Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:16])[NH:11][CH2:12][C:13](O)=[O:14])[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(=O)(=O)(O)O.N(CC(O)=O)C(N)=O.O>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[CH2:12][NH:11][C:10]2=[O:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)CNC(=O)Nc1cc(Cl)cc(Cl)c1
Agent: NC(=O)NCC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Clc1ccccc1
Product: O=C1CNC(=O)N1c1cc(Cl)cc(Cl)c1
Temperature: 15 °C
Yield: 95.6 %

Procedure:
To a suspension of 3-(3,5-dichlorophenyl)-ureidoacetic acid (813 g.) in chlorobenzene (3,500 cc.) is added concentrated sulphuric acid (d = 1.83) (16 cc.), representing 0.095 mol per mol of ureidoacetic acid. The water formed in the reaction is removed by azeotropic distillation. After 45 minutes' distillation, a limpid solution is obtained. After cooling to about 15° C, the precipitate formed is filtered off and washed on the filter with ethanol (500 cc.) at 10° C. After drying, 3-(3,5-dichlorophenyl)-hydantoin (724 g.) melting at 199° C is obtained. Yield: 95.4%.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([C:9](F)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:6]([CH2:19][CH2:20][CH3:21])=[CH:5][C:3]=1[NH2:4].[CH3:22][O-:23].[Na+]>CO>[CH3:22][O:23][C:9]([C:7]1[C:6]([CH2:19][CH2:20][CH3:21])=[CH:5][C:3]([NH2:4])=[C:2]([CH3:1])[CH:8]=1)([C:14]([F:16])([F:15])[F:17])[C:10]([F:12])([F:11])[F:13]
Reactant: CCCc1cc(N)c(C)cc1C(F)(C(F)(F)F)C(F)(F)F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCc1cc(N)c(C)cc1C(OC)(C(F)(F)F)C(F)(F)F
Temperature: 0 °C
Yield: 79 %

Procedure:
2-Methyl-5-n-propyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline (1.6 g, 5 mmol) was dissolved in a 28% solution (9.6 g) of sodium methoxide in methanol, and the mixture was heated under reflux for 3 hr. After allowing to cool, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give the desired compound (1.31 g).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[CH2:2][CH3:3].Cl.[NH2:16][OH:17]>>[CH2:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][C:11](=[N:16][OH:17])[CH2:10][CH2:9]1)[CH2:2][CH3:3]
Reactant: CCCOCCCN1CCC(=O)CC1
Reactant: NO
Agent: Cl
Product: CCCOCCCN1CCC(=NO)CC1

Procedure:
1-(3-Propoxypropyl)-4-piperidone oxime is prepared from 1-(3-propoxypropyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [CH2:1](I)C.[NH2:4][CH2:5][CH2:6][CH2:7][C@:8]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:12]([C:13](=[O:18])[C@@H:14]([O:16][CH3:17])[CH3:15])[N:11]=[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[S:9]1>>[NH2:4][CH2:5][CH2:6][CH2:7][C@:8]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:12]([C:13](=[O:18])[C@@H:14]([O:16][CH2:17][CH3:1])[CH3:15])[N:11]=[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[S:9]1
Reactant: CCI
Reactant: CO[C@@H](C)C(=O)N1N=C(c2cccc(F)c2)S[C@@]1(CCCN)c1ccccc1
Product: CCO[C@@H](C)C(=O)N1N=C(c2cccc(F)c2)S[C@@]1(CCCN)c1ccccc1

Procedure:
Prepared as described in Example 64 using ethyl iodide in place of methyl iodide. MS (+) m/z 416 (M+1) detected; 1H NMR (400 MHz, 10:1 CDCl3:CD3OD) δ 7.39 (m, 7H), 7.30 (m 1H), 7.20 (m, 1H), 4.85 (br q, 1H, J=6.3 Hz), 3.68-3.53 (m, 2H), 3.27 (m, 1H), 3.11 (m, 2H), 2.58 (m, 1H), 2.21 (m, 1H), 1.72 (m, 1H), 1.47 (d, 3H, J=6.3 Hz), 1.24 (m, 3H). Stereochemistry was assigned by inference from (S)-1-((S)-2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.
Reaction SMILES: C([CH:4]1[C:9]2[N:10]=[C:11](Cl)[N:12]=[C:13]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])[C:8]=2[CH2:7][CH2:6][N:5]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])C=C.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=2)O1>>[NH2:43][C:40]1[N:41]=[CH:42][C:37]([C:11]2[N:12]=[C:13]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]3[CH3:20])[C:8]3[CH2:7][CH2:6][N:5]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:4][C:9]=3[N:10]=2)=[CH:38][N:39]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: C=CCC1c2nc(Cl)nc(N3CCOC[C@@H]3C)c2CCN1C(=O)OC(C)(C)C
Product: C[C@H]1COCCN1c1nc(-c2cnc(N)nc2)nc2c1CCN(C(=O)OC(C)(C)C)C2

Procedure:
Compound fh was prepared according to the procedure described in Example 2 step 2 by reacting tert-butyl 8-allyl-2-chloro-4-((S)-3-methylmorpholino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine. LC-MS: m/z=+428 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:23](OC(=O)C)(=[O:25])[CH3:24].C(=O)(O)[O-].[Na+]>ClCCl.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][O:14][C:23](=[O:25])[CH3:24])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C1O[C@@H](CO)CN1c1cccc(F)c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC[C@H]1CN(c2cccc(F)c2)C(=O)O1
Reaction time: 18 h
Yield: 103.4 %

Procedure:
(5R)-3-(3-Fluorophenyl)-5-hydroxymethyloxazolidin-2-one (40 g, 0.189 M, see Upjohn WO 94-13649) was suspended by stirring in dry dichloromethane (400 ml) under nitrogen. Triethylamine (21 g, 0.208 M) and 4-dimethylaminopyridine (0.6 g, 4.9 mM) were added, followed by dropwise addition of acetic anhydride (20.3 g, 0.199 M) over 30 minutes, and stirring continued at ambient temperature for 18 hours. Saturated aqueous sodium bicarbonate (250 ml) was added, the organic phase separated, washed with 2% sodium dihydrogen phosphate, dried (magnesium sulfate), filtered and evaporated to give the desired product (49.6 g) as an oil.
Reaction SMILES: [C:1]([C:3]1([NH:8][C:9](=O)[CH2:10][CH2:11][CH2:12][CH3:13])[CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].C[OH:16]>>[CH2:10]([C:9]1[NH:2][C:1](=[O:16])[C:3]2([CH2:7][CH2:6][CH2:5][CH2:4]2)[N:8]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCC(=O)NC1(C#N)CCCC1
Reactant: CO
Product: CCCCC1=NC2(CCCC2)C(=O)N1

Procedure:
To 19.6 g (0,1 mol) of 1-cyano-1-n-pentanoylaminocyclopentane dissolved in 70 ml of methanol, 5 g of Varion AD resin was added the reaction mixture was heated under reflux conditions for 3 hours. After filtration and evaporation 16.5 g (71.7%) of title compound was obtained, assay by GC: 92%.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([N:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:14]=CC)=[N:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.Cl>C(O)C>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([N:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[NH2:14])=[N:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CC=NN(c1ccc(OC)cc1)c1ncnc2cc(Cl)ccc12
Agent: Cl
Solvent: CCO
Product: COc1ccc(N(N)c2ncnc3cc(Cl)ccc23)cc1
Reaction time: 3 h

Procedure:
A suspension of acetaldehyde N1 -(7-chloroquinazolin-4-yl)-p-methoxyphenylhydrazone hydrochloride (15.0g.) in ethanol (120ml.; dried over magnesium ethoxide) was cooled and stirred at 5°-10° C for 3 hrs. during the passage of dry hydrogen chloride. The mixture was then left at 0°-5° C. for 3 days before separation by filtration. The solid was washed with dry ether (10ml.), and then dissolved in a mixture of water (30ml.), saturated sodium acetate solution (5ml.) and ethyl acetate (25ml.). The aqueous layer was extracted with more ethyl acetate (2 × 15ml.), and the extracts washed with water (20ml.), dried (Na2SO4) and evaporated to give N1 -(7-chloroquinazolin-4-yl)-p-methoxyphenylhydrazine, m.p. 124°-127° C.
Reaction SMILES: C([C:3]1[N:10]=[CH:9][C:8]([C:11]2[N:20]=[C:19]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:12]=2)=[CH:7][C:4]=1[C:5]#[N:6])C.Cl.[NH2:36][OH:37].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:37][NH:36][C:5](=[NH:6])[C:4]1[CH:7]=[C:8]([C:11]2[N:20]=[C:19]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:12]=2)[CH:9]=[N:10][CH:3]=1
Reactant: NO
Reactant: CCc1ncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)cc1C#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N=C(NO)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Temperature: 80 °C
Yield: 186.2 %

Procedure:
To a solution of ethyl 5-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)nicotinonitrile (described in Example 6, 0.10 g, 0.24 mmol) in ethanol (5 mL) was added hydroxylamine hydrochloride (0.033 g, 0.48 mmol) and potassium carbonate (0.076 g, 0.72 mmol). The reaction mixture was heated to reflux at 80° C. for 16 h. The ethanol solvent was evaporated under reduced pressure and the residue was dissolved in DCM, and washed with water. The organic layer was dried, filtered and concentrated to provide N-hydroxy-5-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)nicotinimidamide (0.2 g) which was used without further purification. LCMS Method X: retention time 1.788 min; [M+1]=448.0.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[S:16]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[Cl:29])[C:23](Cl)=[O:24])(=[O:19])(=[O:18])[NH2:17]>COCCOC>[C:1]1([NH:7][NH:8][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:28]([Cl:29])=[C:20]([S:16](=[O:18])(=[O:19])[NH2:17])[CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNc1ccccc1
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: NS(=O)(=O)c1cc(C(=O)NNc2ccccc2)ccc1Cl
Reaction time: 144 h
Yield: 44.8 %

Procedure:
In a 1 liter round bottom flask were placed phenyl hydrazine (54.1 g, 0.5 mol), triethylamine (50.5 g, 0.5 mol), and 150 ml of 1,2 dimethoxyethane. Then the mixture was cooled to ice-bath temperature and with good stirring and over 10 minutes a solution of 3-sulfamoyl-4-chlorobenzoyl chloride 97.1% (61 g, 0.24 mol) in 150 ml 1,2 dimethoxyethane was added dropwise. The reaction was permitted to reach ambient temperature. After standing for 6 days the solvent was evaporated under vacuum and the residue taken up in 500 ml of ethyl acetate. The organic phase was washed twice with 2N H2SO4, with water and finally with 1 molar sodium bicarbonate solution. The ethyl acetate phase was separated and dried with magnesium sulfate, clarified and concentrated to crystallization. 35 g of product mp 189°-190° C. were obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10](=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[CH:18]2.C(O)(=O)C.C(=O)([O-])O.[Na+]>CO>[CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[NH:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[CH:18]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)C1
Reactant: Nc1ccc2[nH]ncc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc(CN2CCCC2Nc2ccc3[nH]ncc3c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.3 %

Procedure:
1-Benzyl-3-pyrrolidinone (105 mg), 5-aminoindazole (67 mg), and acetic acid (0.02 ml) were dissolved in methanol (1 ml), and a borane-pyridine complex (0.06 ml) was added dropwise to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was then added thereto, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC [chloroform/methanol] to give the title compound (49 mg, yield 34%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:11]=[C:10](Cl)[CH:9]=[C:8]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:7]=1)[CH2:2][CH2:3][CH3:4].[NH2:19][NH2:20]>O1CCOCC1>[CH2:1]([O:5][C:6]1[N:11]=[C:10]([NH:19][NH2:20])[CH:9]=[C:8]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: NN
Reactant: CCCCOc1nc(Cl)cc(N2CCOCC2)n1
Solvent: C1COCCO1
Product: CCCCOc1nc(NN)cc(N2CCOCC2)n1
Temperature: 95 °C
Reaction time: 12 h
Yield: 80.7 %

Procedure:
To a solution of 2-n-butoxy-4-chloro-6-(morpholin-4-yl)pyrimidine (1.38 g, 5.1 mmol) in dioxane (50 ml), anhydrous hydrazine (1.6 mL, 50 mmol) was added. The obtained reaction mixture was heated to 95° C., and stirred for 12 h under N2. After cooling to room temperature, the reaction mixture was quenched with ice-brine and extracted with EtOAc (200 mL). The organic extract was washed with brine, water, and dried over Na2SO4. The solvent was removed under reduced pressure. The crude residue was recrystallized from methanol to obtain 2-n-butoxy-4-hydrazino-6-(morpholin-4-yl)pyrimidine as white crystals (1.10 g, 81%).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=2)=[CH:23][CH:22]=1
Reactant: COc1cc(Br)ccc1C=O
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(-c2ccc(F)cc2)ccc1C=O
Temperature: 25 °C
Yield: 59.8 %

Procedure:
Palladium acetate (2.61 g) was added to a mixture of 4-bromo-2-methoxybenzaldehyde (25.0 g), tripotassium phosphate (74.0 g), (4-fluorophenyl)boronic acid (24.4 g), tricyclohexylphosphine (20% toluene solution, 41.3 mL), toluene (250 mL), and water (125 mL), and the resultant mixture was stirred at 90° C. for 3 hours in an argon atmosphere. The reaction mixture was allowed to cool to room temperature, and then, the organic layer was separated. The aqueous layer was subjected to extraction with ethyl acetate. Combined organic layers were washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was crystallized from methanol (150 mL) to obtain the title compound (16.0 g).
Reaction SMILES: [CH2:1]([N:3](CC)[C:4](=[O:32])[CH:5]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)[C:6]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])=[O:7])[CH3:2]>C(N)C.CO>[CH2:1]([NH:3][C:4](=[O:32])[CH:5]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=1)[C:6]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=[O:10])=[O:11])=[O:7])[CH3:2]
Reactant: CCN(CC)C(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Agent: CCN
Solvent: CO
Product: CCNC(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Yield: 54.4 %

Procedure:
In the same manner as in Example 1 (4), a crude product was obtained using the compound (400 mg) obtained in Example 6 (4) and 40% ethylamine-methanol solution (500 μL). This was purified by silica gel column chromatography to give the title compound (205 mg) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]2[CH:28]=[CH:27][C:19]([C:20]([O:22]C(C)(C)C)=[O:21])=[C:18]([F:29])[CH:17]=2)=[N:4][C:5]([C@@H:8]2[CH2:13][CH2:12][C@@H:11]([OH:14])[C@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1.Cl.O1CCOCC1>C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:16]2[CH:28]=[CH:27][C:19]([C:20]([OH:22])=[O:21])=[C:18]([F:29])[CH:17]=2)=[N:4][C:5]([C@@H:8]2[CH2:13][CH2:12][C@@H:11]([OH:14])[C@H:10]([F:15])[CH2:9]2)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2nc([C@@H]3CC[C@@H](O)[C@H](F)C3)cnc2N)cc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1ncc([C@@H]2CC[C@@H](O)[C@H](F)C2)nc1-c1ccc(C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of tert-butyl 4-(3-amino-6-((1R,3R,4R)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzoate (Scheme 84: 365 mg, 0.9 mmol) in DCM (2 mL) was added 4 M HCl in dioxane (8 mL, 32.0 mmol). The reaction mixture was stirred for 3 days at room temperature. After the volatile materials were evaporated in vacuo to yield 4-(3-amino-6-((1R,3R,4R)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-2-fluorobenzoic acid, which was used for the next step without further purification. LCMS (m/z): 350.3 (MH+), 0.48 min.
Reaction SMILES: C([O:4][CH2:5][C:6]1[S:10][C:9]2=[CH:11][N:12]=[CH:13][N:8]2[CH:7]=1)(=O)C>CO.C(=O)([O-])[O-].[K+].[K+]>[OH:4][CH2:5][C:6]1[S:10][C:9]2=[CH:11][N:12]=[CH:13][N:8]2[CH:7]=1
Reactant: CC(=O)OCc1cn2cncc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: OCc1cn2cncc2s1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A 846 mg potion of 2-acetoxymethylimidazo[5,1-b]thiazole was dissolved in a mixed solution of 17 ml of methanol and 1 ml of an aqueous saturated potassium carbonate solution, followed by stirring at room temperature for 1.5 hours. Then, the reaction solution was filtered, and the filtrate was then concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatograph to obtain 550 mg of the title compound.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([F:23])([F:22])[F:21])[C:3]1=[O:24].C1C([N+]([O-])=O)=CC=C([Cl-][C:35]([O-])=[O:36])C=1.C(N(CC)CC)C.Br.Br.[O:47]=[C:48]1[NH:56][C:51]2[CH:52]=[N:53][CH:54]=[CH:55][C:50]=2[N:49]1[CH:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1>O1CCCC1.CS(C)=O>[O:24]=[C:3]1[C@H:2]([NH:1][C:35]([N:60]2[CH2:61][CH2:62][CH:57]([N:49]3[C:50]4[CH:55]=[CH:54][N:53]=[CH:52][C:51]=4[NH:56][C:48]3=[O:47])[CH2:58][CH2:59]2)=[O:36])[N:8]=[C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]1[CH2:19][C:20]([F:21])([F:23])[F:22]
Reactant: O=c1[nH]c2cnccc2n1C1CCNCC1
Reactant: NC1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O
Agent: Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O=C(N[C@@H]1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O)N1CCC(n2c(=O)[nH]c3cnccc32)CC1
Reaction time: 1 h
Yield: 53.9 %

Procedure:
A solution of (3R) 3-amino-2-oxo-5-phenyl-1-(2,2,2-trifluorethyl)-2,3-dihydro-1H-1,4-benzodiazepine (0.030 g, 0.090 mmol) and 4-nitrophenylchloroformate (0.018 g, 0.090 mmol) in dry tetrahydrofuran (0.5 mL) was cooled to 0° C. under argon. Triethylamine (0.013 mL, 0.090 mmol) was added and the reaction stirred for 1 h. A solution of 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazol[4,5-c]pyridine dihydrobromide (0.034 g, 0.90 mmol) and triethylamine (0.065 mL) in dimethylsulfoxide (0.5 mL) was added. The reaction was allowed to come to room temperature and stirred until complete. The crude product was purified by reverse phase HPLC (C-18, 5% to 95% 0.1% trifluoroacetic acid/acetonitrile in 0.1% aqueous trifluoroacetic acid gradient elution) to give the title compound (0.028 g, 45% yield). MS 578.2108 (M+1)
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([O:18][CH3:19])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-]>CO.[Zn]>[C:1]([O:5][C:6](=[O:27])[N:7]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([O:18][CH3:19])[CH:10]=1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(CN(Cc2ccccc2)C(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: COc1cc(CN(Cc2ccccc2)C(=O)OC(C)(C)C)ccc1N
Temperature: 60 °C
Yield: 85.3 %

Procedure:
To a solution of benzyl-(3-methoxy-4-nitro-benzyl)-carbamic acid tert-butyl ester (1.2 g, 3.22 mmol) in methanol (24 mL) was added a saturated aqueous solution of NH4Cl (24 mL) and zinc powder (1.05 g 16.11 mmol). The reaction was heated to 60° C. for 2 hours then the reaction mass was cooled to room temperature and filtered through celite. The solvents were removed under reduced pressure then the residue was partitioned between EtOAc (24 mL) and water (24 mL). The separated aqueous layer was extracted with EtOAc (12 ml), and then the combined organic extracts were washed with water (24 mL), brine (24 mL), dried (Na2SO4) and concentrated under reduced pressure to give the title compound (0.94 g, 85%).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[S:6][CH:5]([CH2:7]O)[CH2:4][S:3]1.S(Cl)([Cl:12])=O>C1(C)C=CC=CC=1>[Cl:12][CH2:7][CH:5]1[CH2:4][S:3][C:2]([CH3:9])([CH3:1])[S:6]1
Reactant: O=S(Cl)Cl
Reactant: CC1(C)SCC(CO)S1
Solvent: Cc1ccccc1
Product: CC1(C)SCC(CCl)S1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.5 %

Procedure:
To a solution of 3.46 g (0.021 mole) of 2,2-dimethyl-4-hydroxymethyl-1,3-dithiolan in 15 mL of toluene was added dropwise 2.35 g (0.020 mole) of thionyl chloride, and the mixture was heated gradually to 80°-85° C., maintained at that temperature for 0.75 hour, then stirred at room temperature for 16 hours. The mixture was filtered, and the filtrate concentrated to dryness at 60° C./100 mm Hg to give a residual oil. Distillation of the oil gave 1.81 g of product, bp 75°-78° C./1.25-1.35 mm Hg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][CH2:8][CH:9]2[C:16]3[CH:15]=[C:14]([C:17]([O:19]C)=[O:18])[NH:13][C:12]=3[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.O.[OH-].[Li+]>>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][CH2:8][CH:9]2[C:16]3[CH:15]=[C:14]([C:17]([OH:19])=[O:18])[NH:13][C:12]=3[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2CCc1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(CCC2CCc3[nH]c(C(=O)O)cc32)cc1
Yield: 63.8 %

Procedure:
The title compound was synthesized from methyl 4-(4-methoxyphenethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (235 mg, 0.78 mmol) and lithium hydroxide monohydrate (132 mg, 3.14 mmol) according to General Procedure 7. Silica gel was added, the solvent stripped off and the silica gel-imbedded material was purified by flash chromatography (0-80% EtOAc/Heptane) to give 4-(4-methoxyphenethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylic acid (34) as a light yellow solid (142 mg, 63%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.64-1.84 (m, 2H), 1.96-2.08 (m, 1H), 2.53-2.78 (m, 5H), 2.85-2.97 (m, 1H), 3.75 (s, 3H), 6.67 (s, 1H), 6.77-6.86 (m, 2H), 7.06-7.16 (m, 2H); LCMS-MS (ESI+) 286.1 (M+H); HPLC (UV=100%), (ELSD=100%).