Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:15]([CH:17]1[O:19][CH2:18]1)Cl.[OH-].[K+]>C(O)C.O>[OH:1][CH:2]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[O:14][CH2:15][CH:17]1[CH2:18][O:19]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: ClCC1CO1
Reactant: CCCCCC(O)c1cccc(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCC(O)c1cccc(OCC2CO2)c1

Procedure:
19.4 g. (0.1 mole) 3-(1-hydroxyhexyl)-phenol and 28.6 g. epichlorohydrin are dissolved in 25 ml. ethanol and heated to the boil. A solution of 6.6 g. potassium hydroxide in 3 ml. water and 25 ml. ethanol is then added dropwise thereto in the course of 15 minutes. The reaction mixture is boiled under reflux for 2 hours, the solvent is then distilled off and the residue is taken up in water. Extraction is carried out with ethyl acetate, the ethyl acetate phase is washed twice with aqueous sodium hydroxide solution and water, dried and evaporated to give 22.4 g. (89% of theory) of the title compound in the form of an oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7](Br)=[CH:6][CH:5]=2.[CH2:12]([O:14][C:15](=[O:35])[CH:16]=[C:17](C1C=CC=C2C=1C(C#N)=CN2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:35])[CH:16]=[C:17]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2]([CH3:1])=[CH:10]2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:13]
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Reactant: Cc1cc2cc(Br)ccc2[nH]1
Product: CCOC(=O)C=C(c1ccccc1)c1ccc2[nH]c(C)cc2c1

Procedure:
3-(2-Methyl-1H-indol-5-yl)-3-phenyl-acrylic acid ethyl ester LXVII (1.25 g, 57%) was prepared from 2-methyl-5-bromoindole using the procedure described above for 3-(3-cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LVIII (see Example 14).
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH2:6][C:7]([O:9]C(C)(C)C)=[O:8])([O-:3])=O.C(OC([CH:21]=[CH:22][CH2:23][NH2:24])=O)(C)(C)C>CC(C)=O>[NH2:24][CH2:23][CH:22]1[O:3][N:1]=[C:4]([CH2:5][CH2:6][C:7]([OH:9])=[O:8])[CH2:21]1
Reactant: CC(C)(C)OC(=O)CCC[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)C=CCN
Solvent: CC(C)=O
Product: NCC1CC(CCC(=O)O)=NO1

Procedure:
The racemic product is prepared starting from tert.-butyl 4-nitrobutyrate and N-tert.-butoxycarbonylallylamine in analogy to Example 12. After cleavage of the protecting groups, it is taken up in acetone and the betaine is precipitated by adjusting the pH to 6 by means of conc. aq. ammonia. The melting point is 201° C. (with dec.).
Reaction SMILES: OCCCCC[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][S:13]([C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([CH3:26])[CH:25]=1)[N:22]=[CH:21][C:20]([C:27]([NH2:29])=[O:28])=[C:19]2[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=1)(=[O:15])=[O:14].[Br:39]C1C=C(SC2C=C3C(=C(C)C=2)N=CC(C(N)=O)=C3NC2C=CC=C(OC)C=2)C=CC=1>>[Br:39][C:10]1[CH:11]=[C:12]([S:13]([C:16]2[CH:17]=[C:18]3[C:23](=[C:24]([CH3:26])[CH:25]=2)[N:22]=[CH:21][C:20]([C:27]([NH2:29])=[O:28])=[C:19]3[NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)(=[O:15])=[O:14])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(Sc4cccc(Br)c4)cc23)c1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)CCCCCCCCCCCO)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(Br)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 61, using Intermediate 59 as a substrate. ES/MS calcd. for C24H2BrN3O4S+ 526.0. Found m/z=526.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:8][C:3]=1[C:4](OC)=[O:5].CC(O)=O.[CH:23]([NH2:25])=O>>[CH3:13][O:12][C:10]1[CH:11]=[C:2]2[C:3]([C:4](=[O:5])[NH:25][CH:23]=[N:1]2)=[CH:8][C:9]=1[O:14][CH2:15][CH2:16][O:17][CH3:18]
Reactant: COCCOc1cc(C(=O)OC)c(N)cc1OC
Reactant: NC=O
Solvent: CC(=O)O
Product: COCCOc1cc2c(=O)[nH]cnc2cc1OC
Temperature: 140 °C
Yield: 69 %

Procedure:
According to the procedure described in Example 6A Step 4, a mixture of methyl 2-amino-4-methoxy-5-(2-methoxyethoxy)benzoate (3.05 g, 11.9 mmol) and AcOH (5.4 mL) in formamide (15.25 mL) was heated at 140° C. overnight, to afford 7-methoxy-6-(2-methoxyethoxy)quinazolin-4(3H)-one as a solid (2.07 g, 69%). 1H NMR (300 MHz, DMSO-d6) δ 12.0 (br, 1H), 7.99 (s, 1H), 7.45 (s, 1H), 7.14 (s, 1H), 4.19 (t, 2H), 3.91 (s, 3H), 3.71 (t, 2H), 3.32 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([CH3:14])([CH3:13])[CH3:12].[CH2:15](O)[CH:16]=[CH2:17].S(=O)(=O)(O)O>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:17][CH:16]=[CH2:15])=[O:7])=[CH:4][C:3]=1[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cc(C(=O)O)ccc1O
Reactant: C=CCO
Agent: O=S(=O)(O)O
Product: C=CCOC(=O)c1ccc(O)c(C(C)(C)C)c1
Temperature: 100 °C
Yield: 83 %

Procedure:
Into a round bottom flask, there are introduced 9.71 g (50 mmoles) of 4-hydroxy-3-tert.butyl benzoic acid and 55 ml of allyl alcohol. 1.3 ml of concentrated sulfuric acid are added and the mixture in heated at 100° C. for 18 hours. The reaction mixture is then evaporated to dryness and 200 ml of water are added. The mixture is then neutralized with sodium bicarbonate and extracted with ethyl ether. The organic phase is decanted, washed with water, dried over magnesium sulfate and evaporated. The resulting residue is purified by chromatography on a silica column by eluting with dichloromethane. After evaporation of the solvents, 9.78 g (83% yield) of the expected ester whose melting point is 131°-132° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:20]O>CC1C=CC(S(O)(=O)=O)=CC=1.CC(O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:20][NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][C:4]=1[C:9](=[O:14])[C:10]([F:12])([F:13])[F:11]
Reactant: COc1ccc(CO)cc1OC
Reactant: Nc1ccc(Cl)cc1C(=O)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: COc1ccc(CNc2ccc(Cl)cc2C(=O)C(F)(F)F)cc1OC
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 68 %

Procedure:
4-Chloro-2-trifluoroacetylaniline (4.96 g, 40 mmol) and 3,4-dimethoxybenzyl alcohol (7.39 g, 44 mmol) were added to 2-propanol (40 mL). TsOH (76 mg, 0.4 mmol) was added and the mixture heated to 60° C. and held 3.5 hours. The solution was concentrated in vacuo to 1/2 the original volume, diluted with water (10 mL) and stirred at room temperature. The resulting slurry was filtered and the product dried in vacuo at 30° C. to give 10.16 g (68%) of the title compound as a yellow powder. An analytical sample was obtained by recrystallization from acetonitrile: mp 82-84° C.; 1H NMR (CDCl3) δ 9.05 (brs, 1H), 7.75 (brt, J=2 Hz, 1H), 7.35 (dd, J=2, 8 Hz, 1H), 6.8 (d, J=8 Hz, 3H), 6.75 (d, J=8 Hz, 1H), 4.43 (d, J=5 Hz, 2H), 3.88 (s, 3H), 3.87 (s, 3H); 13C NMR (CDCl3) δ 179.9, 151.9, 149.4, 148.7, 137.4, 130.8, 130.8, 130.7, 129.4, 119.4, 114.5, 111.5, 111.4, 110.3, 56.1, 56.0, 47.0; 19F NMR (CDCl3) δ 69.61.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][S:4](=O)[S:5][CH2:6][CH:7]=[CH2:8].[OH2:10].CO>O.CC(C)=O>[CH2:1]=[CH:2][CH2:3][S:4][S:5]/[CH:6]=[CH:7]/[CH2:8][S+:4]([O-:10])[CH2:3][CH:2]=[CH2:1]
Reactant: O
Reactant: C=CCSS(=O)CC=C
Solvent: CO
Solvent: CC(C)=O
Product: C=CCSS/C=C/C[S+]([O-])CC=C

Procedure:
1 gram of Allicin as prepared above (in Example 4) was dissolved in 10 ml of 40% water-acetone solution and the solution was heated between 63–64 C for 4 hours. The reaction mixture was diluted with 30 ml of 50% water-methanol and washed 5 times with 10 ml of n-pentane. The pentane was kept aside for further processing. The lower water-acetone-methanolic layer was then saturated with ammonium sulphate and extracted with 20 ml dichloromethane. The dichloromethane layer was separated, dried with Magnesium Sulphate, filtered and evaporated to yield crude Ajoene.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].[CH3:24][O:25][CH2:26][CH2:27][C:28]1([NH2:31])[CH2:30][CH2:29]1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:31][C:28]4([CH2:27][CH2:26][O:25][CH3:24])[CH2:30][CH2:29]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:7][CH:8]=1)#[N:2]
Reactant: COCCC1(N)CC1
Reactant: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Product: COCCC1(NC(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4)c3O)nc2)CC1

Procedure:
The title compound was prepared in a manner similar to Example 198 using 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-(2-methoxyethyl)cyclopropanamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.58-0.73 (m, 4H) 1.79 (t, J=6.9 Hz, 2H) 3.14 (s, 3H) 3.39 (t, J=6.9 Hz, 2H) 7.72 (d, J=8.6 Hz, 2H) 8.07 (d, J=7.8 Hz, 2H) 8.27-8.34 (m, 1H) 8.37 (br. s., 1H) 8.57 (br. s., 1H) 8.77 (s, 1H) 8.79-8.83 (m, 1H) 13.46 (br. s., 1H). MS m/z 404 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C:9]2=[O:14])=[CH:6][CH:5]=[CH:4][C:3]=1[S:15]([NH:18][C@@H:19]([CH2:23][C:24]1[CH:28]=[C:27]([C:29]2[S:30][C:31]([Cl:34])=[CH:32][CH:33]=2)[O:26][N:25]=1)[C:20]([OH:22])=O)(=[O:17])=[O:16].[NH:35]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>>[N:35]1([C:20](=[O:22])[C@@H:19]([NH:18][S:15]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][C:9]3=[O:14])[C:2]=2[Cl:1])(=[O:17])=[O:16])[CH2:23][C:24]2[CH:28]=[C:27]([C:29]3[S:30][C:31]([Cl:34])=[CH:32][CH:33]=3)[O:26][N:25]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: O=C(O)[C@H](Cc1cc(-c2ccc(Cl)s2)on1)NS(=O)(=O)c1cccc(N2CCOCC2=O)c1Cl
Reactant: C1CCCNCC1
Product: O=C([C@H](Cc1cc(-c2ccc(Cl)s2)on1)NS(=O)(=O)c1cccc(N2CCOCC2=O)c1Cl)N1CCCCCC1

Procedure:
Intermediate 12 (300 mg, 0.55 mmol) and azepane (54 mg, 0.55 mmol) were coupled using the procedure described in example 1; 1.9.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:20]=[CH:19][C:11]2[N:12]=[C:13]([NH:15][CH:16]([CH3:18])[CH3:17])[S:14][C:10]=2[CH:9]=1.[Cl:21][C:22]1[C:27]([NH:28][S:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][N:23]=1>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.CCO>[Cl:21][C:22]1[C:27]([NH:28][S:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[CH:26][C:25]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][CH:16]([CH3:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)=[CH:24][N:23]=1
Reactant: COc1ccc(S(=O)(=O)Nc2cc(B3OC(C)(C)C(C)(C)O3)cnc2Cl)cc1
Reactant: CC(C)Nc1nc2ccc(Br)cc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)Nc2cc(-c3ccc4nc(NC(C)C)sc4c3)cnc2Cl)cc1
Temperature: 80 °C
Yield: 22.6 %

Procedure:
A reaction tube was charged with Pd(Ph3P)4 (13.6 mg, 11.8 μmol), 2.0 M aqueous sodium carbonate (235 μl, 471 μmol), 6-bromo-N-isopropylbenzo[d]thiazol-2-amine (63.9 mg, 235 μmol), N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-4-methoxybenzenesulfonamide (100 mg, 235 μmol) and 0.9 mL EtOH. The tube was sealed and the mixture was heated at 80° C. for 3 h. The mixture was concentrated and the crude material was purified by silica gel chromatography 0-10% MeOH/CH2Cl2 and reverse phase chromatography to provide N-(2-chloro-5-(2-(isopropylamino)benzo[d]thiazol-6-yl)pyridin-3-yl)-4-methoxybenzenesulfonamide (26 mg, 23%) as an off-white solid. MS (ESI pos. ion) m/z calc'd for C22H21ClN4O3S2: 489.0/491.0. found 488.9/491.0.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[F:18][C:19]([F:36])([F:35])[C:20]1[CH:21]=[CH:22][C:23]([O:26][C:27]2[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=2)=[N:24][CH:25]=1.[BH4-].[Na+]>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([NH:1][CH2:31][C:30]3[CH:29]=[CH:28][C:27]([O:26][C:23]4[CH:22]=[CH:21][C:20]([C:19]([F:36])([F:18])[F:35])=[CH:25][N:24]=4)=[CH:34][CH:33]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: CCO
Product: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1NCc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Yield: 42.6 %

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide (300 mg) was suspended in EtOH (5 mL) and 4-[{5-(Trifluoromethyl)pyridin-2-yl}oxy]benzaldehyde (318 mg, 1 eq.) and piperidine (3 drops) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain product as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr (360 mg, 60% yield). Resulting imine (360 mg) was suspended in 10 mL MeOH and sodium borohydride (10 eq., 272 mg) was added. HPLC confirmed reaction was complete (absence of imine). After completion (1 hr), precipitate was filtered to obtain D33 as a light yellow powder. Product was washed with deionized water to remove excess sodium borohydride. Product was allowed to dry under vacuum for 18 hrs. 255 mg (70% yield) of final product was obtained.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].CC(C)([O-])C.[K+].Br[C:13]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:18])[C:14]([O:16][CH3:17])=[O:15].C(=O)=O.CO>C1COCC1>[C:3]([CH:2]([C:1]#[N:5])[C:13]([CH3:18])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])#[N:4]
Reactant: N#CCC#N
Reactant: COC(=O)C(C)(Br)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=C=O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C(C)(c1ccccc1)C(C#N)C#N
Temperature: 25 °C

Procedure:
Malononitrile (4.29 g, 65 mmol) and potassium t-butoxide (7.29 g, 65 mmol) were added to a THF (100 mL) solution containing the intermediate from Step B (15.8 g, 65 mmol). The reaction solution was then placed in an 85° C. oil bath for 4 hours. The solution was then cooled to room temperature and partitioned between saturated aqueous ammonium chloride and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated racemic product. 1H NMR (500 MHz, CHCl3-d): δ 7.44-7.42 (m, 3H); 7.38-7.36 (m, 2H); 4.50 (s, 1H); 3.80 (s, 3H); 2.00 (s 3H). The racemic material was resolved on a Berger SFC II preparative instrument using a ChiralPak AD-H, 250×30 mm I.D. column and a SFC CO2/Methanol eluent.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1.[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C:21](=[O:27])[CH2:20]2.[OH-].[Na+]>O.C(OCC)C>[CH3:18][O:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:21]1([OH:27])[CH:22]3[CH2:25][CH2:26][N:19]([CH2:24][CH2:23]3)[CH2:20]1)[CH:16]=[CH:15]2
Reactant: O=C1CN2CCC1CC2
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: COc1ccc2cc(C3(O)CN4CCC3CC4)ccc2c1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
Butyllithium (2.5 M, 1.86 ml, 4.64 mmol) was added to a mixture of 2-bromo-6-methoxynaphthalene (1.0 g, 4.22 mmol) and diethyl ether (10 ml) at 20° C. The temperature was kept below 35° C. for 30 min. The mixture was cooled to −70° C. and 3-quinuclidinone (0.53 g, 4.22 mmol) was added at −70° C. The mixture was stirred at −70° C. for 1 h. The mixture was allowed to reach room temperature. Water (1 ml) was added followed by aqueous sodium hydroxide (1 M, 10 ml). The crystalline product was filtered and was washed with cold diethyl ether (2 ml). Yield 0.49 g (41%). Mp >330° C.
Reaction SMILES: Br[CH:2]([CH:11]([OH:18])[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].[H-].[Na+]>C1COCC1.C(OCC)(=O)C>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH:11]2[CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])[O:18]2)[CH:13]=1
Reactant: COC(=O)CCCCC(Br)C(O)c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CCCCC1OC1c1cccnc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
16.3 g of methyl 6-bromo-7-hydroxy-7-(3-pyridyl)-heptanoate is dissolved in 200 ml of THF and 4.5 g of 50% sodium hydride in mineral oil added in portions. After stirring at room temperature for 3 h, the reaction mixture is diluted with ethyl acetate, filtered and concentrated to give crude product which is further purified by column chromatography on silica gel using ethyl acetate as eluent to yield 2-(3-pyridyl)-3-(4-methoxycarbonylbutyl)-oxirane.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([SH:14])[CH2:11][CH2:12][SH:13].B(F)(F)F.CCOCC.[OH-].[K+]>C(Cl)Cl>[C:1]1([CH2:7][CH:8]2[S:14][CH2:10][CH2:11][CH2:12][S:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: SCCCS
Reactant: O=CCc1ccccc1
Agent: FB(F)F
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: c1ccc(CC2SCCCS2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To a solution of 33.9 g (280 mmol) of phenylacetaldehyde and 35.6 g (330 mmol) of 1,3-propanedithiol in 300 mL of methylene chloride at 0° C., was added, dropwise over a period of 30 minutes, 10 mL of boron trifluoride etherate. The reaction mixture was allowed to warm to ambient temperature and stirred for 3 h at ambient temperature. The reaction mixture was made basic by the addition of 180 mL of 5% aqueous potassium hydroxide solution and the resultant mixture was stirred for 0.5 h. The layers were separated and the aqueous layer was extracted with methylene chloride. The combined organic extract was washed with 1N aqueous sodium hydroxide solution and brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was distilled to afford 53.62 g (91% yield) of the title compound, b.p. 150° C. (2 mm Hg); 1H NMR (CDCl3) δ1.75-1.95 (1H, m), 2.05-2.17 (1H, m), 2.75-2.91 (4H, m), 3.03 (2H, d, J=9 Hz), 4.25 (1H, t, J=9 Hz), 7.17-7.38 (5H, m).
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6]([CH3:27])=[N:7][C:8]2[N:9]([CH:19]=[C:20]([C:22]([O:24]CC)=[O:23])[N:21]=2)[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])=[N+:2]=[N-:3].O[Li].O>C1COCC1.O>[N:1]([CH2:4][C:5]1[C:6]([CH3:27])=[N:7][C:8]2[N:9]([CH:19]=[C:20]([C:22]([OH:24])=[O:23])[N:21]=2)[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])=[N+:2]=[N-:3]
Reactant: CCOC(=O)c1cn2c(-c3ccc(Cl)cc3Cl)c(CN=[N+]=[N-])c(C)nc2n1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2nc(C(=O)O)cn2c(-c2ccc(Cl)cc2Cl)c1CN=[N+]=[N-]
Temperature: 50 °C
Yield: 93.8 %

Procedure:
To a stirred solution of (+)-ethyl 6-(azidomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxylate (1 g, 2.47 mmol) in THF (20 mL) and H2O (2 mL) was added LiOH.H2O (155 mg, 3.70 mmol). After heating to 50° C. for 16 h, the reaction was concentrated under reduced pressure and diluted with EtOAc. The aqueous layer was acidified by 1N HCl to pH=1. The organic layer was washed with satd aq NH4Cl and brine before drying over MgSO4. Filtration, concentration under reduced pressure provided (+)-6-(azidomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxylic acid (874 mg, 94%) as a white solid.
Reaction SMILES: [C:1]1([CH:7]2[CH2:15][C:14]3[NH:13][CH:12]=[CH:11][C:10]=3[C:9](=O)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([NH:20][NH2:21])([NH2:19])=[NH:18].[ClH:22].Cl.O>C(O)C>[ClH:22].[NH:20]([N:21]=[C:9]1[CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:15][C:14]2[NH:13][CH:12]=[CH:11][C:10]1=2)[C:17]([NH2:19])=[NH:18]
Reactant: O=C1CC(c2ccccc2)Cc2[nH]ccc21
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: N=C(N)NN=C1CC(c2ccccc2)Cc2[nH]ccc21
Yield: 44.3 %

Procedure:
A mixture of 6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.11 g), aminoguanidine hydrochloride (0.06 g), concentrated hydrochloric acid (0.026 ml), water (0.026 ml) and ethanol (10 ml) was refluxed for 20 minutes. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with diethylether, and to the mixture was added 1N sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic layer was dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethanol. To the solution was added 4N hydrochloric acid, and the solvent was evaporated. The residue was recrystallized from ethanol to give 4-guanidinoimino-6-phenyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 1) (70 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4](Cl)[N:3]=1.C(OCC)(=O)C.O.[NH:18]([CH3:20])[CH3:19]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([N:18]([CH3:20])[CH3:19])[N:3]=1
Reactant: CNC
Reactant: OCc1cc(Cl)nc(Cl)c1
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)c1cc(CO)cc(Cl)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of crude (2,6-dichloropyridin-4-yl)methanol in 7 mL of (CH3)2NH (40 wt % solution in H2O) was stirred at r.t. for 45 min. The temperature was increased to 50° C., and the solution was stirred at 50° C. for about 24 h. Ethyl acetate and H2O (15 mL) were added, and the aqueous layer was extracted with EtOAc. The combined extracts were washed with brine, and the aqueous layer was extracted with EtOAc. The combined extracts were dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (40% EtOAc/hexanes) provided 1.01 g of (2-chloro-6-(dimethylamino)pyridin-4-yl)methanol with some impurity (unreacted starting material).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][NH2:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:23]2[C:28]([OH:29])=[CH:27][CH:26]=[CH:25][C:24]=2[O:30][CH2:31][CH:32]2[CH2:34][CH2:33]2)[N:3]=1.C(N(CC)CC)C.[C:42](OC(=O)C)(=[O:44])[CH3:43]>O1CCCC1>[C:42]([NH:9][CH2:8][C:7]1[C:2]([NH2:1])=[N:3][C:4]([C:23]2[C:28]([OH:29])=[CH:27][CH:26]=[CH:25][C:24]=2[O:30][CH2:31][CH:32]2[CH2:33][CH2:34]2)=[CH:5][C:6]=1[CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1)(=[O:44])[CH3:43]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3c(O)cccc3OCC3CC3)nc(N)c2CN)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NCc1c(C2CCCN(C(=O)OC(C)(C)C)C2)cc(-c2c(O)cccc2OCC2CC2)nc1N
Temperature: 0 °C
Reaction time: 4 h
Yield: 54.6 %

Procedure:
To a cold (0° C.) solution of tert-butyl 3-{2-amino-3-(aminomethyl)-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-pyridinyl}-1-piperidinecarboxylate (1.9 g, 4.055 mmol) and triethylamine (1.13 mL, 8.109 mmol) in tetrahydrofuran (40.0 mL) was added acetic anhydride (0.457 mL, 4.865 mmol). The mixture was stirred at 0° C. for 4 hrs. After quenched by water, the mixture was extracted with ethyl acetate and water. The separated organic phase was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue (yellow solid) was purified by recrystallization from ethyl acetate/diisopropyl ether to give tert-butyl 3-{3-(acetylamino-methyl)-2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-pyridinyl}-1-piperidinecarboxylate (1.13 g, yield; 55%).