Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26]Cl)[CH:21]=1.O>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][CH2:26][C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCOCc2cccnc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
A solution of 1-(tert-butoxycarbonyl)-4-(2-hydroxyethyl)piperidine (459 mg, 2.0 mmol) in anhydrous DMF (10 mL) was cooled to 0° C., and NaH (60% dispersion in oil, 200 mg, 5 mmol, 2.5 equiv.) was added all at once. Alkoxide formation was effected by stirring at room temperature for 2 h under N2, then 3-picolyl chloride hydrochloride (345 mg, 2.1 mmol, 1.05 equiv.) and tetra-n-butylammonium iodide (7.4 mg, 20 μmol, 0.01 equiv.) were added. The mixture was warmed to 80° C. and stirred at that temperature for 4 h. After cooling to room temperature, H2O was added, and the product was extracted into EtOAc. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by CC (SiO2, EtOAc/hexane 1:1) to afford 1-(tert-butoxycarbonyl)-4-[2-(3-pyridylmethoxy)ethyl]piperidine (574 mg, 80%) after evaporation as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 8.39 (s, 1H), 8.33 (d, 1H, J=4.8 Hz), 7.54 (d, 1H, J=8.0 Hz), 7.11 (m, 1H), 4.71 (s, 2H), 3.89 (m, 2H), 3.46 (t, 2H, J=6.4 Hz), 2.74 (m, 2H), 1.44 (m, 3H), 1.31 (m, 2H), 1.24 (s, 9H), 0.88 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 154.6, 149.1, 149.0, 136.2, 133.2, 123.5, 78.9, 59.2, 42.8, 39.0, 32.3, 31.9, 28.2.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:11](=[O:12])[C@@H:10]([NH:13][C:14](=[O:21])[C@@:15]([F:20])([CH3:19])[C:16](O)=[O:17])[C:9]3[CH:22]=[CH:23][CH:24]=[CH:25][C:8]=3[C:7]3[CH:26]=[CH:27][CH:28]=[CH:29][C:6]2=3)[CH2:3][CH2:2]1.[F:30][C:31]([F:39])([C:35]([F:38])([F:37])[F:36])[CH2:32][CH2:33][NH2:34]>>[CH:1]1([CH2:4][N:5]2[C:11](=[O:12])[C@@H:10]([NH:13][C:14](=[O:21])[C@@:15]([F:20])([CH3:19])[C:16]([NH:34][CH2:33][CH2:32][C:31]([F:39])([F:30])[C:35]([F:38])([F:37])[F:36])=[O:17])[C:9]3[CH:22]=[CH:23][CH:24]=[CH:25][C:8]=3[C:7]3[CH:26]=[CH:27][CH:28]=[CH:29][C:6]2=3)[CH2:2][CH2:3]1
Reactant: NCCC(F)(F)C(F)(F)F
Reactant: C[C@@](F)(C(=O)O)C(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21
Product: C[C@@](F)(C(=O)NCCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21

Procedure:
(S)-N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-fluoro-2-methyl-malonamic acid was coupled with 3,3,4,4,4-pentafluoro-butylamine in analogy to the procedure described for example 73 to yield (R)-N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2-fluoro-2-methyl-N′-(3,3,4,4,4-pentafluoro-butyl)-malonamide as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1Cl.[CH:13]1([N:16]2[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]2)[CH2:15][CH2:14]1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1[NH:22][CH:19]1[CH2:20][CH2:21][N:16]([CH:13]2[CH2:15][CH2:14]2)[CH2:17][CH2:18]1
Reactant: NS(=O)(=O)c1cnc(Cl)c(Cl)c1
Reactant: NC1CCN(C2CC2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cnc(NC2CCN(C3CC3)CC2)c(Cl)c1

Procedure:
A mixture of EXAMPLE 387A (0.4 g), 1-cyclopropylpiperidin-4-amine (0.3 g) and N,N-diisopropylethylamine (0.37 mL) in dioxane (3 mL) was heated at 100° C. for 18 hours. The crude product was isolated by concentration and was purified on silica gel, which was eluted with ethyl acetate to give the title compound.
Reaction SMILES: [O:1]=[C:2]([CH3:19])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:18])OCC(Cl)(Cl)Cl)=[CH:6][CH:5]=1.[C:20]1([C:26]2[N:30]=[C:29]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:28][N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[O:1]=[C:2]([CH3:19])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([N:34]2[CH2:35][CH2:36][N:31]([C:29]3[S:28][N:27]=[C:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:30]=3)[CH2:32][CH2:33]2)=[O:18])=[CH:8][CH:9]=1
Reactant: CC(=O)Cc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(=O)Cc1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)cc1

Procedure:
A solution of 2,2,2-trichloroethyl [4-(2-oxopropyl)phenyl]carbamate (200 mg, 0.616 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (152 mg, 0.616 mmol), diisopropylethylamine (0.107 ml, 0.616 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product as a solid. This was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the desired product (45.2 mg, 17.4%) as a solid.
Reaction SMILES: C[O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][OH:13])=[CH:6][CH:5]=1.[OH-].[Na+]>CO>[OH:13][CH2:12][CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:14])=[O:2])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(OCCO)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(OCCO)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 41.4 %

Procedure:
4-(2-Hydroxy-ethoxy)-benzoic acid methyl ester (400 mg, 2.04 mmol) is combined with a mixture of 1 N NaOH (3 mL) and MeOH (3 mL) and the mixture is stirred at 80° C. for 1 h. The solvents are evaporated and the resulting residue is dissolved in a small amount of water and acidified with 1 N HCl. The crystals are collected, washed with water, and dried to provide 154 mg (42%) of the titled compound. NMR (DMSO-d6): δ 12.64 (br, 1H), 7.90 (d, 2H, J=8.2 Hz), 7.03 (d, 2H, J=8.2 Hz), 4.93 (br, 1H), 4.07 (t, 2H, J=4.9 Hz), 3.75 (m, 2H).
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[OH:14][CH2:15][CH2:16][C:17]#[N:18]>CN(C=O)C>[Si:6]([O:14][CH2:15][CH2:16][C:17]#[N:18])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: N#CCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCC#N
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.7 %

Procedure:
Imidazole (33.6 g, 495 mmol) and tert-butyldimethylsilyl chloride (27.2 g, 180 mmol) were added to a 0° C. solution of 3-hydroxypropanenitrile (10.6 g, 150 mmol) in DMF 50 mL). The mixture was allowed to warm to rt, then was stirred at rt for 12 hrs. The mixture was quenched with water (500 mL), and then extracted with EtOAc (3×). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (gradient elution 0-5% EtOAc/petroleum ether) to give 3-(tert-butyldimethylsilyloxy)propanenitrile (18 g, 75%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 3.74 (t, J=6.0 Hz, 2H), 2.43 (t, J=6.0 Hz, 2H), 0.81 (s, 9H), 0.00 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:28]=1[C:9]1([CH2:14][CH2:13][N:12]([C:15](=[O:27])[NH:16][CH:17]3[CH:24]4[CH2:25][CH:20]5[CH2:21][CH:22]([CH2:26][CH:18]3[CH2:19]5)[CH2:23]4)[CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH:29]([CH3:35])[C:30]([O:32]CC)=[O:31].O[Li].O>CO.O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:28]=1[C:9]1([CH2:10][CH2:11][N:12]([C:15](=[O:27])[NH:16][CH:17]3[CH:18]4[CH2:26][CH:22]5[CH2:21][CH:20]([CH2:25][CH:24]3[CH2:23]5)[CH2:19]4)[CH2:13][CH2:14]1)[CH2:8][CH:7]2[CH:29]([CH3:35])[C:30]([OH:32])=[O:31]
Reactant: CCOC(=O)C(C)C1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2c(Br)cccc21
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CC(C(=O)O)C1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution (±)-ethyl 2-(7-bromo-1′-(2-adamantylcarbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)propanoate (63 mg, 0.122 mmol) in anhydrous MeOH (1 mL) was added LiOH.H2O (10 mg, 0.244 mmol) in H2O (0.1 mL). The reaction mixture was stirred at rt overnight. The mixture was concentrated to give crude product, which was purified by preparative TLC to afford 2-(7-bromo-1′-((2-adamantyl)carbamoyl)-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)propanoic acid. 1H NMR: (400 MHz, CDCl3): δ=1.04 (s, 3H), 1.21 (s, 3H), 1.34-1.43 (m, 2H), 1.60-1.71 (m, 3H), 1.76-2.08 (m, 13H), 2.29-2.40 (m, 1H), 2.51-2.61 (m, 1H), 2.99-3.27 (m, 3H), 3.89 (m, 2H), 4.02-4.14 (m, 2H), 7.01 (m, 1H), 7.21-7.33 (m, 2H).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si](OS(C(F)(F)F)(=O)=O)(CC)(CC)CC.ClC(Cl)(Cl)C(=N)O[C@H:28]1[O:49][C@H:48]([CH2:50][O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C@@H:39]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@H:34]([O:35][CH2:36][CH:37]=[CH2:38])[C@H:29]1[O:30][C:31](=[O:33])[CH3:32].C(N(CC)CC)C>ClCCl>[C:31]([O:30][C@@H:29]1[C@@H:34]([O:35][CH2:36][CH:37]=[CH2:38])[C@H:39]([O:40][CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C@@H:48]([CH2:50][O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[O:49][C@H:28]1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:33])[CH3:32]
Reactant: OCc1ccccc1
Reactant: C=CCO[C@@H]1[C@@H](OC(C)=O)[C@@H](OC(=N)C(Cl)(Cl)Cl)O[C@H](COCc2ccccc2)[C@H]1OCc1ccccc1
Agent: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCO[C@@H]1[C@@H](OC(C)=O)[C@H](OCc2ccccc2)O[C@H](COCc2ccccc2)[C@H]1OCc1ccccc1
Yield: 91 %

Procedure:
1.62 mL (3 eq.) of benzyl alcohol and 130 μL (0.1 eq.) of TESOTf are added to 3.07 g (1 eq.) of 2-O-acetyl-3-O-allyl-4,6-di-O-benzyl-α-D-gluco-pyranosyl trichloroacetimidate (M=586.5) in 25 mL of dichloromethane at 0° C. in the presence of 2.5 g of 4 Å molecular seives. After 1 hour of reaction at 0° C., the medium is neutralised with triethylamine, filtered and concentrated. Purification over silica gel [flash; eluent: toluene/ethyl acetate (98/2; v/v)] enables isolating 2.52 g of benzyl 2-O-acetyl-3-O-allyl-4,6-di-O-benzyl-β-D-glucopyranoside (M=532).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14](Cl)=[O:15])=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([Cl:35])[C:21]2[O:25][C:24]([CH2:26][CH:27]3[NH:32][CH2:31][CH2:30][N:29]([CH3:33])[CH2:28]3)=[CH:23][C:22]=2[CH:34]=1>>[Cl:17][C:18]1[CH:19]=[C:20]([Cl:35])[C:21]2[O:25][C:24]([CH2:26][CH:27]3[CH2:28][N:29]([CH3:33])[CH2:30][CH2:31][N:32]3[C:14]([C:9]3[N:10]=[C:11]([CH3:13])[S:12][C:8]=3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:15])=[CH:23][C:22]=2[CH:34]=1
Reactant: Cc1nc(C(=O)Cl)c(-c2ccc(F)cc2)s1
Reactant: CN1CCNC(Cc2cc3cc(Cl)cc(Cl)c3o2)C1
Product: Cc1nc(C(=O)N2CCN(C)CC2Cc2cc3cc(Cl)cc(Cl)c3o2)c(-c2ccc(F)cc2)s1

Procedure:
The title compound (80 mg) was prepared from 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carbonyl chloride (498 mg) and (RS)-3-(5,7-dichloro-benzofuran-2-ylmethyl)-1-methyl-piperazine, D65 (530 mg) by a procedure similar to that described for Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[N:25]1[CH2:30][CH2:29][CH:28]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH2:27][CH2:26]1)[NH2:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:21][C:20]3[CH:22]=[CH:23][C:24]([N:25]4[CH2:30][CH2:29][CH:28]([N:31]5[CH2:36][CH2:35][O:34][CH2:33][CH2:32]5)[CH2:27][CH2:26]4)=[C:18]([Cl:17])[CH:19]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(N2CCC(N3CCOCC3)CC2)c(Cl)c1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(Cl)c2)cnn1-c1ccc(Cl)cc1
Yield: 42.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.6 g) and 3-chloro-4-(4-morpholinopiperidin-1-yl)aniline (0.7 g), the title compound (0.51 g) was obtained, melting point: 238–240° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23])=[CH:16][CH:15]=1>N1C=CC=CC=1.C(OCC)(=O)C>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][S:22]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=2[S:9]([NH2:12])(=[O:10])=[O:11])(=[O:24])=[O:23])=[CH:18][CH:19]=1
Reactant: Cc1ccc(N)c(S(N)(=O)=O)c1
Reactant: O=S(=O)(Cl)CCc1ccc(Br)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(NS(=O)(=O)CCc2ccc(Br)cc2)c(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.7 %

Procedure:
A mixture of 2-amino-5-methyl-benzenesulfonamide (0.1 g, 0.53 mmol) and 2-(4-bromo-phenyl)-ethanesulfonyl chloride (0.14 g, 0.49 mmol) in anhydrous pyridine (4 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (20 mL) and the organic phase was washed with aqueous hydrochloric acid (1 M, 20 mL), saturated sodium bicarbonate (20 mL) and brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC, using 5% methanol in dichloromethane as the eluent, to give 80 mg (38% yield) of title compound.
Reaction SMILES: C(OC(=O)CN1C(=O)/C(=C/C2OC(C3C=CC=C([Sn](CCCC)(CCCC)CCCC)C=3)=CC=2)/NC1=S)C.[CH:39]([C:41]1[O:45][C:44](B(O)O)=[CH:43][CH:42]=1)=[O:40].[Br:49][C:50]1[CH:51]=[C:52](I)[CH:53]=[CH:54][CH:55]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[Br:49][C:50]1[CH:55]=[C:54]([C:44]2[O:45][C:41]([CH:39]=[O:40])=[CH:42][CH:43]=2)[CH:53]=[CH:52][CH:51]=1
Reactant: Brc1cccc(I)c1
Reactant: O=Cc1ccc(B(O)O)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[Sn](CCCC)(CCCC)c1cccc(-c2ccc(/C=C3\NC(=S)N(CC(=O)OCC)C3=O)o2)c1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: O=Cc1ccc(-c2cccc(Br)c2)o1

Procedure:
Synthesis of (Z)-ethyl-2-(5-oxo-2-thioxo-4-((5-(3-(tributylstannyl)phenyl)furan-2-yl)methylene)imidazolidin-1-yl)acetate may be carried out in accordance with a known method, for example, a method described in non-patent document 2. First, substantially equivalent amounts of 5-formyl-2-furanboronic acid and 3-bromoiodobenzene are dissolved in 1,2-dimethoxyethane, and sodium carbonate and a catalytic amount of tetrakis(triphenylphosphine)palladium are added thereto. This solution is heated to reflux while stirring so as to carry out a reaction. After the reaction is complete, the solvent is removed by evaporation. Then, purification is carried out to give 5-(3-bromophenyl)furan-2-carbaldehyde (FIG. 1, step 1).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:16]=1)[CH2:9][C:8]12[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:4].[OH-].[Na+]>O1CCCC1.CO.O>[O:24]1[CH2:25][CH2:26][N:21]([C:17]2[CH:16]=[C:15]([CH:10]3[CH2:9][C:8]4([CH2:30][CH2:29][CH2:28][CH2:27]4)[C:7]4[C:12](=[CH:13][CH:14]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=4)[NH:11]3)[CH:20]=[CH:19][CH:18]=2)[CH2:22][CH2:23]1
Reactant: COC(=O)c1ccc2c(c1)C1(CCCC1)CC(c1cccc(N3CCOCC3)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2c(c1)C1(CCCC1)CC(c1cccc(N3CCOCC3)c1)N2
Temperature: 80 °C
Reaction time: 6 h
Yield: 89.9 %

Procedure:
To a stirred solution of 2′-(3-morpholinophenyl)-2′,3′-dihydro-1′H-spiro[cyclopentane-1,4′-quinoline]-6′-carboxylic acid methyl ester (406.0 mg, 1.0 mmol) in tetrahydrofuran (10.0 mL) and methanol (10.0 mL) was added 3 N sodium hydroxide (2.0 mL). The reaction mixture was stirred at 80° C. for 6 h, and then diluted with water (10.0 mL), extracted with diethyl ether (20.0 mL). The organic layer was discarded. The aqueous layer was acidified with concentrated hydrochloric acid to pH 4 and extracted with ethyl acetate (40 mL×3). The combined organic layers were dried over anhydrous sodium sulfate. The solvent was removed in vacuo and afforded 2′-(3-morpholinophenyl)-2′,3′-dihydro-1′H-spiro[cyclopentane-1,4′-quinoline]-6′-carboxylic acid (352.8 mg, 90%) as a light yellow powder: MS (ESI) M+1=393.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27])([CH3:4])([CH3:3])[CH3:2].[CH3:29][N:30]1[CH:34]([CH2:35][CH2:36]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:33][N:32]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=2)[C:31]1=[O:59].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:28])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:36][CH2:35][CH:34]2[CH2:33][N:32]([CH2:48][C:49]3[CH:54]=[CH:53][C:52]([C:55]([F:57])([F:58])[F:56])=[CH:51][CH:50]=3)[C:31](=[O:59])[N:30]2[CH3:29])=[CH:11][C:10]=1[CH2:16][N:17]1[C:18](=[O:27])[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]1=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1
Reactant: CC(C)(C)OC(=O)CCc1ccc(O)cc1CN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)N(Cc2ccc(C(F)(F)F)cc2)CC1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CN2C(=O)c3ccccc3C2=O)c1
Temperature: 60 °C
Yield: 72.1 %

Procedure:
To a solution of 3-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4-hydroxy-phenyl]-propionic acid tert-butyl ester (57 mg, 0.15 mmol) and Toluene-4-sulfonic acid 2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethyl ester (75 mg, 0.16 mmol) in DMF (1 ml) is added Cs2CO3 (64 mg, 0.19 mmol), and the mixture heated at 60° C. for 14 hours. The mixture is cooled, diluted with water (25 ml) and extracted with ethyl acetate (2×25 ml). The combined organic extracts were washed with brine (30 ml), dried (Na2SO4), and concentrated to an oil. Purification by flash chromatography on a Biotage silica cartridge (gradient elution, 5:1 to 1:1 hexanes:acetone) produced an oil (72 mg, 73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][N:6]=[C:5]([OH:12])[CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C.O>[Si:23]([O:22][CH2:21][CH2:20][O:12][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][N:6]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: COc1cc(O)ncc1[N+](=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OCCO[Si](C)(C)C(C)(C)C)ncc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 94.5 %

Procedure:
Step A To a solution of 4-methoxy-5-nitropyridin-2-ol (0.5 g, 2.9 mmol) in anhydrous DMF (12 mL) were added K2CO3 (0.82 g, 5.9 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (0.7 g, 2.9 mmol) sequentially. The reaction mixture was heated at 70° C. for 2 h. The mixture was cooled to room temperature, and diluted with water. The mixture was extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated to give 2-(2-(tert-butyldimethylsilyloxy)ethoxy)-4-methoxy-5-nitropyridine as a white solid (0.9 g, 93%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:32][CH3:33])=[CH:4][C:5]([C:10]2[CH:11]=[N:12][C:13]([O:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=2)=[N:6][C:7]=1[C:8]#[N:9].Cl.[N:35]([O-])=O.[Na+]>O.O1CCOCC1>[C:8]([C:7]1[C:2]2[N:1]=[N:35][N:32]([CH3:33])[C:3]=2[CH:4]=[C:5]([C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:17])[F:18])[C:13]([O:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[N:12][CH:11]=2)[N:6]=1)#[N:9]
Reactant: O=N[O-]
Reactant: CNc1cc(-c2cnc(OCCN(C)C(=O)OC(C)(C)C)c(C(F)(F)F)c2)nc(C#N)c1N
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CN(CCOc1ncc(-c2cc3c(nnn3C)c(C#N)n2)cc1C(F)(F)F)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 85.5 %

Procedure:
To a suspension of tert-butyl 2-(5-amino-6-cyano-4-(methylamino)-5′-(trifluoromethyl)-2,3′-bipyridin-6′-yloxy)ethyl(methyl)carbamate (160 mg) in water (3 ml) and 1,4-dioxane (3 ml), 2N hydrochloric acid (192 mg) was added at 0° C. and sodium nitrite (34.2 mg) in water (1 ml) was added then stirred at 0° C. for 10 min then at 20° C. for 20 h. The reaction mixture was filtered, washed with water, dried in vacuum oven to give 140 mg light yellow solid as tert-butyl 2-(5-(4-cyano-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-3-(trifluoromethyl)pyridin-2-yloxy)ethyl(methyl)-carbamate (85%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[C:11]1[S:10][C:9]([C:15]#[N:16])=[N:8][C:7]=1[CH:6]=[CH:5]2.N[C@@H:18]([C:21]([OH:23])=[O:22])[CH2:19][SH:20].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[C:11]1[S:10][C:9]([C:15]3[S:20][CH2:19][CH:18]([C:21]([OH:23])=[O:22])[N:16]=3)=[N:8][C:7]=1[CH:6]=[CH:5]2
Reactant: N#Cc1nc2ccc3cc(N)ccc3c2s1
Reactant: N[C@H](CS)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Nc1ccc2c(ccc3nc(C4=NC(C(=O)O)CS4)sc32)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 34.4 %

Procedure:
A solution of 7-aminonaphtho[2,1-d]thiazole-2-carbonitrile (24 mg, 0.106 mmol) in acetonitrile was treated with an aqueous solution containing D-cysteine (41 mg, 0.233 mmol) and K2CO3 (45 mg, 0.326 mmol). After stirring at RT for 20 min, the product was isolated by preparative HPLC eluting with a gradient of 5→100% MeCN in 10 mM aqueous NH4OAc. The appropriate fractions were concentrated under reduced pressure and then lyophilized to afford 12 mg of a yellow solid. 1H NMR (DMSO-d6) d 7.77-7.87 (m, 2H); 7.59 (d, 1H); 7.01 (dd, 1H); 6.94 (d, 1H); 5.69 (br s, 2H); 5.18 (t, 1H); 3.57-3.68 (m, 2H).
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10]3[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=3[S:8][C:7]=2[NH:6][C:5]1=[O:19])[CH2:2][CH3:3].CCOC(/N=N/C(OCC)=O)=O>C(#N)C>[CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[C:7]([S:8][C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[N:11]=2)=[N:6][C:5]1=[O:19])[CH2:2][CH3:3]
Reactant: CCCn1c(=O)[nH]c2c(c1=O)Nc1ccccc1S2
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CC#N
Product: CCCn1c(=O)nc2sc3ccccc3nc-2c1=O
Reaction time: 2 h
Yield: 78.8 %

Procedure:
To a solution of the 1,5-dihydro-3-propyl-2H-pyrimido[4,5-b][1,4]benzothiazine-2,4(3H)-dione (0.55 g) in acetonitrile (40 ml) was added dropwise diethylazodicarboxylate (0.52 g) at room temperature. The mixture was stirred for two hours. After the solvent was removed, the residue was triturated with diethylether and filtered to give 3-propyl-2H-pyrimido[4,5-b][1,4]benzothiazine-2,4(3H)-dione (0.43 g, 78% yield).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[OH:17][CH2:16][CH2:15][NH:14][C:4]1[N:5]=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[C:7]([C:8]#[N:9])=[C:2]([N:29]2[CH2:28][CH2:27][N:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[O:19][CH3:18])[CH2:31][CH2:30]2)[N:3]=1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Reactant: COc1ccccc1N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccccc1N1CCN(c2nc(NCCO)nc(NCCO)c2C#N)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 1-(2-methoxy-phenyl)-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at 60° C. to yield the 2,4-bis-(2-hydroxy-ethylamino)-6-[4-(2-methoxy-phenyl)-piperazin-1-yl]-pyrimidine-5-carbonitrile as a yellowish lyophilisate; MS: [M+H]+=414.