Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]([N:13]2[CH2:18][CH2:17][N:16]([N:19]=O)[CH2:15][CH2:14]2)[C:5]2[CH:21]=[CH:22][CH:23]=[CH:24][C:4]=2[CH:3]=1.CCOCC.[Li+].[AlH4-].[OH-].[Na+]>O.O1CCCC1>[Br:1][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]([N:13]2[CH2:14][CH2:15][N:16]([NH2:19])[CH2:17][CH2:18]2)[C:5]2[CH:21]=[CH:22][CH:23]=[CH:24][C:4]=2[CH:3]=1
Reactant: O=NN1CCN(C2c3ccccc3C=C(Br)c3ccccc32)CC1
Agent: [AlH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: NN1CCN(C2c3ccccc3C=C(Br)c3ccccc32)CC1

Procedure:
To a suspension of 20 parts of 1-(10-bromo-5H-dibenzo[a,d]cyclohepten-5-yl)-4-nitrosopiperazine in 1400 parts of anhydrous ether is slowly added 7 parts of lithium tetrahydroaluminate(1-). The resultant mixture is stirred at room temperatures for 5 hours, then cooled to around 5° and maintained thereat while a solution of 14 parts of water in 25 parts of tetrahydrofuran, 18 parts of aqueous 25% sodium hydroxide, and 14 parts of water are consecutively introduced. Insoluble solids are removed by filtration and washed with tetrahydrofuran. The washings and filtrate are combined, dried over anhydrous magnesium sulfate, and stripped of solvent by vacuum distillation. The residual yellow solid is crystallized from a mixture of tetrahydrofuran and hexane to give 1-(10-bromo-5H-dibenzo[a,d]cyclohepten-5-yl)-4-piperazineamine as colorless crystals melting at 187.5°-190.5°.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[CH:7]=[CH:8][C:9]([OH:24])=[C:10]([C:12]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[O:22]C)([CH3:14])[CH3:13])[CH:11]=1.O>ClCCl>[C:12]([C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[OH:22])([C:10]1[CH:11]=[C:6]([F:5])[CH:7]=[CH:8][C:9]=1[OH:24])([CH3:14])[CH3:13]
Reactant: COc1ccc(F)cc1C(C)(C)c1cc(F)ccc1O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC(C)(c1cc(F)ccc1O)c1cc(F)ccc1O
Reaction time: 1 h
Yield: 79 %

Procedure:
Boron tribromide (1 ml) in dichloromethane (10 ml) was added dropwise to a solution of 2-(5-fluoro-2-hydroxyphenyl)-2-(5-fluoro-2-methoxyphenyl)propane (0.5 g) in dichloromethane (10 ml) at -70° C. The solution was stirred at this temperature for one hour and water was then added. The organic layer was separated, dried (Na2SO4) and the solvent removed to give a colourless product which crystallised from hexane to give colourless prisms of 2,2'-isopropylidene bis(4-fluorophenol) (0.375 g); m.p. 155° C.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[CH:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.FC(F)(F)S(O)(=O)=O.FC(F)(F)S(O)(=O)=O.[SH:67][C@@H:68]1[CH2:72][N:71]([C:73]([O:75][CH2:76][C:77]2[CH:82]=[CH:81][C:80]([N+:83]([O-:85])=[O:84])=[CH:79][CH:78]=2)=[O:74])[C@H:70]([C:86]([N:88]2[CH2:94][CH2:93][CH2:92][N:91]([CH3:95])[CH2:90][CH2:89]2)=[O:87])[CH2:69]1>C(#N)C>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])=[C:8]([S:67][C@@H:68]3[CH2:72][N:71]([C:73]([O:75][CH2:76][C:77]4[CH:82]=[CH:81][C:80]([N+:83]([O-:85])=[O:84])=[CH:79][CH:78]=4)=[O:74])[C@H:70]([C:86]([N:88]4[CH2:94][CH2:93][CH2:92][N:91]([CH3:95])[CH2:90][CH2:89]4)=[O:87])[CH2:69]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CN1CCCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCCN(C)CC4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Temperature: 0 °C
Yield: 46.5 %

Procedure:
340 mg of 4-nitrobenzyl (1R, 5R, 6S)-6[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate were dissolved in 3.5 ml of anhydrous acetonitrile, and the solution was placed on an ice bath. Whilst the solution was still on the ice bath, 210 μl of diphenylphosphoryl chloride and 180 μl of diisopropylethylamine were added dropwise to it, and the resulting mixture was stirred for 1 hour at this ice-cooled temperature. 580 μl of diisopropylethylamine and 5 ml of an anhydrous acetonitrile solution containing 640 mg of (2S, 4S)-4-mercapto-2-(4-methyl-1-homopiperazinylcarbonyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine bis(trifluoromethanesulfonate) [prepared as described in step (1) above] were then added dropwise to the reaction mixture, still on an ice bath, and the resulting mixture was stirred overnight at this ice-cooled temperature. At the end of this time, the mixture was treated and purified by means similar to those described in Example 1(2), to give 316 mg of the title compound.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([S:10](Cl)(=[O:12])=[O:11])=[CH:5][C:4]=1[C:14]1([OH:22])[CH2:18][S:17][C:16](=[N:19][CH3:20])[N:15]1[CH3:21].[NH3:23]>CO>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([S:10](=[O:12])(=[O:11])[NH2:23])=[CH:5][C:4]=1[C:14]1([OH:22])[CH2:18][S:17][C:16](=[N:19][CH3:20])[N:15]1[CH3:21]
Reactant: CN=C1SCC(O)(c2cc(S(=O)(=O)Cl)c(Cl)cc2Cl)N1C
Reactant: N
Agent: Br
Solvent: CO
Product: CN=C1SCC(O)(c2cc(S(N)(=O)=O)c(Cl)cc2Cl)N1C
Reaction time: 8 h

Procedure:
4.4 g of 4-(2,4-dichlor-5-chlorosulfonylphenyl)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol-hydrobromide were introduced, while stirring, into a solution of 10 g of gaseous ammonia in 70 ml of methanol. After having allowed the whole to stand overnight at room temperature, the solution was concentrated to about 30 ml of its volume under reduced pressure and the 4-(2,4-dichloro-5-sulfamoylphenyl)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol was precipitated with 100 ml of water. M.p. 186°-189° C (decomposition ).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[O:17]1[CH:19]([CH2:20][CH3:21])[CH2:18]1>C(O)(C)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH:19]([OH:17])[CH2:20][CH3:21])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CCC1CO1
Solvent: CC(C)O
Product: CCC(O)CN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 65 °C
Yield: 26.8 %

Procedure:
A stirred mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (5.5 g, 25 mmol) and 1,2-epoxybutane (1.89 g, 26.3 mmol) in isopropyl alcohol (100 ml) was heated at 65° C. for 2 days. This mixture was cooled and the solvent was removed to leave a brown oil which was purified by flash chromatography over a silica gel column (SiO2, 70 g; eluted with DCM, 1 l and MeOH:DCM 2%:98%) to give an off-white solid weighing 6.3 g. Recrystallization from hot ethanol yielded 1.96 g of fine crystals, m.p. 87-88° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][C@H:10]([C@H:13]([CH2:24]O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([O:22][CH3:23])[CH:16]=2)[CH2:11][OH:12])[CH:6]=[CH:5][C:4]=1[OH:26].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(#N)C>[CH2:9]([CH:10]1[CH:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([O:22][CH3:23])[CH:16]=2)[CH2:24][O:12][CH2:11]1)[C:7]1[CH:6]=[CH:5][C:4]([OH:26])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(C[C@@H](CO)[C@H](CO)Cc2ccc(O)c(OC)c2)ccc1O
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: C1CCOC1
Product: COc1cc(CC2COCC2Cc2ccc(O)c(OC)c2)ccc1O
Temperature: 40 °C
Reaction time: 5.5 h
Yield: 81 %

Procedure:
(−) secoisolariciresinol (100 mg,) was dissolved in THF (5 ml) and to it was added a solution of triphenyl phosphine chloride in acetonitrile (1 ml) and the mixture was stirred at 0-80° C. for 1-10 hours. After completion of the reaction, the reaction mixture was concentrated under vacuum and the residue thus obtained was chromatographed over florosil column. Elution of the column with 30% EtOAC in pet. ether gave (−-3,4-divanillyl tetrahydrofuran (77 mg), m.p. 114-116° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:25][CH3:26])[C:4]1[CH:24]=[CH:23][C:7]([C:8]([C:10]2[C:18]([Cl:19])=[C:17]([Cl:20])[C:16]([Cl:21])=[C:15]([Cl:22])[C:11]=2[C:12]([OH:14])=[O:13])=O)=[CH:6][CH:5]=1)[CH3:2].[CH2:27]([N:29]([CH2:41][CH3:42])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]([CH2:39][CH3:40])[CH2:37][CH3:38])[CH:31]=1)[CH3:28].C(OC(=O)C)(=O)C>CO>[CH2:39]([N:36]([CH2:37][CH3:38])[C:32]1[CH:31]=[C:30]([N:29]([CH2:41][CH3:42])[CH2:27][CH3:28])[CH:35]=[CH:34][C:33]=1[C:8]1([C:7]2[CH:23]=[CH:24][C:4]([N:3]([CH2:25][CH3:26])[CH2:1][CH3:2])=[CH:5][CH:6]=2)[C:10]2[C:11](=[C:15]([Cl:22])[C:16]([Cl:21])=[C:17]([Cl:20])[C:18]=2[Cl:19])[C:12](=[O:13])[O:14]1)[CH3:40]
Reactant: CCN(CC)c1cccc(N(CC)CC)c1
Reactant: CCN(CC)c1ccc(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)cc1
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: CCN(CC)c1ccc(C2(c3ccc(N(CC)CC)cc3N(CC)CC)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)cc1
Temperature: 90 °C
Yield: 61.6 %

Procedure:
A mixture of 2-(4-(diethylamino)benzoyl)-3,4,5,6-tetrachlorobenzoic acid (8.70 g.), N,N,N',N'-tetraethyl-m-phenylenediamine (4.85 g.) and acetic anhydride (5 ml.) was heated (to 90° C.). Addition of methanol (10 ml.) and slurrying the resulting product with methanol (20 ml.) afforded 3-(2,4-bis(diethylamino)phenyl)-3-(4-(diethylamino)-phenyl)-4,5,6,7-tetrachlorophthalide (I: X = Y4 = (CH3CH2)2N, Y2 = H, Z4 = Z5 = Z6 = Z7 = Cl) (7.85 g., m.p. 196°-197° C.).
Reaction SMILES: [C:1]([CH:4]([OH:22])[C@H:5]1[O:9][C@@H:8]([N:10]2[CH:17]=[C:16](I)[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[N:19]=[N+:20]=[N-:21])(=[O:3])[CH3:2].[C-]#N.[K+].CC([O-])=O.[K+].[N:31]([C@@H:34]1[C@@H](CO)O[C@@H](N2C=C(C)C(=S)NC2=O)C1)=[N+]=[N-]>CS(C)=O>[C:1]([CH:4]([OH:22])[C@H:5]1[O:9][C@@H:8]([N:10]2[CH:17]=[C:16]([C:34]#[N:31])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[N:19]=[N+:20]=[N-:21])(=[O:3])[CH3:2]
Reactant: CC(=O)C(O)[C@H]1O[C@@H](n2cc(I)c(=O)[nH]c2=O)C[C@@H]1N=[N+]=[N-]
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=S
Agent: CC(=O)[O-]
Agent: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)C(O)[C@H]1O[C@@H](n2cc(C#N)c(=O)[nH]c2=O)C[C@@H]1N=[N+]=[N-]

Procedure:
5'-Acetyl-3'-azido-2',3'-dideoxy-5-iodouridine(0.5 g, 1.2 mMol, Ex.) was treated with KCN(0.1 g, 1.6 mMol) and KOAc(0.15 g, 1.6 mMol) in anhydrous DMSO at 105° C. for 90 minutes in a method analogous to (1). The DMSO was evaporated in vacuo and the residue chromatographed on silica gel, eluted with CHCl3 then with 20:1 CHCl3/MeOH (v/v). Collection of appropriate fractions followed by evaporation of the solvents gave pure 5'-acetyl-3'-azido-5-cyano-2',3'-dideoxyuridine. This material was dissolved in NH3 saturated MeOH at ambient temperature and allowed to stand overnight. The solvents were evaporated in vacuo and the residue chromatographed on silica gel using 9:1 CHCl3/MeOH (v/v) as the eluting solvent. Collection and evaporation of the appropriate fractions yielded the title compound as a clear oil: UV(nm): at pH 1 λmax=276,214 (ε=13700,12800), λmin=238 (ε=2200); at pH 13 λmax=275 (ε=10000), λmin=245(ε=3200); H NMR(DMSO-d6) δ8.81(s,1H,H6), 5.95(dd,1H,H1',J=2.34,4.11 Hz), 5.45(t,1H,5'OH,J=5.08 Hz), 4.4-4.3(m,1H,H3'), 3.9-3.8(m,1H,H4'), 3.8-3.5(m,2H,H5'), 2.45-2.30(m,2H,H2').
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][NH2:10].[BH4-].[Na+]>CO>[CH3:9][NH:10][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
A solution of benzaldehyde (2.0 ml, 20.0 mmol) and methylamine (2.0M in THF) (20.0 ml, 40.0 mmol) and methanol (20 ml) was stirred at room temperature for 20 h under a nitrogen atmosphere. Sodium borohydride (2.27 g, 60.0 mmol) was added to the solution and it was stirred at room temperature for 2 h. The solvent was removed out under reduced pressure and the residue dissolved in chloroform. The chloroform was washed with brine, and dried over magnesium sulphate. The solvent was removed under reduced pressure to yield a yellow oil (1.32 g, 55%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][CH2:9][NH:10]C(=O)OC(C)(C)C)[CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][CH2:9][NH2:10])[CH:2]=1
Reactant: CC(C)(C)OC(=O)NCC#Cc1cccnc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC#Cc1cccnc1
Yield: 97.5 %

Procedure:
To a solution of 47 (104 mg, 0.45 mmol) in CH2Cl2 (1 mL) was added TFA (2 mL, excess) and the resultant solution was stirred at room temperature for 1 h. The solvent and excess TFA were removed under a stream of nitrogen and the residue was partitioned between HCl(aq) (1.0 M, 2 mL) and EtOAc (10 mL). The aqueous fraction was collected and subsequently washed with EtOAc (2×10 mL). To the remaining aqueous fraction was added CH2Cl2 (20 mL) and water (20 mL) and the pH was adjusted to 10 with NaOH(aq) (10 N) while stirring. The organic fraction was collected and the remaining aqueous fraction was extracted with CH2Cl2 (2×15 mL). The combined organic fractions were dried (Na2SO4), filtered and the solvent was removed in vacuo to afford the title compound 48 (free base, 58 mg, 97% yield) as a brown oil. Due to the high potential of autooxidation, the dihydrochloride salt was made by dissolving the amine free base in Et2O and precipitating with etherial HCl. The solvent and excess HCl were removed in vacuo, the solid dihydrochloride was triturated with Et2O and collected by filtration to afford the title compound 48 (dihydrochloride, 91 mg, 99% yield) as a white solid: 1H NMR (D2O) δ 8.94 (m, 1H), 8.79 (m, 1H), 8.65 (m, 1H), 8.06 (m, 1H), 4.15 (s, 2H); LRMS (ESI) m/z calcd for C8H9N2 [M+H]+ 133. found 133; HRMS (ESI) m/z calcd for C8H9N2 [M+H]+ 133.0766. found 133.0763; HPLC>98% (tR=5.70 min, 60 (A):40 (B): 0.02 (C); tR=3.05 min, 60 (A):40 (B): 0.07 (C)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH2:9][CH2:10][NH2:11])[CH:8]=1.[CH2:15]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C:23]1=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH2:15]([N:22]1[CH2:27][CH2:26][CH:25]([NH:11][CH2:10][CH2:9][C:7]2[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[N+:12]([O-:14])=[O:13])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCCCN1Cc1ccccc1
Reactant: COc1ccc([N+](=O)[O-])c(CCN)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc([N+](=O)[O-])c(CCNC2CCN(Cc3ccccc3)CC2)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
Under a nitrogen atmosphere a mixture of 9.98 g (50.9 mmol) 2-(5-methoxy-2-nitrophenyl)-ethylamine, 9.80 mL (54.9 mmol) N-benzylpiperidone and 6.30 mL (114 mmol) acetic acid in 270 mL DCM was cooled to 0° C. in an ice bath. At this temperature 14.2 g (67.0 mmol) sodium triacetoxyborohydride were added batchwise within 20 min. The reaction mixture was stirred for a further 4 h at 0° C. and left to warm up to RT overnight. Then the mixture was combined with 400 mL of a 15% (w/v) aqueous potassium carbonate solution and stirred for 1 h at RT. The organic phase was separated off, dried and concentrated by rotary evaporation. 18.8 g of the desired product were obtained.
Reaction SMILES: [Cl-].[Li+].C([Mg]Cl)=C.[S:7](Cl)([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)(=[O:9])=[O:8].[CH3:18][C@@H:19]([OH:23])[CH2:20][CH:21]=[CH2:22]>C1COCC1.[Cu]Cl>[C:13]1([CH3:14])[CH:15]=[CH:16][C:10]([S:7]([O:23][C@@H:19]([CH2:20][CH:21]=[CH2:22])[CH3:18])(=[O:9])=[O:8])=[CH:11][CH:12]=1
Reactant: C=CC[C@@H](C)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl[Cu]
Agent: C=C[Mg]Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=CC[C@@H](C)OS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C

Procedure:
Copper(I) chloride (645 g, 6.52 mol) and lithium chloride (550 g, 12.9 mol) were dissolved in THF (140 L) and cooled to 0° C. Vinyl magnesium chloride (349 kg, 633 mol, 16.5% in THF) was added slowly, maintaining the temperature below 5° C. The mixture was cooled to −15° C. A cooled solution of R-propylene oxide (37.8 kg, 651 mol) in THF (900 L) was added slowly, maintaining the temperature below −15° C. The reaction mixture was stirred until more than 98.5% of R-propylene oxide had been consumed (using GC). The mixture was added slowly to a cooled solution of TsCl (127 kg, 664 mol) in THF (470 L). The mixture was heated to ambient temperature and stirred until more than 98% of the 4-penten-2(R)-ol had been consumed (using GC). The reaction mixture was transferred to a mixture of water (630 L) and MTBE (280 L). Hydrochloric acid was added until pH≦2.5. The phases were separated and the aqueous phase was washed with MTBE. The combined organic phases were washed with aqueous sodium chloride solution and the organic phase was distilled to remove MTBE, to yield (R)-4-penten-2-yl p-toluenesulfonate in a THF solution (190 L). THF (120 L) is then added to the solution.
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[CH2:3][N:4]([CH3:23])[C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:15]([NH:17][CH3:18])=[O:16])[CH:6]=1.C(=O)(O)[O-].[Na+].[Br:31]Br>C(Cl)Cl.O>[Br:31][C:6]1[C:7]([NH:11][C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:15]([NH:17][CH3:18])=[O:16])=[N:8][CH:9]=[N:10][C:5]=1[N:4]([CH2:3][C:2]([CH3:25])([CH3:24])[CH3:1])[CH3:23]
Reactant: BrBr
Reactant: CNC(=O)c1ccc(C)c(Nc2cc(N(C)CC(C)(C)C)ncn2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1ccc(C)c(Nc2ncnc(N(C)CC(C)(C)C)c2Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.4 %

Procedure:
To a solution of 3-{6-[(2,2-dimethyl-propyl)-methyl-amino]-pyrimidin-4-ylamino}-4,N-dimethyl-benzamide (0.46 g, 1.34 mmol) in methylene chloride (10 mL), was added sat. aq. sodium bicarbonate (2 mL) and bromine (0.07 mL, 1.37 mmol). The resulting mixture was stirred at room temperature for 18 hours, and the reaction was then diluted with water (20 mL). The organic layer was separated and the aqueous layer was extracted with DCM (10 mL). The combined organic layer was dried (sodium sulfate), filtered and concentrated. The residue was purified by silica gel column chromatography using 2% methanol in DCM as eluent to afford the product (250 mg, yield 44%). MS (m/z): 420 (M+H).
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[F:59][C:60]1[CH:68]=[CH:67][C:63]([C:64](Cl)=[O:65])=[C:62]([C:69]([F:72])([F:71])[F:70])[CH:61]=1>>[F:59][C:60]1[CH:68]=[CH:67][C:63]([C:64]([NH:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]3[CH:49]=[C:48]4[C:44]([CH2:45][N:46]([C@@H:51]([CH:56]([CH3:58])[CH3:57])[C:52]([O:54][CH3:55])=[O:53])[C:47]4=[O:50])=[CH:43][CH:42]=3)=[CH:39][CH:40]=2)=[O:65])=[C:62]([C:69]([F:70])([F:71])[F:72])[CH:61]=1
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(F)cc4C(F)(F)F)cc3)cc2C1=O
Yield: 64 %

Procedure:
The compound of example 197 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 4-fluoro-2-trifluoromethyl benzoyl chloride.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7](B3OC(C)(C)C(C)(C)O3)=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:20].Br[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1[CH:28]=[CH2:29].COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][C:27]=3[CH:28]=[CH2:29])=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:20]
Reactant: CN1C(=O)Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: C=Cc1ccncc1Br
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: ClCCl
Solvent: COCCOC
Product: C=Cc1ccncc1-c1ccc2c(c1)CC(=O)N2C
Temperature: 115 °C

Procedure:
To 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one (135 mg, 0.49 mmol), prepared as described in Example 3a, was added 3-bromo-4-vinyl-pyridine (100 mg, 0.54 mmol), 1,2-dimethoxyethane (3.0 mL), and 2 M aqueous sodium carbonate (0.560 mL, 1.1 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (225 mg, 0.025 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 115° C. for 4 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane, 0 to 6%) to furnish 1-methyl-5-(4-vinyl-pyridin-3-yl)-1,3-dihydro-indol-2-one; MS: (ES+) m/z 251.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][OH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N2CCN(CC2)C1.C(Cl)Cl.[S:33](Cl)([C:36]1[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=1)(=[O:35])=[O:34]>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][O:21][S:33]([C:36]2[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2CO)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C1CN2CCN1CC2
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCc2ccccc2C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 112.2 %

Procedure:
4-(2-Hydroxymethylphenyl)piperidine-1-carboxylic acid t-butyl ester (0.4 g, 1.0 mmol, 1.0 eq.) and triethylenediamine (220 mg, 2.0 mmol, 1.4 eq.) were dissolved in DCM (11 mL, 170 mmol). The mixture was cooled at 0° C. under nitrogen, TsCl (290 mg, 1.5 mmol, 1.1 eq.) was added, and the mixture was stirred at 0° C. for an additional 60 minutes. The mixture was diluted with EtOAc (50 mL) and washed with water (2×25 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to yield the title compound (500 mg), which was used without further purification.