Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[C:5]([C:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][CH:12]=2)=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[N:3]=1.[C:25](=O)([O-])[O-].[K+].[K+].IC>CS(C)=O>[NH2:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[C:5]([C:11]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH3:25])[CH:12]=2)=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[N:3]=1
Reactant: CCn1c(N)nc(-c2cccc(F)c2)c(-c2ccc(=O)[nH]c2)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Product: CCn1c(N)nc(-c2cccc(F)c2)c(-c2ccc(=O)n(C)c2)c1=O
Temperature: 50 °C
Reaction time: 16 h
Yield: 19.6 %

Procedure:
To a solution of 2-amino-3-ethyl-6-(3-fluorophenyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)-3,4-dihydro-4-pyrimidinone (20 mg, 0.06 mmol) in dimethyl sulfoxide (1 mL) were added potassium carbonate (20 mg, 0.12 mmol) and iodomethane (20 μL, 0.30 mmol), followed by stirring at 50° C. for 16 hours. After filtering off the insoluble matters, the filtrate was purified by HPLC, to give the title compound (4 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([S:10][C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[N:8]=[N:9][C:4]=2[CH:3]=1.Br[CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([S:10][C:11]3[CH:12]=[CH:13][C:14]([O:17][CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15][CH:16]=3)[N:8]=[N:9][C:4]=2[CH:3]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ccc(Sc2nnc3cc(Cl)ccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)Oc1ccc(Sc2nnc3cc(Cl)ccc3n2)cc1
Yield: 79.2 %

Procedure:
A mixture of 4-[(7-chloro-1,2,4-benzotriazin-3-yl)thio]phenol (1.83 g), ethyl 2-bromopropionate (1.37 g), anhydrous potassium carbonate (0.96 g) and methyl ethyl ketone (50 ml) was heated under reflux for a period of 3 hours. The solvent was removed by distillation under reduced pressure and the residue was partitioned between water and dichloromethane. The organic phase was separated, dried (over anhydrous magnesium sulfate) and the solvent was removed by distillation under reduced pressure to give a solid. The crude product was purified by chromatography over silica gel (eluent dichloromethane) to give the title compound (1.95 g) as a crystalline solid, mp 86°-88° C.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:11])[NH:5][O:6][CH2:7][C:8]([OH:10])=O)[CH3:2].[NH2:12][C@H:13]([C:26]([N:28]([C@@H:40]([CH3:48])[CH:41]([O:45][CH2:46][CH3:47])[O:42][CH2:43][CH3:44])[CH2:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1)=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]>>[CH2:43]([O:42][CH:41]([O:45][CH2:46][CH3:47])[C@@H:40]([N:28]([CH2:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1)[C:26]([C@H:13]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:24])[CH3:22])[NH:12][C:8](=[O:10])[CH2:7][O:6][NH:5][C:4](=[O:11])[NH:3][CH2:1][CH3:2])=[O:27])[CH3:48])[CH3:44]
Reactant: CCNC(=O)NOCC(=O)O
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Product: CCNC(=O)NOCC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N(Cc1cccc2ccccc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-ethylureidooxy)acetic acid (Compound VI-13) 47 mg (0.29 mmol) was coupled with tert-butyl (S)-5-amino-6-(((S)-1,1-diethoxypropan-2-yl)(naphthalen-1-ylmethyl)amino)-6-oxohexylcarbamate (Compound IV-13) 100 mg (0.19 mmol) to obtain the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:7][CH:6]=1)=[O:4].O.[OH-].[Li+]>C1COCC1.O>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:12]=1[CH2:11][CH2:10][C:8]1[S:9][C:5]([C:3]([OH:4])=[O:2])=[CH:6][N:7]=1
Reactant: COC(=O)c1cnc(CCc2c(-c3ccccn3)noc2C)s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1onc(-c2ccccn2)c1CCc1ncc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 96 %

Procedure:
To a suspension of 2-[2-(5-methyl-3-pyridin-2-yl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid methyl ester (835 mg, 2.54 mmol) in THF (8 mL) was added a solution of lithium hydroxide monohydrate (165 mg, 3.9 mmol) in water (8 mL) and the resulting mixture stirred at room temperature for 45 min. The mixture was then evaporated to half volume and then acidified to pH 1 with HCl (1N) and cooled to 0° C. for 15 min. A solid precipitated and was filtered off and dried to afford the title compound (769 mg, 96%) which was obtained as an off white solid. MS: m/e=314.1 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH:7][C:8](=[O:10])[CH3:9])=[CH:5][N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1.[CH2:17](Br)[CH3:18].[H-].[Na+].CC(C)([O-])C.[Na+]>O1CCCC1>[Cl:1][C:2]1[C:6]([N:7]([CH2:17][CH3:18])[C:8](=[O:10])[CH3:9])=[CH:5][N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1
Reactant: CC(=O)Nc1cn(-c2cccnc2)nc1Cl
Reactant: CCBr
Agent: CC(C)(C)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(C(C)=O)c1cn(-c2cccnc2)nc1Cl

Procedure:
In step 2d, N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)acetamide (2-8) is alkylated with ethyl bromide (EtBr) in the presence of a base, such as sodium hydride (NaH) or sodium tert-butoxide (NaOt-Bu), in a polar aprotic solvent, such as tetrahydrofuran, at temperatures from about 20° C. to about 40° C., over a period of time of about 60 hours to about 168 hours, to yield N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethylacetamide (2-9). It has been discovered that use of an iodide additive, such as potassium iodide (KI) or tetrabutylammonium iodide (TBAI) can decrease the time necessary for the reaction to occur to about 24 hours. It has also been discovered that heating the reaction at about 50° C. to about 70° C. in a sealed reactor (to prevent loss of ethyl bromide) also decreases the reaction time to about 24 hours.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH3:10])[NH:7][C:6](=[O:11])[C:5]=1[CH2:12][NH:13][C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH3:26])[C:17]=1[CH3:33])=[O:15].C([O-])([O-])=O.[K+].[K+].CC#N.CN(C=O)C.Br[CH2:49][CH2:50][F:51]>>[F:51][CH2:50][CH2:49][N:30]1[CH2:29][CH2:28][CH:27]([CH:25]([N:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]([C:14]([NH:13][CH2:12][C:5]3[C:6](=[O:11])[NH:7][C:8]([CH3:10])=[CH:9][C:4]=3[O:3][CH3:2])=[O:15])=[C:17]2[CH3:33])[CH3:26])[CH2:32][CH2:31]1
Reactant: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)C2CCNCC2)c2ccccc12
Reactant: FCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1cc(C)[nH]c(=O)c1CNC(=O)c1c(C)n(C(C)C2CCN(CCF)CC2)c2ccccc12
Temperature: 82 °C
Reaction time: 4 h

Procedure:
A 25 mL vial was charged with a magnetic stir bar, (R or S)-N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(piperidin-4-yl)ethyl)-1H-indole-3-carboxamide hydrochloride (Compound 326) (0.062 g, 0.131 mmol), K2CO3 (0.072 g, 0.524 mmol), MeCN (0.655 ml, 0.131 mmol), DMF (0.262 ml, 0.131 mmol) and 1-bromo-2-fluoroethane (0.020 ml, 0.262 mmol). The reaction was capped and heated to 82° C. with stirring for 4 h. The reaction was allowed to cool to rt, filtered, and the filtrate was pre-absorbed onto silica gel (12 g). The material was purified via SiO2 chromatography (25 g) using DCM/MeOH/Et3N (85:15:0.5) as eluent to afford the title compound as an off white solid (30 mg, 0.059 mmol, 45.1% yield).). LCMS 483 (M+1)+; 1H NMR (DMSO-d6, 400 MHz) δ 11.59 (s, 1H), 7.75-7.68 (m, 2H), 7.60 (d, 1H) 7.09-7.03 (m, 2H), 6.15 (s, 1H) 4.53-4.51 (m, 1H), 4.42-4.39 (m, 1H), 4.32 (d, 2H), 4.24-4.2 (m, 1H), 3.84 (s, 3H), 2.98 (br. d., 1H), 2.70-2.49 (m, 4H), 2.60 (s, 3H), 2.20 (s, 3H), 2.01 (dt, 1H), 1.92-1.90 (m, 1H), 1.75-1.71 (m, 1H), 1.54 (d, 3H), 1.38-1.36 (m, 1H), 1.02-0.98 (m, 1H), 0.7-0.66 (br. d., 1H).
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)=[CH:7][C:5]=2[N:6]=1.[F:24][C:25]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[CH:30][C:26]=1[C:27]([NH2:29])=[O:28].[F-].[K+]>CN(C=O)C.O>[C:27]([C:26]1[CH:30]=[CH:31][C:32]([C:2]2[O:3][C:4]3[CH:10]=[CH:9][C:8]([CH:11]4[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]4)=[CH:7][C:5]=3[N:6]=2)=[CH:33][C:25]=1[F:24])(=[O:28])[NH2:29]
Reactant: CC1(C)OB(c2ccc(C(N)=O)c(F)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3oc(Br)nc3c2)CC1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3oc(-c4ccc(C(N)=O)c(F)c4)nc3c2)CC1
Temperature: 90 °C
Yield: 6.8 %

Procedure:
Intermediate 52 (40 mg, 0.1 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (30 mg, 0.12 mmol) and KF (18 mg, 0.3 mmol) were dissolved in a mixture of DMF (1 ml) and water (0.4 ml). This mixture was purged with N2 for 30 mins. Pd(dppf)Cl2.CH2Cl2 was added to the above mixture and again purged with N2 for 30 mins. This reaction mixture was heated to 90° C. for 12 h. Work up (EtOAc and H2O) followed by purification on combiflash using a gradient mixture of EtOAc and Petether (55:45) as eluent afforded the titled compound (3 mg) as an Off-White solid. MS (m/z): 439.5 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]([CH3:15])[CH3:14])=[O:5])#[N:2].CO[C:18](OC)([N:20]([CH3:22])[CH3:21])[CH3:19]>>[C:1](/[C:3](=[C:18](/[N:20]([CH3:22])[CH3:21])\[CH3:19])/[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]([CH3:15])[CH3:14])=[O:5])#[N:2]
Reactant: COC(C)(OC)N(C)C
Reactant: CC(C)c1ccccc1NC(=O)CC#N
Product: C/C(=C(\C#N)C(=O)Nc1ccccc1C(C)C)N(C)C

Procedure:
As for Example 1, 2-cyano-2'-isopropylacetanilide, off-white crystals, m.p. 74°-78° C. (prepared by the procedure described in U.S. Pat. No. 3,116,312), is heated with N,N-dimethylacetamide dimethylacetal to yield 2-cyano-3-dimethylamino-2'-isopropylcrotonanilide as colorless prisms, m.p. 119°-121° C.
Reaction SMILES: Cl[C:2]1[CH:30]=[CH:29][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[N:21]([CH3:28])[N:22]=[C:23]([CH:25]4[CH2:27][CH2:26]4)[CH:24]=3)=[O:18])[CH2:14][OH:15])[CH2:8]2)=[CH:4][CH:3]=1.N[C@@H](CCN1CC(OC2C=CC([F:48])=CC=2)C1)CO>>[F:48][C:2]1[CH:30]=[CH:29][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[N:21]([CH3:28])[N:22]=[C:23]([CH:25]4[CH2:27][CH2:26]4)[CH:24]=3)=[O:18])[CH2:14][OH:15])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: Cn1nc(C2CC2)cc1NC(=O)N[C@H](CO)CCN1CC(Oc2ccc(Cl)cc2)C1
Reactant: N[C@H](CO)CCN1CC(Oc2ccc(F)cc2)C1
Product: Cn1nc(C2CC2)cc1NC(=O)N[C@H](CO)CCN1CC(Oc2ccc(F)cc2)C1

Procedure:
This compound is prepared analogously to 1-{(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-cyclopropyl-2-methyl-2H-pyrazol-3-yl)-urea in Example 83 except using (S)-2-amino-4-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-butan-1-ol in place of (S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)[C:13](=[O:30])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+].C(COC)OC>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(OCC)(=O)C>[C:2]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)[C:13](=[O:30])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C1CN(S(=O)(=O)c2ccc(I)cc2)CCN1CC1CCN(c2ccncc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=C1CN(S(=O)(=O)c2ccc(-c3ccccc3)cc2)CCN1CC1CCN(c2ccncc2)CC1
Yield: 58.6 %

Procedure:
A mixture of 4-(4-iodobenzenesulfonyl)-1-[1-(4-pyridyl)-4-piperidylmethyl]-2-piperazinone (216 mg), phenylboronic acid (98 mg), tetrakis(triphenylphosphine)palladium (46 mg), 1M sodium carbonate solution (1.2 ml). and dimethoxyethane (10 ml) was refluxed for 2 hours and cooled, and to the reaction solution was added ethyl acetate. The mixture was washed with water and saturated brine, dried and concentrated, and the residue was purified with silica gel column chromatography (acetone:methanol=9:1→1:1) and washed with water to give colorless crystals of 4-[(1,1′-biphenyl)-4-ylsulfonyl]-1-[1-(4-pyridyl)-4-piperidylmethyl]-2-piperazinone (115 mg), which were dissolved in ethanol and a solution of 4N hydrochloric acid in ethyl acetate. The solution was concentrated under reduced pressure to give amorphous of the title compound.
Reaction SMILES: C(OC(=O)[CH2:5][NH:6][NH:7][C:8](=[O:18])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=1)C.P(Cl)(Cl)(Cl)=[O:21]>>[CH:15]([C:12]1[CH:13]=[CH:14][C:9]([C:8]2[O:18][C:5](=[O:21])[NH:6][N:7]=2)=[CH:10][CH:11]=1)([CH3:17])[CH3:16]
Reactant: CCOC(=O)CNNC(=O)c1ccc(C(C)C)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)c1ccc(-c2n[nH]c(=O)o2)cc1
Yield: 58 %

Procedure:
Ethyl[2-(4-isopropylbenzoyl)hydrazino]acetate (4.85 g, 19.4 mmol) is treated with phosphorus oxychloride (50 mL), heated to reflux for 3 h, and then poured onto ice. The precipitate is collected and washed thoroughly with water and dried in the air to furnish 5-(4-isopropylphenyl)-1,3,4-oxadiazol-2(3H)-one (2.30 g, 58%) MS (ES+): m/e 205.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[C:15]1([CH2:21][CH2:22][C:23](Cl)=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1(C)C=CC=CC=1.O1CCCC1>[C:15]1([CH2:21][CH2:22][CH2:23][N:11]2[CH2:12][CH2:13][CH2:14][C@H:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:10]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc([C@H]2CCCNC2)c1
Reactant: O=C(Cl)CCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cccc([C@H]2CCCN(CCCc3ccccc3)C2)c1

Procedure:
The title compound was prepared by acylation of 1.0 g (5.2 mmole) of the (R)(-)-3-(3-methoxyphenyl)piperidine from preparation 7, Part C, with 1.3 g (7.8 mmole) of 3-phenylpropionyl chloride in toluene, followed by reduction with 910 mg (24 mmole) of lithium aluminum hydride in tetrahydrofuran, using the procedure of Preparation 3. This afforded 1.9 g of an oil.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:20]([C:21]3[CH:22]=[CH:23][C:24]4[N:25]([C:27]([C:30]5[S:31][CH:32]=[CH:33][CH:34]=5)=[CH:28][N:29]=4)[CH:26]=3)=[CH:19][N:18]([C:35]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:17]=2)=[CH:12][CH:11]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O>[Br:1][C:32]1[S:31][C:30]([C:27]2[N:25]3[CH:26]=[C:21]([C:20]4[C:16]([C:13]5[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=5)=[N:17][N:18]([C:35]([C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:48]5[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=5)[CH:19]=4)[CH:22]=[CH:23][C:24]3=[N:29][CH:28]=2)=[CH:34][CH:33]=1
Reactant: Fc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4cccs4)n3c2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccc(Br)s4)n3c2)cc1
Reaction time: 1 h
Yield: 108.2 %

Procedure:
160 mg N-bromosuccinimide was added to 5 mL solution of 500 mg 6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]-3-(2-thienyl)imidazo[1,2-a]pyridine obtained in Example 3 in N,N-dimethylformamide, and the mixture was stirred for 1 hour. An aqueous sodium thiosulfate solution was added thereto and stirred for 30 minutes, and the reaction solution was extracted with ethyl acetate and dried over magnesium sulfate. The residue was purified by NH silica gel column chromatography (hexane/dichloromethane/ethyl acetate) to give 612 mg of the title compound as pale yellow crystals.
Reaction SMILES: O=[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[O:5][C:4]2[C:11]3[C:16]([CH:17]=[CH:18][C:3]1=2)=[CH:15][CH:14]=[CH:13][CH:12]=3.[H][H]>[Pd].COCCO>[O:5]1[CH:6]([C:8]([OH:10])=[O:9])[CH2:7][CH2:2][C:3]2[CH:18]=[CH:17][C:16]3[C:11]([C:4]1=2)=[CH:12][CH:13]=[CH:14][CH:15]=3
Reactant: O=C(O)c1cc(=O)c2ccc3ccccc3c2o1
Reactant: [H][H]
Agent: [Pd]
Solvent: COCCO
Product: O=C(O)C1CCc2ccc3ccccc3c2O1

Procedure:
A mixture of 4-oxo-4H-naphto[1,2-b]pyran-2-carboxylic acid (12 g) and 2-methoxyethanol (100 ml) was hydrogenated at normal pressure and at room temperature in the presence of palladium on activated carbon 10% (2 g) as a catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 7g (61.4%) of 3,4-dihydro-2H-naphto[1,2-b]pyran-2-carboxylic acid (interm. 9-a).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([NH:8][CH2:9][CH2:10]Cl)=[O:7])=[CH:4][CH:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.N>O>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=C(NCCCl)c1ccc(Cl)cc1
Agent: N
Solvent: O
Product: O=C(NCCN1CCOCC1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
5.45 G. of p-chloro-N-(2-chloroethyl)-benzamide and 8.7 g. of morpholine are stirred together for 2 hours at 100° C. The mixture is cooled to room temperature and 50 ml. of water are added. Then, the mixture is rendered basic with 10% ammonia solution and extracted three times with 50 ml. of methylene chloride each time. The methylene chloride extract is dried over sodium sulfate and evaporated. The residue is chromatographed over a silica gel column with a mixture of chloroform and ethanol. The product is recrystallized from isopropanol, and 2.2 g. of p-chloro-N-(2-morpholinoethyl)-benzamide are obtained, which is identical to the product obtained in Example 1.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]2)(=O)=O)=CC=1.[C:20]([C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29]([N+:33]([O-:35])=[O:34])=[CH:28][CH:27]=2)([CH3:23])([CH3:22])[CH3:21].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:20]([C:24]1[N:25]([CH2:12][C@@H:13]2[CH2:17][O:16][C:15]([CH3:18])([CH3:19])[O:14]2)[C:26]2[C:31]([CH:32]=1)=[CH:30][C:29]([N+:33]([O-:35])=[O:34])=[CH:28][CH:27]=2)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@@H](Cn2c(C(C)(C)C)cc3cc([N+](=O)[O-])ccc32)O1
Temperature: 80 °C
Reaction time: 20 h
Yield: 65.7 %

Procedure:
To a stirred solution of (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (1.58 g, 5.50 mmol) in anhydrous DMF (10 mL) under nitrogen gas was added 2-tert-butyl-5-nitro-1H-indole (1.00 g, 4.58 mmol) followed by Cs2CO3 (2.99 g, 9.16 mol). The mixture was stirred and heated at 80° C. under nitrogen gas. After 20 hours, 50% conversion was observed by LCMS. The reaction mixture was re-treated with Cs2CO3 (2.99 g, 9.16 mol) and (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 4-methylbenzenesulfonate (1.58 g, 5.50 mmol) and heated at 80° C. for 24 hours. The reaction mixture was cooled to room temperature. The solids were filtered and washed with ethyl acetate and hexane (1:1). The layers were separated and the organic layer washed with water (2×10 mL) and brine (2×10 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane/hexane=1.5/1) to give (R)-2-tert-butyl-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-5-nitro-1H-indole (1.0 g, 66%). 1H NMR (400 MHz, CDCl3) δ 8.48 (d, J=2.2 Hz, 1H), 8.08 (dd, J=2.2, 9.1 Hz, 1H), 7.49 (d, J=9.1 Hz, 1H), 6.00 (s, 1H), 4.52-4.45 (m, 3H), 4.12 (dd, J=6.0, 8.6 Hz, 1H), 3.78 (dd, J=6.0, 8.6 Hz, 1H), 1.53 (s, 3H), 1.51 (s, 9H), 1.33 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.[Li+].[OH-]>C1COCC1.CO>[N:17]1[CH:16]=[CH:15][C:14]([CH2:13][O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:20])=[O:2])=[CH:7][CH:8]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)CCc1ccc(OCc2ccncc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(OCc2ccncc2)cc1
Reaction time: 8 h

Procedure:
To a solution of 3-[4-(Pyridin-4-ylmethoxy)-phenyl]-propionic acid methyl ester (0.28 g, 1.03 mmol) in THF (5 ml) and MeOH (5 ml) at room temperature is added 2 N LiOH (0.52 ml, 1.032 mmol) and the resulting solution is stirred overnight. Further 2 N LiOH (0.103 ml) is added and the reaction mixture stirred for a further 1 hour. The reaction mixture is concentrated in vacuo and the residue is diluted with water (50 ml) followed by EtOAc. The aqueous phase is acidified to pH2 with 1 N HCl, and extracted with DCM. The organic phase is concentrated to a third of its volume in vacuo until a white powder precipitates which is collected by filtration to yield the title compound; [M+H]+ 258.0
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][NH:7][C:6]2=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>N1C=CC=CC=1>[Br:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][NH:7][C:6]2=[S:19]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=c1[nH]ncc2c(Br)nc(-c3ccccc3)n12
Solvent: c1ccncc1
Product: S=c1[nH]ncc2c(Br)nc(-c3ccccc3)n12
Temperature: 100 °C

Procedure:
To a solution of 8-bromo-6-phenyl-imidazo[1,5-d]-as-triazin-4(3H)-one (5 gm.) in pyridine (100 ml.) is added phosphorus pentasulfide (5 gm.). The mixture is heated at 100° C. for 6 hours, cooled, and the product isolated by filtration and then washed with dilute hydrochloric acid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[CH:12]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:17][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: NC1CCCC1
Product: O=C(NC1CCCC1)c1ccc(Br)cc1F

Procedure:
The sub-title compound was prepared by the method of example 18 step a) using 4-bromo-2-fluorobenzoic acid and cyclopentanamine.
Reaction SMILES: B.[Cl:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[CH2:12][C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=O>C1COCC1>[Cl:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[CH2:12][CH2:13][N:15]([CH2:16][CH3:17])[CH2:18][CH3:19]
Reactant: CCN(CC)C(=O)Cc1ccc([N+](=O)[O-])cc1Cl
Agent: B
Solvent: C1CCOC1
Product: CCN(CC)CCc1ccc([N+](=O)[O-])cc1Cl
Temperature: 100 °C
Reaction time: 4 h

Procedure:
65 mL (65.000 mmol) borane (1 M in THF) was added at RT to a solution of 3.702 g (13.673 mmol) 2-(2-chloro-4-nitro-phenyl)-N,N-diethyl-acetamide in 130 mL THF and the mixture was stirred for 4 h . The reaction mixture was evaporated down i. vac., the residue was combined with 15 mL MeOH and 15 mL semiconc. aqueous HCl and heated to 100° C. for 15 min. Water was added, the mixture was made basic with aqueous sodium carbonate solution and the aqueous phase was extracted with EtOAc. The combined org. phases were washed with water and saturated aqueous NaCl solution, dried over sodium sulphate and evaporated down i. vac. The crude product was purified by column chromatography (Alox, neutral, act. II-III, gradient petroleum ether/EtOAc 8:1→4:1).