Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=3)[CH:17]=[C:16]([C:31]#[C:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:15]=2)=[CH:9][C:8]=1[CH3:39])C.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C(O)C>[CH3:39][C:8]1[CH:9]=[C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=3)[CH:17]=[C:16]([C:31]#[C:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:15]=2)[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:40])=[O:3]
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccccc3)cc(Oc3ccc(C(F)(F)F)cn3)c2)cc1C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(Sc2cc(C#Cc3ccccc3)cc(Oc3ccc(C(F)(F)F)cn3)c2)ccc1OCC(=O)O
Reaction time: 0.5 h

Procedure:
{2-Methyl-4-[3-phenylethynyl-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (150 mg; 0.266 mmol) was dissolved in THF (2 mL) and ethanol (4 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1/2 h. acidified with 5% aqueous citric acid and extracted with ethyl acetate, dried and evaporated to dryness. Yield: 100 mg (75%). HPLC-MS: m/z: 535.7 (M)+; Rt: 2.78 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23](O)=[O:24].[CH3:43][N:44]1[CH2:49][CH2:48][N:47]([CH2:50][CH:51]2[CH2:56][CH2:55][CH2:54][CH2:53][NH:52]2)[CH2:46][CH2:45]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([N:52]1[CH2:53][CH2:54][CH2:55][CH2:56][CH:51]1[CH2:50][N:47]1[CH2:46][CH2:45][N:44]([CH3:43])[CH2:49][CH2:48]1)=[O:24]
Reactant: CN1CCN(CC2CCCCN2)CC1
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Product: CN1CCN(CC2CCCCN2C(=O)CCC(Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)c2nc3cc(Cl)ccc3[nH]2)CC1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and 2-(4-methyl-piperazin-1-ylmethyl)-piperidine with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[C:5]1([Mg]Br)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C:14]1=[O:22]>C1COCC1>[C:5]1([C:14]2([OH:22])[CH2:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:13]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C1Cc2ccccc2C1
Reactant: Br[Mg]c1ccccc1
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: OC1(c2ccccc2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of anhydrous cerium chloride (40.60 g, 164.7 mmol) in THF (270 mL) was stirred at room temperature for 2 hours under nitrogen. Phenylmagnesium bromide (46.5 mL of 3.0 M solution in diethyl ether, 139.5 mmol) was added at 0° C. and stirred for 3.5 h. A solution of 2-indanone (14.21 g, 107.7 mmol) in THF (20 mL) was added at the same temperature. After stirring at 0° C. for 3 hours, the mixture was allowed to warm to room temperature and kept at ambient temperature for 12 h. It was then treated with 5% aqueous hydrochloric solution. The solution was extracted with diethyl ether (4*200 mL). All etheral layers were combined, washed with water (100 mL), dried over anhydrous magnesium sulphate and concentrated to give the crude product. Kugelrohr distillation (150° C./0.25 mm Hg yielded 18.58 g (82%) of 2-phenyl-2-indanol in solid form (mp 54° C.). 1H-N.M.R. (CDCl3) d 2.24 (br s, 1H), d 3.20 (d, J=16.2 Hz, 2H), d 3.43 (d, J=16.2 Hz, 2H), d 7.18-7.40 (m, 7H), d 7.51(br d, J=7.1 Hz, 2H)
Reaction SMILES: [CH3:1][P:2]([O:6]C)(=O)OC.[C:8]([OH:13])(=[O:12])[C:9]([CH3:11])=[CH2:10].[CH3:14]O>>[CH3:14][P:2]([CH3:1])([CH2:10][CH:9]([CH3:11])[C:8]([OH:13])=[O:12])=[O:6]
Reactant: C=C(C)C(=O)O
Reactant: CO
Reactant: COP(C)(=O)OC
Product: CC(CP(C)(C)=O)C(=O)O
Yield: 41.3 %

Procedure:
108 g of dimethyl methanephosphonate are added dropwise at 70° C. to a solution of 86 g of methacrylic acid and 32 g of methanol in the course of 30 minutes. After a reaction time of 3 hours the reaction mixture is worked up by vacuum distillation. 59 g of 3-(dimethylphosphinyl)-2-methylpropionic acid are obtained with a 91.1% purity, which corresponds to a theoretical yield of 29.5%.
Reaction SMILES: C([O:4][CH:5]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=1)[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15](Br)[C:16]([O:18]C)=O)=[CH:10][CH:9]=1)(=O)C.[NH2:28][C:29](N)=[S:30].C([O-])(=[O:34])C.[Na+].Cl>C(O)C>[OH:4][CH:5]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=1)[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH:15]2[S:30][C:29](=[O:34])[NH:28][C:16]2=[O:18])=[CH:12][CH:13]=1
Reactant: COC(=O)C(Br)Cc1ccc(OCC(OC(C)=O)c2cccc(C)n2)cc1
Reactant: NC(N)=S
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(C(O)COc2ccc(CC3SC(=O)NC3=O)cc2)n1

Procedure:
A mixture of methyl 3-{4-[2-acetoxy-2-(6-methyl-2-pyridyl)ethoxy]phenyl}-2-bromopropionate (3.2 g), thiourea (558 mg), sodium acetate (599 mg) and ethanol (30 ml) was heated under reflux for 4 hours, and then 6N-hydrochloric acid (30 ml) was added to the mixture, followed by heating under reflux for 16 hours. After neutralization with aqueous sodium hydrogencarbonate solution, the reaction mixture is extracted with chloroform, and the chloroform layer was washed with water and dried (MgSO4). After the solvent was distilled off, the residue was chromatographed on a silica-gel (100 g) column and elution was effected with benzene-acetone (10:1, V/V) to give 5-{4-[2-hydroxy-2-(6-methyl-2-pyridyl)ethoxy]benzyl}-2,4-thiazolidinedione in the form of crystals. Yield of 0.95 g. Recrystallization from ethyl acetate-hexane produced colorless prisms. m.p. 154°-155° C.
Reaction SMILES: [OH:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH3:12])[C:6]=2[CH:5]=[C:4]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH:3]=1.Cl[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[F:29])[O:22][CH2:21][CH2:20]1>>[F:29][C:27]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:28]=1[CH:19]([O:1][C:2]1[C:10]3[N:9]=[C:8]([CH3:11])[N:7]([CH3:12])[C:6]=3[CH:5]=[C:4]([C:13]([N:15]([CH3:16])[CH3:17])=[O:14])[CH:3]=1)[CH2:20][CH2:21][O:22]2
Reactant: Fc1cccc2c1C(Cl)CCO2
Reactant: Cc1nc2c(O)cc(C(=O)N(C)C)cc2n1C
Product: Cc1nc2c(OC3CCOc4cccc(F)c43)cc(C(=O)N(C)C)cc2n1C
Yield: 35 %

Procedure:
The title compound was prepared as a pale brown solid in 35% yield (69 mg) from 4-hydroxy-N,N,1,2-tetramethyl-1H-benzimidazole-6-carboxamide (120 mg, 0.51 mmol, WO 2004054984) and 4-chloro-5-fluorochromane (100 mg, 0.54 mmol, STEP 2) by the same manner in STEP 1 of Example 1:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([S:9](Cl)(=[O:11])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Br.[Br:16][CH2:17][CH2:18][CH2:19][NH2:20].C(=O)([O-])O.[Na+]>CC(C)=O.O>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([S:9]([NH:20][CH2:19][CH2:18][CH2:17][Br:16])(=[O:11])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: NCCCBr
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)Nc1ccc(S(=O)(=O)NCCCBr)cc1
Temperature: 2.5 °C
Yield: 166.7 %

Procedure:
To a stirred solution of N-acetylsulfanilyl chloride (57.15 g, 0.244 mol) in acetone (500 mL) and H2O (187.5 mL) at 0° C. was added 3-bromopropylamine hydrobromide (25.0 g, 0.114 mol). When a clear solution was obtained, a solution of sodium hydrogencarbonate (44.15 g, 0.526 mol) in H2O (550 mL) was added dropwise, maintaining the internal temperature at 0-5° C. When the addition was completed, the reaction mixture was heated at 50° C. for 5 h, then cooled to room temperature and poured into ice H2O with stirring. After stirring at 5° C. for 4 h, the suspension was filtered and the filter cake was washed with H2O and dried in vacuo to give 34.6 g (90%). An additional reaction was performed to give an additional 63.7 g of similar material.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:14]([CH3:15])=[CH:13][C:12]([C:16]3[S:17][C:18]([C:22]([OH:24])=[O:23])=[C:19]([CH3:21])[N:20]=3)=[N:11]2)=[CH:4][CH:3]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]CN)[CH:26]=1.F[P-](F)(F)(F)(F)F.[N:41]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:14]([CH3:15])=[CH:13][C:12]([C:16]3[S:17][C:18]([C:22]([OH:24])=[O:23])=[C:19]([CH3:21])[N:20]=3)=[N:11]2)=[CH:4][CH:3]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][NH:41][C:22]([C:18]2[S:17][C:16]([C:12]3[CH:13]=[C:14]([CH3:15])[N:10]([CH2:9][CH2:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[N:11]=3)=[N:20][C:19]=2[CH3:21])=[O:24])[CH:26]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: NCCc1cccnc1
Agent: Cc1nc(-c2cc(C)n(CCc3ccc(F)cc3)n2)sc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2cc(C)n(CCc3ccc(F)cc3)n2)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.5 %

Procedure:
To a solution of 2-{1-[2-(4-fluoro-phenyl)-ethyl]-5-methyl-1H-pyrazol-3-yl}-4-methyl-thiazole-5-carboxylic acid (0.15 g, 0.43 mmol) in methylene chloride (10 mL) was added 2-pyridin-3-yl-ethylamine (0.05 g, 0.48 mmol), benzotriazol-1-yloxytris-(dimethylamino)phosphonium hexafluorophosphate (0.21 g, 0.48 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.87 mmol). The reaction mixture was stirred under nitrogen at room temperature for 16 hr. The reaction mixture was diluted with methylene chloride (50 mL), washed with water (50 mL) and brine (2×50 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by preparative thin layer chromatography over silica gel (methylene chloride:methanol, 98:2) to provide 2-{1-[2-(4-fluoro-phenyl)-ethyl]-5-methyl-1H-pyrazol-3-yl}-4-methyl-thiazole-5-carboxylic acid (pyridin-3-ylmethyl-amide as a white solid (0.052 g, 29% yield). 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.57 (d, J=4 Hz, 1H), 7.73 (d, J=4 Hz, 1H), 7.27-7.32 (m, 1H), 6.90-6.99 (m, 4H), 6.49 (s, 1H), 6.05-6.11 (bm, 1H), 4.64 (d, J=4 Hz, 2H), 4.23 (t, J=7 Hz, 2H), 3.13 (t, J=7 Hz, 2H), 2.76 (s, 3H), 1.56 (s, 3H); MS (M+H)+=435.9; Rt=1.31 min; HRMS (M+H)+=436.16.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Br:46][C:47]1[CH:48]=[C:49]2[C:53](=[CH:54][CH:55]=1)[NH:52][CH2:51][CH2:50]2>CN(C)C=O>[Br:46][C:47]1[CH:48]=[C:49]2[C:53](=[CH:54][CH:55]=1)[N:52]([C:10](=[O:12])[CH2:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[F:1])[CH2:51][CH2:50]2
Reactant: Brc1ccc2c(c1)CCN2
Reactant: O=C(O)Cc1cc(F)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cc1cc(F)ccc1F)N1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
To a mixture of (2,5-difluorophenyl)acetic acid (0.869 g, 5.05 mmol) and HATU (2.112 g, 5.55 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added Hunig's base (0.882 mL, 5.05 mmol), and the resulting mixture was stirred for 15 minutes at room temperature. 5-bromo-2,3-dihydro-1H-indole (1 g, 5.05 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The mixture was poured onto water, and the resulting aqueous mixture was filtered to afford 5-bromo-1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indole (1.6 g) as a tan solid.
Reaction SMILES: [CH:1]1(Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[OH:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25])[C:17]([O:19][CH3:20])=[O:18]>CN(C)C=O>[CH:1]1([O:13][C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=2[N+:24]([O-:26])=[O:25])[C:17]([O:19][CH3:20])=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc([N+](=O)[O-])c(OC2CCCC2)c1
Reaction time: 4 h
Yield: 102.2 %

Procedure:
Cyclopentyl bromide (38.7 g, 0.26 mol) is added slowly (over 1 hour) to a stirred suspension of potassium carbonate (41.4 g, 0.3 mol) in N,N-dimethylformamide (200 mL) containing methyl 3-hydroxy-4-nitrobenzoate (39.4 g, 0.2 mol) at 65° C. and then the stirring is continued for 4 hours. The mixture is allowed to cool and then filtered. The filtrate is diluted with water (700 mL) containing sodium chloride (50 g) and then extracted with toluene (3×200 mL). The combined organic extract is washed with 1 N sodium hydroxide solution (1×200 mL) and then water (2×200 mL) and then evaporated under reduced pressure to give methyl 3-cyclopentyloxy-4-nitrobenzoate (54.2 g, 100%) as a pale green solid which is used without further purification.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH:8]([OH:10])[C:7]2[S:11][CH:12]=[CH:13][C:6]=2[CH2:5]1.[Cl:14][C:15]1[CH:16]=[C:17](F)[CH:18]=[CH:19][C:20]=1[Cl:21]>>[ClH:14].[Cl:14][C:15]1[CH:16]=[C:17]([O:10][CH:8]2[CH2:9][N:4]([CH2:3][CH2:2][F:1])[CH2:5][C:6]3[CH:13]=[CH:12][S:11][C:7]2=3)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: OC1CN(CCF)Cc2ccsc21
Reactant: Fc1ccc(Cl)c(Cl)c1
Product: Cl
Product: FCCN1Cc2ccsc2C(Oc2ccc(Cl)c(Cl)c2)C1

Procedure:
The same method as in Reference Example 3 was conducted using 5-(2-fluoroethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-7-ol (Reference Example 17) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:10]=1.C(N(CC)CC)C.[CH3:39][N:40]=[C:41]=[O:42]>C(Cl)Cl>[CH3:39][NH:40][C:41]([N:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:11]2[N:10]=[C:9]([NH2:8])[C:14]([C:15](=[O:16])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])=[CH:13][N:12]=2)[CH2:27][CH2:28]1)=[O:42]
Reactant: CN=C=O
Reactant: COc1ccccc1C(=O)c1cnc(NC2CCNCC2)nc1N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)N1CCC(Nc2ncc(C(=O)c3ccccc3OC)c(N)n2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To a solution of [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone trifluoroacetic acid salt (92.4 mg, Example 11) in methylene chloride (3 mL) were added triethylamine (0.12 mL, 0.861 mmol, Aldrich) and methyl isocyanate (6.2 mg, 0.107 mmol, Fluka) at 0° C . After stirring for 1 hour at 0° C., the reaction mixture was concentrated in vacuo and crude product was purified on silica gel with 95:5 of dichloromethane/methanol to give 4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid methylamide (32.8 mg). HRMS, observed: 385.1985; Calcd for (M+H)+: 385.1983.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15]CC1C=CC=CC=1)=[O:6]>CO.[Pd]>[OH:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])=[O:6]
Reactant: O=C(NCCO)NCc1ccccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(NCCO)NCc1ccccc1O
Reaction time: 2 h

Procedure:
59.6 g of N-(2-hydroxyethyl)-N'-(2-benzyloxybenzyl)urea are dissolved in 600 ml of methanol and hydrogenated in the presence of 6 g of Pd/C-catalyst (5%). After 2 hours the hydrogenation ceases. The catalyst is suction-filtered, and the filtrate concentrated by evaporation in vacuo. The residue is recrystallised from 350 ml of ethyl acetate; the pure product melts at 100°-101°.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:26])=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:10][C:11](=[O:24])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[N:13]=2)[CH:8]=1.[C:27](Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>C1COCC1>[Cl:25][C:6]1[C:7]([C:9]2[NH:10][C:11](=[O:24])[N:12]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=3)[N:13]=2)=[CH:8][C:3]([CH2:2][NH:1][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[C:4]([F:26])[CH:5]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCc1cc(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c(Cl)cc1F
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1cc(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c(Cl)cc1F
Yield: 44.3 %

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 5-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-2-(4-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-70, 0.080 g, 0.206 mmol), pivaloyl chloride (0.027 g, 0.227 mmol), THF (5.0 mL) and TEA (0.2 mL) to afford 0.043 g of the desired product. 1H NMR (400 MHz, DMSO d6): δ 1.13 (s, 9H), 4.31-4.32 (m, 2H), 7.86 (d, J=6.5 Hz, 2H), 8.13-8.18 (m, 3H), 12.70 (s, 1H); MS (m/z): 471.14 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1.[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])=[CH:13][CH:14]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Cc1ccc(Sc2ccc(O)cc2)c(Nc2ccnc3nc(C)ccc23)c1
Product: CCS(=O)(=O)Oc1ccc(Sc2ccc(C)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 5 (100 mg, 0.24 mmol) was reacted with ethanesulfonyl chloride (31.0 mg, 0.24 mmol) for 18 h following the procedure from Example 58 giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (20 mg, 14%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 10.98 (s, 1H) 8.89 (d, J=8.46 Hz, 1H) 8.39 (d, J=6.99 Hz, 1H) 7.76 (d, J=8.82 Hz, 1H) 7.45-7.50 (m, 1H) 7.36-7.42 (m, 2H) 7.25 (d, 2H) 7.17 (d, 2H) 6.33 (d, J=6.99 Hz, 1H) 3.47 (q, J=7.35 Hz, 2H) 2.75 (s, 3H) 2.40 (s, 3H) 1.34 (t, J=7.35 Hz, 3H); MS (DCI NH3+) m/z 466 (M+H)+.
Reaction SMILES: C(O[C:4](=[O:37])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:36]=[CH:35][C:12]([CH2:13][C@@H:14]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[NH:15][C:16]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:19]=[N:18][N:17]=2)=[CH:11][CH:10]=1)C.[NH2:38][C:39]1[NH:40][CH2:41][CH2:42][CH2:43][N:44]=1>C(Cl)Cl>[O:37]=[C:4]([NH:38][C:39]1[NH:44][CH2:43][CH2:42][CH2:41][N:40]=1)[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C@@H:14]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[NH:15][C:16]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:19]=[N:18][N:17]=2)=[CH:35][CH:36]=1
Reactant: NC1=NCCCN1
Reactant: CCOC(=O)CCCOc1ccc(C[C@H](Nc2nnnn2Cc2ccccc2)C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCCN2)cc1)Nc1nnnn1Cc1ccccc1
Reaction time: 24 h
Yield: 24.2 %

Procedure:
The ester 5-1 (150 mg) is mixed with 2-amino-1,4,5,6-tetrahydropyrimidine (42 mg) in 5 ml of CH2Cl2 and agitation is carried out at ambient temperature for 24 hours. Evaporation is then carried out under reduced pressure and the dry extract obtained is purified by chromatography, eluting with a CH2Cl2/MeOH/water/AcOH mixture 90/10/1/1. 40 mg of the expected product 5-2 is obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Cl:11][S:12](O)(=[O:14])=[O:13]>N1C=CC=CC=1>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:12]([Cl:11])(=[O:14])=[O:13])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH2:5]([NH2:4])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:9][CH2:10][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)Nc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Product: CCCCCCCCCCCCN

Procedure:
Twenty grams of 4-acetylaminophenylsulfonyl-chloride obtained from acetanilide and chlorosulfonic acid and 6.5 g of dodecylamine and 8.1 g of pyridine were added to 100 ml of acetonitrile, and the mixture was refluxed with heating for 3.5 hours. The solvent was distilled off under reduced pressure. 100 ml of ethyl acetate were added to this, and the organic phase was washed with a 5% potassium carbonate solution and a 1% hydrochloric acid solution, and then washed with water. After dehydration of the product by magnesium sulfate, the ethyl acetate was distilled off, whereby 17.7 g of a crude product was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH2:32][CH3:33])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C4C=CC=CC=4)=[CH:16][CH:15]=3)[CH:13]=2)=[CH:5][CH:4]=1)#[N:2].[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[S:41]([NH2:44])(=[O:43])=[O:42]>>[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[S:41]([NH:44][C:23]([NH:22][CH2:21][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([N:12]2[CH:13]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[N:10]=[C:11]2[CH2:32][CH3:33])=[CH:19][CH:18]=1)=[O:24])(=[O:43])=[O:42]
Reactant: NS(=O)(=O)c1ccccc1Cl
Reactant: CCc1nc(-c2ccc(C#N)cc2)cn1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Product: CCc1nc(-c2ccc(C#N)cc2)cn1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccccc2Cl)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from phenyl 2-{4-[4-(4-cyanophenyl)-2-ethyl-1H-imidazol-1-yl]phenyl}ethylcarbamate and 2-chlorobenzenesulfonamide. MS (ESI) m/z 534 [M+H]+, 532 [M−H]−, 1H-NMR (CDCl3)δ1.26 (3H, t, J=7.5 Hz), 2.70 (2H, q, J=7.7 Hz), 2.86 (2H, t, J=7.1 Hz), 3.47-3.55 (2H, m), 6.58 (1H, br), 7.23-7.31 (3H, m), 7.36 (1H, s), 7.41-7.47 (1H, m), 7.57-7.66 (4H, m), 7.89 (2H, d, J=8.6 Hz),8.01 (1H, d, J=8.4 Hz)
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[H-].[Na+].[Cl:7][C:8]1[N:9]=[N:10][C:11]([Cl:15])=[CH:12][C:13]=1Cl.BrC1C(Cl)=C(Cl)N=NC=1>O1CCCC1>[Cl:7][C:8]1[N:9]=[N:10][C:11]([Cl:15])=[CH:12][C:13]=1[O:3][CH2:2][CH2:1][OH:4]
Reactant: OCCO
Reactant: Clc1cc(Cl)c(Cl)nn1
Agent: Clc1nncc(Br)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCOc1cc(Cl)nnc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A solution of ethylene glycol (55 ml) in tetrahydrofuran (200 ml) was treated at around 0° C. (ice bath cooling) with sodium hydride (60% dispersion in oil, 5.9 g) over 40 minutes. After the addition was complete, 3,4,6-trichloropyridazine (27 g) containing isomers of bromo-dichloropyridazine as impurity was added portionwise and washed in with more dry THF (50 ml) and the mixture was stirred at 0° C. for 1 hour and then at room temperature overnight. The mixture was concentrated (to ⅓ volume) then diluted with aqueous sodium bicarbonate solution and extracted with chloroform (5×) and ethyl acetate (3×). The combined organic extracts were washed with water, dried over sodium sulphate and evaporated and the solids filtered off and washed with CHCl3 (×3) and dried in a vacuum oven overnight at 40° C. affording a white solid (25.5 g, 83%), containing some bromo-derivative (10-15%).