Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[C:26](Cl)[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1.[N-:31]=[N+:32]=[N-:33].[Na+].O>CN(C=O)C>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[C:26]([N:31]=[N+:32]=[N-:33])[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)N1CCc2cc(Oc3cc(Cl)ncn3)ccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=Nc1cc(Oc2ccc3c(c2)CCN3C(=O)Nc2cccc(C(F)(F)F)c2)ncn1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a solution of 4.70 g (10.8 mMol) 5-(6-chloro-pyrimidin-4-yloxy)-2,3-dihydro-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide (WO 03/099771; Ex. 163) in 50 ml DMF, 1.4 g (21.6 mMol) NaN3 are added at rt. Then the mixture is stirred for 3 h at 70° C., cooled to rt and pored into water and extracted tree times with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated, yielding the title compound: m.p.: 167-168° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Si:12]([O:29][CH2:30][CH2:31]Br)([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[Si:12]([O:29][CH2:30][CH2:31][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)([C:25]([CH3:26])([CH3:27])[CH3:28])([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)[Si](OCCBr)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1

Procedure:
A mixture of methyl 4-hydroxybenzoate (3.25 g, 22.0 mmol, 2-(tert-butyldiphenylsilyloxy) ethyl bromide (8.0 g, 22.0 mmol, powdered anhydrous potassium carbonate (12 g) and potassium iodide (0.1 g) in acetone (250 ml) was heated under reflux for 48 h. The solid was then filtered and the filtrate was evaporated under reduced pressure.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:11][C:12]1[CH:13]=[C:14]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH:18]([CH2:22][NH:23][C:24]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:25])[CH2:17]1.C(N(CC)C(C)C)(C)C>ClCCl>[C:1]([N:30]1[CH2:31][CH2:32][CH:27]([NH:26][C:24]([NH:23][CH2:22][CH:18]2[O:19][CH2:20][CH2:21][N:16]([CH2:15][C:14]3[CH:33]=[CH:34][C:35]([Cl:36])=[C:12]([Cl:11])[CH:13]=3)[CH2:17]2)=[O:25])[CH2:28][CH2:29]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)NC1CCNCC1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)NC1CCN(C(=O)c2ccccc2)CC1
Temperature: 23 °C
Reaction time: 5 h

Procedure:
Benzoyl choride (0.014 ml) was added to a solution of Intermediate 16 (0.04 g) and N,N-diisopropylethylamine (0.048 ml) in dichloromethane (3 ml). The solution was stirred for 5 h at 23° C. The solvent was removed in vacuo and the residue purified by solid phase extraction (Isolute SCX sulphonic acid column) eluting with methanol followed by 10% 0.880 ammonia solution in methanol. The basic fraction was concentrated in vacuo and the residue was further purified using a silica gel solid phase extraction cartridge (1 g Varian Bond Elut), eluting sequentially with dichloromethane, ethyl acetate, acetone, acetonitrile, and methanol, to give the title compound as a clear gum (0.024 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[H-].[Na+].[C:13]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14].C(N(CC)C(C)C)(C)C>O1CCCC1>[NH2:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]=[C:2]([NH:1][C:21]([C:20]2[CH:24]=[CH:25][C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:18][CH:19]=2)=[O:22])[CH:7]=1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: CSc1nc(N)cc(N)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc(N)cc(NC(=O)c2ccc(C(C)(C)C)cc2)n1
Temperature: 50 °C

Procedure:
To a solution of 4,6-diamino-2-methylmercaptopyrimidine (50 mg, 0.032 mmol) in anhydrous tetrahydrofuran was added sodium hydride, followed by the addition of 4-t-butylbenzoyl chloride (0.084 mL, 0.32 mmol) and N, N-diisopropylethylamine. The mixture was heated at 50° C. for 16 hours after which it was subjected to aqueous work up. The product was extracted with ethyl acetate and purified by HPLC to give N-(6-amino-2-methylthiopyrimidin-4-yl)[4-(tert-butyl)phenyl]carboxamide. M+1=317.3.
Reaction SMILES: [NH:1]([C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[NH2:2].[CH:12]([O-])([O-])OCC.C1(C)C(C)=CC=CC=1>C(O)C>[N:1]1[N:2]=[CH:12][N:7]2[C:6]3[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=3[S:4][C:3]=12
Reactant: NNc1nc2ccccc2s1
Reactant: CCOC([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1C
Product: c1ccc2c(c1)sc1nncn12
Temperature: 105 °C

Procedure:
2-Hydrazinobenzothiazole (125 grams; 0.76 mole), ethyl orthoformate (112.4 grams, 0.76 mole), and 2 liters of xylene were heated together with stirring in a three-necked 5-liter flask. An 8-inch column with a condenser was placed in one neck. The reaction was heated to 105° C. and soon all the solid had gone into solution and the solution turned red. Ethanol began to distill from the reaction and about 125 milliliters of it was collected before the reaction was stopped and allowed to cool to room temperature. The yellow precipitate was collected and triturated with diethyl ether. The s-triazolo(3,4-b)benzothiazole product thus obtained was recrystallized from chloroform, m.p. 174.5°-7° C.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11]3[N:12]=[C:13]([NH2:21])[N:14]=[C:15]([C:16]4[O:17][CH:18]=[CH:19][CH:20]=4)[C:10]=3[N:9]=[N:8]2)=[CH:4][C:3]=1[CH3:24].Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27].O>N1C=CC=CC=1>[NH2:21][C:13]1[N:14]=[C:15]([C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[C:10]2[N:9]=[N:8][N:7]([CH2:6][C:5]3[CH:22]=[CH:23][C:2]([NH:1][C:26](=[O:27])[O:28][CH2:29][CH3:30])=[C:3]([CH3:24])[CH:4]=3)[C:11]=2[N:12]=1
Reactant: Cc1cc(Cn2nnc3c(-c4ccco4)nc(N)nc32)ccc1N
Reactant: CCOC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(Cn2nnc3c(-c4ccco4)nc(N)nc32)cc1C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
A suspension of 3-(4-amino-3-methylbenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (260 mg, 0.812 mmol) in pyridine (5 mL) at room temperature was treated dropwise with ethyl chloroformate (0.155 mL, 1.62 mmol), stirred for 30 min, poured into water (30 mL), extracted with EtOAc (2×10 mL) and the combined organic phase was dried (MgSO4) and concentrated in vacuo to give the title compound (318 mg, 100%) as a beige solid.
Reaction SMILES: [N+](C1C=CC(C2SC=CC=2)=CC=1NC(=O)C1C=CC(C2NN=NN=2)=CC=1)([O-])=O.[CH3:29][O:30][C:31]1[CH:53]=[CH:52][C:34]([C:35]([NH:37][C:38]2[CH:43]=[C:42]([C:44]3[NH:45][N:46]=[N:47][CH:48]=3)[CH:41]=[CH:40][C:39]=2[N+:49]([O-])=O)=[O:36])=[CH:33][CH:32]=1.CO>C(OCC)(=O)C>[NH2:49][C:39]1[CH:40]=[CH:41][C:42]([C:44]2[NH:45][N:46]=[N:47][CH:48]=2)=[CH:43][C:38]=1[NH:37][C:35](=[O:36])[C:34]1[CH:52]=[CH:53][C:31]([O:30][CH3:29])=[CH:32][CH:33]=1
Reactant: COc1ccc(C(=O)Nc2cc(-c3cnn[nH]3)ccc2[N+](=O)[O-])cc1
Agent: O=C(Nc1cc(-c2cccs2)ccc1[N+](=O)[O-])c1ccc(-c2nnn[nH]2)cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(C(=O)Nc2cc(-c3cnn[nH]3)ccc2N)cc1
Yield: 25 %

Procedure:
Following the same procedure as described in Example 48, step 3 (scheme 36) but substituting compound 171 for the compound 272 and using ethyl acetate as a solvent instead of methanol, the title compound 273 was obtained in 25% yield (over two steps). 1H NMR: (400.2 MHz, DMSO) δ (ppm): 9.62 (s, 1H); 8.08 (bs, 2H); 7.97 (d, J=8.5 Hz; 2H); 7.62 (s, 1H); 7.45 (d, J=8.2 Hz; 1H); 7.03 (d, J=8.5 Hz; 2H); 6.82 (d, J=8.2 Hz; 1H); 5.11 (bs, 2H); 3.83 (s, 3H). MS: calc: 309.3; found: 310.1 (M+H)
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][NH2:5].ON1C2C=CC=CC=2N=N1.[CH3:17][N:18]([CH2:28][C:29]1[CH:30]=[C:31]([C:35]2[CH:40]=[CH:39][C:38]([NH:41][C:42]3[CH:50]=[CH:49][CH:48]=[CH:47][C:43]=3[C:44](O)=[O:45])=[CH:37][CH:36]=2)[CH:32]=[CH:33][CH:34]=1)[C:19](=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].CCN=C=NCCCN(C)C.Cl>ClCCl.C(OCC)(=O)C>[CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:44](=[O:45])[C:43]1[CH:47]=[CH:48][CH:49]=[CH:50][C:42]=1[NH:41][C:38]1[CH:37]=[CH:36][C:35]([C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([CH2:28][N:18]([CH3:17])[C:19](=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:30]=2)=[CH:40][CH:39]=1
Reactant: CCCCCCCC(=O)N(C)Cc1cccc(-c2ccc(Nc3ccccc3C(=O)O)cc2)c1
Reactant: CC(C)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCCCCC(=O)N(C)Cc1cccc(-c2ccc(Nc3ccccc3C(=O)NCCC(C)C)cc2)c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 91.3 %

Procedure:
95 mg (1.1 mmol) of 3-methylbutylamine and 160 mg (1.2 mmol) of 1-hydroxybenzotriazole are successively added to a solution of 500 mg (1.1 mmol) of 2-{3′-[(methyloctanoylamino)methyl]biphenyl-4-ylamino}benzoic acid (Example 6) in 15 ml of dichloromethane. The reaction medium is cooled to 0° C. and 230 mg (1.2 mmol) of EDCl are added portionwise. The reaction medium is stirred from 0° C. to room temperature over 6 hours, diluted with ethyl acetate, washed with water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with an 80/20 heptane/ethyl acetate mixture. 530 mg of N-(3-methylbutyl)-2-{3′-[(methyloctanoylamino)methyl]biphenyl-4-ylamino}benzamide are obtained in the form of a yellow oil, in a yield of 93%.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:3]1.[O:23]1[CH:27]=[CH:26][C:25]([CH:28]=O)=[CH:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O1CCCC1>[O:23]1[CH:27]=[CH:26][C:25]([CH2:28][N:19]2[CH2:18][CH2:17][N:16]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH:4]3[CH2:3][C:2]([CH3:22])([CH3:1])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5]3)[CH2:21][CH2:20]2)=[CH:24]1
Reactant: O=Cc1ccoc1
Reactant: CC1(C)CC(c2ccccc2N2CCNCC2)CC(C)(C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)CC(c2ccccc2N2CCN(Cc3ccoc3)CC2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (50 mg, 0.166 mmol) produced in Example (8b), furan-3-carbaldehyde (0.02 mL, 0.231 mmol) and tetrahydrofuran (3 mL) was added sodium triacetoxyborohydride (43 mg, 0.203 mmol), followed by stirring for 20 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The solvent was distilled off by nitrogen stream. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 1-furan-3-ylmethyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine. This compound was dissolved in dichloromethane, and a 4N solution of hydrogen chloride in ethyl acetate was added. The solvent was distilled off by nitrogen stream. Diethyl ether was added to the obtained residue to produce a solid, and after further adding hexane, the solid was triturated by sonication. The supernatant solution was removed and the obtained solid was dried to give 33 mg of the title compound as colorless crystals.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[CH3:21][NH:22][CH2:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1>C(#N)C>[F:1][C:2]1[C:3]([N:26]2[CH2:27][CH2:28][CH:24]([CH2:23][NH:22][CH3:21])[CH2:25]2)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: CNCC1CCNC1
Solvent: CC#N
Product: CNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2OCC4C)C1
Yield: 226.4 %

Procedure:
0.75 g (2.7 mmole) of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid, 40 ml acetonitrile, and 0.91 g (0.80 mmole) of N-methyl-3-pyrrolidinemethanamine were refluxed overnight. The solvent was removed at reduced pressure and the residue tititrated with 40 ml of methanol. The precipitate was filtered, washed repeatedly with 95% ethanol and finally with ether until dry to give 0.68 g of 9-fluoro-2,3-dihydro-3-methyl-10-[3-[(methylamino)methyl]-1-pyrrolidinyl]-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid, mp 235°-237.5° C.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12](Cl)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:16][N:17]([CH2:19][CH:20]([OH:30])[CH2:21][O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)[CH3:18]>C(O)CCC.CO>[NH:1]([C:8]1[N:13]=[C:12]([NH:27][C:26]2[CH:28]=[CH:29][C:23]([O:22][CH2:21][CH:20]([OH:30])[CH2:19][N:17]([CH3:16])[CH3:18])=[CH:24][CH:25]=2)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccnc(Nc2ccccc2)n1
Reactant: CN(C)CC(O)COc1ccc(N)cc1
Agent: Cl
Solvent: CO
Solvent: CCCCO
Product: CN(C)CC(O)COc1ccc(Nc2ccnc(Nc3ccccc3)n2)cc1
Temperature: 80 °C
Yield: 65.7 %

Procedure:
2-Anilino-4-chloropyrimidine (145 mg, 0.71 mmol) was dissolved in n-butanol (20 ml). To this solution was added a hot solution of 4-[3-(N,N-dimethyl)amino-2-hydroxy-propoxy]aniline hydrochloride (Reference Example D-1; 178 mg, 0.63 mmol) in methanol (2 ml). The reaction mixture was heated at 80° C. for 18 hours, allowed to cool to ambient temperature and then evaporated onto silica (3 ml). The residue was purified by column chromatography eluting with 0–8% 2.0M methanolic ammonia solution in DCM to give the title product as a colourless solid (157 mg, 65%). NMR (300 MHz): 2.18 (s, 6H), 2.33 (m, 2H), 3.83 (m, 3H), 4.77 (d, 1H), 6.11 (d, 1H), 6.86 (m, 3H), 7.19 (m, 2H), 7.51 (d, 2H), 7.69 (d, 2H), 7.96 (d, 1H), 9.01 (s, 1H), 9.08 (s, 1H); m/z: (ES+) 380.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:27]/[O:28][C:29]([C:32]([O:34]CC2C=CC([N+]([O-])=O)=CC=2)=[O:33])([CH3:31])[CH3:30])/[C:8]([NH:10][C@@H:11]2[C:21](=[O:22])[N:20]3[C@@H:12]2[CH2:13][S:14][C@H:15]2[C@@:19]3([C:23]([O-:25])=[O:24])[O:18][C:17](=[O:26])[CH2:16]2)=[O:9])[N:6]=1.[Na+:45].P([O-])([O-])([O-])=O.C(O)C.[H][H]>O.[C].[Pd]>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:27]/[O:28][C:29]([C:32]([OH:34])=[O:33])([CH3:31])[CH3:30])/[C:8]([NH:10][C@@H:11]2[C:21](=[O:22])[N:20]3[C@@H:12]2[CH2:13][S:14][C@H:15]2[C@@:19]3([C:23]([O-:25])=[O:24])[O:18][C:17](=[O:26])[CH2:16]2)=[O:9])[N:6]=1.[Na+:45]
Reactant: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2[C@@H]1CS[C@@H]1CC(=O)O[C@]12C(=O)[O-])c1csc(N)n1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2[C@@H]1CS[C@@H]1CC(=O)O[C@]12C(=O)[O-])c1csc(N)n1)C(=O)O
Yield: 77 %

Procedure:
In 5 ml of water was dissolved 0.148 g of the compound obtained in Example 7. To this solution were added 5 ml of a 0.1M phosphate buffer solution, 5 ml of ethanol and 0.075 g of 10% palladium-carbon. Into the mixture was introduced hydrogen gas while stirring under ice-cooling. In 1.5 hour after starting of the reaction, 0.04 g of 10% palladium-carbon was added to the reaction system, followed by stirring for further one hour. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to a volume of about 5 ml. The residue was subjected to a Amberlite XAD-2 column chromatography. Fractions eluted with water were combined and freeze-dried to give 0.091 g of the subject compound as powders.
Reaction SMILES: C(S([C:10]1[N:15]=[C:14]([N:16]2[C:20]3[CH:21]=[CH:22][C:23]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)=[CH:24][C:19]=3[N:18]=[CH:17]2)[CH:13]=[CH:12][N:11]=1)(=O)=O)CCCCC.[NH2:31][CH:32]([CH:34]1[CH2:39][CH2:38][CH2:37][N:36]([C:40]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:41])[CH2:35]1)[CH3:33]>CS(C)=O>[CH2:43]([O:42][C:40]([N:36]1[CH2:37][CH2:38][CH2:39][CH:34]([CH:32]([NH:31][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:25]5[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:33])[CH2:35]1)=[O:41])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CCCCCCS(=O)(=O)c1nccc(-n2cnc3cc(-c4ccncc4)ccc32)n1
Reactant: CC(N)C1CCCN(C(=O)OCc2ccccc2)C1
Solvent: CS(C)=O
Product: CC(Nc1nccc(-n2cnc3cc(-c4ccncc4)ccc32)n1)C1CCCN(C(=O)OCc2ccccc2)C1

Procedure:
The title compound was prepared from 2-hexanesulfonyl-4-[5-(pyridin-4-yl)-benzimidazol-1-yl]pyrimidine and 2-hexanesulfoxide-4-[5-(pyridin-4-yl)-benzimidazol-1-yl]pyrimidine 1:1 mixture and 3-(1-aminoethyl)-1-(benzyloxy-carbonyl)piperidine according to the procedure described in EXAMPLE 17 using DMSO instead of toluene as solvent. Mass spectrum (ESI) 534.4 (M+1)
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])(C)(C)C.[OH-].[Li+].C(O)(=O)C>O1CCCC1>[C:6]([CH2:8][O:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)COC(=O)c1ccc(O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(O)COC(=O)c1ccc(O)cc1
Temperature: 55 °C

Procedure:
To a solution of 4-hydroxy-benzoic acid tert-butoxycarbonylmethyl ester 15 (18 grams, 71.42 mmol) in tetrahydrofuran (100 mL) is added 10% lithium hydroxide solution (35 mL). The mixture is heated at 50-60° C. for 1 hour. The reaction mass is cooled to room temperature, and the pH is adjusted to 4 with dilute acetic acid. The organic phase is separated and distilled to give crude 16, which can be purified in appropriate solvent.
Reaction SMILES: Cl.[N:2]1([CH2:7][CH2:8][C:9]2[CH2:18][CH2:17][C:16]3[CH:15]=[C:14]([NH:19][C:20](=[O:22])[CH3:21])[CH:13]=[CH:12][C:11]=3[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.CCN=C=NCCCN(C)C.[F:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45]C(C(O)=O)=[CH:43][CH:42]=2)=[CH:37][CH:36]=1>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.CN(C)C=O>[F:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][C:21]([C:20]([NH:19][C:14]3[CH:13]=[CH:12][C:11]4[CH:10]=[C:9]([CH2:8][CH2:7][N:2]5[CH2:6][CH2:5][CH2:4][CH2:3]5)[CH2:18][CH2:17][C:16]=4[CH:15]=3)=[O:22])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)cc1
Reactant: CC(=O)Nc1ccc2c(c1)CCC(CCN1CCCC1)=C2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc2c(c1)CCC(CCN1CCCC1)=C2)c1ccc(-c2ccc(F)cc2)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 52.3 %

Procedure:
Concentrated hydrochloric acid (2 ml) was added to N-[6-[2-(1-pyrrolidinyl)ethyl]-7,8-dihydro-2-naphthalenyl]acetamide (98.0 mg, 0.345 mmol) obtained in Reference Example 103, which was stirred at 100° C. for 16 hours. The solvent was distilled out under reduced pressure. Ethyl acetate was added to the residue, which was washed with aqueous potassium carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. WSC (62.5 mg, 0.326 mmol) was added to a dimethylformamide solution (1.5 ml) of the resulting oily substance (79.0 mg, 0.326 mmol), 4′-fluoro-[1,1′-biphenyl]-4-carboxylic acid (64.6 mg, 0.326 mmol) and DMAP (39.8 mg, 0.326 mmol) under ice-cooling, which was stirred at room temperature for 1 day. Ethyl acetate was added to the reaction mixture, which was washed with aqueous potassium carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled out under reduced pressure. The resulting residue was purified by aluminum column chromatography (development solvent; ethyl acetate), powdered with ethyl acetate-isopropyl ether (1:5), to give the titled compound (75.1 mg).
Reaction SMILES: [I:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C@@H:7]([C:9]([NH2:11])=[O:10])[NH2:8])=[CH:4][CH:3]=1.[CH2:14]1[CH2:20][S:17](=[O:19])(=[O:18])[O:16][CH2:15]1>CC(=O)CC.CN(C=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]([C:9]([NH:11][CH2:15][CH2:14][CH2:20][S:17]([OH:19])(=[O:18])=[O:16])=[O:10])[NH2:8])=[CH:12][CH:13]=1
Reactant: NC(=O)[C@@H](N)Cc1ccc(I)cc1
Reactant: O=S1(=O)CCCO1
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: N[C@@H](Cc1ccc(I)cc1)C(=O)NCCCS(=O)(=O)O
Temperature: 25 °C
Yield: 17.6 %

Procedure:
The solid (1.96 g, 5.8 mmol) was dissolved in a minimum amount of water. To the solution was added aqueous NH4OH (28-30%, 15 mL). The reaction mixture was stirred at room temperature over weekend. The solvent was removed under reduced pressure and EtOAc (15 mL) was added. The mixture was heated under reflux. The hot solution was filtered. The filtrate was cooled to room temperature and was stored in the fridge. The solid was collected by filtration, washed with EtOAc, to give 4-iodophenylalanine amide. The amide (1.3 g, 4.4 mmol) was dissolved in 15 mL of 2-butanone with a few drops of DMF before 1,3-propane sultone (560 mg, 4.9 mmol) was added. The reaction mixture was stirred at reflux for 2 hours. The mixture was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×20 mL) and dried in vacuo. The solid was suspended in MeOH (25 mL) and a small amount of water (1 mL). The suspension was stirred at reflux. The solid material was collected by filtration while the mixture was still hot. The solid was washed with hot MeOH (2×10 mL). Compound CO was obtained as a white solid (320 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.[Li+].[CH3:21]C([N-]C(C)C)C.IC>C1COCC1>[CH3:1][O:2][C:3](=[O:19])[C:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)([C:5]1[CH:6]=[CH:7][C:8]([Cl:11])=[CH:9][CH:10]=1)[CH3:21]
Reactant: COC(=O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 17 %

Procedure:
A solution of bis-(4-chloro-phenyl)-acetic acid methyl ester (1.19 g, 4.0 mmol) in THF (20 ml) was cooled to −78° C. under nitrogen. A solution of LDA (3.0 mL, 6.0 mmol, 2M in heptane/THF/ethylbenzene) was added over 5 minutes, then after a further 20 minutes, iodomethane (0.63 ml, 10.1 mmol) was added. After 4 hours the reaction was quenched by the addition of saturated ammonium chloride solution and allowed to warm to room temperature then concentrated in vacuo to remove organic solvents. The mixture was diluted with ethyl acetate/petrol 1:4 and washed with saturated ammonium chloride solution then brine, dried (MgSO4), filtered and concentrated to give a residue which was purified by column chromatography (SiO2), eluting with an ethyl acetate/petrol gradient (1% to 2%), to afford the title compound as a colourless oil (210 mg, 17%); LCMS (PS-B3) Rt 4.01 min, No ionisation. 1H NMR (CDCl3) δ 1.88 (3H, s), 3.73 (3H, 5), 7.11-7.14 (4H, m), 7.26-7.30 (4H, m).