) was then added and the mixture was stirred for 1 h at room temperature (TLC monitoring). When the conversion was complete, acetic acid was added to the mixture and the methanol was then distilled off. The residue was taken up in water (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic phases were dried (Na2SO4) and concentrated in vacuo. The resulting crude product was purified by column chromatography (silica gel, 30% ethyl acetate/hexane). Yield: 1.2 g (80%)