Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1[CH:30]=[CH:29][C:15]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:28])[CH2:25][CH2:26][CH3:27])[CH:18]=2)=[CH:14][CH:13]=1.C(N(CC)CC)C>O1CCCC1>[C:24]([NH:23][C:19]1[CH:18]=[C:17]([O:16][C:15]2[CH:14]=[CH:13][C:12]([NH:11][C:2](=[O:3])[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:30][CH:29]=2)[CH:22]=[CH:21][N:20]=1)(=[O:28])[CH2:25][CH2:26][CH3:27]
Reactant: CCCC(=O)Nc1cc(Oc2ccc(N)cc2)ccn1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1cc(Oc2ccc(NC(=O)Oc3ccccc3)cc2)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phenyl chloroformate (0.14 ml) was added dropwise to an ice-cooled stirred solution of 4-(4-aminophenoxy)-2-(butyrylamino)pyridine (0.3 g), triethylamine (0.14 ml) and tetrahydrofuran (10 ml). The cooling bath was removed and the mixture was stirred at room temperature overnight. Silica gel was added to the reaction solution, the solvent was distilled off under reduced pressure and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with silica gel, and column purification was performed (hexane:ethyl acetate=2:1, followed by 1:1). The solvent was distilled off under reduced pressure to obtain the target substance as a colorless solid.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[N:13]1([CH2:18]/[CH:19]=[CH:20]/[CH2:21][OH:22])[CH2:17][CH2:16][CH2:15][CH2:14]1.[Cl:23][N:24]([C:32]1[C:41]2[C:36](=[CH:37][C:38](O)=[C:39]([O:42][CH3:43])[CH:40]=2)[N:35]=[CH:34][N:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)[Cl:65]>>[ClH:23].[Cl:65][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:32]2[C:41]3[C:36](=[CH:37][C:38]([O:22][CH2:21]/[CH:20]=[CH:19]/[CH2:18][N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[C:39]([O:42][CH3:43])[CH:40]=3)[N:35]=[CH:34][N:33]=2)=[C:26]([F:31])[CH:27]=1
Reactant: ClCCl
Reactant: OC/C=C/CN1CCCC1
Reactant: COc1cc2c(N(Cl)c3ccccc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OC/C=C/CN1CCCC1
Product: Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 33 %

Procedure:
Diethyl azodicarboxylate (5.91 ml, 37 mmol) was added dropwise to a stirred mixture of (E)-4-(pyrrolidin-1-yl)but-2-en-1-ol (3.97 g, 28 mmol), 4-(chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (3.0 g, 9 mmol), (prepared as described for the starting material in Example 2), and triphenylphosphine (9.84 g, 38 mmol) in methylene chloride (300 ml). The reaction mixture was stirred for 18 hours at ambient temperature. The volatiles were removed by evaporation and the residue was purified by column chromatography eluting with methylene chloride/methanol (a gradient from 80/20 to 70/30). The purified product was dissolved in methylene chloride/methanol and 1M ethereal hydrogen chloride (25 ml) was added. The precipitated product was collected by filtration, washed with ether and dried to give (E)-4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(4-(pyrrolidin-1-yl)but-2-en-1-yloxy)quinazoline hydrochloride (1.62 g, 33%).
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]([C:15]12[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][C:17]([C:25](O)=[O:26])([CH2:18]3)[CH2:16]1)[CH2:22]2)([OH:14])=[O:13].[CH3:28][OH:29]>>[CH3:28][O:29][C:25]([C:17]12[CH2:18][CH:19]3[CH2:20][CH:21]([CH2:22][C:15]([C:12]([O:14][CH3:1])=[O:13])([CH2:24]3)[CH2:16]1)[CH2:23]2)=[O:26]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CO
Reactant: O=C(O)C12CC3CC(C1)CC(C(=O)O)(C3)C2
Product: COC(=O)C12CC3CC(C1)CC(C(=O)OC)(C3)C2

Procedure:
In the presence of an acid catalyst (p-toluenesulfonic acid), 1,3-dicarboxyadamantane obtained in Example 2 was allowed to react with an excess amount of methanol to give 1,3-dimethoxycarbonyladamantane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([O:31]C)[C:20](OC)=[CH:19][C:18]3[CH:17]([C:23](=[O:30])CCCCC=O)NCC[C:13]=3[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:33]([Mg]Br)[CH3:34].[Cl-].[NH4+:38]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([OH:31])([CH2:12][CH3:13])[CH2:20][CH2:19][CH2:18][CH2:17][C:23]([N:38]2[CH2:34][CH2:33][C:6]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[CH:7]=3)[CH2:11]2)=[O:30])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC1=CC2=C(CCNC2C(=O)CCCCC=O)CC1(OC)c1ccc(OC)c(OC)c1
Reactant: [NH4+]
Reactant: CC[Mg]Br
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCC(O)(CCCCC(=O)N1CCc2cc(OC)c(OC)cc2C1)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3.0 g of 2-[6-(3,4-dimethoxyphenyl)-1,6-dioxohexyl-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline and 15.0 mL of ethyl magnesium bromide (1M) in tetrahydrofuran in 20.0 mL of anhydrous tetrahydrofuran is stirred at room temperature overnight. The mixture is poured into a mixture of ice and saturated solution of ammonium chloride and extracted with diethyl ether. The diethyl ether extract is washed with brine, dried, filtered. The filtrate is evaporated to afford 3.0 g of the desired product as a colorless oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9](=[O:53])[CH2:10][C:11]1[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][C:12]=1[CH2:13][CH2:14][C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]=[C:17]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]3[CH2:37][CH2:36][N:35]([C:38](OC(C)(C)C)=O)[CH2:34][CH2:33]3)=[CH:28][CH:27]=2)[N:16]=1.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:38][N:35]1[CH2:36][CH2:37][CH:32]([C:29]2[CH:30]=[CH:31][C:26]([NH:25][C:17]3[N:16]=[C:15]([CH2:14][CH2:13][C:12]4[CH:45]=[C:46]([C:49]([F:52])([F:50])[F:51])[CH:47]=[CH:48][C:11]=4[CH2:10][C:9]([NH2:8])=[O:53])[C:20]([C:21]([F:22])([F:24])[F:23])=[CH:19][N:18]=3)=[CH:27][CH:28]=2)[CH2:33][CH2:34]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4cc(C(F)(F)F)ccc4CC(N)=O)n3)cc2)CC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4cc(C(F)(F)F)ccc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 7.5 %

Procedure:
TFA (0.1 mL) was added to a solution of tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)-5-(trifluoromethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A62) (0.170 g, 0.261 mmol) in DCM (4 mL) and the resulting mixture stirred for 24 hours at room temperature. The volatiles were evaporated under reduced pressure then the residue adsorbed onto silica gel and purified by column chromatography (SiO2, 1-50% MeOH in DCM). The volatiles were removed in vacuo and the residue dissolved in dry MeOH (5 mL). Formaldehyde (37 wt. % in H2O; 0.030 mL, 0.36 mmol) was added and the resulting mixture was stirred for 30 minutes at room temperature. Sodium triacetoxyborohydride (0.077 g, 0.362 mmol) was added under nitrogen and the resulting mixture stirred at room temperature for 2 hours. The volatiles were evaporated under reduced pressure then the residue dissolved in EtOAc and washed with 10% NaHCO3 (20 mL). The organics were dried (MgSO4) and the volatiles removed under reduced pressure. The residue was adsorbed onto silica gel, then purified by silica gel column chromatography (Biotage Isolera, SiO2 cartridge, 50-100% MeOH in EtOAc then 10% NH3 in EtOH). Further purification by semi preparative HPLC was required to give the title compound 17 as a pale cream solid (0.011 g, 26%); 1H NMR (400 MHz, d4-MeOH) δ 8.55 (s, 1H), 7.67-7.60 (m, 2H), 7.50-7.40 (m, 3H), 7.28-7.19 (m, 2H), 3.74 (s, 2H), 3.54-3.40 (m, 2H), 3.31-3.25 (m, 2H), 3.14-3.12 (m, 2H), 2.95 (t, J=11.5 Hz, 2H), 2.80 (m, 4H), 2.08 (d, J=13.8 Hz, 2H), 1.97-1.92 (m, 2H). LCMS-B: rt 4.52 min; m/z 566 [M+H]+.
Reaction SMILES: COC(=O)C([N:6]1[C@H:9]([S:10][C:11](=[O:13])[CH3:12])[CH2:8][C:7]1=[O:14])=O.C(OC)(=O)C.O>CO>[C:11]([S:10][C@H:9]1[NH:6][C:7](=[O:14])[CH2:8]1)(=[O:13])[CH3:12]
Reactant: COC(=O)C(=O)N1C(=O)C[C@H]1SC(C)=O
Solvent: O
Solvent: CO
Solvent: COC(C)=O
Product: CC(=O)S[C@@H]1CC(=O)N1
Reaction time: 20 h

Procedure:
A solution of 140 mg of 2-[(4R)-4acetylthio-2-oxoazetidin-1-yl]-2-oxoacetic acid methyl ester (crude product) in a mixture of 20 ml of methanol, 2 ml of methyl acetate and 0.4 ml of water is allowed to stand for 20 hours at room temperature, concentrated in vacuo and evaporated again with benzene. The residue is chromatographed over silica gel thick layer plates with toluene/ethyl acetate (2:1) and yields the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:20][CH:21]2[CH2:38][CH2:37][C:24]3([CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)[CH2:23][CH2:22]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[C:16]([CH:17]=2)=[N:15][N:14]([CH3:18])[C:13]=3[CH3:19])=[N:6][CH:7]=1.Cl.CCOC(C)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:20][CH:21]2[CH2:22][CH2:23][C:24]3([CH2:25][CH2:26][NH:27][CH2:28][CH2:29]3)[CH2:37][CH2:38]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[C:16]([CH:17]=2)=[N:15][N:14]([CH3:18])[C:13]=3[CH3:19])=[N:6][CH:7]=1
Reactant: Cc1c2ccc(Nc3ncc(Cl)c(NC4CCC5(CC4)CCN(C(=O)OC(C)(C)C)CC5)n3)cc2nn1C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1c2ccc(Nc3ncc(Cl)c(NC4CCC5(CCNCC5)CC4)n3)cc2nn1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a solution of tert-butyl 9-((5-chloro-2-((2,3-dimethyl-2H-indazol-6-yl)amino)pyrimidin-4-yl)amino)-3-azaspiro[5.5]undecane-3-carboxylate (161.5 mg, 0.30 mmol) in DCM (10 mL) was added a solution of HCl in EtOAc (10 mL, 40 mmol). The reaction mixture was stirred at rt for 2 h and concentrated in vacuo. The residue was dissolved in water (30 mL) and adjusted to pH=10 with a saturated Na2CO3 aqueous solution, then extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/10) to give the title compound as a beige solid (131.6 mg, 100%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].[N+:10]([CH:13]=[C:14](SC)[S:15][CH3:16])([O-:12])=[O:11]>C(O)C>[N+:10]([CH:13]=[C:14]([S:15][CH3:16])[NH:6][CH2:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2])([O-:12])=[O:11]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: CCOC(CN)OCC
Solvent: CCO
Product: CCOC(CNC(=C[N+](=O)[O-])SC)OCC
Yield: 57.9 %

Procedure:
(a)(i) A solution of aminoacetaldehyde diethylacetal (8 g, 0.06 mol) and 1-nitro-2,2-bis-methylthioethylene (10 g, 0.06 mol) in ethanol (100 ml) was refluxed for 20 hours. The solvent was removed in vacuo. The residue was chromatographed on a silica gel column eluted with carbon tetrachloride/chloroform (7:3) and the product was crystallised from propan-2-ol to give 1-nitro-2-methylthio-2-(2,2-diethoxyethylamino)ethylene (8.7 g, 58%) m.p. 73°-73.5°.
Reaction SMILES: [CH3:1][P:2]([C:5]1[N:6]=[C:7]([O:12][CH3:13])[C:8]([NH2:11])=[N:9][CH:10]=1)([CH3:4])=[O:3].ClC1N=C(Cl)C(Cl)=CN=1.Cl[C:24]1[N:29]=[C:28]([NH:30]C2C(OC)=NC(P(C)(C)=O)=CN=2)[C:27]([Cl:43])=[CH:26][N:25]=1.[N:44]1([CH:50]2[CH2:55][CH2:54][N:53]([C:56]3[S:60][C:59](N)=[N:58][N:57]=3)[CH2:52][CH2:51]2)[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1>>[N:44]1([CH:50]2[CH2:55][CH2:54][N:53]([C:56]3[S:60][C:59]([N:11]([C:8]4[C:7]([O:12][CH3:13])=[N:6][C:5]([P:2]([CH3:1])([CH3:4])=[O:3])=[CH:10][N:9]=4)[C:24]4[N:29]=[C:28]([NH2:30])[C:27]([Cl:43])=[CH:26][N:25]=4)=[N:58][N:57]=3)[CH2:52][CH2:51]2)[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1
Reactant: COc1nc(P(C)(C)=O)cnc1Nc1nc(Cl)ncc1Cl
Reactant: COc1nc(P(C)(C)=O)cnc1N
Reactant: Nc1nnc(N2CCC(N3CCCCC3)CC2)s1
Agent: Clc1ncc(Cl)c(Cl)n1
Product: COc1nc(P(C)(C)=O)cnc1N(c1ncc(Cl)c(N)n1)c1nnc(N2CCC(N3CCCCC3)CC2)s1

Procedure:
This compound can be prepared as in Example 32 by reacting 5-(dimethylphosphoryl)-3-methoxypyrazin-2-amine (prepared In example 33) with 2,4,5-trichloropyrimidine to generate 2,5-dichloro-N-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]pyrimidin-4-amine. 2,5-dichloro-N-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]pyrimidin-4-amine is then reacted with 5-(1,4′-bipiperidin-1′-yl)-1,3,4-thiadiazol-2-amine according to the procedure described in Example 321.
Reaction SMILES: Br.[Cl:2][C:3]1[N:8]=[N:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14](F)[CH:13]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[C:16]([NH:10][CH2:9][C:6]2[N:7]=[N:8][C:3]([Cl:2])=[CH:4][CH:5]=2)[CH:17]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: NCc1ccc(Cl)nn1
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(Br)cc1NCc1ccc(Cl)nn1
Temperature: 0 °C
Yield: 99.2 %

Procedure:
A solution of compound 10C (1.00 g, 4.46 mmol) and 4-bromo-2-fluoro-1-nitro-benzene (10D) (0.97 g, 4.40 mmol) in DMF (50 mL) with DIEA (1.30 g, 10 mmol) was stirred at 65° C. for two hours. The reaction was poured into ice/water and the solid precipitate was collected by filtration, washed with water and dried in vacuum over P2O5 overnight to give 1.5 g of desired product (10E). ESI-MS:m/z 342.9 (M+H)+.
Reaction SMILES: Br[CH:2]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)[CH:3]=O.[S-:14][C:15]#[N:16].[K+].[CH:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>CO>[CH:18]1([NH:24][C:15]2[S:14][C:2]([C:5]3[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=3)=[CH:3][N:16]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=CC(Br)c1ccc([N+](=O)[O-])cc1
Reactant: NC1CCCCC1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CO
Product: O=[N+]([O-])c1ccc(-c2cnc(NC3CCCCC3)s2)cc1
Temperature: 0 °C

Procedure:
A solution of bromo(4-nitrophenyl)acetaldehyde and potassium thiocyanate (1.2 equivalents) in methanol is stirred at room temperature for 1 hour. The cyclohexylamine (1,05 equivalents) is added drop-wise and the mixture is heated under reflux until completion of the reaction (5-12 hours). After cooling to 0° C. the precipitate is filtered off and washed with water. The crude material is purified by usual silica gel chromatography to give the desired compound.
Reaction SMILES: Cl[CH:2]1[N:7](C(OC(C)(C)C)=O)[CH2:6][CH:5]([C:15]2[N:23]3[C:18]([C:19]([NH2:24])=[N:20][CH:21]=[N:22]3)=[C:17]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=4)=[C:27]([O:39][CH3:40])[CH:26]=3)[CH:16]=2)[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O.C(OCC)(=O)C.CCCCCC.C(Cl)[Cl:61]>>[Cl:61][C:16]1[C:17]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=3)=[C:27]([O:39][CH3:40])[CH:26]=2)=[C:18]2[N:23]([C:15]=1[CH:5]1[CH2:4][CH2:3][CH2:2][NH:7][CH2:6]1)[N:22]=[CH:21][N:20]=[C:19]2[NH2:24]
Reactant: ClCCl
Reactant: COc1cc(-c2cc(C3CCC(Cl)N(C(=O)OC(C)(C)C)C3)n3ncnc(N)c23)ccc1Oc1cccc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc(-c2c(Cl)c(C3CCCNC3)n3ncnc(N)c23)ccc1Oc1cccc(Cl)c1
Reaction time: 2 h

Procedure:
The compound (40 mg, 0.068 mmol) prepared in Example 30 was taken up in DCM and treated with TFA (0.5 mL). The reaction was stirred for 2 hours and monitored by TLC (1:1 ethyl acetate/hexane). The solvent was removed under vacuum and the residue was taken up in ethyl acetate and the organic layer was washed with 1N sodium hydroxide. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water, brine and dried over anhydrous sodium sulfate. The solution was filtered and solvent removed. The product is used in next reaction without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1O[CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.[NH4+:20]>C(O)C>[OH:1][CH2:2][C:3]1[NH:20][CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1
Reactant: [NH4+]
Reactant: COc1ccc(COc2coc(CO)cc2=O)cc1
Solvent: CCO
Product: COc1ccc(COc2c[nH]c(CO)cc2=O)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 84 %

Procedure:
2-(Hydroxymethyl)-5-[(4-methoxybenzyl)oxy]-4H-pyran-4-one (1.2 g, 4.56 mmol) was dissolved in ethanol (3.0 mL), added an aqueous solution of ammonium (9.0 mL), sealed, and stirred at 100° C. for 6 hours. This operation was conducted for 4 lots, and the following treatments were conducted as a whole. The reaction solution was concentrated in vacuo. After adding diethylether, the reaction solution was cooled with ice. The deposited solid was filtered, washed with diethylether, and concentrated in vacuo. The title compound (4.0 g (yield 84%)) was obtained as a brown powder crystal.
Reaction SMILES: [CH2:1]([O:17][C:18]([O:20][CH2:21][C:22](=[CH2:32])[CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31])=[O:19])[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].[CH3:33][S:34](Cl)(=[O:36])=[O:35].N1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:17][C:18]([O:20][CH2:21][C:22](=[CH2:32])[CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][S:34]([CH3:33])(=[O:36])=[O:35])=[O:19])[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: CS(=O)(=O)Cl
Reactant: C=C(COCCCCCCO)COC(=O)OCCCCCCCCCCCCCCCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C(COCCCCCCOS(C)(=O)=O)COC(=O)OCCCCCCCCCCCCCCCC
Reaction time: 2.5 h

Procedure:
3-Hexadecyloxycarbonyloxy-1-(6-hydroxyhexyloxy)-2-methylenepropane (from Preparation 51) (0.54 g) and methanesulfonyl chloride (0.20 g) were stirred in methylene chloride at 0° C. Pyridine (6 ml) was added and stirring continued for 15 minutes at 0° C. and for 2.5 hours at 22° C. Methylene chloride (10 ml) was added, and the organic phase was washed with water (3×15 ml), dried over magnesium sulfate, filtered and evaporated in vacuo to dryness. Purification was achieved by chromatography on silica gel 60 (70-230 mesh, 15 g) eluting with chloroform/ether/pentane 1:1:10 followed by chloroform/ether 1:1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li:10])CCC.[CH3:11][C:12]1([CH3:43])[CH2:21][CH:20]=[C:19](OS(C(F)(F)F)(=O)=O)[C:18]2[CH:17]=[C:16](/[CH:30]=[CH:31]/[C:32]3[CH:42]=[CH:41][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:34][CH:33]=3)[CH:15]=[CH:14][C:13]1=2>O1CCCC1.[Cl-].[Zn+2].[Cl-].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>[Li:10][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1.[CH3:43][C:12]1([CH3:11])[CH2:21][CH:20]=[C:19]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C:18]2[CH:17]=[C:16](/[CH:30]=[CH:31]/[C:32]3[CH:33]=[CH:34][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:41][CH:42]=3)[CH:15]=[CH:14][C:13]1=2
Reactant: [Li]CCCC
Reactant: CCOC(=O)c1ccc(/C=C/c2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Reactant: c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(/C=C/c2ccc3c(c2)C(c2cccs2)=CCC3(C)C)cc1
Product: [Li]c1cccs1
Temperature: -78 °C
Reaction time: 0.58 h

Procedure:
A solution of lithiothiophene was prepared by the addition of 0.10 g (0.095 mL, 1.2 mmol) of thiophene to a cold solution (-78° C.) of 0.61 g (0.90 mL, 1.4 mmol, 1.6 M in hexanes) of n-butyl lithium in 2.0 mL of tetrahydrofuran. The solution was stirred at -78° C. for 35 min and then a solution of 0.158 g (1.2 mmol) of zinc chloride in 2.0 mL of tetrahydrofuran was added. The resulting solution was stirred at -78° C. to room temperature for 1 h and then the organozinc was added via cannula to a mixture of 0.212 g (0.44 mmol) of ethyl (E)-4-[2-(5,5-dimethyl-8-(trifluoromethylsulfonyl)oxy-5,6-dihydronaphthalen-2-yl)ethenyl] benzoate (Compound A9) and 18 mg (0.016 mmol) of tetrakis(triphenylphosphine)palladium(0) in 2.0 mL of tetrahydrofuran. The resulting mixture was stirred at room temperature for 10 min and then heated at 50° C. for 1 h. The reaction was quenched by the addition of sat. aqueous NH4Cl. The mixture was extracted with EtOAc (2×), and washed with brine. The organic phase was dried over Na2SO4 and then concentrated in vacuo. The crude material product was purified by flash chromatography (silica, 15% ethyl acetate in hexanes) to afford the title compound as a solid.
Reaction SMILES: [ClH:1].[C:2]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[NH:23])OCC)=[CH:15][CH:14]=2)[N:10]=1)(=[O:4])[CH3:3].[Cl-].[NH4+:25].N>C(O)C.CO>[ClH:1].[NH2:25][C:19](=[NH:23])[C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][C:9]2[N:10]=[C:6]([NH:5][C:2](=[O:4])[CH3:3])[S:7][CH:8]=2)=[CH:18][CH:17]=1
Reactant: [NH4+]
Reactant: CCOC(=N)c1ccc(CCc2csc(NC(C)=O)n2)cc1
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: CO
Solvent: CCO
Product: CC(=O)Nc1nc(CCc2ccc(C(=N)N)cc2)cs1
Temperature: 25 °C
Yield: 85 %

Procedure:
Ethyl 4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}benzenecarboximidoate hydrochloride (300 mg) was dissolved in ethanol (6 ml). Then ammonium chloride (68 mg) and ammonia in methanol (1 ml) were added to the solution. The reaction mixture was refluxed for 5 hours under nitrogen atmosphere. After cooled to room temperature, the suspension was filtered in vacuo. The filtrate was concentrated in vacuo, and the residue was solidified with ethanol/diethyl ether to give N-[4-(2-{4-[amino(imino)methyl]phenyl}ethyl)-1,3-thiazol-2-yl]acetamide hydrochloride (234 mg) as a colorless solid.
Reaction SMILES: [C:1]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26](=[C:28]([C:31]#[N:32])[C:29]#[N:30])[OH:27])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:35])=[N-].C(O)(=O)C>CCOCC.ClCCl>[C:1]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26](=[C:28]([C:29]#[N:30])[C:31]#[N:32])[O:27][CH3:35])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC(C#N)=C(O)CCCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(CCCCCNC(c1ccccc1)(c1ccccc1)c1ccccc1)=C(C#N)C#N
Reaction time: 6 h

Procedure:
A suspension of the malononitrile of Example 2 (13 g, 31 mmole) in ether/dichloromethane (900 mL/100 mL), cooled in an ice bath, was treated with a freshly prepared ethereal solution of diazomethane (from 50 mmole of Diazald® (Aldrich Chemical Company)). The solution was stirred for 6 hr and then neutralized with acetic acid (10 mL). The solution was evaporated to dryness and the residue chromatographed on silica gel using dichloromethane/acetone (4/1) as the eluent. Fractions containing product were pooled and evaporated to a syrup. The syrup was triturated with dichloromethane to induce crystallization. The crystals were filtered and dried to give 8.3 g (61%) of chromatographically pure product, useful as an intermediate compound.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[CH:6]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[O:8][C:4]=2[CH:3]=1.Cl[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC(C)=O.CCOC(C)=O>[N:18]1([CH2:17][CH2:16][O:1][C:2]2[CH:14]=[CH:13][C:5]3[CH:6]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[O:8][C:4]=3[CH:3]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COC(=O)c1cc2ccc(O)cc2o1
Reactant: ClCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: COC(=O)c1cc2ccc(OCCN3CCCCC3)cc2o1
Reaction time: 72 h
Yield: 59.8 %

Procedure:
A solution of 394 (350 mg, 1.82 mmol), 1-(2-Chloroethyl)piperidine (269 mg, 1.82 mmol) and K2CO3 (503 mg, 3.64 mmol) in DMF (10 mL) and acetone (10 mL) was stirred at 60° C. for 3 h and then at room temperature for 3 days (or until completion). The crude product was dissolved in AcOEt and washed with water. The organic layer was separated and dried with Na2SO4, filtered and concentrated under vacuum. The residue was purified via Isco (0-25% MeOH/EtOAc) to afford the title compound 395 as a white solid (330 mg, 60% yield).