Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](Cl)=[CH:3][CH:4]=[O:5].[CH2:7]1[CH:9]([C:10]([NH2:12])=[NH:11])[CH2:8]1.Cl.[F:14][C:15]([F:24])([F:23])[C:16]1[CH:17]=[C:18](O)[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC>[CH:9]1([C:10]2[N:12]=[C:4]([O:5][C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([C:15]([F:24])([F:23])[F:14])[CH:21]=3)[CH:3]=[CH:2][N:11]=2)[CH2:8][CH2:7]1
Reactant: N=C(N)C1CC1
Reactant: O=CC=C(Cl)Cl
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: FC(F)(F)c1cccc(Oc2ccnc(C3CC3)n2)c1
Temperature: 25 °C
Yield: 74.9 %

Procedure:
3,3-Dichloroacrolein (10 mmoles) diluted with dimethoxyethane (35 ml), is slowly added to a mixture consisting of a cyclopropylcarbamidine hydrochloride (10 mmoles), 3-trifluoromethylphenol (11 mmoles), potassium carbonate (40 mmoles) and dimethoxyethane (40 ml), which is stirred under reflux. When the addition of 3,3-dichloroacrolein is completed additional cyclopropylcarbamidine hydrochloride (1 mmoles) is added. The reaction mixture is stirred for 3 hours under reflux and subsequently cooled down to ambient temperature over night and filtered through silica. The organic phase is concentrated in vacuo. The residue was purified by chromatography on Al2O3 (petrol ethers/ethyl acetate : 20/1) to yield 2.1 g (75%) of the pure product having as a colorless liquid; 1H NMR (CDCl3); δ=2.10 ppm (m, N═C(═N)—CH).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].ClC1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][CH3:14])=[CH:8][N:7]=1.Cl[CH2:16][Cl:17]>>[Cl:17][C:16]1[N:7]=[CH:8][C:9]([CH2:12][N:13]([CH3:14])[C:3]([NH:2][CH3:1])=[S:4])=[CH:10][CH:11]=1
Reactant: ClCCl
Reactant: CN=C=S
Reactant: CNCc1ccc(Cl)nc1
Product: CNC(=S)N(C)Cc1ccc(Cl)nc1
Reaction time: 0.5 h

Procedure:
On a water bath at about 20° C., a solution of 1.44 g of methyl isothiocyanate in 2 ml of dichloromethane was added dropwise to a mixture of 2.81 g of 2-chloro-5-(methylaminomethyl)pyridine and 10 ml of dichloromethane over a period of 10 minutes and the whole mixture was further stirred for 30 minutes. The reaction mixture was then concentrated and the residue was purified by column chromatography (eluent: dichloromethane-methanol (20:1)) to give 3.33 g of 1-(6-chloro-3-pyridylmethyl)-1,3-dimethylthiourea.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:14]=[N:15][C:16]([N:19]([CH3:21])[CH3:20])=[N:17][CH:18]=1.CC(=CC)C.Cl([O-])=[O:28].[Na+].O.O.OP([O-])(O)=O.[Na+]>C(#N)C.O.C(O)(C)(C)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:28])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:14]=[N:15][C:16]([N:19]([CH3:21])[CH3:20])=[N:17][CH:18]=1
Reactant: [O-][Cl+][O-]
Reactant: CN(C)c1ncc(-c2cc3c(C=O)c[nH]c3cc2Cl)cn1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(C)(C)O
Solvent: O
Product: CN(C)c1ncc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)cn1
Temperature: 0 °C
Reaction time: 20 h
Yield: 40.8 %

Procedure:
6-chloro-5-[2-(dimethylamino)pyrimidin-5-yl]-1H-indole-3-carbaldehyde (100 mg, 0.333 mmol) was dissolved in acetonitrile (6 mL) and warm tert-butanol (6 mL) and treated with 2-methyl-2-butene (4 mL). The reaction mixture was cooled to 0° C. and treated with a solution of sodium chlorite (450 mg, 6.65 mmol) and sodium phosphate monobasic dihydrate (1.04 g, 6.65 mmol) in water (3 mL) dropwise via addition funnel. The reaction mixture was warmed to room temperature and stirred for 20 hours. The reaction mixture was concentrated to remove the organics and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL), dried and concentrated in vacuo. The crude product was purified by prep-HPLC (Column: Agella venusil ASB C18 150×21.2 mm×5 μm; Mobile phase: from 20% MeCN in water (0.1% HCl) to 45% MeCN in water (0.1% HCl) Wavelength: 220 nm) to give 6-chloro-5-[2-(dimethylamino)pyrimidin-5-yl]-1H-indole-3-carboxylic acid (43 mg, 41% yield) as a yellow solid. MS (ES+) 316.9 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 11.98 (s, 1 H), 8.42 (s, 2 H), 8.08 (d, 1 H), 7.93 (s, 1 H), 7.65 (s, 1 H), 3.17 (s, 6 H).
Reaction SMILES: F[C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[C:22]1[S:26][CH:25]=[N:24][CH:23]=1.[CH3:27][C:28]1([OH:33])[CH2:32][CH2:31][NH:30][CH2:29]1>>[OH:33][C:28]1([CH3:27])[CH2:32][CH2:31][N:30]([C:2]2[CH:21]=[CH:20][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)=[O:7])=[CH:4][C:3]=2[C:22]2[S:26][CH:25]=[N:24][CH:23]=2)[CH2:29]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(F)c(-c2cncs2)c1
Reactant: CC1(O)CCNC1
Product: CC1(O)CCN(c2ccc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncs2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 1 using 4-fluoro-3-(thiazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 1.1) and 3-methylpyrrolidin-3-ol to afford a yellow solid. UPLC-MS (Condition 1) tR=2.57 min, m/z=464.1 [M+H]+, m/z=462.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.09-1.30 (m, 3H) 1.63-1.85 (m, 2H) 2.88 (s, 1H) 2.95 (s, 1H) 3.02-3.15 (m, 1H) 3.26-3.30 (m, 1H) 4.72 (s, 1H) 6.94 (d, J=8.80 Hz, 1H) 7.33 (d, J=9.05 Hz, 2H) 7.78-8.00 (m, 6H) 9.15 (s, 1H) 10.14 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3]1.[Br:10][C:11]1[S:15][C:14]([C:16](O)=[O:17])=[CH:13][CH:12]=1.S(Cl)(Cl)=O.C(N(CC)CC)C>ClCCl>[Br:10][C:11]1[S:15][C:14]([C:16]([NH:1][C:2]2([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3]2)=[O:17])=[CH:13][CH:12]=1
Reactant: NC1(C(=O)O)CCOC1
Reactant: O=C(O)c1ccc(Br)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(NC1(C(=O)O)CCOC1)c1ccc(Br)s1

Procedure:
Prepared analogously to Example 53a from 3-amino-tetrahydrofuran-3-carboxylic acid and 5-bromo-thiophene-2-carboxylic acid with thionyl chloride and N,O-bis-(trimethylsilyl)-trifluoroacetamid in dichloromethane with triethylamine.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Br:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([F:21])[CH:15]=1>>[BrH:12].[Cl:11][C:8]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2](=[NH:1])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([F:21])[CH:15]=2)[CH:9]=1
Reactant: NC(=O)c1cc(Cl)cnc1N
Reactant: Cc1ccc(CBr)cc1F
Product: Br
Product: Cc1ccc(Cn2cc(Cl)cc(C(N)=O)c2=N)cc1F

Procedure:
According to the method of Example 172, 2-amino-5-chloronicotinamide was reacted with 4-(bromomethyl)-2-fluoro-1-methylbenzene to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[N:17]=[CH:16][C:10]3[N:11]=[CH:12][NH:13][C:14](=O)[C:9]=3[CH:8]=2)=[N:4][N:3]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:14]1[C:9]2[CH:8]=[C:7]([C:5]3[O:6][C:2]([CH3:1])=[N:3][N:4]=3)[N:17]=[CH:16][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: Cc1nnc(-c2cc3c(=O)[nH]cnc3cn2)o1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nnc(-c2cc3c(Cl)ncnc3cn2)o1
Reaction time: 1 h

Procedure:
6-(5-Methyl-1,3,4-oxadiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-one (0.5 g) was treated with phosphorus oxychloride at room temperature under N2. After 1 hour at room temperature and 1 hour at 50° C., the mixture was concentrated in vacuo, azeotroping with toluene, then taken up in ethyl acetate, washed with sodium bicarbonate solution, dried and concentrated in vacuo to give the title compound (0.17 g) as an orange solid; δH CDCl3 9.68 (1H,s), 9.30 (1H,s), 8.96 (1H,s), 2.75 (3H,s); m/z (M+1+)248.
Reaction SMILES: [CH2:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].Br[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)=[CH:20][CH:19]=1>>[CH2:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]3)=[CH:22][CH:23]=2)=[CH:10][CH:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Product: CCCCNC(=O)c1ccc(-c2ccc(OCC3CCN(C(=O)OC(C)C)CC3)cc2)cc1
Yield: 28.7 %

Procedure:
The title compound (26 mg, 23%) was prepared from {4-[(butylamino)carbonyl]phenyl}boronic acid (44 mg, 0.2 mmol) and 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 9, Step 2, 71 mg, 0.2 mmol) in a manner similar to Example 21, Step 3, and worked up in a manner similar to Example 9, Step 3. 1H NMR (400 MHz, CDCl3): δ 7.80 (d, 2H, J=8.6 Hz), 7.60 (d, 2H, J=8.6 Hz), 7.54 (d, 2H, J=8.9 Hz), 6.96 (d, 2H, J=8.8 Hz), 6.11 (t, 1H, J=5.7 Hz), 5.01-4.83 (m, 1H), 4.21 (bs, 2H), 3.85 (d, 2H, J=6.4 Hz), 3.53-3.39 (m, 2H), 2.83-2.73 (m, 2H), 2.05-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.67-1.55 (m, 2H), 1.46-1.37 (m, 2H), 1.36-1.25 (m, 2H), 1.24 (d, 6H, J=6.2 Hz), 0.96 (t, 3H, J=7.3 Hz); LRMS (ESI), m/z 453 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.[NH2:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=1.C1COCC1>S(Cl)(Cl)=O>[Cl:11][C:7]1[CH:8]=[N:9][CH:10]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=1)=[O:6]
Reactant: O=C(O)c1c(Cl)cncc1Cl
Reactant: Nc1ccc(CO)cc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: O=C(Nc1ccc(CO)cc1)c1c(Cl)cncc1Cl
Temperature: 25 °C
Reaction time: 19 h
Yield: 63.1 %

Procedure:
A suspension of 3,5-dichloroisonicotinic acid (128 mg, 0.667 mmol) in thionyl chloride (2 mL) was heated at reflux for 2 h, then concentrated. To the residue was added 4-aminobenzyl alcohol (123 mg, 0.999 mmol) and THF (2.2 mL), and the mixture was stirred at room temperature for 19 h. The mixture was filtered, and the filtrate was concentrated to give a yellow foam (125 mg, 63%). 1H NMR (CD3OD) δ 4.60 (s, 2H), 7.38 (d, 2H, J=8.7 Hz), 7.63 (d, 2H, J=8.4 Hz), 8.66 (s, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]O.C[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=1.C[S:22](OS(C)(=O)=O)(=O)=O.[Br-].[Li+]>C1COCC1.O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][S:22][C:19]1[CH:18]=[CH:17][C:16]([NH2:15])=[CH:20][CH:14]=1
Reactant: Cc1cccc(C)n1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: COCOc1ccccc1CO
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COCOc1ccccc1CSc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(methoxymethoxy)benzylalcohol (8.0 g) was dissolved in THF, 2,6-dimethylpyridine (8.3 ml) and methanesulfonic acid anhydride (9.9 g) were added to the mixture, and the mixture was stirred at room temperature for 3 hours. Lithium bromide (5.8 g) was added to the mixture, the mixture was stirred for 4 hours at room temperature and the mixture was further stirred for 20 hours at 50° C. After allowing the mixture to be cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was added dropwise to an aqueous solution (104 ml) of 4-aminothiophenol (4.2 g) and sodium hydroxide (2.0 g) in methanol, and the mixture was stirred for 12 hours at room temperature. The solvent was removed under reduced pressure, and water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 4-[[2-(methoxymethoxy)benzyl]sulfanyl]aniline (8.2 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:27])[CH2:15][CH:16]([O:23][C:24](=[O:26])[NH2:25])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>O1CCCC1.O>[C:24]([O:23][CH:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:15][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][C:35](=[O:37])[CH3:36])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1)=[O:27])(=[O:26])[NH2:25]
Reactant: CC(=O)Cl
Reactant: NC(=O)OC(CC(=O)N1CCN(c2ccc(O)cc2)CC1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc(N2CCN(C(=O)CC(OC(N)=O)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The compound ‘carbamic acid 3-[4-(4-hydroxy-phenyl)-piperazin-1-yl]-3-oxo-1-phenyl-propyl ester (2 mmol)’ prepared in Example 18 was dissolved in tetrahydrofuran 25 mL), and triethylamine (2.4 mmol) and acetylchloride (2.4 mmol) were added to the mixture. The reslting mixture was stirred at a room temperature for 5 hours. Then, the reaction mixture was diluted with water, and extracted several times with ethyl acetate to obtain an organic phase. The prepared organic phase was dried over magnesium sulfate, and concentrated under a reduced pressure. The resulting pellet was purified with column chromatography (hexane:ethyl acetate=1:1) to obtain a title compound.
Reaction SMILES: [Cl:1][C:2]([Cl:4])=[CH2:3].[CH2:5]([C:7]1(Cl)[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:6].Cl>[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)Cl>[Cl:1][C:2]([Cl:4])=[CH:3][C:7]1([CH2:5][CH3:6])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CCC1(Cl)CCCC1
Reactant: C=C(Cl)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC1(C=C(Cl)Cl)CCCC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
10 g of anhydrous aluminum chloride were added to 291 g (3 mols) of 1,1-dichloroethene at -20° C., and thereafter 133 g (1 mol) of 1-ethyl-cyclopentyl chloride (Chem. Abstr. 42, 6238 (1948)) were added dropwise at 0° to 10° C. The reaction solution was allowed to warm up to 20° C., a further 5 g of aluminum chloride was added, and the mixture was stirred for a further 2 hours at 20° C. The mixture was poured on to ice, and was worked up with methylene chloride and dilute hydrochloric acid. 158 g (82% of theory) of 1-(2,2-dichlorovinyl)-1-ethyl-cyclopentane of boiling point 45° to 50° C./0.1 mm Hg were obtained by fractional distillation of the organic phase after the latter had been dried over sodium sulphate.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[NH:4][CH2:3]1>C(OCC)(=O)C.[Pd]>[NH2:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH3:14])([CH3:1])[CH2:3][NH:4]2)=[CH:9][CH:8]=1
Reactant: CC1(C)CNc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)CNc2cc(N)ccc21
Yield: 89.5 %

Procedure:
A solution of 3,3-dimethyl-6-nitroindoline (60 mg, 0.31 mmol) in 3 mL of ethyl acetate was hydrogenated under an atmosphere of hydrogen with Pd-C 10% (10 mg) at rt for 3 h. Filtration over celite afforded 45 mg (90%) of 6-amino-3,3-dimethylindoline. Data for 6-amino-3,3-dimethylindoline: 1H NMR (400 MHz, CDCl3)6.80 (d,J=7.8, 1H), 6.08 (dd,J=7.8, 2.1, 1H), 6.01 (d,J=2.1, 1H), 3.60 (bs, 1H), 3.50 (bs, 2H), 3.26 (s, 2H), 1.25 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH:9]1[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:21]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:22]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[CH:23][CH:21]=[O:22])[CH2:10][CH:9]1[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CC(C=O)CCN1C(=O)OC(C)(C)C
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC(C=CC=O)CCN1C(=O)OC(C)(C)C

Procedure:
A solution of 1 g of 1-(tert-butoxycarbonyl)-2-ethoxycarbonylpiperidine-4-carboxaldehyde and 2 g of formylmethylene-triphenylphosphoran in 16 ml of toluene is heated to 100° (bath) for 2 hours. The solution is cooled and purified by flash chromatography using ethyl acetate/hexane (25:75) to yield 1-(tert-butoxycarbonyl)-2-ethoxycarbonylpiperidine-4-acrylaldehyde.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Cl:20][CH2:21][CH2:22][N:23]=[C:24]=[O:25]>>[Cl:20][CH2:21][CH2:22][NH:23][C:24]([N:19]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])=[O:25]
Reactant: CCCCCCN
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C=NCCCl
Product: CCCCCCN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 92.3 %

Procedure:
3.6 g of D-glucose, 2.5 g of n-hexylamine and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 5-(1). 6.8 g of 1-(2-chloroethyl)-3-n-hexyl-3-D-glucopyranosylurea are thereby obtained as brownish caramel.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=O.[CH2:9]1[CH:13]2[CH:14]3[CH:18]=[CH:17][CH:16]([CH:12]2[CH:11]=[CH:10]1)[CH2:15]3.O>>[CH2:9]1[CH:13]2[CH:14]3[CH:18]=[CH:17][CH:16]([CH:12]2[CH:11]=[CH:10]1)[CH2:15]3.[C:4]1(=[O:6])[O:8][C:1](=[O:7])[CH:2]=[CH:3]1
Reactant: O=C(O)/C=C\C(=O)O
Solvent: O
Solvent: C1=CC2C3C=CC(C3)C2C1
Product: O=C1C=CC(=O)O1

Procedure:
The following example is for a case where an addition product of maleic acid to dicyclopentadiene produced from 1 mol (132 g) dicyclopentadiene, 1 mol (98 g) maleic anhydride and 1 mol (18 g) water is dehydrated and condensed with 0.6 mol (37.2 g) ethylene glycol. First, since the theoretic amount of the produced addition product of maleic acid to dicyclopentadiene is 1 mol, the weight is given by the equation: 132 g+98 g+18 g=248 g. Since there are 1.2 mol hydroxyl groups and 1 mol carboxyl groups, 1 mol water is eliminated with the condensation, and its weight is: 18×1=18 g. Therefore, the ratio of the dicyclopentenyl groups is given by the following equation: [133 g/(248 g+37.2 g-18 g)]×100=49.8 percent by weight.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:14](O)[C:15]#[CH:16].C1(N=C=NC2CCCCC2)CCCCC1>CCOC(C)=O>[CH2:16]([O:12][C:11](=[O:13])[CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])[C:15]#[CH:14]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: C#CCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: C#CCOC(=O)CCNC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
N-Boc-β-alanine (1.91 g, 10.1 mmol) and propargyl alcohol (0.675 g, 12 mmol) were dissolved in EtOAc (25 mL). Dicyclohexyl-carbodiimide (DCC, 2.06 g, 10 mmol) was added to the solution and after 16 h of stirring at room temperature, the reaction mixture was filtered and evaporated to dryness under vacuum. Crude product yield
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:7])=[N:5][N:6]=1.[BH4-].[Na+].O.[CH3:11][CH:12](O)[CH3:13]>CC(C)=O>[CH3:7][C:4]1[S:3][C:2]([NH:1][CH:12]([CH3:13])[CH3:11])=[N:6][N:5]=1
Reactant: CC(C)O
Reactant: Cc1nnc(N)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1nnc(NC(C)C)s1

Procedure:
2-Amino-5-methyl-1,3,4-thiadiazole (23 g, 0.2 mole) in IPA (700 ml) and acetone (100 ml) was treated with sodium borohydride (20 g) in portions with stirring and cooling. The reaction mixture was then stirred and heated to reflux for 31/2 hours. The solution was then poured into water (3 L) and extracted with ether (× 3). The ethereal solution was dried, filtered and evaporated to give the title compound as a cream solid. m.p. 145° C.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH3:16])[NH:5][C:6]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[C:8]([Cl:15])[N:7]=1>CO.[Ni].[H][H]>[Cl:15][C:8]1[N:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[NH:12][C:3](=[O:2])[C@H:4]([CH3:16])[NH:5]2
Reactant: COC(=O)[C@H](C)Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: C[C@@H]1Nc2nc(Cl)ccc2NC1=O
Yield: 24.3 %

Procedure:
Compound A (9.0 g, 0.05 mol) was dissolved in 200 ml of methanol and hydrogenated with Raney nickel catalysis under 1 atm of hydrogen. After hydrogen uptake ceased, the catalyst was filtered off with suction, and the solvent was removed in vacuo. The solid product was stirred with diethyl ether, resulting in 2.4 g of pure product (melting point 236°-237° C.).
Reaction SMILES: N[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[BrH:13].N([O-])=O.[Na+]>C(#N)C.O>[Br:13][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: Nc1ccc2c(c1)C(=O)NCC2
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C1NCCc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a solution of 7-amino-3,4-dihydro-1(2H)-isoquinolinone, (0.77 g, 4.77 mmol)(for a synthesis see Girard, Yves; Atkinson, Joseph G.; Belanger, Patrice C.; Fuentes, Jose J.; Rokach, Joshua; Rooney, C. Stanley; Remy, David C.; Hunt, Cecilia A J. Org. Chem. (1983), 48(19), 3220) in acetonitrile (10 ml) at 0° C. was added 48% aqueous HBr (10 ml, precooled to 0° C.). The mixture was stirred at 0° C. for 0.5 h before addition of a solution of NaNO2 (0.379 g, 5.49 mmol) in water (2 ml) over 0.4 h. The reaction was then stirred at 0° C. for 0.5 h and then CuBr (0.822 g, 5.726 mmol) was added portionwise over 10 min. The reaction mixture was then warmed to room temperature, stirred at room temperature for 0.5 h and then at 70° C. for 1 h. The reaction mixture was then cooled to 0° C., water (60 ml) was added and the mixture stirred at 0° C. for 1 h before filtering and drying in vacuo. The residue was dissolved in 10% methanol/dichloromethane, dried with magnesium sulphate and evaporated to give the desired product (0.679 g, 63%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C:4]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1>CCOC(C)=O.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:40])[C@@H:4]([NH:32][C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@H:11]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:18][CH:19]=3)[CH2:12][O:13][C:8]=2[CH:7]=1
Reactant: COC(=O)C(=Cc1ccc2c(c1)OC[C@@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-tert-Butoxycarbonylamino-3-{(R)-2-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-acrylic acid methyl ester (4.9 g) was suspended in 300 mL EtOAc. 400 mg (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(cyclooctadiene)rhodium(I) trifluoromethanesulfonate in 30 mL DCM was added. The mixture was then degassed and a hydrogen balloon was added. The mixture was stirred at room temperature for 2 hours and the solvent was evaporated. The residue was purified by silica gel flash chromatography (hexanes to 8:2 hexanes/EtOAc) to give 4.8 g after drying. 1H NMR (400 MHz, CDCl3): 7.54 (d, 1H), 7.46 (d, 1H), 7.34 (m, 2H), 7.24-7.28 (m, 1H), 6.98 (m, 2H), 6.87 (d, 1H), 6.69 (d, 1H), 6.62 (m, 1H), 5.07-4.96 (m, 4H), 4.54 (m, 1H), 4.30 (m, 1H), 4.0 (m, 1H), 3.74 (s, 3H), 3.0 (m, 2H), 1.43 (s, 9H).