Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].ClC1C=CC(C2C=CC([C@H]3CC[C@H](CC[C@H]4CC[C@H](CCCCCC)CC4)CC3)=CC=2)=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)(=O)[C:62]([Cl:64])=[O:63]>C(Cl)Cl.O>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:11][CH2:12][C@H:13]([CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:62]([Cl:64])=[O:63])=[CH:22][CH:23]=3)[CH2:14][CH2:15]2)=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc([C@H]2CC[C@H](CCc3ccccc3)CC2)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: CCCCCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(-c4ccc(Cl)cc4)cc3)CC2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCCc1ccc([C@H]2CC[C@H](CCc3ccc(C(=O)Cl)cc3)CC2)cc1
Temperature: 0 °C

Procedure:
After 27.6 g of the (2-(trans-4-(4-n-propylphenyl)cyclohexyl)ethyl)benzene obtained in (7) of Example 2 was dissolved in 200 ml of methylene chloride, it was cooled down to 0° C., and 24 g of aluminum chloride was added to the solution and stirred. Oxalyl chloride in an amount of 22.8 g was added dropwise little by little to the solution, and after the temperature of the solution was raised up to room temperature, it was stirred for 2 hours. After finishing of the reaction, it was added to 500 ml of water and extracted with 200 ml of methylene chloride. Organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under a reduced pressure to obtain 20 g of 4-(2-(trans-4-(4-n-propylphenyl)cyclohexyl)ethyl)benzoyl chloride.
Reaction SMILES: C1(N([C@H]2CC[C@H](COC)CC2)C(=O)NC2SC(SC[C:17](O)=[O:18])=CN=2)CCCCC1.[CH:30]1([NH:36][C@H:37]2[CH2:42][CH2:41][C@H:40]([CH2:43][O:44][CH2:45][CH3:46])[CH2:39][CH2:38]2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C([O:49][C:50](=[O:61])[C:51]([S:54][C:55]1[S:59][C:58]([NH2:60])=[N:57][CH:56]=1)([CH3:53])[CH3:52])C>>[CH:30]1([N:36]([C@H:37]2[CH2:42][CH2:41][C@H:40]([CH2:43][O:44][CH2:45][CH3:46])[CH2:39][CH2:38]2)[C:17](=[O:18])[NH:60][C:58]2[S:59][C:55]([S:54][C:51]([CH3:53])([CH3:52])[C:50]([OH:49])=[O:61])=[CH:56][N:57]=2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: COC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCCC2)CC1
Reactant: CCOC[C@H]1CC[C@H](NC2CCCCC2)CC1
Reactant: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CCOC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SC(C)(C)C(=O)O)s2)C2CCCCC2)CC1

Procedure:
Prepared in a similar manner to {2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid via cyclohexyl-(trans-4-ethoxymethyl-cyclohexyl)-amine and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester to give the title compound.
Reaction SMILES: C([O-])(=O)C.[NH4+].[CH2:6]([N:13]1[CH2:18][CH2:17][C:16](=O)[C:15]([CH3:21])([CH3:20])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([BH3-])#[N:23].[Na+]>CO>[NH2:23][CH:16]1[CH2:17][CH2:18][N:13]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:14][C:15]1([CH3:21])[CH3:20]
Reactant: CC1(C)CN(Cc2ccccc2)CCC1=O
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC1(C)CN(Cc2ccccc2)CCC1N
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Ammonium acetate (3.5 g, 45.45 mmol) was added to the stirred solution of 1-benzyl-3,3-dimethyl-4-piperidone (2.0 g, 9.2 mmol), in methanol (20 ml) and stirring was continued for 3 hr at ambient temperature. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (0.58 g, 9.2 mmol) was added. Cooling was removed after 10 min. and resulting mixture was stirred for 6 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 3˜4) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1 M sodium hydroxide solution (pH˜10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to furnish 4-amino-1-benzyl-3,3-dimethyl piperidine. Yield 1.6 g (77%), C14H22N2, m/z 219 (M+1), PMR (CDCl3): 0.84 (s, 3H), 0.98 (s, 3H), 1.48 (bs, 2H, D2O exchangeable), 1.66 (m, 2H), 2.04 (m, 2H), 2.42 (m, 2H), 2.86 (m, 1H), 3.46 (dd, 2H), 7.32 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[C:13]([NH:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=4)[N:14]=[C:15](O)[C:16]=3[N:17]=2)=[CH:4][CH:3]=1.C1C[N:34]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)[CH2:33][CH2:32]1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C(N)C>CN(C=O)C>[CH2:33]([NH:34][C:15]1[C:16]2[N:17]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:9]=[CH:10][C:11]=2[N:12]=[C:13]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[N:14]=1)[CH3:32]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: NS(=O)(=O)c1ccc(CNc2nc(O)c3nc(-c4ccc(F)cc4)ccc3n2)cc1
Agent: CCN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNc1nc(NCc2ccc(S(N)(=O)=O)cc2)nc2ccc(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
4-{[6-(4-Fluoro-phenyl)-4-hydroxy-pyrido[3,2-d]pyrimidin-2-ylamino]-methyl}-benzenesulfonamide (100 mg, 0.23 mmol) and PyBOP (119 mg, 0.23 mmol) were taken up in DMF (2 mL) and DIEA (0.07 mL, 0.46 mmol) was added, followed by ethylamine (2.0M in THF) (0.115 mL, 0.23 mmol) This solution was stirred at room temperature overnight. The DMF was removed in vacuo and the residue diluted with ethyl acetate (2 mL) and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated to afford an oily residue. The residue was purified by RP HPLC using a C18 column with a 0-60% gradient of 0.1% TFA-H2O/0.1% TFA-acetonitrile to afford 55 mg (52%) of Example 297. MS (m/z) 453.4 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[O:15][C:14]([CH:16]=O)=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH2:18]([NH:25][CH3:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([N:25]([CH2:16][C:14]1[O:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)[CH3:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCc1cc(-c2ccc(C=O)o2)c(C)[nH]c1=O
Reactant: CNCc1ccccc1
Product: CCc1cc(-c2ccc(CN(C)Cc3ccccc3)o2)c(C)[nH]c1=O
Yield: 53 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl]furan-2-carbaldehyde is reacted with benzyl methylamine as described in Method A, Example 123 to give the title compound as a solid (53% yield). LC/MS: RT 2.08 min; m/e 337 (M+H); 1H NMR (δ, ppm): 11.6 (1H, s), 7.46 (1H, s); 7.3 (5H, m); 6.4 (2H, dd), 3.6 (2H, s), 3.55 (2H, s), 2.4 (2H, m), 2.36 (2H, s), 2.2 (3H, s), 1.05 (3H, t).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](C)=[CH:9][NH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].Br[CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[C:29]([Cl:31])[C:28]([O:32][CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[C:27]([Cl:38])[CH:26]=2)[N:24]=1)=[O:18].[H-].[Na+]>CN(C=O)C>[Cl:38][C:27]1[CH:26]=[C:25]([C:23]2[N:24]=[C:20]([NH:19][C:17](=[O:18])[CH2:16][N:10]3[C:6]4[C:5](=[O:12])[N:4]([CH3:13])[C:3](=[O:14])[N:2]([CH3:1])[C:7]=4[CH:8]=[CH:9]3)[S:21][CH:22]=2)[CH:30]=[C:29]([Cl:31])[C:28]=1[O:32][CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)COc1c(Cl)cc(-c2csc(NC(=O)CBr)n2)cc1Cl
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ccn2CC(=O)Nc2nc(-c3cc(Cl)c(OCC(C)(C)C)c(Cl)c3)cs2)n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (50 mg, 0.110 mmol) with 2-bromo-N-{4-[3,5-dichloro-4-(2,2-dimethylpropoxy)phenyl]-1,3-thiazol-2-yl}acetamide (23 mg, 0.128 mmol) in the presence of NaH (7 mg, 0.291 mmol) in dry DMF (5.0 mL) to give 30 mg of the product as an off-white solid; 1H NMR (δ ppm, DMSO-d6, 300 MHz) 1.08 (s, 9H), 3.17 (s, 3H), 3.39 (s, 3H), 3.67 (s, 2H), 5.32 (s, 2H), 6.22 (s, 2H), 7.35 (s, 1H), 7.85 (s, 1H), 8.00 (s, 2H), 12.68 (br s, 1H); APCI-MS (m/z) 550.20 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N+:11]([O-])=O)[CH:3]=1.[C:14](N)([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:15]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:11][C:14]([CH3:16])([CH3:15])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:3]=1
Reactant: CC(C)(C)CC(C)(C)N
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Solvent: CCO
Product: CC(C)(C)CC(C)(C)Nc1cc(Cl)ccc1[N+](=O)[O-]
Yield: 46.2 %

Procedure:
A mixture of 20 g of 4-chloro-1,2-dinitrobenzene and 30 g of tert-octylamine in 300 ml of 95° EtOH is refluxed for 16 hours. The solvent is evaporated off under vacuum to give 13 g of the expected product after crystallization from an iso ether/heptane mixture (40/60; v/v). M.p.=108° C.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](CCO)=[C:11]([N+:22]([O-:24])=[O:23])[CH:10]=1>N1C=CC=CC=1.CCOC(C)=O>[C:5]([O:4][CH2:1][CH2:2][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([NH2:8])=[CH:10][C:11]=1[N+:22]([O-:24])=[O:23])(=[O:7])[CH3:6]
Reactant: Nc1cc([N+](=O)[O-])c(CCO)c2ccccc12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OCCc1c([N+](=O)[O-])cc(N)c2ccccc12
Reaction time: 2 h
Yield: 25.7 %

Procedure:
Acetic anhydride (4.0 mL, 42.39 mmol) was added to a solution of 2-[4-amino-2-nitronaphthalen-1-yl]ethanol (3.3 g, 14.21 mmol) in dry pyridine (33 mL) at room temperature and stirred for 2 hr. The mixture was diluted with AcOEt (100 mL). The organic layer was washed with H2O (30 mL), saturated aqueous NaHCO3 (30 mL), saturated aqueous NaCl (30 mL), and then the organic layer was dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography (33% AcOEt-Petroleum ether) afforded 2-[4-amino-2-nitronaphthalen-1-yl]ethyl acetate (1.0 g, 26%) as an orange solid.; mp 108-110 ° C.; 1H NMR (CDCl3, 500 MHz) δ 8.33 (d, 8.5, 1H), 7.84 (dd, 8.0, 0.5, 1H), 7.70 (dt, 7.5, 0.5, 1H), 7.64 (dt, 8.5, 1.5, 1H), 7.11 (s, 1H), 4.44 (t, 8.0, 2H), 4.38 (brs, 2H), 3.49 (t, 8.0, 2H), 2.06 (d, 0.5, 3H); FABMS (NBA) m/z 274 (M+), IR (neat) 3381, 1728, 1636, 1589, 1516, 1469, 1437, 1342, 1241, 1041, 754 cm−1.
Reaction SMILES: [CH:1]1([N:7]2[C:11](=[O:12])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:24][CH2:23][N:22]([C:25]5[CH:30]=[CH:29][C:28]([O:31]C)=[CH:27][CH:26]=5)[CH2:21][CH2:20]4)=[CH:15][CH:14]=3)[CH:9]=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>Br>[CH:1]1([N:7]2[C:11](=[O:12])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:20][CH2:21][N:22]([C:25]5[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=5)[CH2:23][CH2:24]4)=[CH:15][CH:14]=3)[CH:9]=[N:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(N2CCN(c3ccc(-n4cnn(C5CCCCC5)c4=O)cc3)CC2)cc1
Agent: Br
Product: O=c1n(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)cnn1C1CCCCC1
Yield: 92 %

Procedure:
This compound was synthesized as a white amorphous solid from 4k (24.2 mg, 0.056 mmol) in 48% aqueous HBr (1.0 mL) in 92% yield by following general procedure 1.4: MALDI-MS: 420.2 (M+H+), 442.2 (M+Na+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([NH:18][CH2:19][CH:20]([OH:35])[CH:21]([NH:31][C:32](=[O:34])[CH3:33])[CH2:22][C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=3)[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([NH:18][CH2:19][CH:20]([OH:35])[CH:21]([NH:31][C:32](=[O:34])[CH3:33])[CH2:22][C:23]3[CH:24]=[C:25]([F:30])[CH:26]=[C:27]([F:29])[CH:28]=3)[CH2:17][CH2:16][C:11](=[O:12])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)NC(Cc1cc(F)cc(F)c1)C(O)CNC1(c2cccc(Br)c2)CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(=O)NC(Cc1cc(F)cc(F)c1)C(O)CNC1(c2cccc(Br)c2)CCC(=O)CC1
Temperature: 100 °C
Yield: 100.7 %

Procedure:
Compound 18 (0.4 g, 0.78 mmol), p-Toluenesulfonic acid monohydrate (TsOH) (0.16 g, 0.84 mmol), and poly(Ethylene glycol) (8.9 g, 143.4 mmol) were added to 25 mL benzene. The reaction was heated to 100° C. for 30 min. The benzene was removed under reduced pressure and fresh benzene was added. The resulting mixture was treated with saturated NaHCO3 and extracted CH2Cl2. The organic layer was washed with brine and dried with MgSO4, filtered and concentrated under reduced pressure providing 0.4 g of Compound 19.
Reaction SMILES: NC(N)=O.[CH2:5]([O:12][CH2:13][CH2:14][NH:15][S:16]([C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[C:21]([NH2:26])[C:20]=1[OH:27])(=[O:18])=[O:17])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:28][C:29]1[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=1[N:36]=[C:37]=[O:38]>>[CH2:5]([O:12][CH2:13][CH2:14][NH:15][S:16]([C:19]1[C:20]([OH:27])=[C:21]([NH:26][C:37]([NH:36][C:30]2[CH:31]=[CH:32][CH:33]=[C:34]([Cl:35])[C:29]=2[Cl:28])=[O:38])[CH:22]=[CH:23][C:24]=1[Cl:25])(=[O:18])=[O:17])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Nc1ccc(Cl)c(S(=O)(=O)NCCOCc2ccccc2)c1O
Reactant: O=C=Nc1cccc(Cl)c1Cl
Agent: NC(N)=O
Product: O=C(Nc1ccc(Cl)c(S(=O)(=O)NCCOCc2ccccc2)c1O)Nc1cccc(Cl)c1Cl
Yield: 75 %

Procedure:
Following the general procedure for urea formation outlined in example 15, N-(2-benzyloxyethyl)-3-amino-6-chloro-2-hydroxybenzenesulfonamide (119 mg, 0.33 mmol) and 2,3-dichlorophenylisocyanate (44 mg, 0.23 mmol) were coupled to form the desired urea (94 mg, 75%). LC-MS (m/z) 546.0 (M+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=2)=[N:8][C:7]1=[O:19].[F:20][C:21]([F:35])([F:34])[C:22]1[CH:27]=[CH:26][C:25]([C@:28]23[CH2:33][C@H:32]2[CH2:31][NH:30][CH2:29]3)=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C>CCO>[ClH:1].[ClH:1].[CH3:18][C:14]1[N:13]=[C:12]([C:9]2[CH:10]=[CH:11][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:30]3[CH2:31][C@H:32]4[C@:28]([C:25]5[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:35])[F:34])=[CH:27][CH:26]=5)([CH2:33]4)[CH2:29]3)[C:7](=[O:19])[N:8]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cccc(-c2ccn(CCCCCl)c(=O)n2)n1
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(-c2ccn(CCCCN3C[C@@H]4C[C@]4(c4ccc(C(F)(F)F)cc4)C3)c(=O)n2)n1
Product: Cl
Reaction time: 3 h
Yield: 36.9 %

Procedure:
A solution of 1-(4-chloro-butyl)-4-(6-methyl-pyridin-2-yl)-1H-pyrimidin-2-one (Prep17, 48 mg, 0.17 mmol), (1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4, 38 mg, 0.17 mmol), KI (2 mg) and DIPEA (66 mg, 0.51 mmol) in absolute EtOH (2 ml) was placed in a microwave oven and irradiated at 125° C. for 13 hours. The solvent was removed under vacuum and the residue was redissolved in DCM and filtered. The filtrate was stirred in the presence of PS-isocyanate (350 mg) for 3 hours. The mixture was filtered and the solvent removed under vacuum. The crude was purified by flash chromatography with DCM-MeOH—NH4OH (99-1-0.1) to give the title compound (17 mg, 4% yield) as a free base.
Reaction SMILES: Cl.[CH:2]([C:8]1[CH:9]=[C:10]([C:16]2[O:17]CC(C)(C)N=2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15])=[CH:3][CH2:4][CH2:5][CH2:6][CH3:7].[Cl-].[Na+].[OH2:25]>>[CH:2]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:16]([OH:17])=[O:25])=[CH:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCC=Cc1cc(C2=NC(C)(C)CO2)ccc1OC
Reactant: O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Product: CCCCC=Cc1cc(C(=O)O)ccc1OC
Yield: 35 %

Procedure:
6N Hydrochloric acid (20 ml) was added to 2-[3-(1-hexenyl)-4-methoxyphenyl]-4,4-dimethyl-4,5-dihydrooxazole (583 mg, 2.03 mmol), and the mixture was refluxed under heating for 4 hours. Saturated saturated brine (30 ml) was added to this solution, and the aqueous layer was extracted 3 times with ethyl acetate (50 ml). The organic layers were combined, and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane/ethyl acetate=2/1) to give 3-(1-hexenyl)-4-methoxybenzoic acid (164.3 mg, 35%) as a mixture (colorless crystals) of geometrical isomers (1:1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[OH:12])=[CH:4][CH:3]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH2:13]([O:12][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:11]=2)[CH:6]=[CH:7][N:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Oc1nccc2ccc(Br)cc12
Solvent: CN(C)C=O
Product: Brc1ccc2ccnc(OCc3ccccc3)c2c1
Temperature: 80 °C
Yield: 91.3 %

Procedure:
To a 25 mL round-bottom flask containing 7-bromoisoquinolin-1-ol (500 mg, 2.23 mmol) was added TEA (0.467 mL, 3.35 mmol) and benzyl bromide (0.319 mL, 2.68 mmol) in DMF (10 mL) to give a brown solution. The reaction was heated to 80° C. overnight. After cooling to RT, the reaction mixture was concentrated in vacuo, and taken up in DCM and water. The aqueous layer was extracted with DCM (2×), and the combined organics fractions were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purify by flash column chromatography (10-30-50% EtOAc/Heptanes), providing the title compound (640 mg, 2.037 mmol, 91% yield). M+1=316.0. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.62 (d, J=2.01 Hz, 1H), 7.73 (dd, J=2.13, 8.41 Hz, 1H), 7.39 (d, J=8.28 Hz, 1H), 7.28-7.36 (m, 5H), 7.11 (d, J=7.53 Hz, 1H), 6.46 (d, J=7.28 Hz, 1H), 5.23 (s, 2H).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[N:9][CH2:8][CH:7]2[C:14]([O:16][CH3:17])=[O:15].Cl>CO.CCOCC.[Pd]>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][NH:9][CH2:8][CH:7]2[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)C1CN=Cc2ccc(OC)cc21
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C1CNCc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The compound obtained in Step D (9.21g), in the form of a base, is dissolved in 150 ml of methanol and then palladium-on-carbon (900 mg) is added to the solution. The reaction mixture is stirred at ambient temperature under hydrogen for 4 hours. After removal of the palladium-on-carbon by filtration, the organic phase is evaporated under reduced pressure. The oil obtained is taken up in ether saturated with HCl. The precipitate formed is suction-filtered off and recrystallised from acetonitrile to yield the title product in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1([C:24]([NH2:26])=O)[CH2:23][CH2:22]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>O1CCCC1.O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1([C:24](=[S:36])[NH2:26])[CH2:23][CH2:22]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C1(C(N)=O)CC1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C1(C(N)=S)CC1
Temperature: 25 °C
Yield: 25.8 %

Procedure:
To a solution of Example 2 (400 mg, 0.99 mmol) in tetrahydrofuran (32 ml), under nitrogen, was added Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-disulphide, 240 mg, 0.59 mmol). The reaction mixture was heated at reflux for 3 h, cooled to room temperature and diluted with water. The mixture was extracted with ethyl acetate (×3) and the combined extracts were dried (MgSO4) and concentrated in vacuo. The residue was dissolved in acetonitrile (1.2 ml) and purified by automated preparative liquid chromatography (Gilson system, 150 mm×30 mm Phenomenex LUNA C18(2) 10 μm column) using an acetonitrile:water gradient [45:55 to 95:5]. The appropriate fractions were concentrated in vacuo to give the titled compound (64 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[CH:40][C:41]([NH2:44])=[N:42][CH:43]=2)O1>>[NH2:44][C:41]1[N:42]=[CH:43][C:38]([C:2]2[N:3]=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([CH2:18][C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:39][CH:40]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: CN(C)C(=O)CN1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CN(C)C(=O)CN1CCN(Cc2cc3nc(-c4ccc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-[4-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazin-1-yl]-N,N-dimethyl-acetamide was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine in General Procedure A. Purification on silica yielded 163. NMR 400 MHz (CDCl3): 2.61 (8H, b, CH2), 2.94 (3H, s, CH3), 3.07 (3H, s, CH3), 3.19 (2H, s, CH2), 3.82 (2H, s, CH2), 3.87-3.89 (4H, m, CH2), 4.01-4.04 (4H, m, CH2), 4.60 (2H, s, CH2), 6.56 (1H, d (J=9.03), ar), 7.26 (1H, s, ar), 8.45 (1H, dd (J=8.45, 2.29), ar), 9.15 (1H, d (J=1.78), ar). MH+=497.21
Reaction SMILES: [C@@H:1]12[O:11][CH2:10][C@@H:8]([O:9]1)[C@@H:6]([OH:7])[C@@H:4]([OH:5])[C@@H:2]2[OH:3].S(=O)(=O)(O)[OH:13]>>[O:13]=[CH:10][C@H:8]([C@@H:6]([C@@H:4]([C@@H:2]([CH2:1][OH:11])[OH:3])[OH:5])[OH:7])[OH:9]
Reactant: O[C@H]1[C@H](O)[C@@H]2OC[C@@H](O2)[C@H]1O
Reactant: O=S(=O)(O)O
Product: O=C[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO

Procedure:
0.16 g (1.00 mmol) of the compound (3) was dissolved in 5 ml of 1N sulfuric acid, and the resultant solution was kept stirred for 5 hours at 100° C. The reaction mixture was passed through an anion exchange resin (hydroxyl ion type amberlight IRA-410) for neutralizing purposes, followed by removing the solvent by means of distillation under reduced pressure. Formation of the desired compound of the present invention, i.e., D-altrose (compound 4), was confirmed by thin layer chromatography. It was also confirmed that the raw material compound (3) was mixed with the product compound (4). The mixing ratio of these compounds (3) and (4) was about 1:1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([C:23]3[N:27]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:26]4[CH:36]=[CH:37][CH:38]=[CH:39][C:25]=4[N:24]=3)[C:11](=[O:22])[N:12]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:13]=2)[CH:5]=[CH:4][N:3]=1.[NH2:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>>[N:43]1([CH2:42][CH2:41][NH:40][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[C:10]([C:23]4[N:27]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:34])([CH3:33])[CH3:35])[C:26]5[CH:36]=[CH:37][CH:38]=[CH:39][C:25]=5[N:24]=4)[C:11](=[O:22])[N:12]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:21])[CH3:19])[N:13]=3)[CH:5]=[CH:4][N:3]=2)[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccnc(Cl)n2)cc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c1=O
Reactant: NCCN1CCOCC1
Product: C[Si](C)(C)CCOCn1nc(-c2ccnc(NCCN3CCOCC3)n2)cc(-c2nc3ccccc3n2COCC[Si](C)(C)C)c1=O
Temperature: 100 °C

Procedure:
100 mg of 6-(2-chloropyrimidin-4-yl)-2-(2-trimethylsilanylethoxymethyl)-4-[1-(2-trimethylsilanylethoxymethyl)-1H-benzimidazol-2-yl]-2H-pyridazin-3-one are suspended in 0.5 ml of N-(2-aminoethyl)morpholine, and the reaction mixture is heated at 100° C. in a microwave for 20 minutes. The product is purified by preparative RP-HPLC (0-100% acetonitrile (+0.05% formic acid) in water (+0.05% formic acid)).