Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:13]=[C:12]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([S:8][C:9]1[N:13]=[C:12]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]([C:23]2[N:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncccn1
Reactant: c1ccc(CSc2n[nH]c(SCc3ccccc3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(CSc2nc(SCc3ccccc3)n(-c3ncccn3)n2)cc1
Temperature: 0 °C
Yield: 62.4 %

Procedure:
3,5-Bis(benzylthio)-1,2,4-triazole (50 g), 2-chloropyrimidine (18.3 g) and potassium carbonate (22.1 g) were heated in dimethylformamide (200 ml) at 100° C. for 12 hours. After addition to ice-water, the product was extracted into dichloromethane (twice). The dichloromethane solution was washed with water (3 times), dried over magnesium sulphate and run down, leaving 64.4 g of crude title. Recrystallisation from methanol gave 39 g of the desired product, mp 86°-88° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH2:10](OC(OCC)OCC)C>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[CH:10][NH:9][C:4]=2[CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: Nc1ccc(F)cc1N
Solvent: CCO
Product: Fc1ccc2nc[nH]c2c1
Temperature: 150 °C

Procedure:
To the solution of 4-fluoro-benzene-1,2-diamine (10 g, 79.4 mmol) and triethylorthoformate (117 mL, 793 mmol) was added few drop of ethanol and the reaction mixture was refluxed at 150° C. overnight. The reaction mixture was concentrated and the residue was directly taken to the next step. [M+H]=137.
Reaction SMILES: Cl[CH2:2][N:3]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)[C:4](Cl)=[O:5].[F:14][CH:15]([F:33])[O:16][C:17]1[CH:32]=[CH:31][C:20]([CH2:21][NH:22][C:23]([NH:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[S:24])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[F:28][C:27]([F:29])([F:30])[CH2:26][N:25]=[C:23]1[N:22]([CH2:21][C:20]2[CH:31]=[CH:32][C:17]([O:16][CH:15]([F:14])[F:33])=[CH:18][CH:19]=2)[C:4](=[O:5])[N:3]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[CH2:2][S:24]1
Reactant: Cc1ccc(N(CCl)C(=O)Cl)cc1
Reactant: FC(F)Oc1ccc(CNC(=S)NCC(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(N2CSC(=NCC(F)(F)F)N(Cc3ccc(OC(F)F)cc3)C2=O)cc1
Yield: 55 %

Procedure:
0.69 g of N-chloromethyl-N-(4-methylphenyl)carbamoyl chloride and 1.00 g of 1-(4-difluoromethoxybenzyl)-3-(2,2,2-trifluoroethyl)thiourea were dissolved in 30 ml of toluene, and the solution was heated under reflux for 4 hours. After the reaction, toluene was evaporated under reduced pressure. The resulting oily product was purified by column chromatography silica gel; developing solvent hexane/ethyl acetate (10:1)]to give 0.80 g of the captioned compound.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][C:10]=1[NH:20][C:21]([C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1)=[O:22])=O)(C)(C)C.Cl.[CH3:33][P:34]1(=[O:45])[O:39][CH2:38][C:37]2([CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:36][O:35]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C([O-])(O)=O.[Na+]>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][C:10]=1[NH:20][C:21](=[O:22])[C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:42]2[CH2:43][CH2:44][C:37]3([CH2:36][O:35][P:34]([CH3:33])(=[O:45])[O:39][CH2:38]3)[CH2:40][CH2:41]2)=[O:28])=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(C(=O)O)cc1
Reactant: CP1(=O)OCC2(CCNCC2)CO1
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CP1(=O)OCC2(CCN(C(=O)c3ccc(C(=O)Nc4cc(-c5cccs5)ccc4N)cc3)CC2)CO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-({[2-[(tert-Butoxycarbonyl)amino]-5-(2-thienyl)phenyl]amino}carbonyl)-benzoic acid (150 mg, 0.34 mmol), 3-methyl-2,4-dioxa-9-aza-3-phosphaspiro[5.5]undecane 3-oxide hydrochloride (99 mg, 0.41 mmol), EDC (131 mg, 0.68 mmol), HOBT (105 mg, 0.68 mmol), and DIEA (119 μL, 0.68 mmol) were combined in DMF (4 mL) and stirred at room temperature for 18 h. The solution was diluted with saturated NaHCO3 and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried (MgSO4), and evaporated. Purification of the crude by flash chromatography (0-10% MeOH/CH2Cl2) afforded the desired product as a yellow solid. The solid was dissolved in a mixture of CH2Cl2 (4 mL) and TFA (1 mL) and stirred at room temperature for 2 h. The solution was diluted with 1,2-DCE and evaporated. The crude was taken up in EtOAc, washed with saturated NaHCO3 and brine, dried (MgSO4), and evaporated. The residue was dissolved in a minimum amount of MeOH, diluted with EtOAc, concentrated to approximately half-volume, and filtered to isolate the desired product as a colorless solid. 1H NMR (DMSO-d6, 600 MHz) δ 9.80 (s, 1H), 8.04 (d, J=7.3 Hz, 2H), 7.50 (d, J=6.4 Hz, 2H), 7.45 (s, 1H), 7.33 (d, J=4.9 Hz, 1H), 7.28 (d, J=8.1 Hz, 1H), 7.22 (bs, 1H), 7.03 (t, J=3.9 Hz, 1H), 6.79 (d, J=8.3 Hz, 1H), 5.17 (s, 2H), 4.29-4.09 (m, 4H), 3.72-3.56 (m, 2H), 3.39-3.23 (m, 2H), 1.77-1.60 (m, 2H), 1.58-1.51 (m, 3H), 1.51-1.36 (m, 2H). MS: cal'd 526 (MH+), exp 526 (MH+).
Reaction SMILES: CN([CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:17])[NH:15][CH3:16])=[CH:9][CH:8]=1)=[CH2:6])C.C1(OC([Cl:27])=O)C=CC=CC=1>C(Cl)Cl>[Cl:27][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:17])[NH:15][CH3:16])=[CH:9][CH:8]=1)=[CH2:6]
Reactant: C=C(CN(C)C)c1ccc(NC(=O)NC)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Product: C=C(CCl)c1ccc(NC(=O)NC)cc1

Procedure:
To a solution of 13.85 g (0.06 Mol) N'-[4(1-dimethylaminomethyl-ethenyl)phenyl]-N-methyl urea in 180 ml absolute CH2Cl2 are added dropwise, at 20°-30°, within 20 minutes, 9.4 g (0.06 Mol) chloroformic acid phenyl ester in 50 ml absolute CH2Cl2.
Reaction SMILES: C([O:4][CH:5]1[CH2:28][N:27]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[C:8]2=[N:9][C:10]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)[N:12]=[C:7]2[CH:6]1[O:40]C(=O)C)(=O)C.[Li+].[OH-].Cl>C1COCC1.O>[OH:4][CH:5]1[CH2:28][N:27]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])[C:8]2=[N:9][C:10]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=3)[N:12]=[C:7]2[CH:6]1[OH:40]
Reactant: CCOC(=O)CCCCCCN1CC(OC(C)=O)C(OC(C)=O)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCCCCC(=O)O)CC(O)C3O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of rac-5-(7-ethoxy-7-oxoheptyl)-2,3-dip-tolyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine-7,8-diyl diacetate (step 6) (117 mg, 0.199 mmol) in THF (3 ml) and water (1 ml) was added LiOH (28.6 mg, 1.194 mmol). The mixture was stirred at RT for 18 h followed by heated at 60° C. for 1 h. After cooling to RT, the mixture was acidified to pH 4/5 with 2M HCl and extracted with EtOAc. The combined organic extracts were dried (sodium sulphate), filtered and concentrated in vacuo to afford a mixture of the title products;
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([S:14][C:15]1[S:16][C@@H:17]2[C@H:34]([C:35]([OH:38])([CH3:37])[CH3:36])[C:33](=[O:39])[N:18]2[C:19]=1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:21])[CH3:13]>C(Cl)Cl>[CH2:12]([S:14]([C:15]1[S:16][C@@H:17]2[C@H:34]([C:35]([OH:38])([CH3:36])[CH3:37])[C:33](=[O:39])[N:18]2[C:19]=1[C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=1)=[O:21])=[O:6])[CH3:13]
Reactant: CCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](C(C)(C)O)[C@H]2S1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCS(=O)C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](C(C)(C)O)[C@H]2S1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 85% m-chloroperoxybenzoic acid (112 mg, 0.55 mmol) in CH2Cl2 (2.5 ml) is added dropwise over 5 mins. to an ice-cold, stirring solution of p-nitrobenzyl (5R,6R)-2-ethylthio-6-(2-hydroxy-2-propyl)-pen-2-em-3-carboxylate (212 mg, 0.5 mmol) in CH2Cl2 (5 ml). The mixture is stirred for 1 hour at 0°, then treated with excess Amberlyst-21 resin and stirred 5 minutes longer. The mixture is filtered and the filtrate is evaporated under vacuum to provide the crude product.
Reaction SMILES: C(S[C:4]1[NH:5][C:6](=[O:13])[C:7]2[CH2:12][S:11][CH2:10][C:8]=2[N:9]=1)C.Cl.CC(O)=[O:17]>O>[NH:9]1[C:8]2[CH2:10][S:11][CH2:12][C:7]=2[C:6](=[O:13])[NH:5][C:4]1=[O:17]
Reactant: CC(=O)O
Reactant: CCSc1nc2c(c(=O)[nH]1)CSC2
Agent: Cl
Solvent: O
Product: O=c1[nH]c2c(c(=O)[nH]1)CSC2
Yield: 80 %

Procedure:
To the suspension of 2-(ethylthio)thieno[3,4-d]pyrimidin-4-(3H, 5H, 7H)-one (2.88 g, 13.45 mmol) in water (20 mL) was added 2.0 mL of cone. HCl and 4.0 mL of AcOH. The reaction was heated at reflux overnight then cooled and the solid collected by filtration, washed with water and methanol, evaporated and dried to obtain a white solid thieno[3,4-d]pyrimidine-2,4-(1H, 3H, 5H, 7H)-dione (1.80 g, 80%). Without further purification, the crude product was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH2:11][C:12]#[N:13].[CH2:14](Br)[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16]>C(#N)C>[Cl:1][C:2]1[N:10]=[C:5]2[N:6]([CH2:14][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:16])[CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH2:11][C:12]#[N:13]
Reactant: O=C(CBr)c1ccccc1
Reactant: N#CCc1c(Cl)[nH]c2ncccc12
Solvent: CC#N
Product: N#CCc1c2cccn(CC(=O)c3ccccc3)c-2nc1Cl
Yield: 9 %

Procedure:
A solution of 0,66 g (3,4 mmol) 2-chloro-3-cyanomethyl-pyrrolo[2,3-b]pyridine, and 0,65 g (3,8 mmol) phenacyl bromide in 40 ml acetonitrile was refluxed for 20 h. The mixture was allowed to cool and the precipitated product was filtred off and recrystallized from acetonitrile. Chromatography on silica gel eluting with ethyl acetate gave the desired product (0,094g, 9%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([OH:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH:19]([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([O:17][CH:19]([CH3:21])[CH3:20])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Oc1cc(OCc2ccccc2)ccc1C=O
Temperature: 25 °C

Procedure:
A mixture of 4-(benzyloxy)-2-hydroxybenzaldehyde (1 g, 4.38 mol), 2-iodopropane (1.2 eq.) and potassium carbonate (2.5 eq.) in acetone (40 mL) was refluxed overnight. The reaction was cooled to room temperature and filtered through a celite plug, and concentrated to dryness. The crude material was purified by flash column chromatography with ethyl acetate and hexanes to provide 4-(benzyloxy)-2-isopropoxybenzaldehyde (698).
Reaction SMILES: [Br-:1].[CH2:2]([N+:18]([CH2:21]C1C=CC=CC=1)([CH3:20])[CH3:19])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[Cl-]>>[Br-:1].[CH2:2]([N+:18]([CH3:21])([CH3:19])[CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCCC[N+](C)(C)Cc1ccccc1
Agent: [Br-]
Agent: [Cl-]
Product: CCCCCCCCCCCCCCCC[N+](C)(C)C

Procedure:
cetyl benzyl dimethyl ammonium bromide or chloride.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:9])=[CH:5][C:6]=1[CH2:7]Br.C([O-])([O-])=O.[K+].[K+].[C:16]([O:20][C:21](=[O:24])[NH:22][NH2:23])([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C.C(OCC)(=O)C>[C:16]([O:20][C:21]([NH:22][NH:23][CH2:7][C:6]1[CH:5]=[C:4]([CH3:9])[O:3][C:2]=1[CH3:1])=[O:24])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NN
Reactant: Cc1cc(CBr)c(C)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(CNNC(=O)OC(C)(C)C)c(C)o1
Temperature: 65 °C

Procedure:
To a stirred solution of 2,5-dimethyl-3-bromomethylfuran (5.95 mmol theor.) in DMF (30 mL) was added K2CO3 (1.64 g, 11.9 mmol) and tert-butylcarbazate (3.1 g, 23.8 mmol). The reaction was heated to 65° C. for 1 h. The reaction was cooled to room temperature, diluted with ethyl acetate and the layers separated. The organic layer was washed with saturated aqueous NH4Cl, water and brine and dried over Na2SO4. The mixture was filtered, concentrated and distilled on a Kuglerohr apparatus at 100° C. and 35 mTorr to remove the excess DMF and tert-butylcarbazate. This material was then purified using silica gel column chromatography (hexanes—4:1 hexanes:ethyl acetate as eluant) to afford the title compound as a dark yellow oil (670 mg, 2.79 mmol, 47% for the two steps). 1H NMR (300 MHz, DMSO-d6): δ 8.11 (br s, 1H); 5.91 (s, 1H); 4.38 (br s, 1H); 3.54 (s, 2H); 2.16 (s, 3H); 2.14 (s, 3H); 1.39 (s, 9H).
Reaction SMILES: CC[N:3]([CH:7]([CH3:9])C)[CH:4](C)C.[F:10][CH:11]([F:42])[O:12][CH2:13][C@@H:14]([O:16][C:17]1[CH:18]=[C:19]([O:32][C:33]2[N:34]=[CH:35][C:36]([C:39]([OH:41])=O)=[N:37][CH:38]=2)[CH:20]=[C:21]([C:23]([NH:25][C:26]2[CH:30]=[CH:29][N:28]([CH3:31])[N:27]=2)=[O:24])[CH:22]=1)[CH3:15].Cl.N1CCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[N:3]1([C:39]([C:36]2[N:37]=[CH:38][C:33]([O:32][C:19]3[CH:20]=[C:21]([CH:22]=[C:17]([O:16][C@@H:14]([CH3:15])[CH2:13][O:12][CH:11]([F:42])[F:10])[CH:18]=3)[C:23]([NH:25][C:26]3[CH:30]=[CH:29][N:28]([CH3:31])[N:27]=3)=[O:24])=[N:34][CH:35]=2)=[O:41])[CH2:4][CH2:9][CH2:7]1
Reactant: C[C@@H](COC(F)F)Oc1cc(Oc2cnc(C(=O)O)cn2)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: CCN(C(C)C)C(C)C
Agent: C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](COC(F)F)Oc1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.5 %

Procedure:
DIPEA (0.41 mL, 2.33 mmol) was added to a mixture of 5-[(3-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenyl)oxy]pyrazine-2-carboxylic acid (0.27 g, 0.58 mmol), azetidine hydrochloride (109 mg, 1.17 mmol) and HATU (466 mg, 1.22 mmol) in DMF (5 mL) and stirred at RT for 24 hours. Ethyl acetate (40 mL) was added and the organics washed with water (2×30 mL), brine (30 mL), dried (MgSO4), filtered and concentrated in vacuo to give a yellow oil. The residue was chromatographed on silica, eluting with 0-5% methanol in ethyl acetate, to give the desired compound (124 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[N:8]=[C:7]([NH:17][S:18](=[O:30])(=[O:29])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)[C:6]=1[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH3:39].[H-].[Na+].[F:42][C:43]([F:52])([F:51])[C:44]1[CH:45]=[CH:46][C:47](Cl)=[N:48][CH:49]=1>C1COCC1>[F:42][C:43]([F:52])([F:51])[C:44]1[CH:45]=[CH:46][C:47]([O:1][CH2:2][CH2:3][O:4][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[N:8]=[C:7]([NH:17][S:18](=[O:30])(=[O:29])[NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:24][CH:25]=3)[C:6]=2[O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:38][CH3:39])=[N:48][CH:49]=1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)Nc2ccc(C(C)C)cc2)nc(-c2ccncc2)nc1OCCO
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1Oc1c(NS(=O)(=O)Nc2ccc(C(C)C)cc2)nc(-c2ccncc2)nc1OCCOc1ccc(C(F)(F)F)cn1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 64.9 %

Procedure:
4-i-Propyl-phenyl sulfamic acid-[6-(2-hydroxy-ethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidin-4-yl]-amide (50 mg, Example 3) was dissolved in THF (8 ml). Sodium hydride (12 mg, 60% dispersion in mineral oil) was added and stirring continued for 10 min. 5-Trifluoromethyl-2-chloro-pyridine (28 mg) was added and the mixture was heated to 60° C. for 180 min. The solvents were evaporated, water (12 ml) and a 10% solution of citric acid was added until the pH was 3. The precipitate was filtered off, washed with water and purified by recrystallization with diethylether to give 4-i-propyl-phenyl sulfamic acid-[6-[2-(5-trifluoromethyl-pyridin-2-yloxy)-ethoxy]-5-(o-methoxy-phenoxy)-2-(4-pyridyl)-pyrimidin-4-yl]-amide (41 mg). tR=5.81 min, (LC); [M+H]+=697.17 (ES+).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].[Cl-].[NH4+]>ClCCl.O>[CH3:19][S:20]([O:9][CH2:8][C:5]1[CH:6]=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:22])=[O:21]
Reactant: OCc1ccc(Br)nc1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCc1ccc(Br)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(6-Bromopyridin-3-yl)methanol (2.45 g, 13.0 mmol) was dissolved in dichloromethane (20 mL), cooled to 0° C. and treated successively with N,N-diisopropylethylamine (2.73 mL, 15.6 mmol, 1.2 equiv) and methanesulfonyl chloride (1.17 mL, 15.0 mmol, 1.15 equiv). After stirring for 30 minutes, the mixture was treated with ammonium chloride (10 mL, aqueous saturated) and warmed to ambient temperature. The mixture was poured into water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[C:4]([O:20][CH3:21])[CH:3]=1.[F:22][C:23]([F:38])([F:37])[C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[N:32]=1)[C:27](O)=[O:28]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH2:15][C:16]([F:18])([F:17])[F:19])[C:27](=[O:28])[C:26]2[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[N:32]=[C:24]([C:23]([F:38])([F:22])[F:37])[CH:25]=2)=[C:4]([O:20][CH3:21])[CH:3]=1
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: COc1cc(F)ccc1-c1ccncc1NCC(F)(F)F
Product: COc1cc(F)ccc1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-(2,2,2-trifluoro-ethyl)-amine (example 133, intermediate a) and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.) after a reaction time of 96 hours. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). Light brown solid (44%). MS (ESI): m/z=542.09 [M+H]+.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:17]([OH:19])=O)=[N:10][C:11]=2[O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]([CH2:28][CH3:29])([CH2:26][CH3:27])[C:22]([NH:24][CH3:25])=[O:23]>>[CH2:26]([C:21]([NH:20][C:17]([C:9]1[CH:8]=[CH:7][C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[C:11]([O:12][CH2:13][CH:14]2[CH2:15][CH2:16]2)[N:10]=1)=[O:19])([C:22](=[O:23])[NH:24][CH3:25])[CH2:28][CH3:29])[CH3:27]
Reactant: CCC(N)(CC)C(=O)NC
Reactant: O=C(O)c1ccc(C2CCCC2)c(OCC2CC2)n1
Product: CCC(CC)(NC(=O)c1ccc(C2CCCC2)c(OCC2CC2)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 39 b) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70 b) as starting materials, MS (EI): m/e=388.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:16][O:17][C:18]2[CH:27]=[CH:26][C:25]3[CH2:24][CH2:23][C:22]([CH3:29])([CH3:28])[CH2:21][C:20]=3[CH:19]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9]C(C)(C)C)=[O:8].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH2:16][O:17][C:18]2[CH:27]=[CH:26][C:25]3[CH2:24][CH2:23][C:22]([CH3:29])([CH3:28])[CH2:21][C:20]=3[CH:19]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([OH:9])=[O:8]
Reactant: CC1(C)CCc2ccc(OCc3cc(F)c(C(=O)OC(C)(C)C)cc3Cl)cc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CCc2ccc(OCc3cc(F)c(C(=O)O)cc3Cl)cc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 5-chloro-4-((7,7-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)methyl)-2-fluorobenzoate (220 mg, 0.53 mmol) in DCM (5 mL) was added trifluoroactic acid (5 mL). After stirred at room temperature for 3 h, the reaction mixture was concentrated under reduced pressure and the residue was used in next step without further purification (0.22 g, crude). LCMS (ESI) m/z: 361.0 [M−H]+.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH3:5].[H-].[Na+].[I:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1>CN(C=O)C.[Cl-].[Na+].O>[I:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]([CH2:2][CH2:3][O:4][CH3:5])[C:16]2[N:17]=[CH:18][CH:19]=[CH:20][N:21]=2)=[CH:13][CH:14]=1
Reactant: Ic1ccc(Nc2ncccn2)cc1
Reactant: COCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCN(c1ccc(I)cc1)c1ncccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere, 2-bromoethylmethyl ether (0.14 ml) and sodium hydride (48 mg) were added to a solution of N-(4-iodophenyl)pyrimidin-2-amine (300 mg) in anhydrous DMF (1 ml), and the resulting mixture was stirred at room temperature overnight. Saturated brine was added to the reaction solution and the resulting mixture was extracted with chloroform, followed by drying the organic layer over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent:hexane/chloroform=1/10) to obtain N-(4-iodophenyl)-N-(2-methoxyethyl)pyrimidin-2-amine (233 mg). NMR (H1, CDCl3): δ 3.32 (3H, s), 3.63 (2H, t, J=5.9 Hz), 4.14 (2H, t, J=5.9 Hz), 6.59 (1H, t, J=4.9 Hz), 7.09-7.13 (2H, m), 7.70-7.73 (2H, m), 8.32 (2H, d, J=4.9 Hz)
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=4[Cl:25])=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1ccccc1Cl
Yield: 14.7 %

Procedure:
As described in Example 9, 0.471 g (1.5 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine is reacted with 0.315 g (1.8 mmol) of 2-chlorobenzoyl chloride in dichloromethane. The product is chromatographed on thick layer silica gel plates with hexane-ethyl acetate (1:1) as solvent to give a solid. Recrystallization from hexane-dichloromethane gives 100 mg of crystals, m.p. 110°-115° C. Anal. Calc'd for C28H21ClN2O2 1/2 H2O: C,72.8; H,4.8; N,6.1; Cl,7.7. Found: C,72.6; H,4.5; N,5.8; Cl,8.7.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28](O)[CH:29]=2)[CH:24]=[CH:23][N:22]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:28]2[CH:29]=[C:30]3[C:25]([CH:24]=[CH:23][N:22]=[CH:21]3)=[CH:26][CH:27]=2)[CH2:10][C@H:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc2ccncc2c1
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)[C@@H]1C[C@H](Oc2ccc3ccncc3c2)CN1C(=O)OC(C)(C)C

Procedure:
The title compound was synthesised from (2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid di-tert-butyl ester (CAS Reg. No. 170850-75-6) and isoquinolin-7-ol using the same method as preparation 11 and gave the title compound as an oil in 15% yield.