Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:19])([CH:16]([SH:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.Br[CH2:21][C:22]1[O:23][C:24](=[O:28])[O:25][C:26]=1[CH3:27].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:19])([CH:16]([S:18][CH2:21][C:22]1[O:23][C:24](=[O:28])[O:25][C:26]=1[CH3:27])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: Cc1oc(=O)oc1CBr
Reactant: CC(S)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1oc(=O)oc1CSC(C)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 0.17 h
Yield: 77.8 %

Procedure:
To a solution of (2RS,3RS)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-butanol (0.060 g), 4-bromomethyl-5-methyl-2-oxo-1,3dioxol (0.049 g) in N,N-dimethylformamide (2.0 ml) was added anhydrous potassium carbonate (0.20 g) at -20° C. and the mixture was stirred for 10 minutes. To the reaction mixture were added ethyl acetate (10 ml) and water (10 ml), and organic layer was separated. The mixture was further extracted with ethyl acetate (10 ml×2). The organic layers were combined, washed with saturated aqueous sodium chloride solution (10 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (1 cm×5 cm), and elution was carried out with ethyl acetate-hexane (1:1). The desired fraction was concentrated and the residue was crystallized from chloroform-diethyl ether to give (2RS,3RS)-2-(2,4-difluorophenyl)-3-(5-methyl-2-oxo-1,3-dioxol-4-yl)methylthio-1-(1H-1,2,4-triazol-1-yl)-2-butanol (compound 56, 0.065 g). m.p. 173°-174° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[CH2:10][C:11]1[CH:12]=[C:13]([CH:41]=[CH:42][CH:43]=1)[CH2:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24]2[C:25](=[O:40])[NH:26][C:27](=[O:39])[C:28]=2[C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]([CH3:38])[CH:30]=2)=[CH:16]1)(=O)=O>CN(C)C=O>[N:1]([CH2:10][C:11]1[CH:12]=[C:13]([CH:41]=[CH:42][CH:43]=1)[CH2:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24]2[C:25](=[O:40])[NH:26][C:27](=[O:39])[C:28]=2[C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]([CH3:38])[CH:30]=2)=[CH:16]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Cn1cc(C2=C(c3cn(Cc4cccc(COS(C)(=O)=O)c4)c4ccccc34)C(=O)NC2=O)c2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(C2=C(c3cn(Cc4cccc(CN=[N+]=[N-])c4)c4ccccc34)C(=O)NC2=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium azide (0.144 g, 2.2 mmol) was added to a solution of the product of step b) (0.28 g, 0.5 mmol) in dry dimethylformamide (5 mL). The mixture was stirred at room temperature for 30 min and then partitioned between ethyl acetate and water. The organic phase was washed three times with water and evaporated (with ethanol), to give the crude sub-title product which was used without further purification.
Reaction SMILES: O[CH:2]([CH:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].BrBr.CCCCCCCC>O>[CH2:2]([C:9]1[C:10](=[O:14])[CH2:11][CH2:12][CH:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(O)C1CCCC1=O
Agent: BrBr
Solvent: O
Solvent: CCCCCCCC
Product: CCCCCCCC1=CCCC1=O
Yield: 88 %

Procedure:
In a 100 ml four-neck flask fitted with a thermometer, a reflux condenser and a stirrer were placed 2-(1-hydroxyheptyl)cyclopentanone (40 g) synthesized in Reference Example 3, bromine (0.4 g) and n-octane (10 ml), and water was removed under refluxing, followed by 4 hours of the reaction at 120° C. The reaction mixture was washed with water and the layers were separated from each other. The resulting organic layer was washed with saturated brine and separated. The organic layer was evaporated on a rotary evaporator under reduced pressure to recover n-octane, whereby a crude product (39 g) was obtained. The product was distilled using a Claisen distillation apparatus to obtain 32 g of 2-heptyl-2-cyclopentenone (boiling point: 111° C./900 Pa; GC purity: 97.8%).
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5](=[O:19])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.O.[N:21]1[C:29]([SH:30])=[C:28]2[C:24]([NH:25][CH:26]=[N:27]2)=[N:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[N:21]1[C:29]([S:30][CH2:2][C:3]2[O:4][C:5](=[O:19])[C:6]3[C:11]([C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[C:28]2[C:24]([NH:25][CH:26]=[N:27]2)=[N:23][CH:22]=1
Reactant: O=c1oc(CBr)c(-c2ccccc2)c2ccccc12
Reactant: Sc1ncnc2[nH]cnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1oc(CSc2ncnc3[nH]cnc23)c(-c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
3-(Bromomethyl)-4-phenyl-1H-isochromen-1-one (Intermediate C1, 35 mg, 0.111 mmol), 9H-purine-6-thiol hydrate (18.9 mg, 0.111 mmol) and K2CO3 (15.35 mg, 0.111 mmol) were dissolved in DMF (1 ml) and stirred at RT for 1 hrs 30 min. The reaction mixture was then diluted with water (10 ml) and 0.1 N HClaqueous (1 ml). The mixture was extracted with EtOAc and the collected organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by Preparative HPLC (method 2) to give the title compound (24 mg, 56%).
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([C@@:7]2(O)[CH2:11][N:10]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C@H:9]([C:22]([O:24][CH3:25])=[O:23])[CH2:8]2)=[CH:3][CH:2]=1.[CH3:33][Si:34]([CH2:37][SH:38])([CH3:36])[CH3:35]>C(#N)C.FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([C@:7]2([S:38][CH2:37][Si:34]([CH3:36])([CH3:35])[CH3:33])[CH2:11][N:10]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C@H:9]([C:22]([O:24][CH3:25])=[O:23])[CH2:8]2)=[CH:3][CH:2]=1
Reactant: COC(=O)[C@@H]1C[C@@](O)(c2ccc(-c3ccccc3)cc2)CN1C(=O)OCc1ccccc1
Reactant: C[Si](C)(C)CS
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: CC#N
Product: COC(=O)[C@@H]1C[C@](SC[Si](C)(C)C)(c2ccc(-c3ccccc3)cc2)CN1C(=O)OCc1ccccc1
Reaction time: 26 h
Yield: 43.7 %

Procedure:
To a clear solution of (2S,4R)-1-benzyl 2-methyl 4-(biphenyl-4-yl)-4-hydroxypyrrolidine-1,2-dicarboxylate (2.59 g, 6.00 mmol) and trimethylsilylmethanethiol (1.019 mL, 7.20 mmol) in Acetonitrile (30 mL) was added Scandium(III) trifluoromethanesulfonate (0.295 g, 0.600 mmol) as solid by one portion at room temperature. The formed pink solution was stirred at this temperature for 26 h. TLC analysis showed starting material was completely consumed. Quenched with sat. ammonium chloride, extracted with EtOAc. Washed the organic with brine, dried over MgSO4, filtered, evaporated in vacuo. The residue was purified by BIOTAGE® column, eluted with gradient 5˜40% EtOAc-hexane to afford the mixture of diastereomers 3.10 g (97%). This oily mixture was purified by BIOTAGE® again, eluted with gradient 0˜20% EtOAc-toluene to yield the by-product (2S,4S)-1-benzyl 2-methyl 4-(biphenyl-4-yl)-4-((trimethylsilyl)methylthio)pyrrolidine-1,2-dicarboxylate (1.40 g, 2.62 mmol, 43.7% yield) as a wax and the desired product (2S,4R)-1-benzyl 2-methyl 4-(biphenyl-4-yl)-4-((trimethylsilyl)methylthio)pyrrolidine-1,2-dicarboxylate (1.25 g, 2.108 mmol, 35.1% yield) as a white foam. 1H NMR (500 MHz, CHLOROFORM-d) ppm −0.03 (s, 9H), 1.33 (dd, J=28.08, 11.29 Hz, 1H), 1.49 (dd, J=17.70, 11.29 Hz, 1H), 2.62-2.85 (m, 2H), 3.62, 3.77 (s, 3H), 3.97 (t, J=11.60 Hz, 1H), 4.16 (dd, J=74.62, 11.44 Hz, 1H), 4.35-4.56 (m, 1H), 4.99-5.19 (m, 1H), 5.17-5.27 (m, 1H), 7.27-7.40 (m, 8H), 7.39-7.49 (m, 2H), 7.49-7.67 (m, 4H). LC-MS (retention time: 3.62 mm, method B), MS m/z 534 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[N:12]1[CH:14]=[CH:15][CH:16]=[C:11]1[C:10]2=[O:17])=[O:4].O.[OH-].[Li+]>O.CO>[O:17]=[C:10]1[C:9]2[C:13](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7][CH:8]=2)[N:12]2[CH:14]=[CH:15][CH:16]=[C:11]12
Reactant: COC(=O)c1cccc2c1-n1cccc1C2=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc2c1-n1cccc1C2=O
Yield: 83.9 %

Procedure:
In a 250 ml round-bottomed flask, a mixture of 800 mg of 9-oxo-9H-pyrrolo[1,2-a]indole-5-carboxylic acid methyl ester obtained according to the preceding stage and of 740 mg of lithium hydroxide monohydrate in 25 ml of water and 100 ml of methanol is refluxed for 3 hours. The reaction medium is evaporated to dryness under vacuum, and the solid is taken up in 35 ml of water and brought to pH 3 with 5M hydrochloric acid. A precipitate appears and the medium is extracted with 3 times 35 ml of a mixture of dichloromethane and methanol (95/5 v/v). The combined organic extracts are washed with 3 times 15 ml of water, dried over magnesium sulphate, and evaporated to dryness under vacuum. 630 mg of 9-oxo-9H-pyrrolo[1,2-a]indole-5-carboxylic acid are obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.C([O-])([O-])=O.[K+].[K+].Br[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=1.O>CC#N>[CH3:1][N:2]([CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][N:17]=1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: CNC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN(c1ccc([N+](=O)[O-])cn1)C1CCOCC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of N-methyltetrahydro-2H-pyran-4-amine (172.5 mg, 1.5 mmol) in CH3CN (5 mL) was added K2CO3 (207 mg, 1.5 mmol) and 2-bromo-5-nitropyridine (203 mg, 1 mmol). The reaction was stirred at 80° C. for 16 hours. TLC and LC-Ms showed the reaction had completed and the reaction was poured into water, extracted with EA, washed with water and brine, dried and concentrated to give a yellow solid. MS (m/z): 238 (M+H)+
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:23]=[CH:22][C:11]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:10][CH:9]=2)[CH2:3]1.[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[BH4-].[Na+]>C(#N)C.CO>[CH2:24]([N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:9]=[CH:10][C:11]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:22][CH:23]=2)[CH2:3]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=Cc1ccccc1
Reactant: NC(=O)c1ccc(Oc2ccc(C3CCCNC3)cc2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [BH4-]
Solvent: CO
Solvent: CC#N
Product: NC(=O)c1ccc(Oc2ccc(C3CCCN(Cc4ccccc4)C3)cc2)nc1
Yield: 57 %

Procedure:
Combine 6-(4-Piperidin-3-yl-phenoxy)-nicotinamide (free base of compound of example 322) (0.0298 g, 0.101 mmol), benzaldehyde (0.0108 mL, 0.106 mmol), and sodium triacetoxyborohydride (0.0310 mg, 0.146 mmol) in acetonitrile (2.0 mL). Add methanol (0.5 mL) to dissolve insoluble starting material. Add benzaldehyde (0.0200 mL, 0.197 mmol) after 15 min. then stir for 4 h. Add sodium borohydride (0.0083 g, 0.219 mmol) and stir for 10 min., concentrate, and purify by silica gel chromatography (30:1 ethyl acetate:hexanes→20:1 ethyl acetate:methanol) to provide 0.0223 g (57%) of the title compound as a white solid: mass spectrum (electrospray): m/z=388.2 (M+1); 1H NMR (CDCl3): 8.56 (d, 1H, J=2.4 Hz), 8.14 (dd, 1H, J=2.4, 8.8 Hz), 7.33-7.29 (m, 4H), 7.27-7.22 (m, 3H), 5.84 (s br, 2H), 3.57 (m, 2H), 3.06-2.83 (m, 3H), 2.10-1.90 (m, 4H), 1.80-1.70 (m, 2H), 1.50-1.37 (m, 1H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[C:50]([Cl:51])=[C:49]([O:52][CH3:53])[CH:48]=[CH:47][C:46]=1[F:54]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[C:46]([F:54])=[CH:47][CH:48]=[C:49]([O:52][CH3:53])[C:50]=3[Cl:51])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: COc1ccc(F)c(CBr)c1Cl
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: COc1ccc(F)c(Cn2nc3nc(C(C)(C)C)nc(N4CCC(F)(F)C4)c3n2)c1Cl

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-3-chloro-1-fluoro-4-methoxybenzene and isolated as white solid. MS (m/e): 455.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[CH:38]=[C:37]([CH3:39])[C:32]3[NH:33][C:34](=[O:36])[O:35][C:31]=3[CH:30]=2)[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([O:28][C:29]5[CH:38]=[C:37]([CH3:39])[C:32]6[NH:33][C:34](=[O:36])[O:35][C:31]=6[CH:30]=5)[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(Oc4cc(C)c5[nH]c(=O)oc5c4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
64 mg (0.23 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 64 mg (0.23 mmol) 6-(6-chloro-pyrimidin-4-yloxy)-4-methyl-3H-benzoxazol-2-one and 0.10 mL (0.58 mmol) DIPEA were combined in 1.8 mL DMF and stirred for 1 h at RT. Then 40 mg (0.15 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one were added and the mixture was stirred overnight. The reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined, the acetonitrile was evaporated down, the precipitate was suction filtered and dried i. vac.
Reaction SMILES: Cl.NO.Cl.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12](=[O:14])[N:11]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][N:21]([N:24]=CC4C=CC=CC=4O)[CH2:20][CH2:19]3)=[O:17])[C:10]=2[CH:33]=1>C(#N)C>[ClH:5].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12](=[O:14])[N:11]([CH2:15][C:16]([N:18]3[CH2:19][CH2:20][N:21]([NH2:24])[CH2:22][CH2:23]3)=[O:17])[C:10]=2[CH:33]=1
Reactant: O=C(Cn1c(=O)sc2ccc(Cl)cc21)N1CCN(N=Cc2ccccc2O)CC1
Agent: Cl
Agent: NO
Solvent: CC#N
Product: NN1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.6 %

Procedure:
To a solution of hydroxylamine hydrochloride (3.2 g) in a mixed solvent of acetonitrile (40 ml) and 6N-hydrochloric acid (20 ml) was added 5-chloro-3-{[4-(2-hydroxybenzylideneamino)-1-piperazinyl]carbonylmethyl}-2-benzothiazolinone (2 g). The resulting solution was stirred overnight at room temperature. After stirring for five hours under ice cooling, the crystalline precipitates were filtered, and washed successively with water (4 ml) and methylene chloride (10 ml). This product was further washed by suspending in water (4 ml) and filtered to give 5-chloro-3-[(4-amino-1-piperazinyl)carbonylmethyl]-2-benzothiazolinone hydrochloride (1.0 g)
Reaction SMILES: [Cl:1][CH2:2][C:3]1([CH2:7][Cl:8])[CH2:6][O:5][CH2:4]1.S(=O)(=O)(O)[OH:10].C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:1][CH2:2][C:3]([CH2:7][Cl:8])([CH2:6][OH:5])[CH2:4][OH:10]
Reactant: ClCC1(CCl)COC1
Reactant: O=S(=O)(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: OCC(CO)(CCl)CCl

Procedure:
3,3-Bis(chloromethyl)oxetane(BCMO, 15.5 g, 0.1 mole) was added, dropwise, to a stirred, refluxing solution of 0.5 ml of concentrated sulfuric acid in 60 ml of water. The mixture was stirred under reflux for 18 hours. The mixture was cooled to 25° and then sodium carbonate (3 g) was added. When gas evolution had ceased, the mixture was extracted with ethylacetate (3×40 ml). The combined ethylacetate extracts were washed in succession with water (40 ml) and saturated sodium chloride solution (40 ml). After drying (anhydrous sodium sulfate), the solution was concentrated, in vacuo, to remove solvent. The oily, solid residue was then washed with n-heptane-methylene chloride (40 ml, 1:1, v/v) and the crystals collected by filtration. Recrystallization from small amounts of methanol gave pure 2,2-bis(chloromethyl)propane-1,3-diol, 10.8 g (69.7%), mp,75.5°-78.5° (Lit(a) mp,81°). 13C n.m.r. (PPM): 44.94(s,CH2Cl); 46.62(s, C(CH2 --)4); 61.51 (s, CH2OH).
Reaction SMILES: [CH3:1][C:2](=[CH:5][CH2:6][CH3:7])[CH:3]=[O:4].[CH:8]1([Mg]Cl)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH:8]1([CH:3]([OH:4])[C:2]([CH3:1])=[CH:5][CH2:6][CH3:7])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Cl[Mg]C1CCCCC1
Reactant: CCC=C(C)C=O
Product: CCC=C(C)C(O)C1CCCCC1
Temperature: 10 °C
Reaction time: 0.83 h

Procedure:
To a dry 2 liter multi-neck round bottom flask fitted with an air stirrer, nitrogen inlet condenser and an addition funnel 800 ml of 2 M of cyclohexyl magnesium chloride was added and stirred. The flask was cooled to 10° C. 146 g of 99% 2-methyl-2-pentenal was added over the next 135 minutes. The cooling was removed. The first sample was taken 50 minutes later at 13° C. The second sample was taken 35 minutes later at 18° C. 75 minutes later the reaction mixture was quenched with 1000 ml of 20% HAc with cooling. The layers were allowed to settle and the organic layer extracted with 100 ml of toluene. The NMR spectrum of the 1-cyclohexyl-2-methyl-2-penten-1-ol is as follows . . . 0.7-0.9 ppm (q, 1H); 0.9-1.0 ppm (t, 4H); 1.1-1.3 ppm (m, 3H); 1.6 ppm (s, 3H); 1.6-1.8 ppm (m, 4H); 2.0-2.1 ppm (m, 3H); 3.7 ppm (d, 1H); 5.4 ppm (t, 1H)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][CH2:8][OH:9])([O-])=O>C(O)C.O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][CH2:8][OH:9]
Reactant: O=[N+]([O-])c1cccc(CCO)c1
Solvent: O
Solvent: CCO
Product: Nc1cccc(CCO)c1
Yield: 99.7 %

Procedure:
To a solution of 3-nitrophenethyl alcohol (5.13 g, 30.7 mmol), in ethanol (100 ml), was added a slurry of 10% Pd--C (0.5 g), in water (4 ml), and the mixture hydrogenated in a Parr flask, at 45 psi for 0.75 h. The catalyst was removed by filtration and the solvent evaporated to give 3-aminophenethyl alcohol (4.2 g, 100%), mp 61°-64° C., δ (360 MHz, CDCl3) 2.77 (2H, t, J=6.7 Hz, CH2), 3.80 (2H, t, J=6.7 Hz, CH2), 6.55-6.63 (3H, m, Ar--H), 7.08 (1H, dd, J=7.6 and 8.06 Hz, Ar--H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=3)=[C:7]([F:18])[CH:8]=2)[N:3]=1.[C:29]([O:33][C:34]([NH:36][C:37]1[N:42]=[CH:41][C:40](B(O)O)=[CH:39][N:38]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>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.C(O)C>[F:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=1)[N:3]=[C:2]([C:40]1[CH:41]=[N:42][C:37]([NH:36][C:34](=[O:35])[O:33][C:29]([CH3:31])([CH3:30])[CH3:32])=[N:38][CH:39]=1)[N:11]=[C:10]2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CS(=O)(=O)c1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3cc2F)c1
Reactant: CC(C)(C)OC(=O)Nc1ncc(B(O)O)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3cc(F)c(-c4cccc(S(C)(=O)=O)c4)cc3n2)cn1
Temperature: 75 °C
Reaction time: 3 h
Yield: 51.7 %

Procedure:
To a 50 mL round bottom flask, 4-(2-chloro-6-fluoro-7-(3-(methylsulfonyl)phenyl)quinazolin-4-yl)morpholine (0.1 g, 0.0002 mol), (2-((tert-butoxycarbonyl)amino)pyrimidin-5-yl)boronic acid (0.085 g, 0.0003 mol), cesium carbonate (0.192 g, 0.0005 mol), toluene (5 mL), ethanol (5 mL) and water (2 mL) were added. The reaction vessel was degassed with N2 for 5-10 minutes. To the same reaction mixture, Pd(PPh3)2Cl2 (0.008 g, 0.000012 mol) was added and again degassed with N2 for 5-10 minutes. The reaction mixture was stirred at 75° C. for 3 hours. The reaction mixture was cooled and diluted with chloroform. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under the reduced pressure to afford the crude product. The crude product was purified by column chromatography (60-120 silica gel, 50% ethyl acetate in n-hexane) to yield tert-butyl (5-(6-fluoro-7-(3-(methylsulfonyl)phenyl)-4-morpholinoquinazolin-2-yl)pyrimidin-2-yl)carbamate [0.06 g, 43%]. LC-MS (ESI): Calculated mass: 580.1; Observed mass [M+H]+: 581.3 (RT=1.52 min).
Reaction SMILES: C[O:2][C:3](=[O:34])[C@@H:4]([NH:8][C:9]([C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]3[S:25][C:26]4[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:27]=4[N:28]=3)=[CH:19][CH:18]=2)[CH:13]=1)=[N:10][OH:11])[CH:5]([CH3:7])[CH3:6].[Li+].[OH-]>C1COCC1>[F:33][C:31]1[CH:30]=[CH:29][C:27]2[N:28]=[C:24]([NH:23][C:20]3[CH:21]=[CH:22][C:17]([C:14]4[CH:13]=[C:12]([C:9]([NH:8][C@@H:4]([CH:5]([CH3:7])[CH3:6])[C:3]([OH:34])=[O:2])=[N:10][OH:11])[O:16][N:15]=4)=[CH:18][CH:19]=3)[S:25][C:26]=2[CH:32]=1
Reactant: COC(=O)[C@@H](NC(=NO)c1cc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)no1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=NO)c1cc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)no1)C(=O)O
Temperature: 42.5 °C
Reaction time: 48 h
Yield: 55 %

Procedure:
To a solution of (S)-2-({3-[4-(6-Fluoro-benzothiazol-2-ylamino)-phenyl]-N-hydroxy-isoxazole-5-carboximidoyl}-amino)-3-methyl-butyric acid methyl ester (0.3 g; 0.62 mmol) in THF (3 ml) was added 1N LiOH (0.81 ml; 0.81 mmol) under stirring for 48 hours, followed by heating at 40-45° C. for 2 hours. Solvent was removed from the reaction mixture and the residue was diluted with water (5 ml) and acidified to pH 2 with 2N HCl. The semisolid material obtained was extracted with EtOAc, washed with water (2×5 ml), and dried over anhydrous Na2SO4. The residue was purified by flash chromatography with 10-50% MeOH in chloroform. The pure material obtained was triturated with acetone and light petroleum, filtered and dried under vacuum pump to yield 0.16 g (55%) of the title compound. Mass
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([CH:32]2[CH2:34][CH:33]2[C:35]([O:37]CC)=[O:36])=[CH:4][N:3]=1.[OH-].[Na+].Cl>CO>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([CH:32]2[CH2:34][CH:33]2[C:35]([OH:37])=[O:36])=[CH:4][N:3]=1
Reactant: CCOC(=O)C1CC1c1cnc(N)c2c(-c3ccc(NC(=O)c4cc5ccccc5n4C)c(OC)c3)csc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(-c2csc3c(C4CC4C(=O)O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Yield: 14.8 %

Procedure:
Ethyl 2-[4-amino-3-(3-methoxy-4-{[(1-methyl-1H-indol-2-yl)carbonyl]amino}phenyl)thieno[3,2-c]pyridin-7-yl]cyclopropanecarboxylate (433 mg, 0.8018 mmol) in methanol (2 mL) and 2M sodium hydroxide (1.604 mL, 3.207 mmol) was stirred for 23 to hours at 50° C., cooled to room temperature, and acidified to a pH of 4 with 1M hydrochloric acid. Solids were filtered off and washed with water. The material was purified by HPLC preparative to furnish the title compound as a white solid (61 mg 0.119 mmol): LCMS (Conditions a): MH+=513 Rt=2.22 minutes; 1H NMR (DMSO-d6, 400 MHz) 9.51 (1H), 7.99 (1H), 7.71 (2H), 7.57 (2H), 7.34 (2H), 7.19 (1H), 7.15 (1H), 7.07 (1H), 5.46 (1H), 4.04 (3H), 3.91 (3H), 2.39 (1H), 1.73 (1H), 1.46 (1H), 1.39 (1H).