Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[C:8]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)=[C:7]([CH:17]([CH3:19])[CH3:18])[N:6]=[C:5]1[CH2:20]OCC1C=CC=CC=1)[CH:2]=[CH2:3].B(Cl)(Cl)[Cl:30].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:1]([N:4]1[C:8]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)=[C:7]([CH:17]([CH3:19])[CH3:18])[N:6]=[C:5]1[CH2:20][Cl:30])[CH:2]=[CH2:3]
Reactant: C=CCn1c(COCc2ccccc2)nc(C(C)C)c1Sc1cccc(Cl)c1
Reactant: ClB(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCn1c(CCl)nc(C(C)C)c1Sc1cccc(Cl)c1
Temperature: -40 °C
Yield: 13 %

Procedure:
(2)In 5 ml of methylene chloride was dissolved 470 mg (1.13 mmol)of 1-allyl-2-benzyloxymethyl-5-(3-chlorophenylthio)-4-isopropyl-1H-imidazole (17g), with cooling to -40° C., 0.7 ml (1.36 mmol)of methylene chloride solution of boron trichloride (1.94 molar)was addled with stirring, and the mixture was stirred for 30 minutes. To this reaction mixture, a saturated aqueous solution of sodium bicarbonate was added for neutralization, methylene chloride layer was washed with water and dried over sodium sulfate. The solvent was concentrated under reduced pressure and the residue was fractionated by silica gel chromatography (ethyl acetate:methylene chloride=1:4). From the first fraction, 50 mg (yield 13%)of 1-allyl-2-chloromethyl-5-(3-chlorophenylthio)-4-isopropylimidazole (28a)was obtained as oil, and then, 155 mg (yield 43%)of Compound I-17 was obtained. mp 84-86° C.
Reaction SMILES: Br[CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.[NH2:18][CH2:19][C:20]1[S:21][CH:22]=[CH:23][CH:24]=1>>[CH3:15][C:13]1[CH:14]=[C:5]2[CH2:4][CH:3]([CH2:2][NH:18][CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[O:17][C:6]2=[C:7]2[C:12]=1[NH:11][C:10](=[O:16])[CH:9]=[CH:8]2
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CBr)C2
Reactant: NCc1cccs1
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNCc1cccs1)C2
Temperature: 150 °C
Reaction time: 4 h
Yield: 83.1 %

Procedure:
A mixture of 2-bromomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (2.942 g) and 2-aminomethylthiophene (4.528 g) was stirred in a hot bath at 150° C. in the stream of argon gas for 4 hours. The solvent was distilled off under reduced pressure. Chloroform was added to the residue, and washed with sodium bicarbonate water, and water in this order. After dried, the residue was crystallized from ethanol to obtain 2.712 g of a free base of the title compound as pale yellow prisms (mp.: 163°-165° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH3:13])([CH3:14])[C:6]=3[CH:15]=2)=[CH:19][CH:18]=1
Reactant: CN1C(=O)OC(C)(C)c2cc(N)ccc21
Reactant: OB(O)c1ccc(Cl)cc1
Product: CN1C(=O)OC(C)(C)c2cc(Nc3ccc(Cl)cc3)ccc21

Procedure:
Prepared from 6-amino-1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 4-chlorophenyl boronic acid according to the coupling procedure described in example 1. MS (ESI) m/z [M+H]+(317/319); MS (ESI) m/z [M−H]−(315/317); Anal. calcd for C17H17ClN2O2: C, 64.46; H, 5.41; N, 8.84. Found: C, 63.40; H, 5.46; N, 7.97.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH:18]1[CH2:20][CH2:19]1>CC(C)=O>[CH:18]1([CH2:17][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:20][CH2:19]1
Reactant: BrCC1CC1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1ccc(OCC2CC2)cc1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
To a mixture of 4-hydroxybenzaldehyde (2.00 g), potassium carbonate (4.53 g) and acetone (50.0 mL), (bromomethyl)cyclopropane (3.32 g) was added and the mixture was refluxed for 9 hours. After cooling the reaction mixture to room temperature, the resulting precipitate was removed by filtration through Celite (registered trademark). The filtrate was concentrated under reduced pressure and, thereafter, the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10-50:50) to give the titled compound as a colorless oil (2.63 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[O:15]([CH2:23][CH2:24][O:25][C:26]1[C:33]([CH3:34])=[CH:32][C:29]([CH:30]=O)=[CH:28][C:27]=1[CH3:35])[Si](C(C)(C)C)(C)C.II.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:15][CH2:23][CH2:24][O:25][C:26]1[C:33]([CH3:34])=[CH:32][C:29]([C:30]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)=[CH:28][C:27]=1[CH3:35]
Reactant: Cc1cc(C=O)cc(C)c1OCCO[Si](C)(C)C(C)(C)C
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCO)c(C)c3)nc2c1
Temperature: 70 °C
Reaction time: 16 h
Yield: 43.1 %

Procedure:
A solution of 2-amino-4,6-dimethoxybenzamide (0.60 g, 3.06 mmol) and 4-[2-(tert-butyldimethylsilanoxy)ethoxy]-3,5-dimethylbenzaldehyde (0.856 g, 2.78 mmol) in N,N-dimethyl formamide (20 mL) was stirred at 70° C. for 1 h. Iodine (0.846 g, 3.33 mmol) and potassium carbonate (0.384 g, 2.78 mmol) were added and the reaction mixture was stirred at 70° C. for 16 h. The reaction mixture was poured into ice, and extracted with ethyl acetate. The organic layer was washed with water, brine, and dried over anhydrous Na2SO4. Removal of the solvent gave the crude product which was purified by column chromatography to give 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (444 mg, 39%) as a white solid. Selected data: 229-231° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][C@H:6]([CH3:8])[CH2:5][C:4]([C:12]([O-:14])=[O:13])([C:9]([O-:11])=O)[CH2:3]1.[H-].[CH2:16]([Al+]CC(C)C)C(C)C>C(OCC)C>[CH3:16][O:14][C:12]([C:4]1([CH:9]=[O:11])[CH2:5][C@H:6]([CH3:8])[CH2:7][C@H:2]([CH3:1])[CH2:3]1)=[O:13]
Reactant: C[C@@H]1C[C@H](C)CC(C(=O)[O-])(C(=O)[O-])C1
Reactant: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Product: COC(=O)C1(C=O)C[C@H](C)C[C@H](C)C1
Reaction time: 2.5 h

Procedure:
To a solution of (3R,5S)-3,5-dimethyl-cyclohexane-1,1-dicarboxylate (7.38 g, 32.4 mmol) in diethyl ether (250 mL) at −78° C. under a nitrogen atmosphere was added diisobutylaluminum hydride (1.5M in toluene, 43 mL, 64.8 mmol) dropwise. After 2.5 h, the reaction mixture was quenched with saturated aqueous NH4Cl solution (100 mL) then with 1N HCl solution (100 mL). The aqueous phase was extracted with diethyl ether (100 mL×5), was dried (MgSO4) and was evaporated in vacuo to yield the title compound as a clear, colorless oil (5.5 g, 85%) which was used without further purification. MH+199.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12]CC)=[O:11])=[CH:5][CH:4]=1.[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][CH:8]=1
Reactant: CCOC(=O)Cc1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a solution of ethyl 2-(4-methoxyphenyl)acetate (12 g, 0.06 mol) in MeOH (150 mL) was added dropwise a solution of NaOH (9.8 g, 0.24 mol) in water (50 mL). The mixture was then stirred at RT for 1 h and concentrated in vacuo, the residue was acidified with HCl (1N) and extracted with EtOAc (2×400 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to afford 2-(4-methoxyphenyl)acetic acid (10 g, 67%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11](O)=[O:12])[C:4]=2[CH:3]=1.[CH:20]([C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25])([CH3:22])[CH3:21]>>[CH:20]([C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH:25][C:11]([CH:10]1[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[CH2:7][O:6][C:5]2[CH:18]=[CH:19][C:2]([CH3:1])=[CH:3][C:4]1=2)=[O:12])([CH3:22])[CH3:21]
Reactant: Cc1ccc2c(c1)C(C(=O)O)c1ccccc1CO2
Reactant: CC(C)c1ccccc1N
Product: Cc1ccc2c(c1)C(C(=O)Nc1ccccc1C(C)C)c1ccccc1CO2
Yield: 126 %

Procedure:
The similar procedures as in Example 1 were repeated except using 1.0 g of Compound A and 0.63 g of 2-isopropylaniline in place of aniline to obtain 1.84 g of Compound 5.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[C@H:9]1[C:14](=[O:19])[NH:15][CH:16]1[CH2:18][CH2:17]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH:16]1([NH:15][C:14]([C@@H:9]2[C@@H:10]([OH:13])[CH2:11][CH2:12][NH:8]2)=[O:19])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1C(=O)NC1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CC1)[C@H]1NCC[C@@H]1O
Yield: 99.3 %

Procedure:
A solution of (2S,3S)-2-cyclopropylcarbamoyl-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (5.6 g) in 30% of TFA in DCM (50 mL) was stirred at rt for 2 hours. The reaction was concentrated to give 3.5 g of (2S,3S)-3-hydroxy-pyrrolidine-2-carboxylic acid cyclopropylamide as a TFA salt.
Reaction SMILES: C([Li])(C)(C)C.C1C[O:9][CH2:8]C1.[CH2:11]([O:13][CH:14]([O:26][CH2:27][CH3:28])[N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24]#[N:25])=[CH:16]1)[CH3:12]>CN(C=O)C>[CH2:11]([O:13][CH:14]([O:26][CH2:27][CH3:28])[N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24]#[N:25])=[C:16]1[CH:8]=[O:9])[CH3:12]
Reactant: C1CCOC1
Reactant: CCOC(OCC)n1cc(C#N)c2ccccc21
Agent: [Li]C(C)(C)C
Solvent: CN(C)C=O
Product: CCOC(OCC)n1c(C=O)c(C#N)c2ccccc21
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl lithium (18.1 mL, 31 mmol, 1.7M in pentane) was added to a THF (100 mL) solution of 1-diethoxymethyl-1H-indole-3-carbonitrile (6.83 g, 28 mmol) at −78° C. The mixture was warmed to 10° C., stirred for 30 min at this temperature, cooled to −78° C. and heated with DMF (20 mL). The mixture was warmed to 10° C., stirred for 30 min at this temperature, cooled to −78° C. and quenched with a saturated aqueous solution of NaHCO3. The resulting mixture was treated with ether (200 mL); the organic layer was washed with water and brine, dried and evaporated to dryness. NMR (300 MHz, CDCl3, 8): 10.24 (s, 1H), 8.10 (d, J=7.7 Hz, 1H), 7.91 (d, J=7.7 Hz, 1H), 7.53 (t, J=7.7 Hz, 1H), 7.43 (t, J=7.5 Hz, 1H), 7.34 (s, 1H), 3.80 (m, 2H), 3.52 (m, 2H), 1.26 (t, J=6.4 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4([C:24]([O:26]C)=[O:25])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4([C:24]([OH:26])=[O:25])[CH2:22][CH2:23]4)=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C1(c2ccc(CN3CCN(c4ccc(F)cc4)CC3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1(c2ccc(CN3CCN(c4ccc(F)cc4)CC3)cc2)CC1
Temperature: 70 °C
Yield: 79.6 %

Procedure:
Methyl 1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)cyclopropanecarboxylate (2.26 g) was dissolved in ethanol (18 ml) and a solution of sodium hydroxide (0.49 g) in water (4.6 ml) was added, and the mixture was heated at 70° C. for 2 hr. The solvent was evaporated, and the residue was dissolved in water (200 ml). The solution was neutralized with hydrochloric acid and extracted with ethyl acetate (300 ml). The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the title compound (1.73 g) as white crystals, m.p.=74-77° C.
Reaction SMILES: [CH:1](=[N:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])[CH:2]=[CH:3][CH3:4].[Cl:14][CH2:15][C:16](Cl)=[O:17].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:1]([N:5]([C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])[C:16](=[O:17])[CH2:15][Cl:14])=[CH:2][CH:3]=[CH2:4]
Reactant: CC=CC=Nc1c(C)cccc1C
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CC=CN(C(=O)CCl)c1c(C)cccc1C
Temperature: 20 °C
Reaction time: 1 h
Yield: 49.7 %

Procedure:
17.3 g (0.1 mol) of N-but-2-enylidene-2,6-dimethylaniline were added dropwise to a solution of 11.3 g (0.1 mol) of chloroacetyl chloride in 10 ml of toluene at 20° C. The mixture was further stirred at 20° C. for 1 hour and 10.1 g (0.1 mol) of triethylamine were then added dropwise. The mixture was further stirred at 20° C. for 1 hour and the precipitate which separated off was filtered off under suction. The filtrate was washed with dilute aqueous bicarbonate solution and then with water, and was subsequently concentrated in vacuo. The residue was recrystallized from hexane. 12.4 g (49.7% of theory) of N-(1,3-butadienyl)-N-(2,6-dimethylphenyl)chloroacetamide were obtained in the form of colorless crystals of melting point 88° C.
Reaction SMILES: [P:1](Cl)([S:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])([S:3][CH2:4][CH3:5])=[O:2].C(N(CC)CC)C.[OH:21][C:22]1[CH:23]=[C:24]([CH2:28][CH:29]=[O:30])[CH:25]=[CH:26][CH:27]=1>C(Cl)Cl>[P:1]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH:29]=[O:30])[CH:23]=1)([S:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])([S:3][CH2:4][CH3:5])=[O:2]
Reactant: O=CCc1cccc(O)c1
Reactant: CCCCCCSP(=O)(Cl)SCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCSP(=O)(Oc1cccc(CC=O)c1)SCC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of S-ethyl S-hexyl chlorodithiophosphate (0.03 mole) in methylene chloride (50 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. Triethylamine (0.03 mole) is added and the mixture is cooled to a temperature of about 0° C. A solution of 3-hydroxylphenylacetaldehyde (0.03 mole) in methylene chloride (15 ml) is slowly added with stirring while maintaining the temperature of the reaction mixture at about 0° C. After the addition is completed, the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 1 hour. After this time the reaction mixture is transferred to a separatory funnel and methylene chloride (100 ml) is added. The resulting solution is then washed with water, dilute aqueous sodium hydroxide and again with water. The washed solution is dried over anhydrous magnesium sulfate, is filtered and stripped of solvent under vacuum to yield the desired product S-ethyl S-hexyl O-(3-formylmethylphenyl) dithiophosphate.
Reaction SMILES: [BH4-].[Na+].[C:3]1([CH:9]2[C:14](=O)[NH:13][C:12]3[CH:16]=[CH:17][CH:18]=[C:19]([C:20](O)=[O:21])[C:11]=3[O:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:3]1([CH:9]2[CH:14]=[N:13][C:12]3[CH:16]=[CH:17][CH:18]=[C:19]([CH2:20][OH:21])[C:11]=3[O:10]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1cccc2c1OC(c1ccccc1)C(=O)N2
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cccc2c1OC(c1ccccc1)C=N2
Reaction time: 0.17 h
Yield: 89.2 %

Procedure:
Boron trifluoride ether complex (1.83 ml, 14.86 mmol) was added dropwise to a suspension of sodium borohydride (422 mg, 11.14 mmol) in tetrahydrofuran (30 ml) with stirring under ice cooling in 10 min. To this reaction mixture was added a solution of (±)-2-phenyl-1,4-benzoxazin-3-one-8-carboxylic acid (500 mg, 1.86 mmol) in tetrahydrofuran (6 ml) and the mixture was stirred at the same temperature for 5 min. and then at room temperature for 1.5 hrs. The reaction mixture was cooled with ice and water (20 ml) was added dropwise thereto. The mixture was neutralized with saturated sodium bicarbonate solution and then extracted with ethyl acetate. The extract was washed with water and brine in turn and dried. The solvent was distilled off under reduced pressure to give (±)-2-phenyl-1,4-benzoxazine-8-methanol (397 mg, 89%) as a pale orange oil.
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5](Br)[N:4]([CH2:11][CH:12]([OH:14])[CH3:13])[N:3]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(OC(C)C)(C)C>CCO>[CH2:15]([NH:22][C:5]1[N:4]([CH2:11][CH:12]([OH:14])[CH3:13])[N:3]=[C:2]([Br:1])[C:6]=1[N+:7]([O-:9])=[O:8])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: CC(O)Cn1nc(Br)c([N+](=O)[O-])c1Br
Solvent: CCO
Solvent: CC(C)OC(C)C
Product: CC(O)Cn1nc(Br)c([N+](=O)[O-])c1NCc1ccccc1
Yield: 5.8 %

Procedure:
A mixture of 1-(3,5-dibromo-4-nitropyrazol-1-yl)propan-2-ol (3-3) (22 g, 666 mmol), EtOH (300 ml) and benzylamine (102 g, 936 mmol) was refluxed for 1.5 hours. The reaction medium was concentrated to the maximum under reduced pressure. DCM (100 ml) was added to the residue. The organic phase was washed with dilute acid (5×50 ml). The organic phase was dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The brown oil obtained was treated with diisopropyl ether at 0° C. to give the 1-(5-benzylamino-3-bromo-4-nitropyrazol-1-yl)propan-2-ol (13.7 g, 58%) in the form of a yellow solid.
Reaction SMILES: C([C:3]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:5]([CH3:10])=[CH:6][N:7](C)[CH3:8])#N.[ClH:15]>ClCCCl>[CH3:14][O:13][C:11](=[O:12])[C:3]1[CH:4]=[C:5]([CH3:10])[CH:6]=[N:7][C:8]=1[Cl:15]
Reactant: COC(=O)C(C#N)=CC(C)=CN(C)C
Reactant: Cl
Solvent: ClCCCl
Product: COC(=O)c1cc(C)cnc1Cl
Temperature: 50 °C

Procedure:
1-Cyano-4-(N,N-dimethylamino)-1-methoxycarbonyl-3-methyl-1,3-butadiene (33.6 g, 0.173 mol) prepared in a manner analogous to that described in Example 1(i) above was suspended in 1,2-dichloroethane (330 ml) and heated to 50° C. with stirring whereupon a steady stream of hydrogen chloride was passed through the mixture. After 21/4 hours, the clear solution was concentrated. The residue was dissolved in water and this solution was extracted with dichloromethane (3×100 ml). The pooled organic layers were dried with sodium sulphate and evaporated. Crystallisation of the residue from petrol yielded colourless crystals of 2-chloro-5-methylnicotinic acid methyl ester (30.0g, 93.4% of theoretical yield) with m.pt. 31° C.-33° C.
Reaction SMILES: C([NH:4][C:5]1[C:10]2[O:11][CH2:12][O:13][C:9]=2[C:8]([C:14]([O:16]C)=[O:15])=[CH:7][C:6]=1[Cl:18])(=O)C.[OH-].[K+].Cl>O>[NH2:4][C:5]1[C:10]2[O:11][CH2:12][O:13][C:9]=2[C:8]([C:14]([OH:16])=[O:15])=[CH:7][C:6]=1[Cl:18]
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)c2c1OCO2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nc1c(Cl)cc(C(=O)O)c2c1OCO2
Yield: 96.9 %

Procedure:
Intermediate (2-d) (18.2 g) was added to a solution of KOH (37.6 g) in water (380 ml). The resulting reaction mixture was stirred and refluxed for 3 hours. The mixture was cooled, acidified with hydrochloric acid, and the resulting precipitate was filtered off, washed with water, suspended in ACN, filtered off, then dried, yielding 14 g (>95%) of 7-amino-6-chloro-1,3-benzodioxole-4-carboxylic acid (intermediate 2-e). In an analogous way, 3,4-dihydro-9-iodo-2H-1,5-benzodioxepin-6-amine (intermediate 2-f) was prepared.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[N:5]([CH2:8][C:9]#[CH:10])[C:6]=1[Cl:7].[OH-].[Na+].[I:23]I>CO.O>[Cl:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[N:5]([CH2:8][C:9]#[C:10][I:23])[C:6]=1[Cl:7]
Reactant: II
Reactant: C#CCn1c(Cl)c(Cl)c(C#N)c1-c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#Cc1c(Cl)c(Cl)n(CC#CI)c1-c1ccc(Cl)c(Cl)c1
Reaction time: 12 h

Procedure:
To a stirred mixture of 1.91 g (5.5 mmol) of 4,5-dichloro-2-(3,4-dichlorophenyl)-1-(2-propynyl)pyrrole-3-carbonitrile in 500 mL of methanol is added 69 mL of 10% aqueous sodium hydroxide and then 0.70 g (2.7 mmol) of iodine. The mixture is stirred for 12 hours and then acidified and diluted with 200 mL of water. The precipitated solids are collected and recrystallized from methanol to afford 0.51 g while crystals, m.p. 115°-116° C.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[C:5]([O:13][CH2:14][CH2:15][C@@H:16]2[CH2:18][C@@H:17]2[CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[CH2:21][CH2:20]2)=[N:6][CH:7]=[C:8]([N+:10]([O-])=O)[CH:9]=1>CO.C(Cl)Cl.Cl[Ni]Cl>[NH2:10][C:8]1[CH:9]=[C:4]([CH3:3])[C:5]([O:13][CH2:14][CH2:15][C@@H:16]2[CH2:18][C@@H:17]2[CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:26])[CH2:21][CH2:20]2)=[N:6][CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1OCC[C@@H]1C[C@@H]1C1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(N)cnc1OCC[C@@H]1C[C@@H]1C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 0.08 h

Procedure:
To the solution of NiCl2 (Nickel (II) Chloride-hexahydrate) in 12 ml of methanol was added 50 mg of NaBH4 (solution turned dark) at room temperature and the resulting mixture was stirred for 5 minutes. Benzyl 4-((1R,2S)-2-{2-[(3-methyl-5-nitropyridin-2-yl)oxy]ethyl}cyclopropyl)piperidine-1-carboxylate (from Step A; 550 mg, 1.25 mmol) in 5 ml of DCM was then added followed by the addition of 116 mg of NaBH4 in 3 portions. The mixture was then stirred for 20 minutes and then diluted with DCM and filtered through a pad of sodium sulfate (messy). The solution was concentrated to dryness under reduced pressure and taken up in 15 mL DCM. This material was then filtered through a pad of silica gel (extracting with ethyl acetate) and the filtrate was then washed by saturated aq. NaHCO3. The organics were then dried over sodium sulfate, filtered, and concentrated to dryness under reduced pressure to afford the title compound as a crude product which was used for next step. MS (ESI) m/z 410 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C@@H:11]([NH:13][CH2:14][CH3:15])[CH3:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH:29]=O)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C@@H:11]([N:13]([CH2:29][CH:26]3[CH2:27][CH2:28][N:23]([C:21]([O:20][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:22])[CH2:24][CH2:25]3)[CH2:14][CH3:15])[CH3:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CCN[C@@H](C)Cc1ccc2c(c1)CCO2
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCN(CC1CCN(C(=O)OC(C)(C)C)CC1)[C@@H](C)Cc1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.9 %

Procedure:
To a solution of (S)-N-[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]ethylamine (2.38 grams, 11.6 mmol) and 1-(tert-butoxycarbonyl)piperidine-4-carboxaldehyde (2.47 grams, 11.6 mmol) in dichloroethane (20 ml) was added sodium triacetoxyborohydride (3.67 grams,17.4 mmole). The reaction mixture was stirred for 16 hours at room temperature. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic layer was washed with water, dried over potassium carbonate and concentrated under reduced pressure to leave a residue, which was purified by flash chromatography on silica gel using 30% ethyl acetate in hexane. Appropriate fractions were combined and concentrated to give (S)-N-[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]-N-ethyl-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]amine as a oil (3.78 g, 82%), M+H 403.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1/[C:19](=[N:21]/[OH:22])/[NH2:20])(=[O:12])=[O:11].[N:23]1[CH:28]=[CH:27][CH:26]=[N:25][C:24]=1[C:29](O)=[O:30]>>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[C:19](=[N:21][O:22][C:29]([C:24]1[N:25]=[CH:26][CH:27]=[CH:28][N:23]=1)=[O:30])[NH2:20])(=[O:11])=[O:12]
Reactant: N/C(=N\O)C1CCCCN1S(=O)(=O)c1nc2ccccc2[nH]1
Reactant: O=C(O)c1ncccn1
Product: NC(=NOC(=O)c1ncccn1)C1CCCCN1S(=O)(=O)c1nc2ccccc2[nH]1

Procedure:
The title compound was prepared by a similar method to Preparation 20 from (Z)-1-(1H-benzo[d]imidazol-2-ylsulfonyl)-N′2-hydroxy-2-piperidinecarboximidamide [see Preparation 19] and pyrimidine-2-carboxylic acid (see Chem. Ind. (London), 1954, 786) to afford 1-(1H-benzo[d]imidazol-2-ylsulfonyl)-N′2-[(2-pyrimidinylcarbonyl)oxy]-2-piperidinecarboximidamide as a gum. The title compound was used directly in Example 65.