Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([O:11][CH2:12][CH2:13][N:7]3[C@H:6]3[CH2:14][CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][C@@H:5]23)[CH:10]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[C:29]([CH3:36])[CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([O:11][CH2:12][CH2:13][N:7]4[C@H:6]4[CH2:14][CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][C@@H:5]34)[CH:10]=2)=[C:29]([CH3:36])[CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCO3
Reactant: COc1ccc(B(O)O)c(C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2N4CCO3)c(C)c1
Yield: 73.3 %

Procedure:
Tert-butyl(6bR,10aS)-5-(4-methoxy-2-methylphenyl)-1,2,6b,9,10,10a-hexahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole-8(7H)-carboxylate (0.16 g, 73%) was prepared by the general method of Example 89, step C from tert-butyl (6bR,10aS)-5-bromo-1,2,6b,9,10,10a-hexahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole-8(7H)-carboxylate (0.20 g, 0.50 mmol), 4-methoxy-2-methylphenyl boronic acid (0.17 g, 1.0 mmol), Pd(PPh3)2Cl2 (17 mg, 0.025 mmol), Na2CO3 (2.0 M, 1.0 mL, 2.0 mmol) as a white foam. MS (ESI): 437 (base, M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([NH2:16])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:17][N:18]([CH3:36])[C:19]1[CH:35]=[CH:34][C:22]([C:23]([NH:25][C:26]2[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=2)=[O:24])=[CH:21][CH:20]=1>>[NH:8]1[C:7]2[CH:6]=[CH:5][C:4]([C:9]3[CH:15]=[CH:14][C:12]4[N:13]=[C:30]([C:29]5[CH:32]=[CH:33][C:26]([NH:25][C:23](=[O:24])[C:22]6[CH:34]=[CH:35][C:19]([N:18]([CH3:36])[CH3:17])=[CH:20][CH:21]=6)=[CH:27][CH:28]=5)[NH:16][C:11]=4[CH:10]=3)=[CH:3][C:2]=2[N:1]=[C:30]1[C:29]1[CH:28]=[CH:27][C:26]([NH:25][C:23](=[O:24])[C:22]2[CH:34]=[CH:35][C:19]([N:18]([CH3:36])[CH3:17])=[CH:20][CH:21]=2)=[CH:33][CH:32]=1
Reactant: CN(C)c1ccc(C(=O)Nc2ccc(C=O)cc2)cc1
Reactant: Nc1ccc(-c2ccc(N)c(N)c2)cc1N
Product: CN(C)c1ccc(C(=O)Nc2ccc(-c3nc4cc(-c5ccc6nc(-c7ccc(NC(=O)c8ccc(N(C)C)cc8)cc7)[nH]c6c5)ccc4[nH]3)cc2)cc1

Procedure:
Compound 265 was prepared according to the procedure similar to that described in Scheme III from 3,3′-diaminobenzidine and 4-(4-dimethylaminobenzamido)benzaldehyde. [M+H]+ calcd for C44H38N8O2: 711.31; found: 711.38.
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]([CH2:7][O:8][C:9]2[C:10]([CH2:26]O)=[C:11]([CH2:16][NH:17][C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)[CH:12]=[N:13][C:14]=2[CH3:15])=[CH:5][CH:4]=1)#[N:2].C(N(S(F)(F)[F:36])CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([C:3]1[CH:29]=[CH:28][C:6]([CH2:7][O:8][C:9]2[C:10]([CH2:26][F:36])=[C:11]([CH2:16][NH:17][C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)[CH:12]=[N:13][C:14]=2[CH3:15])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: Cc1ncc(CNc2ccc(C#N)cc2)c(CO)c1OCc1ccc(C#N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ncc(CNc2ccc(C#N)cc2)c(CF)c1OCc1ccc(C#N)cc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
To a solution of 4-{[5-(4-cyano-benzyloxy)-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl]-amino}-benzonitrile (8) (1765 mg, 4.60 mmol) in dry dichloromethane (200 mL) was slowly added diethylaminosulfurtrifluoride (DAST) (741 mg, 4.6 mmol) in dry dichloromethane (50 mL) at −78° C. under nitrogen atmosphere. The reaction temperature was warmed to −40° C. and stirred for 30 minutes. The reaction mixture was then poured into a cold solution of saturated aqueous sodium bicarbonate, and the crude product was extracted with dichloromethane, washed with water, and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave a crude residue, which was purified by column chromatography on silica gel using dichloromethane:hexane:methyl alcohol (15:10:1) as an eluant to give 4-{[5-(4-cyano-benzyloxy)-4-fluoromethyl-6-methyl-pyridin-3-ylmethyl]-amino}-benzonitrile (10) (650 mg, 37% yield) as a colorless solid.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[C:19]([O:23][C:24]([N:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:36][CH2:37][CH3:38])[CH:32]=2)[CH:27]1[C:39]([OH:41])=O)=[O:25])([CH3:22])([CH3:21])[CH3:20].[F:42][C:43]1[CH:44]=[C:45]([CH:47]=[C:48]([F:56])[C:49]=1[C:50]([CH3:55])([CH3:54])[CH2:51][O:52][CH3:53])[NH2:46].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O>[F:42][C:43]1[CH:44]=[C:45]([NH:46][C:39]([CH:27]2[C:28]3[C:33](=[CH:32][C:31]([O:36][CH2:37][CH3:38])=[CH:30][CH:29]=3)[CH2:34][CH2:35][N:26]2[C:24]([O:23][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:25])=[O:41])[CH:47]=[C:48]([F:56])[C:49]=1[C:50]([CH3:54])([CH3:55])[CH2:51][O:52][CH3:53]
Reactant: COCC(C)(C)c1c(F)cc(N)cc1F
Reactant: CCOc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2C(=O)Nc1cc(F)c(C(C)(C)COC)c(F)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
T3P (9.88 mL, 16.80 mmol) was added to a solution of 2-(tert-butoxycarbonyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (1.8 g, 5.60 mmol), 3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)aniline (1.206 g, 5.60 mmol), DIEA (4.89 mL, 28.01 mmol) and DMAP (0.684 g, 5.60 mmol) in ethyl acetate (5 mL), and the mixture was stirred overnight at 60° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with 10% aqueous citric acid solution, aqueous sodium hydrogencarbonate solution and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 3→50% ethyl acetate/hexane) to give tert-butyl 1-((3,5-difluoro-4-(1-methoxy-2-methylpropan-2-yl)phenyl)carbamoyl)-6-ethoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.380 g, 4.59 mmol, 82%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[S:6][C:7]([CH2:9][CH:10]3[CH2:14][CH2:13][N:12]([CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)[C:11]3=[O:21])=[CH:8][C:4]=2[CH:3]=1.[CH3:24][O:25][C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)=[O:27]>>[CH3:24][O:25][C:26](=[O:27])[C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:23]=[CH:22][C:5]3[S:6][C:7]([CH2:9][CH:10]4[CH2:14][CH2:13][N:12]([CH:15]5[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]5)[C:11]4=[O:21])=[CH:8][C:4]=3[CH:3]=2)=[CH:30][CH:29]=1
Reactant: O=C1C(Cc2cc3cc(Br)ccc3s2)CCN1C1CCCCC1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Product: COC(=O)c1ccc(-c2ccc3sc(CC4CCN(C5CCCCC5)C4=O)cc3c2)cc1
Yield: 55.9 %

Procedure:
Using the procedure to synthesize Example 17 and using reagents 3-(5-bromo-benzo[b]thiophen-2-ylmethyl)-1-cyclohexyl-pyrrolidin-2-one (250 mg, 0.64 mmol) and 4-methoxycarbonylphenylboronic acid (200 mg, 1 mmol) afford the title compound as a white powder (160 mg, 78%): MS (APCI-pos mode) m/z (rel intensity): 342.2 (M+H, 100%).
Reaction SMILES: N[C@H](C(O)=O)C.[NH2:7][C@H:8]([C:17]([OH:19])=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13](O)=[CH:12][CH:11]=1.NCC(O)=O>>[NH2:7][C@H:8]([C:17]([OH:19])=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: C[C@H](N)C(=O)O
Agent: NCC(=O)O
Product: N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
0.96; Ala: 0.97; Tyr: 0.97; Gly: 0.97
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[OH:13][CH2:14][CH:15]1[C:19]2([CH2:21][CH2:20]2)[NH:18][C:17](=[O:22])[O:16]1.O>C(Cl)Cl>[CH3:1][S:2]([O:13][CH2:14][CH:15]1[C:19]2([CH2:21][CH2:20]2)[NH:18][C:17](=[O:22])[O:16]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1NC2(CC2)C(CO)O1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCC1OC(=O)NC12CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methanesulfonyl chloride (1.36 g, 11.1 mmol) and triethylamine (2.51 mL, 18.4 mmol) were added to a solution of 7-(hydroxymethyl)-6-oxa-4-azaspiro[2.4]heptan-5-one (1.32 g, 9.2 mmol) in DCM (47 mL) at 0° C. and this mixture was stirred at room temperature for 3 hours. The reaction mixture was then poured into water and extracted with ethyl acetate (10 mL×3). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate) to afford (5-oxo-6-oxa-4-azaspiro[2.4]hept-7-yl)methyl methanesulfonate. MS ESI calc'd. for C7H12NO5S [M+H]+ 222. found 222.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@@H:10]3[O:19][C@@H:9]3[C:8]=2[CH:20]=1)([O-:3])=[O:2].[Cl:21][C:22]1[CH:23]=[C:24]([NH:28][CH2:29][C:30]2[N:31]=[N:32][N:33]([CH3:35])[N:34]=2)[CH:25]=[CH:26][CH:27]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@H:10]([OH:19])[C@@H:9]([N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[CH:23]=3)[CH2:29][C:30]3[N:31]=[N:32][N:33]([CH3:35])[N:34]=3)[C:8]=2[CH:20]=1)([O-:3])=[O:2]
Reactant: Cn1nnc(CNc2cccc(Cl)c2)n1
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](N(Cc2nnn(C)n2)c2cccc(Cl)c2)[C@H]1O
Yield: 46 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using the epoxide compound (150 mg, 0.53 mmol) obtained in step 1 of example 2 and N-(3-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=1:1), to give desired compound (124 mg, yield: 46%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:18]([NH2:21])[CH:19]=[CH2:20].C(=O)([O-])O.[Na+]>>[CH2:18]([NH:21][C:2]1[N:3]=[C:4]([NH:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1)[CH:19]=[CH2:20]
Reactant: CC(C)=CCNc1nc(Cl)nc2c(C)csc12
Reactant: C=CCN
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NCC=C(C)C)c2scc(C)c2n1
Yield: 69.7 %

Procedure:
268 mg (1.0 mmol) of 2-chloro-7-methyl-4-(3-methyl-2-butenylamino)thieno[3,2-d]pyrimidine and 914 mg (16.0 mmol) of allylamine were heated in a sealed tube at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, followed by adding a saturated aqueous sodium hydrogen carbonate solution thereto and extraction with ethyl acetate (50 ml×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 201 mg (yield: 69.8%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][NH2:4].C(O)(=O)C.[NH2:11][C:12]1[N:17]=[C:16]([NH2:18])[C:15]([CH2:19][C:20]2[CH:25]=[C:24]([O:26][CH2:27][CH3:28])[C:23]([C:29]3[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][CH:30]=3)=[C:22]([O:37][CH2:38][CH3:39])[CH:21]=2)=[CH:14][N:13]=1.C([BH3-])#N.[Na+]>CO>[CH2:38]([O:37][C:22]1[CH:21]=[C:20]([CH2:19][C:15]2[C:16]([NH2:18])=[N:17][C:12]([NH2:11])=[N:13][CH:14]=2)[CH:25]=[C:24]([O:26][CH2:27][CH3:28])[C:23]=1[C:29]1[CH:34]=[CH:33][C:32]([CH2:35][NH:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[CH:31][CH:30]=1)[CH3:39]
Reactant: NCC(F)(F)F
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1-c1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1-c1ccc(CNCC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 22.1 %

Procedure:
A solution of 2,2,2-trifluoroethylamine (0.477 ml; 6 mmol) in 4 ml methanol is adjusted to pH 6 with glacial acetic acid, and 4′-(2,4-diamino-pyrimidin-5-ylmethyl)-2′,6′-diethoxy-biphenyl-4-carbaldehyde (392 mg; 1 mmol) is added. The reaction mixture is then cooled to 0° C. and sodium cyanoborohydride (38 mg; 0.6 mmol) is added. After half and hour at 0° C., the mixture is stirred for 3 h at room temperature. After evaporation of the reaction mixture, the residue is stirred in 20 m water and the mixture is adjusted to pH 8 with 1 N aqueous sodium hydroxide solution. The substance which has precipitated out is filtered off with suction and dried under a high vacuum. The residue is stirred in 20 ml methylene chloride and filtered off with suction again and dried. 105 mg (22%) 5-{2,6-Diethoxy-4′-[(2,2,2-trifluoro-ethylamino)-methyl]-biphenyl-4-ylmethyl}-pyrimidine-2,4-diamine are obtained as a colourless powder.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:12]=[CH:11][C:10]=1[C@H:23]1[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25][CH2:24]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClC(Cl)C.C(N(CC)CC)C.[N+:41]([C:44]1[CH:45]=[C:46]([CH:50]=[CH:51][CH:52]=1)[C:47](Cl)=[O:48])([O-:43])=[O:42]>O1CCCC1.ClCCl.CN(C)C1C=CN=CC=1.ClCCl.[OH-].[Na+]>[Si:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17])[CH:12]=[CH:11][C:10]=1[C@H:23]1[CH2:24][CH2:25][C@H:26]([NH:29][C:47](=[O:48])[C:46]2[CH:50]=[CH:51][CH:52]=[C:44]([N+:41]([O-:43])=[O:42])[CH:45]=2)[CH2:27][CH2:28]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](N)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](NC(=O)c3cccc([N+](=O)[O-])c3)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
To a round bottomed flask was added trans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylamine (80 mg) and dichloroethane (7 ml), and the reaction mixture heated to 40° C.,. To the stirred solution was added triethylamine (100 μl), a solution of 3-nitrobenzoyl chloride (101 mg) in tetrahydrofuran/dichloromethane (6 ml, 1:1 v/v) and 4-dimethylamino pyridine (catalytic). The reaction mixture was heated at 40° C. for 24 hr, and then room temperature for 24 hr. The reaction mixture was diluted with dichloromethane (20 ml) and aqueous sodium hydroxide (16 ml, 0.5M) was added. After stirring for 0.2 hr, the layers were separated and the aqueous layer extracted with dichloromethane (2×10 ml). The combined organic phases were washed with saturated sodium hydrogen carbonate solution (15 ml) and brine (16 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via flash chromatography (SiO2, ethyl acetate/petroleum ether, gradient elution using 1:10, 1:8, 1:5, then 1:4, v/v) furnished the title compound (52 mg, 49%) as a colourless gum. δH (CDCl3): 0.18 (6H, s), 0.24 (6H, s), 0.97 (9H, s), 1.03 (9H, s), 1.34-1.61 (4H, m), 1.87-1.96 (2H, m), 2.17-2.27 (2H, m), 2.88 (1H, tt), 4.01-4.13 (1H, m), 6.08 (1H, d), 6.29 (1H, d), 6.43 (1H, dd), 6.97 (1H, d), 7.65 (1H, t), 8.18 (1H, d), 8.35 (1H, d), 8.57 (1H, s).
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH2:18][CH2:19][C:20]#[C:21][CH2:22][CH3:23].C([CH2:27][C:28]([NH:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([OH:35])=[O:34])=[O:29])(O)=O.Cl>C1(C)C=CC=CC=1>[CH2:18]([O:17][C:10]1[CH:11]=[C:12](/[CH:13]=[CH:27]/[C:28]([NH:30][C:31]2[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=2[C:33]([OH:35])=[O:34])=[O:29])[CH:15]=[CH:16][C:9]=1[O:8][CH3:7])[CH2:19][C:20]#[C:21][CH2:22][CH3:23]
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Reactant: CCC#CCCOc1cc(C=O)ccc1OC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCC#CCCOc1cc(/C=C/C(=O)Nc2ccccc2C(=O)O)ccc1OC
Yield: 73.7 %

Procedure:
Piperidine (0.21 mL, 2.2 mmol) was added to a suspension of 4-methoxy-3-(hex-3-ynyloxy)benzaldehyde (0.50 g, 2.2 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.44 g, 2.0 mmol) in toluene (5 mL) and treated according to Procedure 2, acidifying with 1 M HCl. The crude product was recrystallised from EtOH providing (E)-2-[[3-(3-(hex-3-ynyloxy)-4-methoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.58 g, 75%) as a yellow crystalline solid; mp 163-165° C.; δH (400 MHz, DMSO-d6) 1.05 (t, J=7.6 Hz, 3H, CH3), 2.15 (q, J=7.6 Hz, 2H, CH3CH2), 2.62 (t, J=7.6 Hz, 1H, OCH2CH2C), 3.80 (s, 3H, OCH3), 4.09 (t, J=7.6 Hz, 2H, OCH2), 6.80 (d, J=15.6 Hz, 1H, CH═CHCO), 6.99 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.25 (d, J5′,6′=8.0 Hz, 1H, H6′), 7.40 (s, 1H, H2′), 7.55 (d, J=15.6 Hz, 1H, CH═CHCO), 7.60 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.61 (d, J5,6=8.0 Hz, 1H, H6), 11.26 (s, 1H, NH), 13.58 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 11.8, 14.0, 19.3, 55.6, 67.0, 76.2, 83.0, 111.9, 112.0, 116.6, 120.0, 120.3, 122.6, 123.0, 127.3, 131.1, 134.0, 141.0, 141.6, 147.9, 150.8, 164.2, 169.4; HRMS (ESI) calculated for C23H23NO5 [M+H]+ 394.1649. found 394.1648; vmax 755, 1253, 1510, 1604, 1657, 3238, 3524 cm−1.
Reaction SMILES: [H-].[Na+].[ClH:3].[CH3:4][O:5][C:6]1[C:18]2[CH2:17][CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[C:10]=2[CH:9]=[CH:8][C:7]=1[O:19][CH3:20].Br[CH2:22][CH2:23][CH3:24]>CN(C=O)C>[ClH:3].[CH2:22]([N:13]1[CH2:12][CH:11]2[CH:15]([CH2:16][CH2:17][C:18]3[C:6]([O:5][CH3:4])=[C:7]([O:19][CH3:20])[CH:8]=[CH:9][C:10]=32)[CH2:14]1)[CH2:23][CH3:24]
Reactant: CCCBr
Reactant: COc1ccc2c(c1OC)CCC1CNCC21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN1CC2CCc3c(ccc(OC)c3OC)C2C1
Reaction time: 1.5 h
Yield: 49.7 %

Procedure:
A slurry of NaH (0.68 g, 50% in oil, 14.1 mmole, washed 3 times with hexane) and 68 mL dry DMF was stirred under N2 at room temperature as a solution of the compound of example 5 (free base) (3.0 g, 12.9 mmole) in 20 mL dry DMF was added dropwise. The reaction mixture was stirred for 1.5 hr. at room temperature, then 1-bromopropane (1.3 mL, 14.1 mmole) was added dropwise. The reaction mixture was stirred for 1 hr at room temperature, and for 18 hrs. at 30°-35° C. The reaction mixture was evaporated to dryness, water was added and the solution was extracted 3 times with CH2Cl2. The combined CH2Cl2 layers were washed with water, brine, dried (MgSO4), filtered, evaporated, and converted to the HCl salt to yield 2.0 g (50%) gray glass; M+ 246.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH2:37][CH2:38][CH2:39][N:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH:41]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:38]3[CH2:37][CH2:36][CH2:41][N:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH:39]=3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: CC(C)(C)OC(=O)N1C=C(B2OC(C)(C)C(C)(C)O2)CCC1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(C2=CN(C(=O)OC(C)(C)C)CCC2)nc(N2CCOCC2)n1
Yield: 49.7 %

Procedure:
A mixture of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (0.40 g, 1 mmol), tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate (0.382 g, 1.24 mmol), PdCl2(dppf) (63 mg), and 2 M aqueous Na2CO3 (8 mL) in dioxane (40 mL) was refluxed under nitrogen for 2 hrs. The dioxane was removed under vacuum and the residue was extracted into CH2Cl2. Chromatography on silica eluting with hexanes/EtOAc (8:2) gave 0.27 g (50% yield) of tert-butyl 5-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3,4-dihydro-1(2H)-pyridinecarboxylate: 1H NMR (CDCl3) δ 8.59 (s, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.60 (t, JHF=53.6 Hz, 1H), 7.34 (t, J=8.2 Hz, 1H), 6.81 (d, J=8.1 Hz, 1H), 4.04 (s, 3H), 4.02-3.75 (m, 8H), 3.71-3.64 (m, 2H), 2.56 (t, J=6.1 Hz, 2H), 2.00-1.91 (m, 2H), 1.57 (s, 9H).
Reaction SMILES: [CH2:1]([C@@:4]1([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:8]([CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:7][C@@H:6]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@@H:5]1[O:27]S(C)(=O)=O)[CH:2]=[CH2:3]>C(O)C.O.[OH-].[Na+]>[CH2:1]([C@@:4]1([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:8]([CH2:9][O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:7][C@@H:6]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@H:5]1[OH:27])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@@H]1OS(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CC[C@]1(OCc2ccccc2)[C@H](O)[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1COCc1ccccc1

Procedure:
A solution of nucleoside 3 (3.59 g, 6.45 mmol) in ethanol (72 cm3), water (72 cm3) and 1 M aqueous sodium hydroxide (20.6 cm3) was stirred under reflux for 18 h. After neutralisation with dilute hydrochloric acid, the solvent was removed under reduced pressure and the residue was dissolved in dichloromethane (3×150 cm3). The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate (3×200 cm3) and dried (Na2SO4). The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane/methanol (99:1, v/v) as eluent to give 4 as a white solid material (2.32 g, 74%). δH (CDCl3) 7.60 (1 H, d, J 1.2, 6-H), 7.50-7.23 (10 H, m, Bn), 6.22 (1H, d, J 2.9, 1′-H), 5.80 (1H, m, 2″-H), 5.15-5.08 (2 H, m, 3-″Ha, 3″-Hb), 4.86-4.33 (6 H, m, 2×Bn, 2′-H, 4′-H), 3.82-3.71 (2 H, m, 5′-Ha, 5′-Hb), 2.72 (1 H, m, 1″-Ha), 2.52 (1 H, dd, J 7.6, 16.1, 1″-Hb), 1.70 (3 H, d, J 9, CH3). δC (CDCl3) 165.1 (C-4), 150.4 (C-2), 138.4, 136.8 (Bn), 137.7 (C-6), 132.3 (C-2″), 128.77 128.4, 128.3, 128.0, 127.9, 127.6 (Bn), 118.5, (C-3″), 107.8 (C-5), 88.0, 87.8, 83.7 (C-1′, C-3′, C-4′), 73.7, 72.9, 69.4 (Bn, C-2′), 64.7 (C-5′), 31.1 (C-1″), 12.4 (CH3) (Found: C, 67.5; H, 6.3; N, 5.3. C27H30N2O6,0.25H2O requires C, 67.1; H, 6.4; N, 5.8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH:14]2[S:19][CH2:18][CH2:17][CH2:16][S:15]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C([Li])(C)(C)C.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[CH2:30]Cl.O>O1CCCC1.CCCCC>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([CH2:13][C:14]2([CH2:30][C:29]3[CH:32]=[C:33]([O:37][CH3:38])[C:34]([O:35][CH3:36])=[C:27]([O:26][CH3:25])[CH:28]=3)[S:15][CH2:16][CH2:17][CH2:18][S:19]2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(CC2SCCCS2)cc(OC)c1OC
Reactant: COc1cc(CCl)cc(OC)c1OC
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CC2(Cc3cc(OC)c(OC)c(OC)c3)SCCCS2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 46.3 g of the compound prepared in (a) above in 230 ml of tetrahydrofuran at 0° C. was added, over a period of 20 minutes, 99.6 ml of a 1.7M solution of tert.-butyl lithium in pentane. The resultant mixture was then stirred for 20 minutes, after which time 34.9 g of 3,4,5-trimethoxybenzyl chloride in 150 ml of tetrahydrofuran at 0° C. was added over a period of 15 minutes. The reaction mixture was then stirred for 45 minutes, while the temperature was maintained at 0° C., and then 100 ml of water was carefully added. The resultant slurry was then extracted with a mixture of ethyl acetate and water and dried. The organic layer was then evaporated and the crude product was washed with diethyl ether to yield a solid.