Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([C:10]([O:12]C)=[O:11])[CH:4]=1.[OH-].[Na+]>O.CO>[CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([C:10]([OH:12])=[O:11])[CH:4]=1
Reactant: COC(=O)c1cc(OC)nc(C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)O)nc(C)n1
Yield: 43.4 %

Procedure:
62.6 g of methyl 6-methoxy-2-methylpyrimidine-4-carboxylate are added to a stirred solution of 14.4 g of sodium hydroxide in 100 ml of water and 350 ml of methanol and stirring is continued until hydrolysis is complete (TLC checking). 200 ml of methanol are added to the reaction mixture, and the sodium salt is filtered off with suction and then washed with methanol/diethyl ether (1:1) on the suction filter. The filter residue (59.3 g; melting point above 265° C.) dried in vacuo at 50° C. is introduced in portions into a solution of 24.5 g of acetyl chloride in 300 ml of methanol. The mixture is then stirred at room temperature for 1/2 h, the solid is filtered off with suction and the filter residue is then washed with abs. methanol. The filtrate is concentrated in vacuo on a rotary evaporator and the residue is dried at high vacuum. 25.1 g of 6-methoxy-2-methylpyrimidine-4-carboxylic acid of melting point 184°-188° C. (dec.) are obtained in this way.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=2)=[CH:6][CH:5]=1
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: OCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ccc(CCO)cc2)nc1
Temperature: 120 °C
Yield: 48.1 %

Procedure:
Combine 4-(2-hydroxy-ethyl)-phenol (2.0 g, 14.5 mmol), 6-chloronicotinamide (2.3 g, 14.5 mmol) and K2CO3 (5.0 g, 36.2 mmol) in DMF (40 mL) under nitrogen, stir and heat at 120° C. overnight. Cool to ambient temperature and pour into water, extract the aqueous layer with ethyl acetate. Combine the organic layers and dry over Na2SO4. Eliminate the solvent and purify by flash chromatography on silica gel (eluent: CHCl3/7% EtOH/0.7% NH4OH) to give the title compound (1.8 g, 49%). Electrospray MS M+1 ion=259, 1H-NMR (DMSO-d6, 400 MHz): 8.58 (d, 1H, J=2.7 Hz), 8.22 (dd, 1H, J=2.7 and 8.8 Hz), 8.00 (bs, 1H), 7.46 (bs, 1H), 7.25 (m, 2H), 7.05-7.02 (m, 3H), 4.65 (t, 1H, J=5.3 Hz), 3.63-3.58 (m, 2H), 2.72 (t, 2H, J=6.9 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C[O-].[Na+].[CH3:13][N:14]1[C:19]2[CH:20]=[CH:21][C:22]([CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:23][C:18]=2[S:17](=[O:32])(=[O:31])[C:16]([C:33](OC)=[O:34])=[N:15]1>CO>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:33]([C:16]2[S:17](=[O:31])(=[O:32])[C:18]3[CH:23]=[C:22]([CH2:24][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:21]=[CH:20][C:19]=3[N:14]([CH3:13])[N:15]=2)=[O:34])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: COC(=O)C1=NN(C)c2ccc(CN3CCOCC3)cc2S1(=O)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN1N=C(C(=O)NCc2ccc(Cl)cc2)S(=O)(=O)c2cc(CN3CCOCC3)ccc21
Temperature: 70 °C
Yield: 83 %

Procedure:
4-Chlorobenzylamine (0.66 mL) and a 0.5 M solution of NaOMe in CH3OH (0.060 mL) is added to a solution of methyl 1-methyl-6-(4-morpholinylmethyl)-1H-4,1,2-benzothiadiazine-3-carboxylate 4,4-dioxide (Preparation 41, 0.16 g) in CH3OH (15 mL) at room temperature. The mixture is heated for 12 hours at 70° C. and then the solvent is evaporated. The crude material is triturated with CH3CN and the organic layer is decanted. The remaining solid is chromatographed with MeOH/CH2Cl2 (1-5%) to obtain 0.174 g (83%) of the title compound as a white solid. Physical characteristics: MS (ESI+) m/z 463 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:4]=1[CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=1.[NH2:25][CH:26]1[CH2:30][CH2:29][O:28][CH2:27]1.F[B-](F)(F)F.C[N+](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:4]=1[CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:25][CH:26]2[CH2:30][CH2:29][O:28][CH2:27]2)=[O:22])=[CH:18][N:17]=1
Reactant: NC1CCOC1
Reactant: O=C(O)c1ccc(OCc2c(-c3ccccn3)noc2CO)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCOC1)c1ccc(OCc2c(-c3ccccn3)noc2CO)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
To a solution of 6-(5-hydroxymethyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (70 mg, 0.21 mmol) in DMF (5 mL) was added 3-aminotetrahydrofuran (26 mg, 0.30 mmol), N,N,N′,N′-tetramethyl-O-(benzotriazole-1-yl)-uronium tetrafluoroborate (96 mg, 0.30 mmol) and N,N-diisopropyl ethylamine (0.15 mL, 0.84 mmol). The reaction mixture was stirred overnight at room temperature. After evaporation of the solvent the residue was partitioned (ethyl acetate/aqueous saturated sodium bicarbonate solution) and the organic phase was dried (Na2SO4) and concentrated. Chromatography (silica, dichloromethane:methanol=100:0 to 97:3) afforded the title compound (58 mg, 68%) as a colorless oil. MS: m/e=397.1 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][N:12]2[C:16]([CH:17]=1)=[C:15]([C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:14]([CH2:24][C:25]([CH3:32])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:13]2[C:33]([C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)=[O:34])C1C=CC=CC=1>CCO.[Pd]>[Cl:41][C:38]1[CH:37]=[CH:36][C:35]([C:33]([C:13]2[N:12]3[C:16]([CH:17]=[C:9]([OH:8])[CH:10]=[CH:11]3)=[C:15]([C:18](=[O:23])[C:19]([CH3:21])([CH3:22])[CH3:20])[C:14]=2[CH2:24][C:25]([CH3:31])([CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:34])=[CH:40][CH:39]=1
Reactant: CCOC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(OCc3ccccc3)ccn2c1C(=O)c1ccc(Cl)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(O)ccn2c1C(=O)c1ccc(Cl)cc1
Reaction time: 1.5 h
Yield: 84.7 %

Procedure:
To a stirred solution of ethyl 3-[7-(benzyloxy)-3-[(4-chlorophenyl)carbonyl]-1-(2,2-dimethylpropanoyl)indolizin-2-yl]-2,2-dimethylpropanoate (3.50 g, 6.10 mmol) in EtOH (50 mL) is added 10% Pd/C (480 mg). The suspension is stirred under an atmosphere of hydrogen for 1.5 h then filtered through a pad of diatomaceous earth and washed with EtOH. The filtrate is concentrated in vacuo to give ethyl 3-{3-[(4-chlorophenyl)carbonyl]-1-(2,2-dimethylpropanoyl)-7-hydroxyindolizin-2-yl}-2,2-dimethylpropanoate (2.50 g, 85%). Also obtained is ethyl 3-[1-(2,2-dimethylpropanoyl)-7-hydroxy-3-(phenylcarbonyl)indolizin-2-yl]-2,2-dimethylpropanoate (0.28 g, 10%). A suspension of ethyl 3-{3-[(4-chlorophenyl)carbonyl]-1-(2,2-dimethylpropanoyl)-7-hydroxyindolizin-2-yl}-2,2-dimethylpropanoate (100 mg, 0.207 mmol), 2-(chloromethyl)quinoline-HCl (66.0 mg, 0.310 mmol), and potassium carbonate (114 mg, 0.826 mmol) in DMF (3 mL) is stirred for 24 h at 23° C. The mixture is filtered and concentrated in vacuo to give ethyl 3-{3-[(4-chlorophenyl)carbonyl]-1-(2,2-dimethylpropanoyl)-7-(quinolin-2-ylmethoxy)indolizin-2-yl}-2,2-dimethylpropanoate that is dissolved in THF (2 mL), MeOH (3 mL), and 6M aqueous NaOH (2 mL) and heated at 70° C. for 1 h then cooled to 23° C. and acidified to pH=1 with concentrated aqueous HCl. The mixture is partitioned between CH2Cl2 and brine then organics are dried with MgSO4, filtered, and concentrated in vacuo. Purification of the crude by HPLC (25 to 75% CH3CN/0.1% TFA in water) gives the title compound (60 mg, 49%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([N:10]([CH2:32][CH3:33])[CH:11]1[CH2:15][CH2:14][N:13]([C:16]([C:18]2[C:22]([CH3:23])=[C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[CH:31])[CH:25]=3)[NH:20][N:19]=2)=[O:17])[CH2:12]1)[CH3:9]>>[CH2:32]([N:10]([CH2:8][CH3:9])[CH:11]1[CH2:15][CH2:14][N:13]([C:16]([C:18]2[C:22]([CH3:23])=[C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[C:31][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:25]=3)[NH:20][N:19]=2)=[O:17])[CH2:12]1)[CH3:33]
Reactant: C#Cc1cccc(-c2[nH]nc(C(=O)N3CCC(N(CC)CC)C3)c2C)c1
Reactant: Ic1ccccc1
Product: CCN(CC)C1CCN(C(=O)c2n[nH]c(-c3cccc(C#Cc4ccccc4)c3)c2C)C1
Yield: 70 %

Procedure:
In analogy to the procedure described in Example 31F], iodobenzene and (3-diethylamino-pyrrolidin-1-yl)-[5-(3-ethynyl-phenyl)-4-methyl-1H-pyrazol-3-yl]-methanone (Example 31E]) gave the title compound in 70% yield light yellow semisolid. MS: 427.3 (MH+).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@H:33]6[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N:49]1([C:54](Cl)=[O:55])[CH2:53][CH2:52][CH2:51][CH2:50]1>>[N:49]1([C:54]([O:39][C@H:36]2[CH2:37][CH2:38][C@H:33]([C:30]3[CH:31]=[CH:32][C:27]([C:23]4[N:22]=[C:21]5[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:18]([O:17][C@@H:16]6[CH2:15][O:14][C@@H:13]7[C@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[CH2:10][O:11][C@H:12]67)=[N:19][C:20]5=[CH:25][C:24]=4[Cl:26])=[CH:28][CH:29]=3)[CH2:34][CH2:35]2)=[O:55])[CH2:53][CH2:52][CH2:51][CH2:50]1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@H](O)CC4)cc3)nc2n1COCC[Si](C)(C)C
Reactant: O=C(Cl)N1CCCC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@H](OC(=O)N5CCCC5)CC4)cc3)nc2n1COCC[Si](C)(C)C
Temperature: 100 °C

Procedure:
The title compound is prepared from (trans)-4-(4-(2-((3R,3aR,6R,6aS)-6-(tert-butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)cyclohexanol and pyrrolidine-1-carbonyl chloride following a procedure analogous to that described for Intermediate 12 Step 2 but heating the mixture for 48 hours at 100° C. LC (method 5): tR=1.32 min.
Reaction SMILES: C(OC(N1CCC2N(C)C3C(C(F)(F)F)=CC(NC4C=CC=CN=4)=CC=3C2C1)=O)(C)(C)C.C(OC([N:40]1[CH2:56][CH2:55][C@@H:43]2[N:44]([CH3:54])[C:45]3[C:46]([C:52]#[N:53])=[CH:47][C:48](Br)=[CH:49][C:50]=3[C@@H:42]2[CH2:41]1)=O)(C)(C)C.[Cl:57][C:58]1[C:63]([NH2:64])=[C:62]([C:65]([F:68])([F:67])[F:66])[CH:61]=[C:60]([Cl:69])[N:59]=1.CC([O-])(C)C.[Na+]>>[Cl:57][C:58]1[C:63]([NH:64][C:48]2[CH:49]=[C:50]3[C:45](=[C:46]([C:52]#[N:53])[CH:47]=2)[N:44]([CH3:54])[C@H:43]2[CH2:55][CH2:56][NH:40][CH2:41][C@@H:42]32)=[C:62]([C:65]([F:66])([F:67])[F:68])[CH:61]=[C:60]([Cl:69])[N:59]=1
Reactant: Nc1c(C(F)(F)F)cc(Cl)nc1Cl
Reactant: CN1c2c(C#N)cc(Br)cc2[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Agent: CC(C)(C)[O-]
Agent: CN1c2c(cc(Nc3ccccn3)cc2C(F)(F)F)C2CN(C(=O)OC(C)(C)C)CCC21
Agent: [Na+]
Product: CN1c2c(C#N)cc(Nc3c(C(F)(F)F)cc(Cl)nc3Cl)cc2[C@@H]2CNCC[C@@H]21

Procedure:
The title compound was prepared by following the general method for (5-methyl-6-trifluoromethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indol-8-yl)-pyridin-3-yl-amine (Method A) as an oil (35 mg, 16%) from (4aS,9bR)-8-bromo-6-cyano-5-methyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 158, 196 mg, 0.5 mmol), 2,6-dichloro-4-trifluoromethyl-pyridin-3-ylamine(186 mg, 1.5 mmol) and NaOt-Bu (144 mg, 1.5 mmol). MS (ESI): 443 (base, M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:4].[OH-].[Li+]>CO.O>[F:16][C:13]([F:14])([F:15])[CH2:12][O:11][C:10]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1ncccc1OCC(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ncccc1OCC(F)(F)F
Reaction time: 2 h

Procedure:
A solution of 3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid methyl ester (216 mg, 0.9 mmol) in methanol (1 ml) was treated with a solution of lithium hydroxide (78 mg, 3.3 mmol) in water (0.1 ml) and stirring was continued at 22° C. for 2 hours. The solution was evaporated and the residue triturated with 1N aqueous hydrochloric acid. The suspension was filtered, the residue washed with water and dried to give 3-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid as a colorless solid. MS (ISN): m/z=220 [M−H]−.
Reaction SMILES: [Br-].[CH2:2]([O:9][CH2:10][CH2:11][CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].[Br:38][C:39]1[CH:40]=[CH:41][C:42]([OH:47])=[C:43]([CH:46]=1)[CH:44]=O.O>C1COCC1>[CH2:2]([O:9][CH2:10][CH2:11][CH:12]=[CH:44][C:43]1[CH:46]=[C:39]([Br:38])[CH:40]=[CH:41][C:42]=1[OH:47])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: c1ccc(COCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc(Br)cc1C=CCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
60.0 g (122 mmol) of (3-benzyloxypropyl)triphenylphosphonium bromide are initially introduced in 400 ml of THF, and a solution of 25.0 g (223 mmol) of potassium tert-butoxide in 100 ml of THF is added dropwise at −10° C. A solution of 20.0 g (99.5 mmol) of 5-bromo-2-hydroxybenzaldehyde in 200 ml of THF is subsequently added dropwise at 0° C., and the batch is stirred overnight at room temp. The reaction mixture is subsequently hydrolysed using water and extracted three times with MTB ether. The combined org. phases are washed with water and sat. sodium chloride soln. and dried over sodium sulfate. The solvent is removed in vacuo, and the residue is filtered through silica gel with heptane/ethyl acetate (4:1), giving a mixture of cis- and trans-2-(4-benzyloxybut-1-enyl)-4-bromophenol as a colourless oil, which is reacted without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[CH:6][C:5]=1[CH3:11].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:37]1[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][C:5]1[CH:6]=[CH:7][C:8]([C:37]2[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=2)=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:12]
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: COC(=O)c1cc(Br)ccc1C
Agent: [Pd+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2ccc([N+](=O)[O-])cc2)ccc1C
Temperature: 80 °C

Procedure:
The compound of example 2 (0.592 g, 0.0026 mol, 1.0 eq), bis(pinacolato)diboron (0.711 g, 0.0028 mol, 1.05 eq), palladium acetate (17.4 mg, 0.0007 mol, 3 mol % eq) and potassium acetate (0.765 g, 0.0078 mol, 3 eq) were taken in 10 mL of dry DMF. The mixture was degassed by gently bubbling argon through it for 30 min at room temperature. The mixture was then heated at 80° C. under argon atmosphere until completion of reaction (3 h). After completion of reaction, the reaction mixture was cooled to room temperature, followed by addition of 1-bromo-4-nitrobenzene (0.52 g, 0.0026 mol, 1.0 eq), cesium carbonate (1.27 g, 0.00039 mol, 1.5 eq) and Pd(PPh3)4 (0.090 g, 0.078 mol, 3 mol %). The reaction mixture was then heated at 80° C. for about 16 h under argon, then cooled to room temperature and diluted with water (20 mL) and ethyl acetate (20 mL). Black particles were removed by passing through a pad of celite. The organic layer was separated and washed twice with 15 mL of brine solution. After drying over anhydrous sodium sulfate, the solvent was removed to give crude 2-(4′-nitro-biphenyl-4-methyl)methyl benzoate, which was purified by column chromatography (silicagel, 1-5% ethyl acetate in petroleum ether) to obtain the title compound.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([OH:19])=[O:18])=[C:15]([O:20][CH3:21])[C:14](Br)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][N:24](C=O)C>COC(C)(C)C.[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([OH:19])=[O:18])=[C:15]([O:20][CH3:21])[C:14]([C:23]#[N:24])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1c(Br)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: COC(C)(C)C
Product: COc1c(C#N)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O
Temperature: 180 °C

Procedure:
A mixture of 6-(benzenesulphonylmethyl)-3-bromo-2-methoxybenzoic acid (Example 7, 0.1 g), zinc cyanide (0.036 g) and tetrakis-(triphenylphosphine) palladium (0.015 g) in DMF was stirred and heated in the microwave at 180° C. for 10 minutes. After cooling, the mixture was diluted with t-butyl methyl ether, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by preparative HPLC (C18), eluting with a mixture of methanol and water containing 0.1% formic acid with a gradient of 35-98% to give 6-(benzenesulphonylmethyl)-3-cyano-2-methoxybenzoic acid (0.02 g) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:49]=[CH:48][C:12]([CH2:13][NH:14][C:15]2[N:20]=[C:19]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[N:18]=[C:17]([NH:27][C:28]3[CH:47]=[CH:46][C:31]([C:32]([NH:34][CH:35]([CH:40]4[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]4)[C:36]([O:38]C)=[O:37])=[O:33])=[CH:30][CH:29]=3)[N:16]=2)=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+].O.Cl>CC(C)=O>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][NH:14][C:15]2[N:20]=[C:19]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[N:18]=[C:17]([NH:27][C:28]3[CH:29]=[CH:30][C:31]([C:32]([NH:34][CH:35]([CH:40]4[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]4)[C:36]([OH:38])=[O:37])=[O:33])=[CH:46][CH:47]=3)[N:16]=2)=[CH:48][CH:49]=1
Reactant: COC(=O)C(NC(=O)c1ccc(Nc2nc(NCc3ccc(OCCCCCCN)cc3)nc(OCC(F)(F)F)n2)cc1)C1CCCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: NCCCCCCOc1ccc(CNc2nc(Nc3ccc(C(=O)NC(C(=O)O)C4CCCNC4)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 85 °C
Yield: 81.7 %

Procedure:
A mixture of methyl 2-(4-(4-(4-(6-aminohexyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-2-(piperidin-3-yl)acetate (50 mg) and K2CO3 (50.2 mg) in acetone (2 mL)/water (2 mL) was heated at 85° C. for 4 hours. After cooling to room temperature, the mixture was acidified with 1N HCl to pH=3. All the solvents were removed under vacuum. The residue was purified by preparative HPLC to give 2-(4-(4-(4-(6-aminohexyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-2-(piperidin-3-yl)acetic acid (40 mg).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[S:8][CH:9]=[CH:10][C:11]=1[C:12]([NH2:14])=[O:13])=O.Cl>[OH-].[Na+].C(O)C>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]1[NH:14][C:12](=[O:13])[C:11]2[CH:10]=[CH:9][S:8][C:7]=2[N:6]=1
Reactant: NC(=O)c1ccsc1NC(=O)c1ccccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=c1[nH]c(-c2ccccc2F)nc2sccc12
Yield: 68 %

Procedure:
2-(2-Fluoro-benzoylamino)-thiophene-3-carboxylic acid amide (8.56 g, 32.4 mmole) was dissolved in a mixture of 20 ml 1 M sodium hydroxide and 60 ml ethanol. The mixture was brought to reflux for 4 hours. The reaction mixture was cooled and poured onto ice. The solution was acidified with dilute hydrochloric acid and the product was isolated by filtration. Upon vacuum drying 5.42 g of product was obtained (Yield: 68%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:13]2=[O:14])[C:9]([OH:11])=O)=[CH:3][CH:2]=1.[NH2:23][CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:26].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>N1C=CC=CC=1>[O:14]=[C:13]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21](=[O:22])[N:12]1[C@@H:8]([CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[C:9]([NH:23][CH2:24][C:25](=[O:26])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:11]
Reactant: O=C(O)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Reactant: NCC(=O)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Product: O=C(CNC(=O)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.9 %

Procedure:
N-Phthaloyl-L-phenylalanine (290 mg, 1 mmol) and 2-aminoacetophenone (171 mg, 1 mmol) were dissolved in 10 mL of pyridine. Bop reagent (470 mg, 1.1 mmol) was added The mixture was stirred at rt under N2 for 12 h. The solvent was removed. The residue was dissolved in EtOAc and washed with water and sat. NaHCO3. The organic layer was dried over Na2SO4, filtered, and concentrated to yield 412 mg of the product (100% yield). MS 413.2 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[Si:3]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[C:17]([O:23][CH3:24])[CH:16]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]>C1COCC1.CO.O.[Cl-].[Na+].O>[Si:3]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][OH:20])=[C:17]([O:23][CH3:24])[CH:16]=1)([C:6]([CH3:8])([CH3:7])[CH3:9])([CH3:4])[CH3:5]
Reactant: COc1cc(OCCCO[Si](C)(C)C(C)(C)C)ccc1C=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(OCCCO[Si](C)(C)C(C)(C)C)ccc1CO
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86.3 %

Procedure:
Sodium borohydride (1.24 g) was added to a solution of the product from step (i) (21.3 g) in THF (100 mL), methanol (15 mL) and stirred at RT for 2.5 h. The mixture was diluted with water and brine, and extracted with EtOAc. And the combined organic solutions were dried and concentrated. The residue was purified by silica gel chromatography eluting with hexane/EtOAc to give the subtitle compound (18.5 g) as a colourless oil; 1H NMR: 7.14 (1H, d), 6.42-6.48 (2H, m), 4.61 (2H, d), 4.06 (2H, t), 3.84 (3H, s), 3.80 (2H, t), 2.15 (1H, t), 1.94-2.02 (2H, m), 0.89 (9H, s), 0.04 (6H, s).