Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].C(N(CC)CC)C.Cl[CH2:15][O:16][CH:17]1[CH:24]2[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:26][CH:18]1[CH2:19]3)[CH2:23]2>O1CCCC1>[CH:18]12[CH2:26][CH:22]3[CH2:21][CH:20]([CH2:25][CH:24]([CH2:23]3)[CH:17]1[O:16][CH2:15][O:5][C:1](=[O:6])[C:2]([CH3:4])=[CH2:3])[CH2:19]2
Reactant: ClCOC1C2CC3CC(C2)CC1C3
Reactant: C=C(C)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCOC1C2CC3CC(C2)CC1C3
Temperature: 25 °C

Procedure:
6.9 g of methacrylic acid was dissolved in 200 ml of tetrahydrofuran, and 8.0 g of triethylamine was added. Following stirring at room temperature, a solution containing 15 g of 2-adamantyl chloromethyl ether dissolved in 100 ml of tetrahydrofuran was added dropwise to the reaction solution. Following stirring for 12 hours at room temperature, the precipitated salt was removed by filtration. The solvent was removed from the remaining filtrate by evaporation, the residue was dissolved in 200 ml of ethyl acetate, and following washing with pure water (100 ml×3), the solvent was removed by evaporation. The residue was then allowed to stand under ice cooling, thereby yielding a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[CH3:30][CH:31]([OH:33])[CH3:32].CC(C)([O-])C.[Na+]>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([O:33][CH:31]([CH3:32])[CH3:30])[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1
Reactant: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(Cl)c34)cc2o1
Reactant: CC(C)O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(OC(C)C)c34)cc2o1
Temperature: 70 °C
Yield: 101 %

Procedure:
6-(2,4-Dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbenzo[d]oxazole (1 equiv), propan-2-ol (1.1 equiv), sodium tert-butoxide (1.1 equiv), and 1,4-dioxane (0.1 M) were combined and the resulting mixture was allowed to stir at 70° C. for several hours. The reaction was cooled and concentrated to an oil under reduced pressure that was purified by silica gel chromatography (0-30% ethyl acetate/hexane) to afford the title compound (101% yield) that was used without further purification. MS (ESI) m/z 473.3 [M+1]+.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].[Cl:8][C:9]1[C:14]([F:15])=[C:13](Cl)[N:12]=[CH:11][N:10]=1>C1COCC1>[Cl:8][C:9]1[C:14]([F:15])=[C:13]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[N:12]=[CH:11][N:10]=1
Reactant: Fc1c(Cl)ncnc1Cl
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1c(Cl)ncnc1OCC1CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.55 mL (5.99 mmol) cyclopropane methanol in 15 mL THF are charged with 0.31 g (7.19 mmol) NaH and the reaction mixture is stirred at r.t. for 10 min. Then 1.00 g (5.99 mmol) 4,6-dichloro-5-fluoro-pyrimidine are added and stirred at r.t. for 1 h. Afterwards the reaction is quenched by the addition of water and extracted with EtOAc. The organic layers are combined, washed with water (2×), dried over MgSO4, filtered and the solvent is removed in vacuo.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O-:8])=[CH:4][CH:3]=1.[K+].Cl[CH2:11][C:12]([C:14]1[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[C:17]([OH:23])=[C:16]([CH:24]([CH3:26])[CH3:25])[CH:15]=1)=[O:13].Cl>CN(C)C=O>[OH:23][C:17]1[C:18]([CH:20]([CH3:22])[CH3:21])=[CH:19][C:14]([C:12](=[O:13])[CH2:11][O:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:15][C:16]=1[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)c1cc(C(=O)CCl)cc(C(C)C)c1O
Reactant: Cc1ccc([O-])cc1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(OCC(=O)c2cc(C(C)C)c(O)c(C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
To a solution of 4.47 g (30.6 mmol) of potassium 4-methylphenolate in 150 ml of dimethyl-formamide a solution of 3.90 g (15.3 mmol) of 2-chloro-1-(4-hydroxy-3,5-di-isopropylphenyl)-ethanone in 70 ml dimethylformamide is added at room temperature within a period of 100 minutes. After additional 2 hours of stirring at room temperature the pH is adjusted to 6-7 with 1 N HCl and the mixture is extracted with ethyl acetate. The collected organic phases are washed with water, dried and evaporated. Crystallization of the crude product from ethyl acetate/hexane gives 1.8 g of compound 105, m.p. 124-125° C.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C@H:15]2[CH2:19][CH2:18][C@@H:17]([NH:20][C:21]([C@:23]34[CH2:49][CH2:48][C@@H:47]([C:50]([CH3:52])=[CH2:51])[C@@H:24]3[C@@H:25]3[C@@:38]([CH3:41])([CH2:39][CH2:40]4)[C@@:37]4([CH3:42])[C@@H:28]([C@:29]5([CH3:46])[C@@H:34]([CH2:35][CH2:36]4)[C:33]([CH3:44])([CH3:43])[C@@H:32]([OH:45])[CH2:31][CH2:30]5)[CH2:27][CH2:26]3)=[O:22])[CH2:16]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:59]1(=[O:66])[O:65][C:63](=[O:64])[CH2:62][CH2:61][CH2:60]1>C(OCC)(=O)C>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C@H:15]2[CH2:19][CH2:18][C@@H:17]([NH:20][C:21]([C@:23]34[CH2:49][CH2:48][C@@H:47]([C:50]([CH3:52])=[CH2:51])[C@@H:24]3[C@@H:25]3[C@@:38]([CH3:41])([CH2:39][CH2:40]4)[C@@:37]4([CH3:42])[C@@H:28]([C@:29]5([CH3:46])[C@@H:34]([CH2:35][CH2:36]4)[C:33]([CH3:44])([CH3:43])[C@@H:32]([O:45][C:59](=[O:66])[CH2:60][CH2:61][CH2:62][C:63]([OH:65])=[O:64])[CH2:31][CH2:30]5)[CH2:27][CH2:26]3)=[O:22])[CH2:16]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCC(=O)O1
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCC(Cc5ccccc5)CC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCC(Cc5ccccc5)CC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CCCC(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-N-((1R,3S)-3-((4-benzylpiperidin-1-yl)methyl)cyclopentyl)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxamide (Example 32, 0.24 mmol) in pyridine (5 ml) dimethyl amino pyridine (0.32 g, 0.48 mmol) and glutaric anhydride (1.3 ml) were added and the contents were refluxed for about 16 hours and completion of the reaction monitored by TLC. The reaction mixture was diluted with ethyl acetate (30 ml). The organic layer was washed with 5% aqueous HCl, washed with water followed by brine solution, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% MeOH in DCM as eluent to furnish the title compound (0.1 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.82-0.95 (m, 17H) 1.13-3.01 (m, 48H); 3.05-3.12 (m, 4H), 3.13-3.54 (m, 2H), 4.18-4.21 (m, 1H), 4.45-4.17 (m, 1H), 4.58 (s, 1H), 4.72 (s, 1H); 6.28-6.30 (m, 1H), 7.11-7.13 (m, 2H), 7.14-7.22 (m, 1H), 7.24-7.29 (m, 2H); ES Mass: [M+] 825 (100%); HPLC: 90%.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)=[O:12]>>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C:11](=[O:12])[CH:10]=[CH:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:14][CH:15]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: O=Cc1ccc(Cl)cc1
Product: O=C(C=Cc1ccc(Cl)cc1)c1ccc(Br)cc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 4-chlorobenzaldehyde and 4-bromoacetophenone, 1-(4-bromophenyl)-3-(4-chlorophenyl)prop-2-en-1-one was obtained as yellowish solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([CH2:12][CH2:13]O)=[CH:10][NH:11][C:6]2=[CH:5][CH:4]=1.C(Br)(Br)(Br)[Br:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:16][CH2:13][CH2:12][C:9]1[C:7]2=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=[C:6]2[NH:11][CH:10]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc2[nH]cc(CCO)c2n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc2[nH]cc(CCBr)c2n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)ethanol (353 mg, 1.84 mmol) in DCM (5.0 mL), CBr4 (700 mg, 2.11 mmol) was added, then the reaction mixture was cooled to 0° C. and PPh3 (554 mg, 2.11 mmol) was added. After stirring at rt for 2 h the solvent was removed under reduced pressure. Purification was performed by FC (EtOAc/hex 1:9 to 3:7) to yield the title compound as a brown oil, which was stored in the freezer. LC-MS conditions B: tR=0.45 min, [M+H]+=255.03.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[F:25]>>[F:18][C:19]1[CH:20]=[C:21]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)[N:3]=2)[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: OB(O)c1ccc(F)c(F)c1
Product: Fc1ccc(-c2nc(Nc3cc[nH]n3)cc3ccccc23)cc1F

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3,4-difluoro-phenylboronic acid to give [1-(3,4-difluoro-phenyl)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 323(MH+).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)#[CH:12].N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)[O:1][N:2]=2)[CH:5]=1
Reactant: C#Cc1ccc(C)cc1
Reactant: ON=C(Cl)c1cccnc1
Agent: N
Product: Cc1ccc(-c2cc(-c3cccnc3)no2)cc1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and 1-ethynyl-4-methylbenzene (Apollo, 58 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 2.43 (s, 3H), 7.30 (s, 1H), 7.36 (d, J=7.8 Hz, 2H), 7.60 (dd, J=7.6, 4.6 Hz, 1H), 7.81 (d, J=8.5 Hz, 2H), 8.36 (dt, J=8.2, 1.8 Hz, 1H), 8.66 (dd, J=4.9, 1.5 Hz, 1H), 9.09 (d, J=3.1 Hz, 1H) ppm; MS (DCI/NH3) m/z 237 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][C:3]=1[NH:10][C:11]([C:13]1[CH:17]=[C:16]([CH3:18])[O:15][N:14]=1)=[O:12].[Cl:19][C:20]1[CH:21]=[C:22]([C@H:26]([NH2:28])[CH3:27])[CH:23]=[CH:24][CH:25]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:28][C@@H:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=2)[CH3:27])=[CH:4][C:3]=1[NH:10][C:11]([C:13]1[CH:17]=[C:16]([CH3:18])[O:15][N:14]=1)=[O:12]
Reactant: C[C@@H](N)c1cccc(Cl)c1
Reactant: Cc1cc(C(=O)Nc2cc(C=O)ccc2Cl)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: Cc1cc(C(=O)Nc2cc(CN[C@H](C)c3cccc(Cl)c3)ccc2Cl)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.6 %

Procedure:
To a solution of N-(2-chloro-5-formylphenyl)-5-methylisoxazole-3-carboxamide 3 (0.117 g, 0.44 mmol) in DCE (3 mL) was added (R)-1-(3-chlorophenyl)ethanamine (0.079 g, 0.51 mmol), acetic acid (0.030 mL, 0.52 mmol), and NaBH(OAc)3 (0.108 g, 0.51 mmol). The reaction mixture was stirred at room temperature for 16 h and diluted with EtOAc. The organic phase was washed with saturated NaHCO3 (1×), brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 20% to 60% EtOAc in hexanes) gave (R)—N-(2-chloro-5-((1-(3-chlorophenyl)ethylamino)methyl)phenyl)-5-methylisoxazole-3-carboxamide 4 (0.131 g, 73% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 1.36 (d, J=6.5 Hz, 3H), 2.53 (s, 3H), 3.60 (d, J=13.7 Hz, 1H), 3.66 (d, J=13.7 Hz, 1H), 3.79 (q, J=6.5 Hz, 1H), 6.53 (s, 1H), 7.04 (d, J=8.2 Hz, 1H), 7.21-7.36 (m, 6H), 8.41 (s, 1H), 9.10 (s br, 1H). Mass spectrum: calculated for C20H19Cl2N3O2 403.1. found 404.1 (M++1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][CH2:19][O:20][C:21]([CH2:23]Br)=[O:22]>CN(C=O)C>[C:8]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:23][C:21]([O:20][CH2:19][CH3:18])=[O:22])=[CH:7][CH:6]=1)(=[O:11])[CH2:9][CH3:10]
Reactant: CCOC(=O)CBr
Reactant: CCC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C(=O)CC)cc1
Reaction time: 3 h
Yield: 94.3 %

Procedure:
To a solution of 1-(4-hydroxyphenyl)propan-1-one (33 g, 0.2200 moles) in DMF (165 mL), potassium carbonate (60.7 gm, 0.4400 moles) and ethyl bromo acetate (40.6 gm, 0.2420 moles) were added and the reaction mixture was srirred at 50° C. for 3 hours. The reaction mixture was poured into ice cold water and extracted with ethyl acetate. The combined ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evaporated under reduced pressure to yield 49 gm (94%) of product as thick liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[SH:12].Cl[C:14]1[S:15][C:16]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:17]=2[N:18]=1>>[Cl:23][C:20]1[CH:21]=[CH:22][C:16]2[S:15][C:14]([S:12][C:4]3[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=3[O:2][CH3:1])=[N:18][C:17]=2[CH:19]=1
Reactant: Clc1ccc2sc(Cl)nc2c1
Reactant: COc1cc([N+](=O)[O-])ccc1S
Product: COc1cc([N+](=O)[O-])ccc1Sc1nc2cc(Cl)ccc2s1

Procedure:
5-Chloro-2-(2-methoxy-4-nitro-phenylsulfanyl)-benzothiazole (257) was prepared (75%) from 2-methoxy-4-nitrobenzenethiol (249) and 2,5-dichlorobenzothiazole (250), in a similar manner as described in example 251.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([OH:23])=O)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].ON1C(=O)CCC1=O.[NH2:47][CH2:48][CH2:49][C:50]([NH:52][C@H:53]([C:57]([OH:59])=[O:58])[C@@H:54]([CH3:56])[OH:55])=[O:51].Cl>O1CCOCC1.CN(C)C=O.O.C(N(CC)CC)C>[C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([NH:47][CH2:48][CH2:49][C:50]([NH:52][C@H:53]([C:57]([OH:59])=[O:58])[C@@H:54]([CH3:56])[OH:55])=[O:51])=[O:23])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C[C@@H](O)[C@H](NC(=O)CCN)C(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)O
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)NCCC(=O)N[C@H](C(=O)O)[C@@H](C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
3-Hexadecanoyloxyoctadecanoic acid (150 mg) prepared by the method described in Preparation 2-(3) and N-hydroxysuccinimide (38 mg) were dissolved in dioxane (3 ml). N,N-Dicyclohexylcarbodiimide (68 mg) was added thereto under ice cooling. The mixture was reached to room temperature and stirred at ambient temperature overnight. The crystallized urea was filtered off and the filtrate was concentrated to give a residue which was dissolved in N,N-dimethylformamide (7 ml). To this solution was added a solution of N-β-alanyl-L-threonine (110 mg) and triethylamine (100 μl) in water (5 ml) at 0° C. The resulting mixture was reached to room temperature and stirred at ambient temperature overnight. The reaction mixture was acidified with 1 N hydrochloric acid, extracted with ethyl acetate, washed with water and dried over magnesium sulfate. Ethyl acetate was distilled off to give a residue which was subjected to preparative thin layer chromatography (Merck, 0.25 mm×5) and eluted with a mixture of benzene, dioxane and acetic acid (10:5:1). The band containing the object compound was extracted with a mixture of methanol and chloroform (3:7) and the solvent was evaporated off under reduced pressure to afford powder of N-[N-(3-hexadecanoyloxyoctadecanoyl)-β-alanyl]-L-threonine (95 mg).
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)(C)(C)C.Cl.O1CCOCC1>>[ClH:28].[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@H:9]3[CH2:10][CH2:11][CH2:12][N:8]3[CH2:7][C:6]([OH:29])=[O:5])=[CH:16][CH:17]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)CN1CCC[C@@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CN1CCC[C@@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 173.3 %

Procedure:
To the product from step 5 (0.60 g, 1.42 mmol) was added a 1:1 mixture of concentrated HCl/dioxane (28 mL). The resulting solution was stirred at 60° C. for 4 h. The solvent was removed in vacuo. The crude product was triturated with ether and dried under reduced pressure to afford the title compound (0.49 g, 52%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].Cl.Cl[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>[OH-].[Na+]>[N:14]1([CH2:13][CH2:12][O:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH2:4][OH:5])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: OCc1ccccc1O
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: OCc1ccccc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 2-hydroxybenzyl alcohol (1.295 g, 10.4 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (1.94 g, 10.4 mmol) in 2N NaOH (10.5 mL) was stirred at rt for 14 hours. The precipitate was collected by vacuum filtration, washed with 1N NaOH, redissolved in DCM and washed with 1N NaOH. The aqueous layer was extracted with more DCM (2×). The combined DCM was dried and concentrated to give [2-(2-morpholin-4-yl-ethoxy)-phenyl]-methanol which was used without further purification.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[S:14][CH:13]=[C:12]([C:15]#[N:16])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:17][OH:18]>>[Si:1]([O:8][CH2:9][C:10]1[S:14][CH:13]=[C:12]([C:15](=[N:17][OH:18])[NH2:16])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(C#N)cs1
Product: CC(C)(C)[Si](C)(C)OCc1cc(C(N)=NO)cs1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1d) using 5-({[t-butyl(dimethyl)silyl]oxy}methyl)thiophene-3-carbonitrile (4.3 g, 17 mmol) that was obtained in Example 3 (3a) and a 40% aqueous solution of hydroxylamine (2.2 ml). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:10 to 2:5) as the eluent to afford the title compound (4.7 g) in a yield of 97% as a white crystalline solid.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1([C:10]#[N:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1>CCCCCCCCCCCCCCCC[N+](C)(C)C.[Cl-]>[N:3]([C:4]1([C:10]#[N:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[N:3][C:4]1([C:10]#[N:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: N#CC1(N)CCCCC1
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Product: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 162.2 %

Procedure:
The pH is adjusted to 7 at 20° C. and 3 ml of `Arquad 16-29` is added followed by a further 2.2 equivalents of caustic soda and 23 g of 1-amino-1-cyanocyclohexane over 20 minutes with cooling to maintain a temperature of 20° C. The reaction is stirred for a further five minutes and filtered, washed and dried to yield 36.7 g of the title compound, as a white solid (89%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.[OH-].[Na+].Cl.[CH3:25][CH2:26][OH:27]>>[CH2:26]([O:27][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1)[CH3:25]
Reactant: Clc1ccc2ncc(Cc3ccc4ncccc4c3)n2n1
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOc1ccc2ncc(Cc3ccc4ncccc4c3)n2n1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
6-(6-Chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-quinoline (Example 14, 112 mg, 0.380 mmol) was suspended in EtOH (1 mL). 2 M NaOH (950 μL, 1.900 mmol) was added and the RM was stirred at 80° C. for 1 h. The mixture was neutralized with 2 M HCl until pH=6 and then concentrated. The residue was diluted with DCM and the obtained solution was dried over Na2SO4, filtered and concentrated. The residue was crystallized in Et2O and small amount of isopropanol. The resulting solid was purified by flash chromatography (Flashmaster, with a 20 g silica gel column, TBME/MeOH: 100:0→85:15) and crystallized again in Et2O to afford the title compound as a yellow solid (tR 1.67 min (conditions 6), MH+=305.2, 1H-NMR in DMSO-d6: 8.85 (m, 1H); 8.30 (m, 1H); 7.95 (m, 2H); 7.89 (m, 1H); 7.75 (m, 1H); 7.56 (s, 1H); 7.50 (dd, 1H); 6.80 (d, 1H); 4.44 (s, 2H); 4.35 (q, 2H); 1.31 (t, 3H)).
Reaction SMILES: [I:1]I.[C:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[N:16]2[CH:17]=[N:18][CH:19]=[C:15]2[CH:14]=[CH:13][CH:12]=1)([OH:5])=[O:4].C(=O)(O)[O-].[Na+]>O.C(O)C>[I:1][C:19]1[N:18]=[CH:17][N:16]2[C:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:3]([OH:5])=[O:4])=[CH:12][CH:13]=[CH:14][C:15]=12
Reactant: O=C(O)CCCCCc1cccc2cncn12
Reactant: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)CCCCCc1cccc2c(I)ncn12
Reaction time: 0.75 h

Procedure:
Iodine crystals (1.9 g) are added to a well-stirred solution of 1.16 g of 5-(5-carboxypentyl)-imidazo[1,5-a]pyridine and 1.68 g of sodium bicarbonate in 10 ml of water and 1 ml of ethanol. Additional 4 ml of ethanol are added to dissolve the bulk of the iodine and stirring is continued for 45 minutes. The reaction mixture is diluted with 125 ml of water and extracted twice with methylene chloride at pH 8 (NaHCO3 added if necessary). The aqueous phase is concentrated in vacuo, charcoaled and adjusted to pH 4.5 with 2 N HCl. The precipitate is collected, dried and recrystallized from methanol/ether to give 1-iodo-5-(5-carboxypentyl)-imidazo[1,5-a]pyridine melting at 163°-165°.
Reaction SMILES: ClC1N=C(N[C:9]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])C(Cl)=CN=1.NC1C=CC=CC=1>>[F:19][C:16]1[CH:17]=[CH:18][CH:9]=[C:10]([CH:15]=1)[C:11]([NH:13][CH3:14])=[O:12]
Reactant: CNC(=O)c1cc(F)ccc1Nc1nc(Cl)ncc1Cl
Solvent: Nc1ccccc1
Product: CNC(=O)c1cccc(F)c1

Procedure:
The following 2-(5-Chloro-2-(subst. phenylamino)-pyrimidin-4-ylamino)-5-fluoro-N-methyl-benzamide are prepared from 2-(2,5-Dichloro-pyrimidin-4-ylamino)-5-fluoro-N-methyl-benzamide and the corresponding aniline following the procedure of Example 2: