Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH2:15]([OH:19])[C:16]#[C:17][CH3:18].[H-].[Na+].O>CN(C)C=O>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:7]=[C:2]([O:19][CH2:15][C:16]#[C:17][CH3:18])[N:3]=[CH:4][N:5]=2)=[CH:9][CH:10]=1
Reactant: CC#CCO
Reactant: Fc1ccc(-c2cc(Cl)ncn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCOc1cc(-c2ccc(F)cc2)ncn1
Temperature: 25 °C
Reaction time: 9 h
Yield: 57.4 %

Procedure:
In 8 ml of N,N-dimethylformamide were dissolved 207 mg of 4-chloro-6-(4-fluorophenyl)pyrimidine and 83 mg of 2-butyn-1-ol, to which 48 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 9 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 138 mg of 4-(4-fluorophenyl)-6-(2-butynyloxy)pyrimidine (the present compound (59)).
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC([O-])(C)C.[K+].[SiH:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17]>O1CCCC1>[CH2:16]([Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:8][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:17]
Reactant: CSc1ccccc1
Reactant: CC[SiH](CC)CC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)CSc1ccccc1
Yield: 67.9 %

Procedure:
The reaction was conducted according to the General Procedure by heating thioanisole (62 mg, 0.5 mmol, 1 equiv.), KOt-Bu (11 mg, 0.1 mmol, 0.2 equiv) and Et3SiH (239 microliters, 1.5 mmol, 3 equiv.) in 1 mL of tetrahydrofuran for 65 hours at 65° C. After aqueous work up, the crude reaction mixture was purified by chromatography on silica using hexanes (isochratic) to obtain 81 mg (68%) of the title compound as a colourless oil. 1H NMR (500 MHz, THF-d8) δ 7.31-7.26 (m, 2H), 7.25-7.19 (m, 2H), 7.11-7.01 (m, 1H), 1.03 (t, J=7.9 Hz, 9H), 0.78-0.60 (m, 6H). 13C NMR (126 MHz, THF-d8) δ 140.73, 128.31, 125.69, 124.19, 13.01, 6.62, 3.06. HRMS: [C13H21SSi] calculated 237.1140. measured 237.1133. The HSQC spectra of the thioanisole and its reaction product as provided in FIGS. 7A and 7B.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:24])=[C:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[NH:9][C:10]=1[CH2:11][C:12]([O:14]CC)=[O:13])=[O:5])[CH3:2].CO.[OH-].[Li+]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:24])=[C:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[NH:9][C:10]=1[CH2:11][C:12]([OH:14])=[O:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1[nH]c(C(=O)OC(C)(C)C)c(C)c1C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1c(CC(=O)O)[nH]c(C(=O)OC(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.6 %

Procedure:
A solution of 5-ethoxycarbonylmethyl-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester (30 g, 88.5 mmol) in tetrahydrofuran (268 ml), and methanol (134 ml) was added with aqueous lithium hydroxide solution (0.465 mol lithium hydroxide in 197 ml of water). Upon completion of the addition, the mixture was stirred for 1.5 hours at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was added with water (200 ml) and extracted with ethyl ether. The water phase was adjusted to pH 1˜3 with 20% hydrochloric acid solution. The resulting solid was filtered, washed with ethyl ether, and dried in vacuo to give 5-carboxymethyl-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester (20 g, 72.3%) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[C:4]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[NH:11][CH:10]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.[N+:18]([O-])([OH:20])=[O:19]>S(=O)(=O)(O)O>[N+:18]([C:13]1[C:12](=[O:15])[NH:11][CH:10]=[C:9]([C:4]2[C:3]([C:2]([F:16])([F:1])[F:17])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH:14]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])O
Reactant: O=c1ccc(-c2ncccc2C(F)(F)F)c[nH]1
Agent: O=S(=O)(O)O
Product: O=c1[nH]cc(-c2ncccc2C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 92 %

Procedure:
To a solution of 3-trifluoromethyl-1′H-[2,3′]bipyridinyl-6′-one (25 g, 0.1 mol) in concentrated sulfuric acid (100 mL) at 0° C., add dropwise a solution of fuming nitric acid (35 mL) and concentrated sulfuric acid (10 mL). Heat the reaction mixture to 70° C. for 1 hour, cool and pour onto ice (500 mL). Filter the mixture and treat the filtrate with 10 M sodium hydroxide until the solution is at pH 4–5. Collect the precipitate by filtration and air dry to give the title compound (26.2 g, 92%) as a white solid.
Reaction SMILES: [C:1]1([CH:7]2[NH:11][CH:10]([C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19]1[CH:20]=[C:21]([NH:25][C:26](=[O:32])[NH:27][CH2:28][C:29](O)=[O:30])[CH:22]=[CH:23][CH:24]=1>ClCCCl.S(Cl)(Cl)=O>[CH3:18][C:19]1[CH:20]=[C:21]([NH:25][C:26](=[O:32])[NH:27][CH2:28][C:29]([N:11]2[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH2:9][CH:10]2[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])=[O:30])[CH:22]=[CH:23][CH:24]=1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Reactant: CC(C)OC(=O)C1CCC(c2ccccc2)N1
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: Cc1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)C)CCC2c2ccccc2)c1
Yield: 22 %

Procedure:
By proceeding in a fashion similar to that described in Example 1, but starting from 3 g of isopropyl (2RS,5SR)-5-phenylprolinate, 2.7 g of 2-[3-(3-methylphenyl)ureido]acetic acid in a suspension in 75 cm3 of anhydrous 1,2-dichloroethane and 1 cm3 of sulphinyl chloride, 1.2 g of isopropyl (2RS,5SR)-1-{2-[3-(3-methylphenyl)ureido]acetyl}-5-phenylprolinate are obtained after purification [proton NMR (200 MHz, CDCl3, δ in ppm), 2 rotamers at room temperature, preponderant rotamer description: 1.1 (d, 6H, (CH3)2); 1.7 to 2.5 (m, 4H, H in position 3 and 4 on pyrrolidine); 2.15 (s, 3H, CH3); 3 and 4.1 (2bd, 2H, CH2N); 4.4 (bt, 1H, H in position 2 on pyrrolidine); 4.9 (m, 2H, isopropyl CH and H in position 5 on pyrrolidine); 6.6 to 7.5 (m, 9H, aromatic). Infrared spectrum (KBr), characteristic bands in cm-1 : 3365, 3150, 3060, 3030, 2980, 2935, 2875, 1738, 1700, 1645, 1615, 1595, 1560, 1495, 1450, 1430, 1375, 1305, 1295, 1280, 1210, 1190, 1145, 1120, 915, 890, 860, 780, 755 705].
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4][CH2:3]1.[CH3:17][Li].[NH4+].[Cl-]>O1CCCC1.CCOCC>[OH:1][C:2]1([CH3:17])[CH2:3][CH2:4][CH:5]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:6][CH2:7]1
Reactant: [Li]C
Reactant: CC(C)(C)OC(=O)NCC1CCC(=O)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(O)CCC(CNC(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1.2 h

Procedure:
To a vigorous stirring solution of tert-butyl (4-oxocyclohexyl)methylcarbamate (1.7 g) in tetrahydrofuran (40 mL) at −78° C. was dropwise added 1.6 M methyllithium (14.02 mL) in ether. After completion of the addition, the mixture was stirred at −78° C. for 1.2 hours and poured into a cold aqueous NH4Cl solution. The resulting mixture was extracted with dichloromethane (3×100 mL) and the organic layer was dried over Na2SO4, filtered and concentrated. The residue was dissolved in dichloromethane and loaded onto an Analogix purification system, eluted with 0-50% ethyl acetate in dichloromethane to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH:31]([F:33])[F:32])[CH:25]=3)(=[O:23])=[O:22])[CH:17]=[CH:16][C:15]=2[O:34][CH3:35])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:38](Br)[CH3:39]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([N:20]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH:31]([F:32])[F:33])[CH:25]=3)(=[O:23])=[O:22])[CH2:38][CH3:39])[CH:17]=[CH:16][C:15]=2[O:34][CH3:35])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCBr
Reactant: COc1ccc(NS(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Product: CCN(c1ccc(OC)c(N2CCN(C(=O)OC(C)(C)C)CC2)c1)S(=O)(=O)c1cccc(OC(F)F)c1

Procedure:
The compound was prepared by analogy to the methods described for Preparation Example 2 and Examples 1 and 5 from 4-{5-[(3-difluoromethoxybenzenesulfonyl)-amino]-2-methoxyphenyl}-piperazine-1-carboxylic acid tert-butyl ester, which was reacted with sodium hydride and ethylbromide to yield 4-{5-[(3-difluoromethoxy-benzenesulfonyl)-ethyl-amino]-2-methoxy-phenyl}-piperazine-1-carboxylic acid tert-butyl ester, which was deprotected and subsequently subjected to reductive amination with aqueous formaldehyde and sodium triacetoxyborohydride as described for example 5 to yield the title compound.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[N:21]1[N:22]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[N:23]=[CH:24][CH:25]=1>>[N:21]1[N:22]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH2:29][N:1]2[CH:2]([C:11]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=3[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]2=[O:9])[N:23]=[CH:24][CH:25]=1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-n2nccn2)c1
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cccc(-n2nccn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with 3-(2H-1,2,3-triazol-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.88 min.; [M+H]+: 407.09 g/mol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][C:20]1([C:23]([O:25][CH3:26])=[O:24])[CH2:22][CH2:21]1>C(Cl)(Cl)Cl.CO>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][C:20]2([C:23]([O:25][CH3:26])=[O:24])[CH2:22][CH2:21]2)=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)C1(N)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)C1(NC(=O)[C@H](C)NC(=O)Cc2cc(F)cc(F)c2)CC1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 1-aminocyclopropane-1-carboxylate hydrochloride (Sigma), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.3 in 95:5 CHCl3/MeOH) and the product was purified by silica gel chromatography using 97:3 CHCl3/MeOH as the eluent.
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)(C)(C)C.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>ClCCl>[OH:33][C:31]([C:30]([F:35])([F:34])[F:29])=[O:32].[CH2:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[CH2:7][C:6]([OH:28])=[O:5])=[CH:16][CH:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)CN1CCC[C@H]1COc1ccc(Cc2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CN1CCC[C@H]1COc1ccc(Cc2ccccc2)cc1
Reaction time: 4 h
Yield: 94 %

Procedure:
[(S)-2-(4-Benzyl-phenoxymethyl)-pyrrolidin-1-yl]-acetic acid tert-butyl ester (30 mg, 0.079 mmol) was added to a solution of trifluoroacetic acid and dichloromethane (1:3, 4 mL). The reaction was run at room temperature for 4 h. The Mixture was concentrated to dryness and dried in a vacuum over at 50° C. The residue was triturated with diethyl ether and dried to obtain the title product (24.1 mg, 0.074 mmol, 94% yield) was confirmed by LCMS: m/z 325.41 (free amine). found 325 (M); 1H NMR (400 MHz, DMSO-d6) δ 1.78-1.83 (m, 1H), 1.96-2.05 (m, 2H), 2.19-2.25 (m, 1H), 3.31 (s, 1H), 3.68 (s, 1H), 3.88 (s, 2H), 3.98 (s, 1H), 4.18-4.34 (m, 4H), 6.88-6.90 (d, J=8.8, 2H), 7.17-7.21 (m, 5H), 7.26-7.29 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:25])=[CH:15]/[C:16]3[CH:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:38](O)[CH2:39][OH:40].O>C1C=CC=CC=1>[CH3:23][C:22]1([C:19]2[CH:20]=[CH:21][C:16](/[CH:15]=[C:14](/[C:6]3[CH:5]=[CH:4][C:3]4[C:2]([CH3:26])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=4[CH:7]=3)\[CH3:25])=[CH:17][CH:18]=2)[O:40][CH2:39][CH2:38][O:24]1
Reactant: OCCO
Reactant: CC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: C/C(=C\c1ccc(C2(C)OCCO2)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
3.0 g of 4'-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-acetophenone (prepared as described in Example 22) dissolved in 40 ml of benzene are treated with a catalytic amount of p-toluenesulphonic acid and 0.6 g of ethyleneglycol and warmed in a Dean-Stark apparatus, the water formed being concurrently separated off. After heating under reflux for 2 days, the mixture is cooled down, introduced into ice/saturated sodium bicarbonate solution and exhaustively extracted with ether. The ether extract is washed twice with a saturated sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure to remove the solvent. The oily residue is purified by adsorption on silica gel using hexane/ether (9:1) for the elution. The 2-methyl-2-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-phenyl]-1,3-dioxolane obtained from the eluate melts at 122°-123° C. after recrystallisation from ether.
Reaction SMILES: [N+]([C:4]1[CH:13]=[C:12]([N+:14]([O-])=O)[C:11]([F:17])=[CH:10][C:5]=1[O:6][CH2:7][C:8]#[N:9])([O-])=O.C(O)(=[O:20])C>[Fe]>[F:17][C:11]1[C:12]([NH2:14])=[CH:13][C:4]2[NH:9][C:8](=[O:20])[CH2:7][O:6][C:5]=2[CH:10]=1
Reactant: CC(=O)O
Reactant: N#CCOc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Fe]
Product: Nc1cc2c(cc1F)OCC(=O)N2
Yield: 71.7 %

Procedure:
Iron powder (5.6 g) was suspended in 5% acetic acid (112 g), and a solution of 2,4-dinitro-5-fluorophenoxyacetonitrile (2.4 g) in acetic acid (48 g) was dropwise added thereto under reflux, followed by refluxing for an additional 1 hour. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The extract was concentrated, and the precipitated crystals were collected by filtration and washed with a mixture of hexane and ether to give 7-fluoro-6-amino-2H-1,4-benzoxazin-3-(4H)-one (1.3 g; yield, 71.7%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]([C:15]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](=[O:28])[C:18]2=[CH:29][CH:30]=[CH:31][N:17]2[N:16]=1)[CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:12]([C:15]1[N:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](=[O:28])[C:18]2=[CH:29][CH:30]=[CH:31][N:17]2[N:16]=1)[CH2:13][CH3:14])[C:38](=[O:39])[C:37]1[CH:41]=[CH:42][C:34]([Cl:33])=[CH:35][CH:36]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCC(NCCCNC(=O)OC(C)(C)C)c1nn2cccc2c(=O)n1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC(c1nn2cccc2c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.3 %

Procedure:
{3-[1-(3-Benzyl-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-propylamino]-propyl}-carbamic acid tert-butyl ester (Example 47, 25 mg, 0.0569 mmol) in CHCl3 (10 mL) at 25° C. was treated with 4-chloro-benzoylchloride (31.5 μL, 0.248 mmol) and triethylamine (23.0 μL, 0.166 mmol). The resulting mixture was stirred at 25° C. for 18 h, then concentrated under vacuum and purified by preparative HPLC using a YMC S10 ODS 20×100 mm column affording the desired compound (17.2 mg, 52.3%) as a colorless film: LC/MS 86% at 3.74 min (ESI+) 578 (M++H).
Reaction SMILES: O.O.[Sn](Cl)Cl.[Cl:6][C:7]1[N:12]=[C:11]([NH:13][CH3:14])[C:10]([N+:15]([O-])=O)=[C:9]([Cl:18])[N:8]=1>CCO>[Cl:6][C:7]1[N:12]=[C:11]([NH:13][CH3:14])[C:10]([NH2:15])=[C:9]([Cl:18])[N:8]=1
Reactant: CNc1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CNc1nc(Cl)nc(Cl)c1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.9 %

Procedure:
Tin (II) chloride dihydrate (2.0 g) was added to a solution of 2,6-dichloro-N-methyl-5-nitropyrimidine-4-amine (680 mg) in EtOH (13 mL) at room temperature. The mixture was stirred at room temperature for 3 hours, and stirred at 90° C. for 2 hours. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. EtOAc and a saturated aqueous NaHCO3 solution were added to the residue, and the insoluble material was separated by filtration using Celite. Extraction was performed on the filtrate using EtOAc, and the extract was washed with water and saturated brine. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex:EtOAc=80:20 to 50:50), whereby 2,6-dichloro-N4-methylpyrimidine-4,5-diamine (482 mg) was obtained as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[CH3:11][N:12]1[C:16]([C:17](Cl)=[O:18])=[CH:15][C:14]([CH3:20])=[N:13]1.O>CN(C)C(=O)C>[CH3:11][N:12]1[C:16]([C:17]([NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:18])=[CH:15][C:14]([CH3:20])=[N:13]1
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(C(=O)Nc2cccc([N+](=O)[O-])c2)n(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
To a solution of 3-nitroaniline (1.0 g, 7.2 mmol) in N,N-dimethylacetamide (6 mL) was added a solution of 1,3-dimethyl-1H-pyrazole-5-carbonylchloride (1260 mg, 8.0 mmol) in N,N-dimethylacetamide (2 mL), and the mixture was stirred at room temperature for 30 min. Water (200 mL) was added to the mixture under ice-cooling, and the mixture was filtrated. The obtained solid was washed with water and diethyl ether to give 1,3-dimethyl-N-(3-nitrophenyl)-1H-pyrazole-5-carboxamide (1850 mg, 7.1 mmol). To a solution of the obtained 1,3-dimethyl-N-(3-nitrophenyl)-1H-pyrazole-5-carboxamide (1850 mg, 7.1 mmol) in ethanol (50 mL) was added 10% palladium/carbon (190 mg). Hydrazine monohydrate (1090 mg, 22 mmol) was slowly added to the mixture at room temperature and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was filtrated, and the filtrate was evaporated under reduced pressure. To the residue were added ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate (×4). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate/hexane to give the title compound (1650 mg, 99%) as a pale-yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH3:26])=[C:12]([NH:14][C:15]([C:17]3[N:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]4=[N:19][CH:18]=3)=[O:16])[CH:13]=2)[N:4]=1.CCN(C(C)C)C(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[CH3:36][S:37]([O:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH3:26])=[C:12]([NH:14][C:15]([C:17]3[N:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]4=[N:19][CH:18]=3)=[O:16])[CH:13]=2)[N:4]=1)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(-c2noc(CO)n2)cc1NC(=O)c1cnc2ccccn12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(-c2noc(COS(C)(=O)=O)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.2 %

Procedure:
To a solution of N-(5-(5-(hydroxymethyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (43) (210 mg, 0.6 mmol) and DIEA (0.32 mL, 1.8 mmol) in DCM (5 mL) was added MsCl (138 mg, 1.2 mmol). The mixture was stirred at room temperature for 10 minutes then subjected to standard aqueous work up. The crude product was purified by silica chromatography to yield (3-(3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)methyl methanesulfonate (44) (180 mg, 70% yield). MS m/z 428.1 (M+1)+.
Reaction SMILES: P(Br)(Br)([Br:3])=O.[Br:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[NH:15][C:14](=O)[CH:13]=[CH:12]2>>[Br:3][C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[C:7]([Br:6])[CH:8]=[CH:9][CH:10]=2)[N:15]=1
Reactant: O=c1ccc2cccc(Br)c2[nH]1
Reactant: O=P(Br)(Br)Br
Product: Brc1ccc2cccc(Br)c2n1
Temperature: 125 °C
Yield: 62.8 %

Procedure:
A mixture of phosphorus oxybromide (1.59 g, 5.55 mmol) and 8-bromo-2(1H)-quinolinone (0.250 g, 1.11 mmol) was heated at 125° C. for 2 h before being poured onto ice. The resulting precipitate was filtered and crystallized from MeOH to give 2,8-dibromo-quinoline (0.2 g, 64%) as colorless prisms. MS (ESI, pos. ion) m/z: 287.8 (M+1).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23](B(O)O)[CH:22]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[F:18][C:17]([F:20])([F:19])[C:14]1[CH:15]=[CH:16][C:10]2[O:9][C:8]([C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)=[N:12][C:11]=2[CH:13]=1
Reactant: FC(F)(F)c1ccc2oc(-c3ccncc3I)nc2c1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc2oc(-c3ccncc3-c3cccnc3)nc2c1
Temperature: 25 °C
Yield: 102.9 %

Procedure:
To a mixture of 0.40 g of 2-(3-iodopyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.21 g of 3-pyridine boronic acid, 8 ml of 1,4-dioxane and 0.07 g of dichlorobis(triphenylphosphine)palladium (II), a mixture of 0.40 g of sodium carbonate and 3 ml of water was added and heated to reflux for two hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.36 g of 4-(5-trifluoromethyl-benzoxazole-2-yl)-[3,3′]bipyridinyl (hereinafter, referred to as “active compound 128”).
Reaction SMILES: [CH:1]([C:3]1[CH:27]=[CH:26][C:6]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][C:16]3=[O:17])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1)=O.Cl.[NH2:29][OH:30].C([O-])(=O)C.[Na+].O>C(O)C>[OH:30][N:29]=[CH:1][C:3]1[CH:27]=[CH:26][C:6]([C:7]([N:9]2[CH2:10][CH2:11][CH:12]([N:15]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][C:16]3=[O:17])[CH2:13][CH2:14]2)=[O:8])=[CH:5][CH:4]=1
Reactant: NO
Reactant: O=Cc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(c1ccc(C=NO)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Yield: 96 %

Procedure:
1-[1-(4-Formylbenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (1 g), hydroxylamine hydrochloride (580 mg) and sodium acetate (1.6 g) are dissolved in ethanol (20 ml) and water (10 ml) and the mixture is stirred at room temperature overnight. The solvent is concentrated and water is added to the residue. The mixture is extracted with chloroform, dried with sodium carbonate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate=1:2) and recrystallized from n-hexane/ethanol to give 1-[1-(4-hydroxyiminomethylbenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (1 g) as white powder, m.p.: 222°-224° C.