Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C@@H:13]([OH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[C:27]([F:28])=[CH:26][CH:25]=[C:24]([F:29])[C:23]=1O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([C@H:13]([O:20][C:23]2[C:24]([F:29])=[CH:25][CH:26]=[C:27]([F:28])[C:22]=2[Cl:21])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Oc1c(F)ccc(F)c1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]([C@@H](O)c2ccccc2)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H]([C@H](Oc2c(F)ccc(F)c2Cl)c2ccccc2)C1
Yield: 91.5 %

Procedure:
A mixture of (R)-3-((R)-hydroxyphenylmethyl)pyrrolidine-1-carboxylic acid t-butyl ester (10 g, 36.1 mmol), 2-chloro-3,6-difluorophenol (8.9 g, 54.1 mmol) and PPh3 (9.93 g, 37.8 mmol) in THF (20.5 mL, 252 mmol) was sonicated for several minutes. While sonicating, DIAD (7.5 mL, 37.8 mmol) was slowly added dropwise to the mixture over several minutes and sonicated further for 15 minutes. The mixture was concentrated and then triturated in excess hexanes for 16 hours. The PPh3 oxide precipitate was filtered off and the organic layer was concentrated to yield a yellow oil. The crude mixture was diluted in EtOAc (300 mL), washed with 1N NaOH (2×200 mL) and saturated aqueous NaCl (100 mL). The organic layer was dried with anhydrous MgSO4, filtered, and concentrated. The organic material was purified by silica gel chromatography (330 g column, 20-50% EtOAc in hexanes) to yield 14 g of (R)-3-[(S)-(2-chloro-3,6-difluorophenoxy)phenylmethyl]pyrrolidine-1-carboxylic acid t-butyl ester as a yellow oil which was used in the next step without further purification.
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[Cl:8][C:9]1[CH:19]=[CH:18][C:12]([CH:13]=[CH:14][C:15](=O)C)=[CH:11][CH:10]=1.N.[CH2:21](O)C>>[CH3:21][C:14](=[CH:13][C:12]1[CH:11]=[CH:10][C:9]([Cl:8])=[CH:19][CH:18]=1)[CH:15]=[C:7]1[S:1][C:2](=[S:3])[NH:4][C:5]1=[O:6]
Reactant: CC(=O)C=Cc1ccc(Cl)cc1
Reactant: CCO
Reactant: O=C1CSC(=S)N1
Agent: N
Product: CC(=Cc1ccc(Cl)cc1)C=C1SC(=S)NC1=O

Procedure:
A mixture of 1.33 g (0.01 mol) of rhodanine, 1.80 g (0.01 mol) of 4-chlorobenzalacetone, 20 ml of ethanol and 2 ml of aqueous ammonia was heated under reflux for 4 hours. After cooling, the precipitated crystals were recovered by filtration and washed with methanol to give 0.52 g of the desired 5-(α-methyl-4-chlorocinnamylidene)-4-oxo-2-thioxothiazolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[NH2:15]>>[NH2:15][C:14]1[CH:13]=[C:12]([O:11][CH3:10])[C:18]([O:19][CH3:20])=[CH:17][C:16]=1[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])=[O:5]
Reactant: O=Cc1ccccc1Cl
Reactant: COc1ccc(N)cc1OC
Product: COc1cc(N)c(C(=O)c2ccccc2Cl)cc1OC

Procedure:
(2-amino-4,5-dimethoxyphenyl)-(2-chlorophenyl)-methanone (Xx) was prepared by reacting 2-chlorobenzaldehyde with 0.0196 moles of 3,4-dimethoxy aniline in a manner analogous to Example 1. MH+/Z=292.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([CH2:13][C:14]#[N:15])[C:3]=1[C:16]#[N:17].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:21]=1[CH:22]=O.N1CCCCC1>C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([C:14]#[N:15])=[CH:22][C:21]2[C:24]([O:28][CH3:29])=[CH:25][CH:26]=[CH:27][C:20]=2[O:19][CH3:18])[C:3]=1[C:16]#[N:17]
Reactant: N#CCc1nn(-c2ccccc2)c(N)c1C#N
Reactant: COc1cccc(OC)c1C=O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COc1cccc(OC)c1C=C(C#N)c1nn(-c2ccccc2)c(N)c1C#N
Reaction time: 0.25 h
Yield: 37.2 %

Procedure:
1 g (4.48 mmol) of 5-amino-4-cyano-1-phenyl-3-pyrazoleacetonitrile is suspended in 15 mL of toluene, in a round-bottomed flask, under an argon atmosphere, surmonted by a Dean and Stark apparatus. 0.744 g (1 eq.) of 2,6-dimethoxybenzaldehyde and 0.030 mL of piperidine are added to the mixture. The reaction medium is refluxed overnight, and is then allowed to return to ambient temperature. A whitish precipitate forms and is filtered off and washed with toluene. The filtrate is concentrated to dryness and the residue is taken up in ethanol with agitation for 15 minutes. The suspension is filtered and the filtrate is concentrated to dryness. The residue is combined with the precipitate previously obtained, and purified on silica gel (eluent: 98/2 dichloromethane/methanol). 619 mg of product are thus obtained with a yield of 37%.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:23])[C:5]2[C:10]3([CH2:12][CH2:11]3)[C:9](=O)[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:6]=2[N:7]=1.CO>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([Cl:23])[C:5]2[C:10]3([CH2:12][CH2:11]3)[CH2:9][N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:6]=2[N:7]=1
Reactant: COc1ccc(CN2C(=O)C3(CC3)c3c(Cl)nc(Cl)nc32)cc1
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CN2CC3(CC3)c3c(Cl)nc(Cl)nc32)cc1
Temperature: 60 °C
Yield: 62.5 %

Procedure:
To a solution of 2′,4′-dichloro-7′-(4-methoxybenzyl)spiro[cyclopropane-1,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′H)-one (14.0 g, 40.0 mmol) in tetrahydrofuran (200 mL) was added 94% Borane-methyl sulfide complex (8.2 mL, 80.0 mmol) dropwise under nitrogen atmosphere. After the addition was over, the reaction mixture was heated to 60° C. overnight. When the reaction was completed, methanol was added to the reaction solution at 0° C., concentrated in vacuum and the residue was purified by silica gel chromatography to afford the product as a white solid (8.4 g, yield 62.4%). 1H NMR (400 MHz, CDCl3) δ ppm 7.20 (d, J=8.6 Hz, 2H), 6.91-6.86 (m, 2H), 4.59 (s, 2H), 3.81 (s, 3H), 3.48 (s, 2H), 1.71 (q, J=4.9 Hz, 2H), 0.82 (q, J=4.9 Hz, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][N:24]=1)[C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])[N:12]=1)=[O:6].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.O>CN1CCCC1=O>[C:14]1([CH3:21])[CH:15]=[C:16]([CH3:20])[CH:17]=[C:18]([CH3:19])[C:13]=1[C:11]1[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:22]=[CH:23][N:24]=[C:2]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:3]=2)[S:9][CH:10]=1
Reactant: Cc1cc(C)c(-c2csc(NC(=O)c3ccnc(Cl)c3)n2)c(C)c1
Reactant: C1CCNCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(C)c(-c2csc(NC(=O)c3ccnc(N4CCCCC4)c3)n2)c(C)c1
Temperature: 150 °C
Reaction time: 16 h
Yield: 33.3 %

Procedure:
A mixture of 2-chloro-N-(4-mesitylthiazol-2-yl)isonicotinamide (200 mg, 0.60 mmol, 1.0 equiv) and piperidine (0.70 mL, 6.7 mmol, 12 equiv) in methylpyrrolidone (6.0 mL) was stirred at 150° C. for 16 h. The mixture was poured into icy H2O (10.0 mL) and the resultant solids were filtered. The solids were purified by column chromatography on silica gel (15% EtOAc in hexanes as eluant) to provide N-(4-mesitylthiazol-2-yl)-2-(piperidin-1-yl)isonicotinamide (87.2 mg, 0.20 mmol) as yellow solids in 38% yield: 1H NMR (CDCl3, 500 MHz) δ 8.29 (d, J=5.1 Hz, 1 H), 7.15 (s, 1 H), 6.83-6.90 (m, 3 H), 6.79 (s, 1 H), 3.61-3.63 (m, 4 H), 2.31 (s, 3 H), 2.08 (s, 6 H), 1.57-1.67 (m, 6 H); ESI-MS: m/z 407.2 (M+H)+.
Reaction SMILES: Br[CH:2]([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=O.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(O)C.C(=O)([O-])O.[Na+]>O>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:13]=[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]3[C:2]=2[CH3:12])=[CH:6][CH:7]=1
Reactant: CC(Br)C(=O)c1ccc(Br)cc1
Reactant: Nc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1c(-c2ccc(Br)cc2)nc2ccccn12
Yield: 37.1 %

Procedure:
Dissolving 4.3 g (16 mmol) of 2,4′-dibromopropiophenon obtained and 1.4 g (15 mmol) of 2-aminopyridine into 50 milliliter of ethanol, adding 1.9 g of sodium hydrogen carbonate, the resultant suspension was refluxed under heating for 6 hours. After completion of the reaction, adding water and an extraction was carried out using dichloro-methane. Washing the organic layer with water, it was dried with the use of sodium sulfate. The solvent was removed by distillation and the resultant syrup was refined by silica gel column chromatography thereby obtaining 1.6 g of 2-(4-bromo-phenyl)-3-methyl-imidazo [1,2-a] pyridine (yield: 37%).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][CH3:3].[Li+].CC([N-]C(C)C)C.[CH3:15][C:16]([S:19]([N:21]=[C:22]1[CH2:25][O:24][CH2:23]1)=[O:20])([CH3:18])[CH3:17]>C1COCC1>[C:16]([S:19]([NH:21][C:22]1([CH:2]([CH3:3])[C:1]([O:5][CH3:6])=[O:4])[CH2:25][O:24][CH2:23]1)=[O:20])([CH3:15])([CH3:17])[CH3:18]
Reactant: CCC(=O)OC
Reactant: CC(C)(C)S(=O)N=C1COC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C)C1(NS(=O)C(C)(C)C)COC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
Methyl propionate (2.71 g, 30.8 mmol) was dissolved in anhydrous THF (90 mL) and cooled to −78° C. under nitrogen. LDA (2M solution in THF, 15 mL, 30 mmol) was added drop-wise. After 1 hour at −78° C., a solution of 2-methyl-N-oxetan-3-ylidenepropane-2-sulfinamide (Preparation 39, 1.35 g, 7.703 mmol) in anhydrous THF (10 mL) was added. The reaction was gradually warmed to room temperature and stirred for 18 hours. The reaction was quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the title compound as an oil (1.276 g, 63% yield).
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:27])[CH:11]=[C:12]([CH2:15][NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])(=[O:19])=[O:18])[O:13][CH:14]=1)C1C=CC=CC=1.OC1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1>>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[S:17]([NH:16][CH2:15][C:12]1[O:13][CH:14]=[C:9]([OH:8])[C:10](=[O:27])[CH:11]=1)(=[O:18])=[O:19]
Reactant: O=c1cc(CNS(=O)(=O)c2ccccc2Cl)occ1OCc1ccccc1
Agent: O=c1cc(CNS(=O)(=O)c2ccccc2)occ1O
Product: O=c1cc(CNS(=O)(=O)c2ccccc2Cl)occ1O
Yield: 74 %

Procedure:
2-Chloro-N-(5-hydroxy-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (8-03) (15.0 g, crude) was synthesized as a light brown solid from N-(5-benzyloxy-4-oxo-4H-pyran-2-ylmethyl)-2-chloro-benzenesulfonamide (7-03) (26.0 g, 64.19 mmol) following the procedure described for N-(5-hydroxy-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (8-01).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:11]=[C:10]([NH:12][C:13]([N:15]3[CH2:19][CH2:18][C@H:17]([NH2:20])[CH2:16]3)=[O:14])[S:9][C:5]=2[N:6]=[CH:7][N:8]=1.C(N(CC)C(C)C)(C)C.Br[CH2:31][CH2:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=1.O>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]2[N:11]=[C:10]([NH:12][C:13]([N:15]3[CH2:19][CH2:18][CH:17]([NH:20][CH2:31][CH2:32][O:33][C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:41])([F:42])[F:43])[CH:35]=4)[CH2:16]3)=[O:14])[S:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: FC(F)(F)c1cccc(OCCBr)c1
Reactant: COc1ncnc2sc(NC(=O)N3CC[C@H](N)C3)nc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ncnc2sc(NC(=O)N3CCC(NCCOc4cccc(C(F)(F)F)c4)C3)nc12
Temperature: 80 °C
Reaction time: 1 h
Yield: 7.8 %

Procedure:
A mixture of (S)-3-amino-pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide (300 mg, 0.74 mmol) in N,N-dimethylformamide (5 mL) was treated with N,N-diisopropylethylamine (285 mg, 2.20 mmol) and 1-(2-bromoethoxy)-3-(trifluoromethyl) benzene (220 mg, 0.81 mmol). The reaction mixture was allowed to stir at 80° C. for 1 h. At this time, the reaction was poured into water. The aqueous layer was extracted with ethyl acetate. The organics were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Preparative high pressure liquid chromatography afforded 3-[2-(3-trifluoromethyl-phenoxy)-ethylamino]-pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide (28 mg, 8%) as a light brown solid; LRMS for C20H21F3N6O3S (M+H)+ at m/z=482. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][NH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[S:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:25][CH2:26][C:27](Cl)=[O:28]>ClCCl>[Cl:25][CH2:26][C:27]([N:12]1[C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[S:9][C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:13]1)=[O:28]
Reactant: Clc1ccc([C@@H]2CNc3ccccc3S2)cc1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1C[C@@H](c2ccc(Cl)cc2)Sc2ccccc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 108.8 %

Procedure:
To a suspension of (R)-(+)-2-(4-chlorophenyl)-3,4-dihydro-2H-1,4-benzothiazine (1.30 g, 0.005 mole) and triethylamine (1.66 ml, 0.012 mole) in dichloromethane (16 ml) is added dropwise a solution of chloroacetyl chloride (0.79 ml, 0.01 mole) in dichloromethane (4 ml) under ice cooling, and the mixture is stirred at room temperature for 45 minutes. After the solvent is distilled off, to the residue are added ethyl acetate and water, and the ethyl acetate layer is washed with aqueous sodium hydrogen carbonate solution, water and saline, dried over sodium sulfate and distilled to remove the solvent to give (R)-4-chloroacetyl-2-(4-chlorophenyl)-3,4-dihydro-2H-1,4-benzothiazine (1.84 g) as caramel.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17](S(C)=O)[O:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.[CH2:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:26]([NH2:33])[C@@H:25]1[OH:34].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17]([NH:33][C@@H:26]5[C:27]6[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=6)[CH2:24][C@H:25]5[OH:34])[O:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: N[C@@H]1c2ccccc2C[C@H]1O
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2o1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1Cc2ccccc2[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2o1
Temperature: 120 °C
Yield: 21.9 %

Procedure:
A stirred mixture of 6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole (150 mg, 0.384 mmol) from Step 3 of Example 61, (1R,2R)-(−)-trans-1-amino-2-indanol (114 mg, 0.768 mmol), and DIEA (99 mg, 0.768 mmol) in anhydrous DMA (3 mL) in a sealed vial was heated in a Biotage microwave synthesizer at 120° C. for 30 min. After the reaction mixture was cooled to rt, it was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford (1R,2R)-1-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]oxazol-2-yl)amino)-2,3-dihydro-1H-inden-2-ol (40 mg, 22%) as a white solid. 1H NMR (499 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.49 (d, J=2.0 Hz, 1H), 8.36-8.44 (m, 2H), 7.45 (s, 1H), 7.12-7.24 (m, 6H), 5.51 (s, 2H), 5.47 (d, J=5.2 Hz, 1H), 5.01 (t, J=7.6 Hz, 1H), 4.34 (m, 1H), 3.15 (dd, J=7.1, 15.5 Hz, 1H), 2.73 (dd, J=7.6, 15.5 Hz, 1H). LCMS (ESI) m/z 476 and 478 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.C[N:14]([O:21][CH3:22])[C:15](=O)[C:16]([F:19])([F:18])[F:17].Cl.O(N)C>CCOCC.CCCCCC.C1(C)C=CC=CC=1>[CH3:22][O:21]/[N:14]=[C:15](\[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)/[C:16]([F:19])([F:18])[F:17]
Reactant: Brc1cccnc1
Reactant: CON(C)C(=O)C(F)(F)F
Agent: CON
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CO/N=C(\c1cccnc1)C(F)(F)F
Temperature: 25 °C
Yield: 79.9 %

Procedure:
3-Bromopyridine (11.28 g, 0.0714 mol) in dry ether (50 ml) was added dropwise to a solution of n-butyl lithium (49.1 ml of a 1.6M solution in hexane, 0.0785 mol) in ether (150 ml) at -78° C. over 15 minutes. The resulting suspension was stirred for a further 15 minutes before N-methyl-N-methoxytrifluoroacetamide (D4, 11.22 g, 0.0715 mol) in ether (15 ml) was added dropwise. The reaction mixture was allowed to warm to room temperature over 1 h then poured into stirred ice-cold 2M hydrochloric acid (200 ml). The aqueous layer was separated and washed with ether (2×100 ml). The combined organic layers were extracted with 2M hydrochloric acid (150 ml). The combined aqueous layers were then carefully made basic then saturated with potassium carbonate and extracted with chloroform (4×250 ml). The combined chloroform extracts were dried (Na2SO4) and evaporated to give a semi-crystalline solid which was taken-up in toluene (300 ml) and treated with methoxylamine hydrochloride (18 g, 0.216 mol) at reflux under Dean-Stark conditions for 2 h. The reaction mixture was cooled and extracted with 2M hydrochloric acid (3×150 ml). The combined aqueous extracts were washed with ether (2×200 ml) then basified and partially saturated with potassium carbonate then extracted with chloroform (2×300 ml). The combined organic fractions were dried (Na2SO4) and evaporated to give an oil which was distilled to give the title compound (D7) as a colourless oil (11.64 g, 80%) b.p. 135° C. at 120 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20](OC)[CH:21]=3)[NH:16][CH:15]=2)[CH:5]=[C:4]([Cl:27])[C:3]=1[NH:28]C(=O)C.[CH3:32]N1C2C(=CC=CC=2)C(CC(O)=O)=C1.ClC1C=C(C=C(Cl)C=1N)CN>>[NH2:28][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH3:32])[CH:15]=2)=[CH:5][C:4]=1[Cl:27]
Reactant: Cn1cc(CC(=O)O)c2ccccc21
Reactant: COc1ccc2[nH]cc(CC(=O)N=C(N)NCc3cc(Cl)c(NC(C)=O)c(Cl)c3)c2c1
Agent: NCc1cc(Cl)c(N)c(Cl)c1
Product: Cn1cc(CC(=O)N=C(N)NCc2cc(Cl)c(N)c(Cl)c2)c2ccccc21

Procedure:
In a manner similar to that used in the preparation of the compound of example 2, but using 2-(1-methyl-1H-indol-3-yl)acetic acid in step 5 (A) and 3,5-dichloro-4-aminobenzylamine (preparation A) in step 5 (B), the title compound was prepared. MS (ESI) (M+H)+=404.07 1H-NMR(500 MHz, CD3OD) δ 7.54 (d, J=7.93 Hz, 1 H), 7.40 (d, J=8.24 Hz, 1 H), 7.15-7.32 (m, 4 H), 7.04-7.15 (m, 1 H), 4.33 (s, 2 H), 3.95 (s, 2 H), 3.80 (s, 3 H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[S:11][C:12]3[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][C:13]=3[N:14]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.[CH3:22][NH:23][CH3:24].C(O)(=O)C.[BH3-]C#N.[Na+]>C1COCC1.CO>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[S:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:23]([CH3:24])[CH3:22])=[CH:15][C:13]=3[N:14]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CC(C)N1CCN(c2nc3cc(C=O)ccc3s2)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)N1CCN(c2nc3cc(CN(C)C)ccc3s2)CC1
Yield: 45.6 %

Procedure:
To a solution of 2-(4-isopropylpiperazin-1-yl)benzothiazole-5-carbaldehyde (500 mg, 1.73 mmol) and dimethylamine hydrochloride (282 mg, 3.46 mmol) in THF (27.5 mL) and MeOH (13.7 mL) was added acetic acid (166 mg, 2.77 mmol), followed by NaCNBH3 (160 mg, 2.77 mmol). The mixture was heated at reflux overnight. The mixture was concentrated under reduced pressure, neutralized with an aqueous solution of Na2CO3 to pH 7, and filtered. The residue was extracted with dichloromethane (3×10 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC to give 251 mg (46%) of [2-(4-isopropylpiperazin-1-yl)benzothiazol-5-yl-methyl]dimethylamine as a trifluoroacetate salt.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5](=[O:26])[CH2:6][C:7](=[O:25])[N:8]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)[CH2:9][CH2:10][C:11]([O:13]C)=O)[CH3:3].O>C(O)C.C1C=CC=CC=1>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:8]2[CH2:9][CH2:10][C:11](=[O:13])[CH:6]([C:5]([O:4][CH2:2][CH3:3])=[O:26])[C:7]2=[O:25])=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: CCOC(=O)CC(=O)N(CCC(=O)OC)Cc1ccc([N+](=O)[O-])cc1
Agent: [Na]
Solvent: CCO
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C1C(=O)CCN(Cc2ccc([N+](=O)[O-])cc2)C1=O
Reaction time: 1.5 h
Yield: 88.3 %

Procedure:
Sodium (690 mg) is dissolved in ethanol (25 ml), and thereto is added dropwise a solution of ethyl[N-(p-nitrobenzyl)-N-(methoxycarbonylethyl)carbamoyl]acetate (10.0 g) in benzene (160 ml) at room temperature. The mixture was stirred at the same temperature for 1.5 hours. The mixture is poured into water. The aqueous layer is separated, neutralized with 10% HCl and extracted with ethyl acetate. The extract is washed with a saturated sodium chloride solution, dried and then distilled to remove the solvent to give ethyl 1-(p-nitrobenzyl)-2,4-dioxopiperidine-3-carboxylate (8.03 g, 88.4%) as yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([NH:15][CH:16]([C:29]2[CH:30]=[C:31]([O:39][CH3:40])[C:32]3[O:37][CH2:36][O:35][CH2:34][C:33]=3[CH:38]=2)[C:17]2[NH:21][C:20](=[O:22])[N:19]([C:23]3[N:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:18]=2)[CH:12]=[CH:11][C:10]=1[C:41]#[N:42])(C)(C)C.ClCCl.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[NH:42]=[C:41]1[C:10]2[C:9](=[CH:14][C:13]([NH:15][CH:16]([C:29]3[CH:30]=[C:31]([O:39][CH3:40])[C:32]4[O:37][CH2:36][O:35][CH2:34][C:33]=4[CH:38]=3)[C:17]3[NH:21][C:20](=[O:22])[N:19]([C:23]4[N:24]=[CH:25][CH:26]=[CH:27][N:28]=4)[N:18]=3)=[CH:12][CH:11]=2)[CH2:8][NH:7]1
Reactant: COc1cc(C(Nc2ccc(C#N)c(CNC(=O)OC(C)(C)C)c2)c2nn(-c3ncccn3)c(=O)[nH]2)cc2c1OCOC2
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(Nc2ccc3c(c2)CNC3=N)c2nn(-c3ncccn3)c(=O)[nH]2)cc2c1OCOC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.1 %

Procedure:
To a mixture of (2-cyano-5-{[(8-methoxy-4H-benzo[1,3]-dioxin-6-yl)-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl]amino}benzyl)carbamic acid t-butyl ester (83 mg) and dichloromethane (3.0 mL) there was added TFA (0.3 mL), and the mixture was stirred at room temperature for 2 hours. Toluene (10 mL) was added to the mixture, and the solvent in the mixture was distilled off. The residue was purified by reverse-phase high performance liquid chromatography (acetonitrile/water mixed solvent, 0.1% acetic acid) to obtain the target compound (33.8 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][C:10]=1C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OO.S(=O)(=O)(O)[OH:27]>CO>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][C:10]=1[OH:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: O=Cc1cc(Oc2ccccc2)ccc1OCc1ccccc1
Agent: OO
Solvent: CO
Product: Oc1cc(Oc2ccccc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Benzyloxy-5-phenoxybenzaldehyde (22.25 g, 73 mmol) is dissolved in methanol (200 mL) and treated with hydrogen peroxide (31% in water, 32.0 mL) and concentrated sulfuric acid (15.0 mL). The mixture is stirred overnight at room temperature and evaporated. The residue is dissolved in saturated aqueous sodium chloride solution and extracted with ether. The organic phase is dried over magnesium sulfate and evaporated. Purification of the residue by silica-gel flash chromatography gives 2-benzyloxy-5-phenoxyphenol as a colorless solid.