Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9](=[O:15])[CH2:10][C:11](OC)=[O:12]>CCO>[CH2:16]([N:8]1[C:9](=[O:15])[CH2:10][C:11](=[O:12])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)CC(=O)N(Cc1ccccc1)c1ccccc1N
Solvent: CCO
Product: O=C1CC(=O)N(Cc2ccccc2)c2ccccc2N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
methyl 3-((2-aminophenyl)(benzyl)amino)-3-oxopropanoate (200 mg, 0.67 mmol) was dissolved in 10 mL of EtOH and cooled to 0° C., and Na metal (25 mg, 1.07 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 1 h. The mixture was concentrated and the residue was purified by prep-TLC to give 1-benzyl-1H-benzo[b][1,4]diazepine-2,4(3H,5H)-dione (160 mg, 89%). 1H NMR (300 MHz, DMSO): δ 2.89 (d, J=9.9 Hz, 1H), 3.03 (d, J=10.2 Hz, 1H), 3.46 (q, J=21 Hz, 2H), 6.68 (t, J=8.1 Hz, 1H), 6.84-6.91 (m, 2H), 7.08-7.28 (m, 6H).
Reaction SMILES: C12BC(CCC1)CCC2.[CH:10]([C:12]1[CH:24]=[CH:23][C:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:14][CH:13]=1)=[CH2:11].[OH-:25].[Na+].OO>O1CCCC1.O>[OH:25][CH2:11][CH2:10][C:12]1[CH:24]=[CH:23][C:15]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])=[CH:14][CH:13]=1
Reactant: [OH-]
Reactant: C=Cc1ccc(C(=O)OC(C)(C)C)cc1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(CCO)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 9-borabicyclo[3.3.1]nonane (9-BBN, 5.65 g, 46.3 mmol) in anhydrous tetrahydrofuran was added to a solution of t-butyl 4-vinylbenzoate (8.47 g, 42.1 mmol) prepared in the Preparative Example 102 in anhydrous tetrahydrofuran in a nitrogen stream. The obtained mixture was stirred at room temperature for 3 hours. 15 ml of water and 17 ml of 3N NaOH were added to the reaction mixture successively, followed by the dropwise addition of 30% aqueous hydrogen peroxide at 50° C. or below. The obtained mixture was stirred as such for one hour and poured into water. The mixture thus obtained was extracted with ethyl acetate. The organic phase was washed with an aqueous solution of common salt, dehydrated and distilled to remove the solvent. The obtained residue was purified by silica gel column chromatography (developer: n-hexane/ethyl acetate=1:1) to give the objective compound. yield: 8.71 g
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[CH2:19][C@H:13]3[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C@@H:12]3[CH2:11][C:10](=O)[C:9]=2[CH:21]=1)([CH3:3])[CH3:2].O.NN.[OH-].[K+].C(O)COCCO>O>[CH:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[CH2:19][C@H:13]3[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C@@H:12]3[CH2:11][CH2:10][C:9]=2[CH:21]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Nc1ccc2c(c1)C(=O)C[C@H]1CCN(C)C[C@@H]1C2
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: CC(C)Nc1ccc2c(c1)CC[C@H]1CCN(C)C[C@@H]1C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 25.0 g of trans-1,2,3,4,4a,5,11,11a-octahydro-8-isopropylamino-2-methyl-6H-benzo[5,6]-cyclohepta[1,2-c]pyridin-6-one, 16.0 ml of hydrazine hydrate, 16.0 g of potassium hydroxide and 350 ml of diethylene glycol, is heated first for 1 hour at 150° and then for 3 hours at 200° C., whereby the water formed distils off. The mixture is cooled to room temperature, diluted with water and shaken with methylene chloride. The organic phase is washed neutral with water, dried over sodium sulphate and evaporated, and the residue is reacted in ethanol with the theoretical amount of maleic acid to crystallise out the heading compound in hydrogen maleate form, which is filtered off and recrystallised from ethanol, m.p. from 185° (decomp.).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:15]([NH2:19])=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)=[CH:4][CH:3]=1.Br[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>>[CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:15]([NH:19][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(CNc2ccc3c(N)cccc3n2)o1
Reactant: Brc1cccnc1
Product: Cc1ccc(CNc2ccc3c(Nc4cccnc4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=331.3 (M+H+), was prepared from N2-(5-methyl-furan-2-ylmethyl)-quinoline-2,5-diamine and 3-bromopyridine as described in example 1 step B.
Reaction SMILES: [I:1][CH:2]([OH:5])[C:3]#[CH:4].[OH-].[Na+].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>C1COCC1.O>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:5][CH:2]([I:1])[C:3]#[CH:4])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: C#CC(O)I
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C#CC(I)OS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
Into a 500 mL 4-neck round bottom flask, equipped with a magnetic stirrer and an addition funnel, in an ice bath were placed iodopropargyl alcohol (10 g, 54.9 mmol) in THF (20 mL) and sodium hydroxide (3.4 g, 84.6 mmol) in water (20 mL) To the above cold mixture was added a solution of p-toluenesulfonyl chloride (10.4 g, 54.95 mmol) in THF (20 mL) from an addition funnel. The reaction mixture was stirred for 2 hrs. below 5° C. The reaction mixture was then poured into ice water and the precipitate was collected by suction-filtration and washed with water. After drying under vacuum, the precipitate afforded 17.2 g (yield: 93.4%) of iodopropargyl 4-methylbenzenesulfonate as an off-white solid, mp=75°-78° C. An NMR spectrum showed the desired compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[S:3]1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18]>C(N(CC)CC)C.[Pd+2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1([CH3:15])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH:8]=2)[S:3]1
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)CC(C)(C)c2cc(Br)ccc2S1
Agent: Cl[Pd]Cl
Agent: [Pd+2]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC1(C)CC(C)(C)c2cc(C#C[Si](C)(C)C)ccc2S1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A solution of 600 mg (2.11 mmol) of 2,2,4,4-tetramethyl-6-bromothiochroman (Compound 33) in 1.5 ml of triethylamine was placed in a heavy-walled tube and degassed and then treated under argon with 1.4 g (14.3 mmol) of trimethylsilylacetylene and a powdered mixture of 75 mg (0.39 mmol) of cuprous iodide and 150 mg (0.21 mmol) of bis(triphenylphosphine) palladium (II) chloridel. The reaction mixture was degassed again, then placed under argon and the tube was sealed. The mixture was heated at 100 degrees C. for 24 h, allowed to cool to room temperature and then treated with a further 1.4 g (14.3 mmol) of trimethylsilylacetylene and a powdered mixture of 75 mg (0.39 mmol) of cuprous iodide and 150 mg (0.21 mmol) of bis(triphenylphosphine) palladium (II) chloride. The mixture was then degassed, placed under argon and then heated in the sealed tube at 100 degrees C. for 96 h. The mixture was cooled to room temperature and extracted with 3×10 ml of ether. The organic extracts were combined, washed successively with 25 ml of water and 25 ml of saturated sodium chloride solution and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash chromatography (silica; hexanes followed by 3% ethyl acetate in hexanes) to give the title compound as a yellow, crystalline solid. PMR (CDCl3): & 0.23 (9H, s) , 1.36 (6H, s), 1.39 (6H, s), 1.94 (2H, s), 7.17 (1H, dd, J-8.2 Hz, 1.8 Hz), 7.25 (1H, d, J-1.8 Hz), 7.30 (1H, d, J-8.2 Hz). MS exact mass, m/l 302.1519 (calcd. for C18H26S Si, 382.1524).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[Cl:21]N1C(=O)CCC1=O>C(#N)C.O>[F:20][C:2]([F:1])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:21])[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2C
Solvent: CC#N
Solvent: O
Product: COc1cc2c(cc1Cl)C(C)CN(C(=O)C(F)(F)F)CC2
Reaction time: 8 h
Yield: 46.4 %

Procedure:
A solution of N-trifluoroacetyl-7-methoxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.900 g, 2.67 mmol) in acetonitrile (30 mL) was treated with N-chlorosuccinimide (0.357 g, 2.67 mmol) and stirred overnight at 70 C. The product mixture was diluted with water (100 mL), extracted twice with EtOAc (100 mL), the combined organic phases washed with brine (100 mL), dried with Na2SO4 and concentrated. Flash chromatography (20% EtOAc in hexane, silica) resulted in 0.399 g of a clear oil. 1H NMR (400 MHz, CDCl3, mixture of rotamers) d 7.17 (s, 1H), 6.68 (m, 1H), 3.88 (s, 3H), 3.78 (m, 1H), 3.6-3.3 (m, 2H), 3.2-2.9 (m, 4H), 1.34 (m, 3H). MS calculated for C14H15ClF3NO2+H: 322, observed: 322.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:19]=[C:12]2[C:13](Br)=[CH:14][C:15]([Br:17])=[CH:16][N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.C[O-].[Na+].[C:26](O)(=[O:28])C>O>[CH2:1]([S:8][C:9]1[N:19]=[C:12]2[C:13]([O:28][CH3:26])=[CH:14][C:15]([Br:17])=[CH:16][N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cc(Br)c2nc(SCc3ccccc3)nn2c1
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1cc(Br)cn2nc(SCc3ccccc3)nc12

Procedure:
2-Benzylthio-6,8-dibromo[1,2,4]triazolo[1,5-a]pyridine (9.5 g, 23.8 mmol) was mixed with acetonitrile (50 mL) in a round bottom flask. Sodium methoxide (13.1 mL of 25 percent solution in methanol, 57.1 mmol) was added and the mixture was heated at reflux for 2 hours. Glacial acetic acid (10 mL) was added and the entire reaction mixture was poured into a mixture of ice and water (300 mL). The brown precipitate that formed was recovered by filtration and dried. This was chromatographed on silica gel eluting with a 1:1 mixture of ethyl acetate and hexane. Product-containing fractions were combined and concentrated under reduced pressure to obtain 6.58 g (80 percent of theory) of the title compound as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.O.[NH2:22][NH2:23]>N1C=CC=CC=1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:6]2[C:7]([C:8]3[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=3)=[C:2]([NH:22][NH2:23])[N:3]=[N:4][CH:5]=2)=[CH:15][CH:16]=1
Reactant: Fc1ccc(-c2cnnc(Cl)c2-c2ccncc2)cc1
Reactant: NN
Solvent: c1ccncc1
Solvent: O
Product: NNc1nncc(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 100 °C
Yield: 78 %

Procedure:
To a solution of 3-chloro-5-(4-fluorophenyl)4-(pyridin-4-yl)pyridazine (586 mg, 2.05 mmol) in pyridine (3 mL) at RT was added hydrazine monohydrate (0.6 mL). After addition, the reaction was heated to 100° C. for 3 h. After this time, the reaction mixture was cooled to RT. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water. The resulting mixture was then extracted with EtOAc (3×50 mL). The combined organic layers were washed with saturted Nacl. The organic layer was dried (Na2SO4), filtered and concentrated. The resulting residue was triturated with EtOAc-hexane to give the title compound, 1-(5-(4-fluorophenyl)4-(pyridin-4-yl)pyridazin-3-yl)hydrazine (450 mg, 78%) as an off-white solid. LC/MS (method A): RT=1.10 min, (M+H)+=282.
Reaction SMILES: [C:1]12([CH2:11][C:12](Cl)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[CH3:24])[CH2:19][OH:20]>>[OH:20][CH2:19][C:18]1[CH:21]=[CH:22][C:23]([CH3:24])=[C:16]([NH:15][C:12](=[O:13])[CH2:11][C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)[CH:17]=1
Reactant: Cc1ccc(CO)cc1N
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: Cc1ccc(CO)cc1NC(=O)CC12CC3CC(CC(C3)C1)C2
Yield: 37.3 %

Procedure:
Prepared according to the method of Example 1b) from 1-adamantaneacetyl chloride (2.0 g) and 3-amino4-methylbenzyl alcohol (1.29 g). Silica gel chromatography, eluting with 5% ethylacetate in dichloromethane gave the title compound as a white solid (1.10 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16](S(C)=O)=[N:17][CH:18]=3)[NH:13][C:12]2=[O:24])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])[CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16]([NH:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][N:29]4[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]4)=[N:17][CH:18]=3)[NH:13][C:12]2=[O:24])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: CN1CCN(CCCCCN)CC1
Reactant: COc1cc(OC)cc(N2Cc3cnc(S(C)=O)nc3NC2=O)c1
Product: COc1cc(OC)cc(N2Cc3cnc(NCCCCCN4CCN(C)CC4)nc3NC2=O)c1
Yield: 24 %

Procedure:
Using the general procedure above, 3-(3,5-dimethoxy-phenyl)-7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one and 0.1475 g (0.805 mmol) of 5-(4-methyl-piperazin-1-yl)-pentylamine were reacted. The residue was chromatographed over silica gel, eluting with ethyl acetate/ethanol/triethylamine (9:2:1 v/v/v) then ethyl acetate/ethanol/triethylamine (9:3:2 v/v/v) to give 0.0322 g (24%) of the title compound: HPLC=97% pure.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)[CH3:9])[CH2:5][O:6][CH3:7]>C(O)(=O)C>[CH3:7][O:6][CH2:5][CH:4]([N:8]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1)[CH3:9])[CH2:3][O:2][CH3:1]
Reactant: COCC(COC)N(C)Cc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Product: COCC(COC)N(C)Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
In acetic acid (100 ml) was dissolved N-(1,3-dimethoxy-propan-2-yl)-N-methyl-4-nitrobenzylamine (3.1 g), and to the mixture was added reduced iron (3.2 g) little by little. The mixture was stirred at room temperature overnight, and the solvent was evaporated. To the residue was added ethyl acetate, and precipitates were filtered off. The filtrate was washed with sodium hydroxide solution, water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue dissolved in ethyl acetate. To the mixture was added 4N hydrochloric acid-ethyl acetate, and precipitates were filtered and washed with diethylether. The mixture was dissolved in water, and the mixture was neutralized with 1N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 4-((N-(1,3-dimethoxypropan-2-yl)-N-methylamino)methyl)aniline (2.4 g) as red oil.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][CH:6]([OH:8])[CH2:5][CH:4]1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.FC(F)(F)S(O)(=O)=O>C(Cl)Cl.C1CCCCC1>[CH2:1]([CH:3]1[CH2:7][CH:6]([O:8][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:5][CH:4]1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2]
Reactant: CCOC(=O)C1CC(O)CC1CC
Reactant: COc1ccc(COC(=N)C(Cl)(Cl)Cl)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)C1CC(OCc2ccc(OC)cc2)CC1CC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a mixture of ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate (37.78 g, 203 mmol, Preparation #P.1) in DCM (100 mL) and cyclohexane (200 mL) at about 0° C. was added 4-methoxybenzyl 2,2,2-trichloroacetimidate (93.58 g, 331 mmol) followed by dropwise addition of trifluoromethanesulfonic acid (1.6 mL, 18.0 mmol) over about 35 min. The reaction mixture was stirred at about 0° C. for about 30 min. The ice bath was removed and the reaction mixture was stirred at ambient temperature for about 16 h. The suspension was poured into ice-water (500 mL) and stirred for about 30 min. The solid was removed by filtration while washing with DCM (100 mL). The layers in the filtrate were separated and the aqueous layer was extracted with DCM (3×200 mL). The combined organic layers were washed with water (200 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The crude material was purified using silica gel chromatography eluting with a gradient of 0-100% DCM:EtOAc (95:5) in DCM to give ethyl 2-ethyl-4-(4-methoxybenzyloxy)cyclopentanecarboxylate (39.80 g, 64%): LC/MS (Table 1, Method b) Rt=2.90 min; MS m/z: 307 (M+H)+.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH3:10])=[CH:5][CH:4]=1>CO>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:1])=[CH:5][CH:4]=1
Reactant: N
Reactant: CC(=O)c1ccc(Cl)cc1
Solvent: CO
Product: NCCc1ccc(Cl)cc1
Yield: 98 %

Procedure:
EP-A-1201642 therefore describes a process for preparing amines from halogenated aromatics with anhydrous ammonia. In order to prevent dehalogenation of the aromatic, a solid acidic cocatalyst is added. In Example 6, p-chloroacetophenone together with 1.6% by weight of Raney Co and 19% by weight of ZrO2, based on the reactant, in methanol, is reacted with ammonia to give p-chlorophenylethylamine in >98% yield.
Reaction SMILES: CO[C:3]1[C:4](=O)[CH:5]=[CH:6][C:7]([CH3:10])=[CH:8][CH:9]=1.[NH2:12][C:13]([NH2:15])=[S:14].CO.C[O-].[Na+].CO>C(O)(=O)C>[SH:14][C:13]1[N:12]=[C:4]2[CH:5]=[CH:6][C:7]([CH3:10])=[CH:8][CH:9]=[C:3]2[N:15]=1
Reactant: COc1ccc(C)ccc1=O
Reactant: NC(N)=S
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc2nc(S)nc-2cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Methoxy-5-methyl-2,4,6-cycloheptatrien-1-one (165 g) and 84 g of thiourea were added to 255 g of a 28% sodium methoxide methanol solution, and stirred at room temperature for 30 minutes. Then, 600 ml of methanol was added and acetic acid was added until the pH of the solution becomes around 5. Deposited crystals were collected by filtration, throughly washed with methanol and dried.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[C:22]3[CH2:23][CH2:24][CH2:25][CH2:26][C:21]=3[S:20][C:18]=2[N:19]=1>>[Cl:13][C:14]1[N:15]=[C:16]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:17]2[C:22]3[CH2:23][CH2:24][CH2:25][CH2:26][C:21]=3[S:20][C:18]=2[N:19]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: Clc1nc(Cl)c2c3c(sc2n1)CCCC3
Product: Clc1nc(NCCc2ccc3c(c2)OCO3)c2c3c(sc2n1)CCCC3

Procedure:
Following the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 2,4-dichloro-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidine yields 2-chloro-5,6,7,8-tetrahydro-4-(3,4-methylenedioxyphenethylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [H-].[Na+].CCCCCC.[CH2:9]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:19])[C:13]=2[CH2:12][CH2:11][CH2:10]1.Br[CH2:21][CH2:22][NH:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1>C(COC)OC>[CH2:9]1[C:18]2[C:13](=[C:14]([O:19][CH2:21][CH2:22][NH:23][C:24]3[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=3)[CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: Oc1cccc2c1CCCC2
Reactant: CCOC(=O)c1ccc(NCCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCCCCC
Product: CCOC(=O)c1ccc(NCCOc2cccc3c2CCCC3)cc1

Procedure:
To a slurry of 2.3 g. of 57% sodium hydride-in-oil (previously washed free of oil with hexane) in 20 ml. of dimethoxyethane is added 7.4 g. of 1,2,3,4-tetrahydro-5-naphthol in 20 ml. of dimethoxyethane and then 13.6 g. of ethyl 4-(2-bromoethylamino)benzoate. After refluxing for 6 hours and dilution with 300 ml. of water, the solid is collected and recrystallized from acetonitrile, m.p. 133°-135° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:26]=[CH:25][C:8]3[C:9]4[N:10]=[C:11]([C:17]5[N:18]([CH:22]([CH3:24])[CH3:23])[N:19]=[CH:20][N:21]=5)[S:12][C:13]=4[CH2:14][CH2:15][O:16][C:7]=3[CH:6]=2)[CH2:2]1.C(N(C(C)C)CC)(C)C.[CH:36]([S:39](Cl)(=[O:41])=[O:40])([CH3:38])[CH3:37]>>[CH:22]([N:18]1[C:17]([C:11]2[S:12][C:13]3[CH2:14][CH2:15][O:16][C:7]4[CH:6]=[C:5]([CH:3]5[CH2:4][N:1]([S:39]([CH:36]([CH3:38])[CH3:37])(=[O:41])=[O:40])[CH2:2]5)[CH:26]=[CH:25][C:8]=4[C:9]=3[N:10]=2)=[N:21][CH:20]=[N:19]1)([CH3:24])[CH3:23]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Reactant: CC(C)S(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(S(=O)(=O)C(C)C)C3)ccc1-2

Procedure:
Following the procedure for 395, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene free base 235, diisopropylethylamine and isopropylsulfonyl chloride were reacted. The reaction mixture was loaded directly onto a silica column with no aqueous work-up to give 321 isolated as a solid (57 mg, 25%). LCMS: RT=12.20 min, [M+H]+=474. 1H NMR δ (ppm) (CDCl3): 8.39 (1H, d, J=8.20 Hz), 7.93 (1H, s), 7.21 (1H, dd, J=8.21, 1.89 Hz), 7.06 (1H, d, J=1.84 Hz), 5.96-5.88 (1H, m), 4.42 (2H, t, J=5.00 Hz), 4.29 (2H, t, J=8.23 Hz), 4.15 (2H, t, J=7.30 Hz), 3.84-3.78 (1H, m), 3.43 (2H, t, J=5.03 Hz), 3.16 (1H, t, J=6.84 Hz), 1.64 (6H, d, J=6.62 Hz), 1.40 (6H, d, J=6.84 Hz)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:28][C:29](=[O:42])[CH:30]([N:35]([CH3:41])[CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:31][CH:32]([CH3:34])[CH3:33])[C:17](=[O:27])NCCN2CCOCC2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:43][CH2:44][C:45]([NH2:48])([CH3:47])[CH3:46].[N-]=C=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:28][C:29](=[O:42])[CH:30]([N:35]([CH3:41])[CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:31][CH:32]([CH3:34])[CH3:33])[C:17](=[O:27])[NH:48][C:45]([CH3:47])([CH3:46])[CH2:44][OH:43])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(N)CO
Reactant: CC(C)CCN(C)C(CC(C)C)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NCCN1CCOCC1
Agent: [N-]=C=O
Solvent: ClCCl
Product: CC(C)CCN(C)C(CC(C)C)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)CO
Reaction time: 48 h

Procedure:
A suspension of N-(2-methylbutyl)-N-methyl-leucine-tyrosine(OBn)-Kaiser oxime resin (Example 57, IIc) in CH2Cl2 was treated with 1.5 equivalents of 2-hydroxy-1,1-dimethylethylamine. The suspension was shaken for 48 hours. After the reaction was completed, additional CH2Cl2 and 1 equivalent of polymer supported isocyanate was added. After the suspension was shaken for 48 hours, the resin was filtered off, and the solvent was evaporated to yield the title product.