Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:20]([NH:21][C:22](=[O:35])[CH2:23][N:24]2[C:28](=[O:29])[C:27]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]3[C:25]2=[O:34])=[CH:19][CH:18]=[C:17]([Cl:36])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.[CH3:37]N(C)C=O.[H-].[Na+].CI>O>[Cl:1][C:2]1[C:20]([N:21]([C:22](=[O:35])[CH2:23][N:24]2[C:25](=[O:34])[C:26]3=[CH:33][CH:32]=[CH:31][CH:30]=[C:27]3[C:28]2=[O:29])[CH3:37])=[CH:19][CH:18]=[C:17]([Cl:36])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2
Reactant: CN(C)C=O
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(NC(=O)CN4C(=O)c5ccccc5C4=O)c3Cl)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN4C(=O)c5ccccc5C4=O)c3Cl)c2n1
Reaction time: 0.5 h

Procedure:
To a mixture of 8-[2,6-dichloro-3-(phthalimidoacetylamino)benzyloxy]-2-methylquinoline (4.44 g) and N,N-dimethylformamide (44 ml) was added sodium hydride (60% in oil, 375 mg) in an ice-water bath. After stirring for 30 minutes in an ice-water bath, methyl iodide (0.6 ml) was added thereto and the mixture was stirred at ambient temperature for 1 hour. To this mixture was added water (88 ml) in an ice-water bath and the mixture was stirred at the same temperature for 1.5 hours. The precipitate was collected by vacuum filtration wand washed with water and methanol to give 8-[2,6-dichloro-3-[N-(phthalimidoacetyl)-N-methylamino]benzyloxy]-2-methylquinoline (3.99 g) as a yellow powder.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6][NH:7][NH2:8])([O-:3])=[O:2].C([O:15][C:16](=O)[CH:17]=[C:18]([NH2:22])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:22][C:18]1[NH:8][N:7]([CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])[C:16](=[O:15])[CH:17]=1
Reactant: NNCc1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)C=C(N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2ccccc2[N+](=O)[O-])[nH]1
Reaction time: 8 h

Procedure:
47.8 g of o-nitrobenzylhydrazine were added dropwise, under nitrogen, to a solution of 45.5 g of β-amino-β-ethoxyacrylic acid ethyl ester and a pinch of p-toluenesulphonic acid in 200 ml of ethanol. After standing overnight, the solvent was distilled off in vacuo and the residue was treated with a 2:1 mixture of ether and ethanol. The compound identified above which thereupon precipitated was filtered off and recrystallised from ethanol. Melting point: 190°, 23 g (34%).
Reaction SMILES: [CH3:1][N:2]([CH3:52])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:51])[NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:26]=[C:25]4[N:27]([CH2:30][C:31]([F:34])([F:33])[F:32])[N:28]=[CH:29][C:24]4=[C:23]([N:35]4[CH:40]5[CH2:41][N:42](C(OC(C)(C)C)=O)[CH2:43][CH:36]4[CH2:37][O:38][CH2:39]5)[N:22]=3)=[CH:17][CH:16]=2)=[CH:8][CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH:36]12[N:35]([C:23]3[N:22]=[C:21]([C:18]4[CH:19]=[CH:20][C:15]([NH:14][C:13]([NH:12][C:9]5[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:52])[CH3:1])=[CH:11][CH:10]=5)=[O:51])=[CH:16][CH:17]=4)[N:26]=[C:25]4[N:27]([CH2:30][C:31]([F:34])([F:32])[F:33])[N:28]=[CH:29][C:24]=34)[CH:40]([CH2:41][NH:42][CH2:43]1)[CH2:39][O:38][CH2:37]2
Reactant: CN(C)CCOc1ccc(NC(=O)Nc2ccc(-c3nc(N4C5COCC4CN(C(=O)OC(C)(C)C)C5)c4cnn(CC(F)(F)F)c4n3)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCOc1ccc(NC(=O)Nc2ccc(-c3nc(N4C5CNCC4COC5)c4cnn(CC(F)(F)F)c4n3)cc2)cc1

Procedure:
A solution of tert-butyl 9-(6-(4-(3-(4-(2-(dimethylamino)ethoxy)phenyl)ureido)phenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate.TFA (174 mg) in dichloromethane (5 mL) was treated with trifluoroacetic acid (1 mL). After concentration, the residue was purified by reverse-phase high performance liquid chromatography to provide, after concentration, the title compound. MS (ES+): 626.3 (M+H)+
Reaction SMILES: [Br-:1].[OH:2][CH2:3][CH2:4][CH2:5][N+:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH3:16])=[CH:8][CH:7]=1.[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][N:24]1[C:36]2[CH:35]=[CH:34][C:33]([CH:37]=O)=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2.N1CCCCC1>C(O)C>[Br-:1].[OH:2][CH2:3][CH2:4][CH2:5][N+:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](/[CH:16]=[CH:37]/[C:33]2[CH:34]=[CH:35][C:36]3[N:24]([CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH3:17])[C:25]4[C:30]([C:31]=3[CH:32]=2)=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:8][CH:7]=1
Reactant: Cc1cc[n+](CCCO)c2ccccc12
Reactant: COCCOCCn1c2ccccc2c2cc(C=O)ccc21
Agent: [Br-]
Solvent: C1CCNCC1
Solvent: CCO
Product: COCCOCCn1c2ccccc2c2cc(/C=C/c3cc[n+](CCCO)c4ccccc34)ccc21
Temperature: 25 °C
Yield: 41 %

Procedure:
A solution mixture of 7 (0.17 g, 0.6 mmol), 3a (0.24 g, 0.8 mmol) and piperidine (0.1 mL) in ethanol (40 mL) was heated to reflux overnight. After cooling down to room temperature, the organic solvent was removed. The residue was purified by precipitation from methanol and ethyl acetate to afford SLOH-Pr (0.14 g) in 41% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.29 (d, J=6.8 Hz, 1H), 9.15 (d, J=8.4 Hz, 1H), 8.88 (s, 1H), 8.51 (d, J=6.8 Hz, 1H), 8.45 (d, J=16 Hz, 1H), 8.37 (d, J=16 Hz, 1H), 8.28-8.24 (m, 2H), 8.13 (d, J=8.4 Hz, 1H), 8.05 (t, J=8.0 Hz, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 7.31 (t, J=7.2 Hz, 1H), 5.01 (t, J=7.2 Hz, 2H), 4.86 (t, J=5.2 Hz, 1H), 4.63 (t, J=4.8 Hz, 2H), 3.84 (t, J=5.2 Hz, 2H), 3.55 (tr, J=5.2 Hz, 2H), 3.47 (t, J=5.6 Hz, 2H), 3.31 (t, J=4.8 Hz, 2H), 3.11 (s, 3H), 2.13 (t, J=6.0 Hz, 2H). 13C NMR (400 MHz, DMSO-d6) δ 153.3, 147.3, 145.1, 142.2, 140.9, 137.9, 135.0, 128.8, 127.4, 126.8, 126.7, 126.5, 126.4, 122.8, 122.2, 121.8, 120.4, 119.9, 119.0, 116.3, 115.2, 110.5, 110.4, 71.3, 69.8, 68.9, 58.1, 57.6, 54.2, 42.9, 32.0. HRMS (MALDI-TOF) m/z Calcd for C31H33N2O3 481.2485. Found 481.2458 [M]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8](=[O:28])[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[C:10]([CH2:17][CH3:18])[NH:11]2.Cl[C:31](OC(=O)C)([F:33])[F:32]>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:28][CH:31]([F:33])[F:32])=[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[C:10]([CH2:17][CH3:18])=[N:11]2
Reactant: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(OC)cc1
Reactant: CC(=O)OC(F)(F)Cl
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(OC)cc1

Procedure:
The title compound was prepared by the method of Preparation 1d using [2-ethyl-8-fluoro-3-(4-methoxybenzyl)-4-oxo-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester and acetic acid chlorodifluoromethyl ester.
Reaction SMILES: Br.Br[CH2:3][C:4]1[N:5]=[C:6]2[C:11](=[N:12][CH:13]=1)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]2[NH2:15].Cl.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:27][CH2:28][NH2:29])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26].C(=O)(O)[O-]>CN(C)C(=O)C>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:27][CH2:28][NH:29][CH2:3][C:4]2[N:5]=[C:6]3[C:11](=[N:12][CH:13]=2)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]3[NH2:15])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: COc1ccc(CCN)cc1OC
Reactant: Nc1nc(N)c2nc(CBr)cnc2n1
Agent: Br
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)N(C)C
Product: COc1ccc(CCNCc2cnc3nc(N)nc(N)c3n2)cc1OC
Temperature: 50 °C
Reaction time: 8 h
Yield: 6.5 %

Procedure:
To a solution of 6-bromomethyl-2,4-pteridinediamine hydrobromide (55 mg, 0.1638 mmol) in anhydrous N,N dimethylacetamide was added 2-(3,4-dimethoxyphenyl) ethylamine hydrochloride (55 ul, 0.32 mmol). The reaction mixture was stirred at 50° C. overnight. The crude product was poured into saturated bicarbonate solution. The resulted precipitate was collected and purified by preparative HPLC. 3.8 mg product was obtained. Yield: 19.6%; 1H NMR (500 MHz, DMSO-d6): δ 2.75943–2.79062 (t, J=7.37 Hz, 2H), 2.92110–2.95356 (t, J=7.365 Hz, 2H), 3.72197(s, 3H), 3.75135(s, 3H), 4.54559(s, 2H), 6.74441–6.77765 (dd, J1=8.26 Hz, J2=1.955 Hz, 1H), 6.84994 (s, 1H), 6.88406–6.90401 (dd, J1=8.195 Hz, J2=1.735 Hz, 1H); 8.87126(s, 1H); ESI-MS: m/z 356 (M++1)
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:18]2[CH:23]=[CH:22][C:21]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[C:13](Br)[CH:12]=2)[N:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[N:37]1[CH:42]=[CH:41][CH:40]=[C:39](B(O)O)[CH:38]=1.[Al]>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.COCCOC.O.C(O)C>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:18]2[CH:23]=[CH:22][C:21]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:39]3[CH:38]=[N:37][CH:42]=[CH:41][CH:40]=3)[CH:12]=2)[N:3]=1
Reactant: CS(=O)(=O)Oc1ccc(C2(c3cccc(Br)c3)N=C(N)c3ccccc32)cc1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [Al]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)Oc1ccc(C2(c3cccc(-c4cccnc4)c3)N=C(N)c3ccccc32)cc1
Yield: 63.8 %

Procedure:
To methanesulfonic acid 4-[3-amino-1-(3-bromo-phenyl)-1H-isoindol-1-yl]-phenyl ester (Scheme #6, U) (100 mg, 0.18 mmol)) was added potassium phosphate (112 mg, 0.53 mmol), 3-pyridyl boronic acid (33 mg, 0.26 mmol), dichlorobis(triphenylphosphine)palladium(II) (12 mg, 0.018 mmol) and 1,2-dimethoxyethane: water:ethanol (7:3:2, 3.0 mL). The reaction was heated in an aluminium block at 100° C. for 15 minutes. The mixture was filtered through a syringe filter and the filtrate was removed of solvent under reduced pressure. The resulting residue was dissolved in acetonitrile/water with trifluoroacetic acid, (75:25:0.1, 4 mL), and purified using RP-HPLC AG2 (tR=10.6 min). The combined purified fractions were lyophilized to give the title compound (52.3 mg, 59%). 1H NMR (500 MHz, DMSO-d6/TFA-d) δ 9.23 (d, J=1.6 Hz, 1 H), 8.96 (d, J=5.6 Hz, 1 H), 8.87 (d, J=8.2 Hz, 1 H), 8.37 (d, J=7.8 Hz, 1 H), 8.17 (dd, J=8.2, 5.7 Hz, 1 H), 8.02 (d, J=7.9 Hz, 1 H), 7.90 (dd, J=18.6, 7.8 Hz, 2 H), 7.82 (s, 1 H), 7.77 (t, J=7.6 Hz, 1 H), 7.67 (t, J=7.8 Hz, 1 H), 7.56 (d, J=8.2 Hz, 1 H), 7.41 (s, 4 H), 3.39 (s, 3 H); MS (ES+) m/z 456 [M+1]+; tR=1.42 min.
Reaction SMILES: B(Br)(Br)Br.C[O:6][CH2:7][C:8]1[CH:21]=[C:11]2[N:12]=[CH:13][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:15][N:10]2[N:9]=1.O>ClCCl>[OH:6][CH2:7][C:8]1[CH:21]=[C:11]2[N:12]=[CH:13][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:15][N:10]2[N:9]=1
Reactant: CCOC(=O)c1cnc2cc(COC)nn2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cnc2cc(CO)nn2c1
Temperature: 0 °C
Yield: 101 %

Procedure:
Ethyl 2-formyl-3-oxopropionate (775 mg) was added to a solution of the thus obtained 5-methoxymethyl-2H-pyrazol-3-ylamine (684 mg) in ethanol (50 ml), and stirred overnight. The reaction solution was concentrated under reduced pressure, and a saturated sodium bicarbonate solution was added to the residue which were then extracted with ethyl acetate. The organic phase was washed with a saturated saline solution and dried over sodium sulfate anhydrous. The resulting product was concentrated under reduced pressure, and the residue was purified by column chromatography (eluting solvent; n-hexane:ethyl acetate 4:1) to give ethyl 2-methoxymethylpyrazolo[1,5-a]pyrimidine-6-carboxylate (878 mg, Y.:69%). 1 M Boron tribromide solution in dichloromethane (0.51 ml) was added dropwise at −70° C. to a solution of the thus obtained ethyl 2-methoxymethylpyrazolo[1,5-a]pyrimidine-6-carboxylate (20 mg) in dichloromethane (2 ml). The temperature of the mixture under stirring was increased from −70° C. to −50° C. over 4.5 hours and then increased from −50° C. to room temperature over 2 hours. The reaction mixture was cooled to 0° C., water was added to the reaction mixture which was then extracted with ethyl acetate, and the extract was dried over sodium sulfate anhydrous. The resulting product was concentrated under reduced pressure to give ethyl 2-hydroxymethylpyrazolo[1,5-a]pyrimidine-6-carboxylate (19 mg, Y.:quant.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][NH2:19].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:19][CH2:18][C:17]3[CH:20]=[CH:21][CH:22]=[C:15]([Cl:14])[CH:16]=3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: NCc1cccc(Cl)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=c1[nH]nc(Cl)c2cc(NCc3cccc(Cl)c3)ccc12
Yield: 12.2 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (100 mg, 0.385 mmol), 3-chlorobenzylamine (0.052 mL, 0.424 mmol), Pd2(dba)3 (35 mg, 0.0385 mmol), rac-BINAP (75 mg, 0.120 mmol) and NaOt-Bu (111 mg, 1.155 mmol) in DMA (6 mL) was heated at 80° C. for 1 h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-(3-chloro-benzylamino)-2H-phthalazin-1-one (15 mg) as a white solid, 1H (400 MHz, CDCl3) δ: 4.23 (s, 2H), 6.69 (d, 1H), 6.88 (dd, 1H), 7.05 (m, 3H), 7.19 (s, 1H), 7.88 (d, 1H), 11.45 (s, 1H) ppm. m/z (M+1) 320.00.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:1]([O:5][C:6]([C:8]1([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][Br:20])=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C2(C(=O)OC(C)(C)C)CCCC2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)C1(c2ccc(CBr)cc2)CCCC1
Yield: 111.3 %

Procedure:
To a solution of 1-(4-methylphenyl)cyclopentane carboxylic acid t butyl ester (2.00 g, 7.68 mmol) in CCl4 (80 mL) was added N-bromosuccinimide (1.37 g, 7.68 mmol) and benzoyl peroxide (0.050 g). This mixture was brought to reflux by heating, and maintained at reflux for 2 hours using a sun lamp (250 W). Additional N-bromosuccinimide (0.34 g, 1.9 mmol) was added, and after 20 minutes the solution was concentrated to 40 mL. The white precipitate was removed by filtration. The filtrate was concentrated to give 1-(4-bromomethylphenyl)cyclopentane carboxylic acid t butyl ester (2.9 g, 100%) as a yellow oil which was used without additional purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:26]([O:27][CH3:28])=[CH:25][C:6]2[NH:7][C:8]([S:10][C:11]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=3[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[N:9][C:5]=2[CH:4]=1.ClC1C=CC=C(C(OO)=[O:37])C=1>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:26]([O:27][CH3:28])=[CH:25][C:6]2[NH:7][C:8]([S:10]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=3[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:37])=[N:9][C:5]=2[CH:4]=1
Reactant: COc1ccc(-c2ccccn2)c(Sc2nc3cc(OC)c(OC)cc3[nH]2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccccn2)c(S(=O)c2nc3cc(OC)c(OC)cc3[nH]2)c1
Reaction time: 1 h

Procedure:
The product of step (c) above (370 mg) was dissolved in ethyl acetate (90 ml) and cooled to -10°. To the stirred solution was added a solution of m-chloroperbenzoic acid (191 mg of 85%) in ethyl acetate (10 ml). After stirring for 1 hour the solution was washed with sodium bicarbonate solution, sodium metabisulphite solution, water and brine then dried and evaporated. The residue was flash chromatographed to afford the title compound as a buff solid, mp 208°-210°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=2)[C:12]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])=[CH:11]1)([CH3:4])([CH3:3])[CH3:2].[CH3:27][Si](C)(C)[N-][Si](C)(C)C.[K+].IC>O1CCCC1>[C:1]([O:5][C:6](=[O:26])[N:7]([CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=2)[C:12]([C:20](=[O:25])[C:21]([F:22])([F:23])[F:24])=[CH:11]1)[CH3:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CN(CCn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21)C(=O)OC(C)(C)C
Reaction time: 0.33 h

Procedure:
To a solution of 14.1 g (36.1 mmol) {2-[6-chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-ethyl}-carbamic acid tert-butyl ester in 360 ml dry tetrahydrofuran were slowly added 44 ml (40 mmol) of a 0.91 M solution of potassium hexamethyldisilazide in tetrahydrofuran at −78° C. After stirring for 20 min. were added 2.5 ml (40 mmol) iodomethane at −78° C. Stirring was continued for 15 min. at −78° C. The cooling bath was removed and the mixture was stirred for another 3 h at room temperature. Quenching with water was followed by evaporation of the solvent in a rotary evaporator. The residue was diluted with a mixture of 200 ml water and 100 ml of a saturated aqueous solution of ammonium chloride. After extraction with three 250-ml portions of tert-butyl methyl ether the combined organic extracts were washed with 200 ml of an ice-cold 0.2 M aqueous solution of hydrochloric acid and 100 ml brine, dried over sodium sulfate and concentrated in vacuo to give 14.9 g of the crude product as a brown oil.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:44])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][S:14]([N:17]2[CH2:42][CH2:41][C:20]3([N:24]=[C:23]([C:25]4[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([O:35][CH2:36][CH2:37][CH:38]=[CH2:39])[CH:26]=4)[NH:22][C:21]3=[O:40])[CH2:19][CH2:18]2)(=[O:16])=[O:15])=[C:8]([CH3:43])[CH:7]=1>CO>[CH2:36]([O:35][C:27]1[CH:26]=[C:25]([C:23]2[NH:22][C:21](=[O:40])[C:20]3([CH2:41][CH2:42][N:17]([S:14]([CH2:13][CH2:12][C:9]4[CH:10]=[CH:11][C:6]([C:5]([OH:44])=[O:4])=[CH:7][C:8]=4[CH3:43])(=[O:16])=[O:15])[CH2:18][CH2:19]3)[N:24]=2)[CH:30]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:28]=1)[CH2:37][CH:38]=[CH2:39]
Reactant: C=CCCOc1cc(C2=NC3(CCN(S(=O)(=O)CCc4ccc(C(=O)OC)cc4C)CC3)C(=O)N2)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCCOc1cc(C2=NC3(CCN(S(=O)(=O)CCc4ccc(C(=O)O)cc4C)CC3)C(=O)N2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
A 5 N aqueous sodium hydroxide solution (6.6 ml, 33 mmol) was added to a solution of 4-{2-[2-(3-but-3-enyloxy-5-trifluoromethyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-3-methyl-benzoic acid methyl ester (2.10 g) in methanol (22 ml), and the mixture was stirred at room temperature for two hours. The reaction solution was cooled and then quenched with 2 N hydrochloric acid (25 ml), followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give 4-{2-[2-(3-but-3-enyloxy-5-trifluoromethyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-3-methyl-benzoic acid (1.78 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2O[C:16]([CH3:19])=[N:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>[Cl-].[Mg+2].[Cl-]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:27]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:16]([CH3:19])=[N:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nnc(C2CCN(C(=O)OC(C)(C)C)CC2)o1
Reactant: NCc1ccccc1
Agent: [Cl-]
Agent: [Mg+2]
Product: Cc1nnc(C2CCN(C(=O)OC(C)(C)C)CC2)n1Cc1ccccc1
Temperature: 150 °C
Yield: 70.4 %

Procedure:
4-(5-Methyl-[1,3,4]oxadiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (5 g, 18.7 mmol) (see reference WO 0039125), benzylamine (2.5 ml, 22 mmol) and magnesium chloride (100 mg) were heated at 150° C. for 1 hour, a further quantity of benzylamine (2.5 ml, 22 mmol) was added and the mixture was heated at 150° C. for 4 hours. The reaction mixture was cooled to room temperature and the reaction mixture was purified by chromatography on silica gel using methanol in dichloromethane as eluant (3:97). The material isolated was triturated with diethyl ether to give the title compound as a white solid (4.69 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].[N:20]1([C:26]2[S:27][C:28]([C:31]#[N:32])=[CH:29][N:30]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([N:23]1[CH2:24][CH2:25][N:20]([C:26]2[S:27][C:28]([C:31]#[N:32])=[CH:29][N:30]=2)[CH2:21][CH2:22]1)=[O:12])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(OCC(F)(F)F)c(C(=O)O)c1
Reactant: N#Cc1cnc(N2CCNCC2)s1
Product: CS(=O)(=O)c1ccc(OCC(F)(F)F)c(C(=O)N2CCN(c3ncc(C#N)s3)CC2)c1
Yield: 57 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-(2,2,2-trifluoro-ethoxy)-benzoic acid (Example A3) and 2-piperazin-1-yl-thiazole-5-carbonitrile (Example 6(a)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a light brown crystalline solid (yield 57%). MS (m/e): 475.0 (M+H+, 100%), 492.3 (M+NH4+, 90%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH:9]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>CC#N>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:9]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: C1CNCCNC1
Solvent: CC#N
Product: Brc1cnc(N2CCCNCC2)nc1
Yield: 83.9 %

Procedure:
A solution of 5-Bromo-2-chloro-pyrimidine (1.0 g, 5.1 mmol), [1,4]Diazepane (1.0 g, 10.2 mmol) in CH3CN (5.0 mL) was stirred at 50° C. for 3 hrs. Filter of the solid and the solution was washed with brine, and concentrated in vacuo to give the title product (1.1 g, 85%) as a brown solid. ESI MS m/z 258 (M+H+); 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 2H), 3.77 (m, 4H), 2.97 (q, J=10 Hz, 2H), 2.81 (q, J=15 Hz, 2H), 2.02 (s, 1H) 1.83 (qt, J=15 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH:9]1[CH2:15]C(O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[C:23]([NH:25][OH:26])=[NH:24].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH:9]1[C:15]1[O:26][N:25]=[C:23]([C:22]2[CH:27]=[CH:28][CH:29]=[C:20]([Cl:19])[CH:21]=2)[N:24]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: N=C(NO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCNC(=O)C1c1nc(-c2cccc(Cl)c2)no1
Temperature: 135 °C
Yield: 53.9 %

Procedure:
2-Carboxymethyl-3-oxo-piperazine-1-carboxylic acid tert-butyl ester (1.87 g, 7.25 mmol), 3-chloro-N-hydroxy-benzamidine (1.36 g, 7.98 mmol), HOBt (1.08 g, 7.98 mmol) and EDCl (1.53 g, 7.98 mmol) in DMF (20 mL) were stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water (3 times), saturated sodium bicarbonate (2 times) and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was dissolved in DMF (20 mL) and then heated at 135° C. for 4 hours. After cooling, the reaction mixture was diluted with ethyl acetate, washed with water (3 times) and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification was performed by flash chromatography on silica gel using hexanes:dichloromethane (1:1) to afford the titled compound (1.48 g, 52%, white foam solid). 1H NMR (CDCl3) δ (ppm): 8.08 (m, 1H), 7.97 (m, 1H), 7.46 (m, 2H), 6.35 (m, 1H), 5.04 (m, 1H), 4.31 (m, 1H), 3.68 (m,1H), 3.50 ( m, 2H), 3.27 (m, 2H), 1.35 (bs, 9H).