Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH3:4].[C:6]1([CH:12]2[CH2:17][NH:16][CH2:15][C:14]3[CH:18]=[CH:19][S:20][C:13]2=3)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[CH2:1]([N:16]1[CH2:17][CH:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:13]2[S:20][CH:19]=[CH:18][C:14]=2[CH2:15]1)[CH2:2][CH2:3][CH3:4]
Reactant: c1ccc(C2CNCc3ccsc32)cc1
Reactant: CCCCBr
Product: CCCCN1Cc2ccsc2C(c2ccccc2)C1

Procedure:
Butyl bromide is condensed with 7-phenyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (Example 4) according to the procedure of Example 8.
Reaction SMILES: [F:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[N:25]=[C:26]=[O:27]>>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[NH:25][C:26]([NH:16][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([C:3]2[N:4]([CH3:7])[N:5]=[CH:6][C:2]=2[F:1])[CH:9]=1)=[O:27]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: COc1ccc(N)cc1-c1c(F)cnn1C
Product: COc1ccc(NC(=O)Nc2ccc(F)cc2F)cc1-c1c(F)cnn1C
Yield: 58 %

Procedure:
3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 2,4-difluorophenylisocyanate, in a similar manner as described in Example 1.68, providing 21 mg (58% yield) of Compound 37: LCMS m/z (%)=377 (M+H, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.50 (s, 1H), 8.24 (m, 1H), 7.98 (s, 1H), 7.64 (dd, J1=9.0 Hz, J2=2.6 Hz, 1H), 7.51 (d, J=2.4 Hz, 1H), 7.38 (d, JH,F=4.8 Hz, 1H), 7.14 (d, J=8.8 Hz, 1H), 7.06 (ddd, J1=11.4 Hz, J2=8.6 Hz, J3=2.8 Hz, 1H), 6.99 (dd, J1=9.6 Hz, J2=9.6 Hz, 1H), 3.83 (s, 3H), 3.65 (s, 3H). 19F NMR (376 MHz, acetone-d6) δ: −119.93 (m, 1F), −127.63 (m, 1F) −177.41 (d, JH,F=4.1 Hz, 1F).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C@H:17]3[CH2:21][CH2:20][C@@:19]4([CH2:25][CH2:24][N:23]([CH3:26])[C:22]4=[O:27])[NH:18]3)[CH:12]=1)[NH:7][N:6]=[CH:5]2.N(C(OC(C)(C)C)=O)=NC(O[C:33](C)(C)[CH3:34])=O.C(O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:33]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([C@H:17]4[CH2:21][CH2:20][C@@:19]5([CH2:25][CH2:24][N:23]([CH3:26])[C:22]5=[O:27])[NH:18]4)[CH:12]=3)[CH:9]=2)[CH:5]=[N:6]1)[CH3:34]
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Reactant: CN1CC[C@@]2(CC[C@H](c3cc(-c4cc5[nH]ncc5cc4F)ccn3)N2)C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: C1CCOC1
Product: CCn1ncc2cc(F)c(-c3ccnc([C@H]4CC[C@@]5(CCN(C)C5=O)N4)c3)cc21
Temperature: 800 °C

Procedure:
To a Smith microwave vial was added (2R,5S)-2-[4-(5-fluoro-1H-indazol-6-yl)-2-pyridyl]-7-methyl-1,7-diazaspiro[4.4]nonan-6-one (which may be prepared as described in Example 186) (40 mg, 0.1100 mmol), di-tert-butyl azodicarboxylate (126.03 mg, 0.5500 mmol), ethanol (0.03 mL, 0.5500 mmol) and triphenyl phosphine (143.56 mg, 0.5500 mmol) in THF (1 mL). The reaction mixture was heated by microwave at 800° C. for 45 minutes. The reaction mixture was cooled and eluted on an SCX-2 cartrige (0.5 g) and washed with DCM followed by MeOH. The desired product was eluted off the cartridge with ammonia in MeOH (0.2M). Evaporation of solvents gave a colourless oil. The crude residue was purified by silica gel chromatography (silica 10 g) eluting with methanol (containing 10% 0.88 ammonia) in ethyl acetate (0-80%), to give the products as a mixture of isomers. These were separated by HPLC using a ChiralPak IA column and eluting with ethanol/n-heptane (20%:80%) to give (2R,5S)-2-[4-(1-ethyl-5-fluoro-indazol-6-yl)-2-pyridyl]-7-methyl-1,7-diazaspiro[4.4]nonan-6-one as the major isomer;
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6](/[CH:30]=[CH:31]/[C:32]([O:34]C)=[O:33])[CH:7]=[CH:8][C:9]=1[CH:10]1[C:15]2[NH:16][C:17]3[C:22]([C:14]=2[CH2:13][C:12]([CH3:24])([CH3:23])[N:11]1[CH2:25][C@H:26]([CH3:29])[CH2:27][F:28])=[CH:21][CH:20]=[CH:19][CH:18]=3.C1COCC1>CO>[F:3][C:4]1[CH:5]=[C:6](/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33])[CH:7]=[CH:8][C:9]=1[CH:10]1[C:15]2[NH:16][C:17]3[C:22]([C:14]=2[CH2:13][C:12]([CH3:24])([CH3:23])[N:11]1[CH2:25][C@H:26]([CH3:29])[CH2:27][F:28])=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: COC(=O)/C=C/c1ccc(C2c3[nH]c4ccccc4c3CC(C)(C)N2C[C@H](C)CF)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](CF)CN1C(c2ccc(/C=C/C(=O)O)cc2F)c2[nH]c3ccccc3c2CC1(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2M Sodium hydroxide (3.31 ml, 6.63 mmol) was added to a solution of (E)-methyl 3-(3-fluoro-4-(2-((S)-3-fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (600 mg, 1.33 mmol) (mixture of diastereoisomers) in methanol (5 ml), and THF (20 ml) and the mixture stirred at ambient temperature for 4 hours. The mixture was concentrated to a volume such that all of the organic solvent had been removed, diluted with water (50 ml), acidified with dilute HCl to pH 6 and extracted with ethyl acetate (2×50 ml). The extracts were combined and evaporated under reduced pressure. The residue was purified by preparative HPLC (Chiralpak IA column, 20 ml silica, 20 mm diameter, 250 mm length), Heptane:IPA 90:10, 0.2% acetic acid at 80 ml/min. Fractions containing the desired compounds were combined and analysed to yield (E)-3-(3-fluoro-4-(2-((S)-3-fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid (isomer 1, first eluted, 130 mg, 22.36%) and (E)-3-(3-fluoro-4-(2-((S)-3-fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahyrdo-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid (isomer 2, second eluted, 30.0 mg, 5.16%). 1H NMR (500 MHz, DMSO, 30° C.) δ 0.49 (3H, d), 1.03 (3H, s), 1.14-1.21 (1H, m), 1.28 (3H, s), 2.17 (1H, dd), 2.59-2.71 (1H, m), 2.8-2.99 (2H, m), 4.09-4.34 (2H, m), 4.99 (1H, s), 6.59 (1H d), 6.86-7.07 (2H, m), 7.1-7.19 (1H, m), 7.18-7.29 (1H, m), 7.36-7.49 (2H, m), 7.49-7.66 (2H, n), 10.31 (1H, s), CO2H not observed. m/z: ES+ [M+H]+ 439. *Stereochemistry inferred to be (R) at the undefined centre by analogy with other examples.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])([F:13])[F:12])[C:5](O)=[O:6].[CH2:22]([NH2:32])[CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:20]([O:19][P:14]([C:11]([C:10]1[CH:9]=[CH:8][C:4]([C:5](=[O:6])[NH:32][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:3][C:2]=1[Br:1])([F:13])[F:12])(=[O:15])[O:16][CH2:17][CH3:18])[CH3:21]
Reactant: NCCCCc1ccccc1
Reactant: CCOP(=O)(OCC)C(F)(F)c1ccc(C(=O)O)cc1Br
Product: CCOP(=O)(OCC)C(F)(F)c1ccc(C(=O)NCCCCc2ccccc2)cc1Br

Procedure:
The 3-bromo-4-[(diethoxyphosphoryl)difluoromethyl)benzoic acid (Compound 35) was coupled to phenbutyl amine following the procedures of Example 39 to give {[2-bromo-4-(4-phenylbutylcarbamoyl)phenyl]difluoromethyl}-phosphonic acid diethyl ester which was treated in a manner similar to Example 40 to give Compound 62. MS (ion spray):m/z 459.98/461.95 (M−H)
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:15][C:14]3([CH2:24][C:23](=[O:25])[C:22]4[C:17](=[CH:18][CH:19]=[C:20](/[CH:26]=[CH:27]/[C:28]([NH:30][O:31]C5CCCCO5)=[O:29])[CH:21]=4)[O:16]3)[CH2:13]2)=[CH:3]1.Cl>C(Cl)Cl.O1CCOCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:13][C:14]3([CH2:24][C:23](=[O:25])[C:22]4[C:17](=[CH:18][CH:19]=[C:20](/[CH:26]=[CH:27]/[C:28]([NH:30][OH:31])=[O:29])[CH:21]=4)[O:16]3)[CH2:15]2)=[CH:3]1
Reactant: Cn1cc(CN2CC3(CC(=O)c4cc(/C=C/C(=O)NOC5CCCCO5)ccc4O3)C2)c2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cn1cc(CN2CC3(CC(=O)c4cc(/C=C/C(=O)NO)ccc4O3)C2)c2ccccc21
Yield: 100.3 %

Procedure:
(E)-3-[1′-(1-Methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)acrylamide (102 mg, 0.203 mmol) in DCM (5 ml) was treated with 4 M HCl in dioxane (1 ml) as described in Example 30, Step C, giving (E)-3-[1′-(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-hyroxy-acrylamide (85 mg, hydrochloride salt) as a light brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([CH:18]3[CH2:23][CH2:22][CH:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[O:31][CH3:32].[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>ClCCl>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:33](=[O:40])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[C:3]([O:31][CH3:32])[CH:4]=3)[C:16]=12
Reactant: COc1cc(-c2nn(C3CCC(N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccccc1
Reaction time: 4 h

Procedure:
To a stirred solution of 3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate AP) (0.31 g, 0.00071 mol) and benzoyl chloride (0.105 g, 0.00075 mol) in anhydrous dichloromethane (10 mL) N-ethyl-N,N-diisopropylamine (0.11 g, 0.00085 moL) was added dropwise over a 5 min. period. The stirring under nitrogen was continued for an additional 4 hours, the solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate (30 mL) and water (25 mL). The organic phase was dried with magnesium sulfate and concentrated under the reduced pressure to yield a yellow oil which was purified by flash column chromatography on silica using dichloromethane/triethylamine/methanol (94:5:1) as a mobile phase to give trans-N-{4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl}benzamide as a white solid (0.250 g, 0.00045 mol). It was dissolved in refluxing ethanol (17 mL) and a preheated solution of maleic acid (0.155 g, 0.00133 mol) in ethanol (8 mL) was added. The mixture was refluxed for 10 min, cooled to ambient temperature and the precipitate collected by filtration, washed with ethyl acetate and dried to give trans—N-{4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl }-2-methoxyphenyl}benzamide dimaleate as a white solid (0.196 g, 0.000254 mol):
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH2:11])[N:10]=2)[N:7]=1.[C:12](Cl)(=[O:15])[CH2:13][CH3:14]>CN(C)C(=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[N:10]=2)[N:7]=1
Reactant: CCC(=O)Cl
Reactant: Nc1cn2nc(I)ccc2n1
Solvent: CC(=O)N(C)C
Product: CCC(=O)Nc1cn2nc(I)ccc2n1
Yield: 72.3 %

Procedure:
Using 6-iodoimidazo[1,2-b]pyridazin-2-amine (1.0 g, 3.85 mmol), N,N-dimethylacetamide (10 mL) and propionyl chloride (0.37 mL, 4.23 mmol) as starting materials and in the same manner as in Reference Example 5, the title compound (0.88 g, 72%) was obtained as a dark brown powder.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].Cl[CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]1[C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[N:22][C:23]([Cl:29])=[CH:24][CH:25]=2)[N:20]=1>O1CCCC1>[Cl:29][C:23]1[N:22]=[C:21]2[C:26]([CH:27]=[CH:28][C:19]([N:10]3[CH:9]([NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]3=[O:18])=[N:20]2)=[CH:25][CH:24]=1
Reactant: CN(C)CCCN
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Solvent: C1CCOC1
Product: CN(C)CCCNC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Temperature: 20 °C
Reaction time: 20 h
Yield: 37.9 %

Procedure:
3-Dimethylaminopropylamine (4.1 g) is added at a temperature in the region of 20° C. to a suspension of 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (6.6 g) in anhydrous tetrahydrofuran (100 cc), and the reaction mixture is heated to reflux for 6 hours. After the reaction mixture has been stirred for a further 20 hours at a temperature in the region of 20° C., it is filtered. The isolated solid is washed with ethyl acetate (3×25 cc). The filtrate is washed with distilled water (3×25 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 60° C. 1N aqueous hydrochloric acid solution (20 cc) is added to the residue obtained. An insoluble product is separated by filtration, washed with 1N aqueous hydrochloric acid solution (2×5 cc) and then discarded. The aqueous filtrates are combined and alkalinized with a saturated aqueous potassium bicarbonate solution to a pH in the region of 8, and then extracted with ethyl acetate (3×40 cc). The organic phases are combined, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 60° C. After recrystallization in ethyl acetate, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-(3-dimethylaminopropylamino)-1-isoindolinone (3 g), m.p. 143° C., is obtained.
Reaction SMILES: C([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([OH:9])=O)(=O)C.[F:14][C:15]([F:25])([F:24])[O:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>>[F:14][C:15]([F:24])([F:25])[O:16][C:17]1[CH:18]=[CH:19][C:20]([NH:21][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[OH:4])=[CH:22][CH:23]=1
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: Nc1ccc(OC(F)(F)F)cc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccccc1O

Procedure:
This compound was obtained as a white solid starting from acetylsalicyclic acid and 4trifluoromethoxyaniline using the same procedure described in example 5.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[NH:12][CH2:13][CH:14](OC)OC.[S-:19][C:20]#[N:21].[K+]>Cl.C(O)C.O>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[N:12]1[CH:13]=[CH:14][NH:21][C:20]1=[S:19]
Reactant: COC(CNC1CCc2c(F)cc(F)cc21)OC
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Fc1cc(F)c2c(c1)C(n1cc[nH]c1=S)CC2
Yield: 48.4 %

Procedure:
A mixture of (4,6-difluoroindan-1-yl)-(2,2-dimethoxyethyl)amine (11.68 g, 45.9 mmol), potassium thiocyanate (4.46 g, 45.9 mmol) in 21.6 mL of 12N hydrochloric acid, 86 mL of ethanol and 86 mL of water was heated at 80° to 85° C. for 15 hours. The mixture was cooled in an ice bath and diluted with water giving a crystalline material. The material was isolated by filtration and the filter residue was rinsed with cold ethanol (2×25 mL) and 50 mL of diethyl ether. Drying gave 1-(4,6-difluoroindan-1-yl)-1,3-dihydroimidazole-2-thione (5.65 g, 22.2 mmol), m.p. 205°-207° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.Br.Br.Br[CH2:25][C:26]1[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[N:30][CH:31]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:25][C:26]3[C:27]([NH2:33])=[N:28][C:29]([NH2:32])=[N:30][CH:31]=3)[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: Nc1ncc(CBr)c(N)n1
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(N2CCN(Cc3cnc(N)nc3N)CC2)cc1
Temperature: 25 °C
Reaction time: 65 h
Yield: 46.5 %

Procedure:
A solution of 0.95 g (0.00494 mol) of 1-(4-methoxy-phenyl)-piperazine in 30 ml of dimethylformamide was treated with 1.37 ml (0.00986 mol) of triethylamine and 0.60 g (0.00164 mol) of 5-bromomethyl-pyrimidine-2,4-diamine dihydrobromide and the mixture was stirred at room temperature under argon for 65 hours. The mixture was completely freed from the solvents. The residue was chromatographed over silica gel with acetonitrile/methanol (1:1 ), digested in diethyl ether and subsequently filtered off under suction. 0.24 g (47%) of 5-[4-(4-methoxy-phenyl)-piperazin-1-ylmethyl]-pyrimidine-2,4-diamine was obtained as white crystals; m.p. 239°-241°.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@H:12]([C@@H:21]([C@@H:30]([CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[OH:31])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:41](Cl)([CH3:44])(=[O:43])=[O:42]>N1C=CC=CC=1>[CH2:1]([O:8][C@H:9]([C@H:12]([C@@H:21]([C@@H:30]([CH2:32][O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[O:31][S:41]([CH3:44])(=[O:43])=[O:42])[O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:10][O:11][S:41]([CH3:44])(=[O:43])=[O:42])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Solvent: c1ccncc1
Product: CS(=O)(=O)OC[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@@H](COCc1ccccc1)OS(C)(=O)=O
Reaction time: 8 h

Procedure:
2,3,4,6-Tetra-O-benzyl-D-glucitol (45 g) was dissolved in pyridine (200 ml) and added over 30 min to a solution of mesyl chloride (15 ml) in pyridine (100 ml) at 0° C. The clear solution was stored at 4° C. overnight, after which time TLC analysis showed completion of the reaction. The reaction mixture was partitioned between ethyl acetate and water/ice. The organic fractions were washed with 5% hydrochloric acid then saturated aqueous sodium bicarbonate solution, dried (Na2SO4) and concentrated to a yellow/orange oil. The oil was azeotroped with toluene and used directly in the next stage.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(O)CCCC.[OH-].[Na+].[CH3:22][C:23]1[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25]>[Cu]>[N+:11]([C:8]1[CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]([NH:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:29]([C:30]([F:31])([F:32])[F:33])[C:23]=2[CH3:22])=[CH:10][CH:9]=1)([O-:13])=[O:12]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: Cc1c(N)cccc1C(F)(F)F
Agent: [Cu]
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCO
Product: Cc1c(Nc2ccc([N+](=O)[O-])cc2C(=O)O)cccc1C(F)(F)F

Procedure:
To a solution of 25 g. of 2-chloro-5-nitro-benzoic acid in 125 ml. of n-pentyl alcohol add 4.8 g. of sodium hydroxide pellets, 25 g. of 2-methyl-3-trifluoromethylaniline and 2 g. of copper powder. With constant stirring, reflux the reaction mixture for 18 hours. Concentrate the mixture to one half volume and dilute with water and ether. Acidify the aqueous layer to obtain a crude product which is recrystallized to yield 5-nitro-N-(2-methyl-3-trifluoromethylphenyl) anthranilic acid, m.p. 244°-245° C.
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[NH:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O>[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[NH:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][C:2]2[C:7]([CH:8]3[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH2:9]3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:28][CH:27]=1
Reactant: CN1CCC(c2cccnc2F)CC1=O
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CN1CCC(c2cccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CC1=O
Temperature: 120 °C
Yield: 37.1 %

Procedure:
Into a sealed tube were added 4-(2-fluoropyridin-3-yl)-1-methylpiperidin-2-one (0.06 g, 0.288 mmol), 4-(benzo[d]thiazol-2-ylamino)phenol (0.223 g, 0.922 mmol), cesium carbonate (0.310 g, 0.951 mmol), and 1-methyl-2-pyrrolidinone (1 mL). After degassing for 5 min, the reaction was heated at 120° C. for 14 h. The cooled mixture was diluted with EtOAc and washed with water; the aqueous layer was back-washed with EtOAc (1×). The combined organic extracts were washed with aqueous 1N NaOH solution, dried (MgSO4), filtered, and concentrated in vacuo. Flash column chromatography (20% to 100% EtOAc/Hexanes) afforded 4-(2-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyridin-3-yl)-1-methylpiperidin-2-one (0.046 g, 37.1% yield) as a tan amorphous solid. MS (ESI, pos. ion) m/z: 431.9 (M+1). IC50 (uM) +++++.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:16])[CH2:7]P(OCC)(OCC)=O)[CH3:4].[CH:17]1([CH:20]=O)[CH2:19][CH2:18]1>C1COCC1>[CH:17]1(/[CH:20]=[CH:7]/[C:6]([O:5][CH2:3][CH3:4])=[O:16])[CH2:19][CH2:18]1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=CC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/C1CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
To a stirred suspension of NaH (60% in oil, 2.1 g, 51.5 mmol) in dry THF (50 mL) was added dropwise ethyl(diethoxyphosphoryl)acetate (10.6 g, 47.1 mmol) at 0° C. under N2 atmosphere. The resulting mixture was stirred at 0° C. for 0.5 hr and added dropwise a solution of cyclopropanecarbaldehyde (3.0 g, 42.9 mmol) in dry THF (50 mL). After the addition, the mixture was stirred at rt for 16 hrs. Then the reaction mixture was quenched by addition of 5% NH4Cl (100 mL) at 0° C. and extracted with EtOAc (100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether: EtOAc=30:1) to give the title compound (5.3 g, 88.3% yield) as a colorless oil.
Reaction SMILES: N[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[CH3:13].[OH:14]S(O)(=O)=O.O.N([O-])=O.[Na+].NC(N)=O>O>[OH:14][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[CH3:13]
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)c1ccc(N)c(C)c1
Agent: NC(N)=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1ccc(O)c(C)c1
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
Ethyl 4-amino-3-methylbenzoate (3.85 g; 21.5 mmol) was dissolved in hot, 35% H2SO4 /water and the mixture then cooled to below 5° C. An ice-cold solution of 1.91 g (22.5 mmol) of sodium nitrite in 20 ml of water was then slowly added to the mixture such that the temperature of the mixture never exceeded 5° C. The mixture was stirred at 5° C. for 10 minutes and then treated with 1 g of urea and stirred for a further 10 minutes. A solution of 50 g (207 mmol) of cupric nitrate trihydrate in 750 ml of water was added to the reaction mixture followed by 2.87 g of cuprous oxide. The mixture was stirred for a further 15 minutes and then extracted with 3×300 ml ether. The ether extracts were combined and then washed with water and saturated NaCl solution and then dried (MgSO4). The solution was filtered, the solvent removed in-vacuo and the residue purified by flash chromatography (silica; 13% ethyl acetate in hexanes to 20% ethyl acetate in hexanes) to give the title compound as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]1([CH3:14])[O:13][CH2:12][CH2:11][O:10]1.C(N(CC)CC)C.[CH3:22][Si:23](Cl)([CH3:25])[CH3:24]>O1CCCC1>[CH3:22][Si:23]([CH3:25])([CH3:24])[O:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]1([CH3:14])[O:10][CH2:11][CH2:12][O:13]1
Reactant: CC1(c2cc(Br)ccc2O)OCCO1
Reactant: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(c2cc(Br)ccc2O[Si](C)(C)C)OCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.6 %

Procedure:
Under ice-cooling, to a solution of 3.11 g (12 mmol) of 2-(2-hydroxy-5-bromophenyl)-2-methyl-1,3-dioxolane in 24 ml of tetrahydrofuran was added dropwise succesively, 1.84 ml (13.2 mmol) of triethylamine and 1.68 ml (13.2 mmol) of trimethylsilyl chloride with stirring. The mixture was stirred at room temperature for 2 hours and filtered. The filtrate was concentrated under reduced pressure to give 4.0 g of the crude product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][C:12]1[S:16][C:15]([CH:17]=O)=[CH:14][CH:13]=1>N1CCCCC1.C(O)C>[CH3:17][C:15]1[S:16][C:12]([CH:11]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])=[CH:13][CH:14]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: Cc1ccc(C=O)s1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1ccc(C=C2C(=O)Nc3ccccc32)s1
Temperature: 90 °C
Reaction time: 3 h
Yield: 97.9 %

Procedure:
A reaction mixture of 134.0 mg of oxindole, 151.42 mg of the 5-methylthiophene-2-carboxaldehyde, and 3 drops of piperidine in 2 mL of ethanol was stirred at 90° C. for 3 h. After cooling, the precipitate was filtered, washed with cold ethanol, and dried to yield 237.8 mg (99%) of the title compound as a yellow solid.