Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:27]1[CH2:31][CH2:30][C@H:29]([NH:32]C(=O)OC(C)(C)C)[CH2:28]1)=[N:8][C:9]=2[NH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[NH2:32][C@H:29]1[CH2:30][CH2:31][N:27]([C:7]2[N:6]=[C:5]3[C:10]([N:11]=[CH:12][N:4]3[CH:1]([CH3:3])[CH3:2])=[C:9]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[CH:18][CH:19]=3)[N:8]=2)[CH2:28]1
Reactant: CC(C)n1cnc2c(Nc3ccc(N4CCN(C)CC4)cc3)nc(N3CC[C@H](NC(=O)OC(C)(C)C)C3)nc21
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1cnc2c(Nc3ccc(N4CCN(C)CC4)cc3)nc(N3CC[C@H](N)C3)nc21
Reaction time: 3 h
Yield: 110.8 %

Procedure:
To a solution of (S)-tert-butyl (1-(9-isopropyl-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-9H-purin-2-yl)pyrrolidin-3-yl)carbamate (1.40 g, 2.61 mmol) in DCM (30 mL) was added TFA (2.11 mL, 21 mmol). The reaction vial was capped and stirred for 3 hr. The volatiles were then removed and methanol (50 mL) and aqueous LiOH (2 M, 20 mL) were added and the mixture stirred for 16 hr. The volatiles were removed to give a white solid residue. Water (30 mL) was added and the mixture was sonicated to give a white suspension. The solid was collected by filtration and dried to give the title product as a white solid (1.26 g, 111% yield, ˜90% purity). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.10 (br. s., 1 H) 7.76-7.94 (m, 3 H) 6.87 (d, J=8.80 Hz, 2 H) 4.60 (dt, J=13.33, 6.66 Hz, 1 H) 3.58-3.72 (m, 2 H) 3.51 (dd, J=10.64, 5.99 Hz, 2 H) 3.06 (br. s., 4 H) 2.45 (br. s., 4 H) 2.22 (s, 3 H) 1.95-2.10 (m, 2 H) 1.58-1.73 (m, 3 H) 1.50 (d, J=6.72 Hz, 6 H). m/z (APCI+) for C23H33N9 436.4 (M+H)+.
Reaction SMILES: [ClH:1].[O:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:12]#[N:13])[CH2:5][CH2:4][CH2:3]1.[CH2:14]([OH:16])[CH3:15]>>[ClH:1].[CH2:14]([O:16][C:12]([C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[O:2][CH2:3][CH2:4][CH2:5]2)=[NH:13])[CH3:15]
Reactant: N#Cc1cccc2c1OCCC2
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1cccc2c1OCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
Hydrogen chloride gas was passed through a solution of chroman-8-carbonitrile (370 mg, 1.736 mmol) in anhydrous ethanol (15 mL) at 0° C. After 1 h, hydrogen chloride gas was stopped and the reaction vessel was sealed with a stopper. After stirring at room temperature for 1 d, the reaction vessel was cooled to 0° C. and the stopper was removed. The solvent was evaporated in vacuo to afford chroman-8-carboximidic acid ethyl ester hydrochloride (491 mg, 88%). It was used without further purification.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH2:5][O:4][C:3]1=[O:8].C(COC)OC.[C:15]1([N:21]=[C:22]=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCCCCC>[O:8]=[C:3]1[N:2]([NH:1][C:22]([NH:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:23])[CH2:7][CH2:6][CH2:5][O:4]1
Reactant: O=C=Nc1ccccc1
Reactant: NN1CCCOC1=O
Solvent: COCCOC
Solvent: CCCCCC
Product: O=C(Nc1ccccc1)NN1CCCOC1=O
Yield: 53 %

Procedure:
To a mixture of 5.4 g of 3-amino-tetrahydro-1,3-oxazine-2-one and 50 ml glyme was added 5.0 ml of phenyl isocyanate. After an exothermic reaction a white solid formed. The mixture was refluxed for 1 hr; cooled; diluted with hexane and filtered. The solid product was crystallized from 200 ml of ethanol to give 5.8 g (53% yield) of white cotton-like needles of 1-(tetrahydro-2-oxo-1,3-oxazin-3-yl)-3-phenylurea, mp 204°-207°.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[C:12](=[S:14])=[S:13]>C(O)C>[CH3:1][C:2]1[NH:3][CH:4]=[N:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12](=[S:13])[SH:14]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: S=C=S
Solvent: CCO
Product: Cc1[nH]cnc1CSCCNC(=S)S
Reaction time: 8 h

Procedure:
A solution of 4-methyl-5-((2-aminoethyl)thiomethyl) imidazole (10.2 g) in ethanol (75 ml) was added slowly, with stirring, to carbon disulphide (200 ml). The mixture was set aside overnight at room temperature and the solid formed was collected and recrystallized from aqueous isopropyl alcohol to afford N-[2-((5-methyl-4-imidazolyl)-methylthio)ethyl]dithiocarbamic acid (9.8 g)., m.p. 127°-129°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18](=[O:26])[C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH:16]=3)[NH:11][C:10](=O)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)([Cl:30])=O>>[Cl:30][C:10]1[N:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[O:26])[CH:16]=2)[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(c1ccc(F)cc1)c1ccc2[nH]c(=O)nc(-c3cccc(Cl)c3)c2c1
Product: O=C(c1ccc(F)cc1)c1ccc2nc(Cl)nc(-c3cccc(Cl)c3)c2c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
Intermediate 5 (0.0528 mol) was added in phosphoryl chloride (200 ml) at room temperature. The mixture was stirred at 100° C. for 3 hours and cooled to room temperature. The solvent was evaporated. The residue was taken up in DCM. The solvent was evaporated till dryness. The residue was taken up in DCM, poured out into ice water, neutralised with K2CO3 solid and extracted with DCM. The organic layer was washed with water, separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue was crystallized from 2-propanone. The precipitate was filtered off and dried, yielding 8.5 g (40%) of intermediate 6. The mother layer was evaporated. The residue was purified by column chromatography over silica gel (eluent: toluene/EtOAc 95/5; 15-35 μm). The pure fractions were collected and the solvent was evaporated. A part (0.5 g) of the residue (8.9 g, 42%) was crystallized from 2-propanone. The precipitate was filtered off and dried, yielding 0.3 g of [2-chloro-4-(3-chlorophenyl)-6-quinazolinyl](4-fluorophenyl)-methanone (intermediate 6), mp. 138° C.
Reaction SMILES: [CH:1]([C:3]([CH3:5])=[O:4])=[CH2:2].[OH-].[Na+].[S:8]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](=[O:18])[C:15]([OH:17])=[O:16])=[CH:9]1.Cl>CO>[S:8]1[CH:12]=[CH:11][C:10]([CH:13]2[C:14]([C:15]([OH:17])=[O:16])([OH:18])[CH2:5][C:3](=[O:4])[CH2:1][CH2:2]2)=[CH:9]1
Reactant: C=CC(C)=O
Reactant: O=C(O)C(=O)Cc1ccsc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CCC(c2ccsc2)C(O)(C(=O)O)C1
Temperature: 20 °C
Reaction time: 2 h
Yield: 699.5 %

Procedure:
17.1 cm3 (21 mmol) of methyl vinyl ketone and 7.2 g (18 mmol) of sodium hydroxide pellets are successively added to a solution, cooled to 0° C., of 22.4 g (13 mmol) of (3-thienyl)pyruvic acid in 150 cm3 of methanol and then the reaction mixture is stirred at a temperature in the region of 20° C. for two hours. After neutralizing with 60 cm3 of a 3N aqueous hydrochloric acid solution, the precipitate formed is filtered off, washed with water and then dried at 20° C. 21.85 g (70%) of 6-(3-thienyl)-3-oxocyclohexan-1-ol-1-carboxylic acid are thus obtained in the form of a yellow powder, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([O:3][C@H:4]([C:28](N1[C@@H](CC2C=CC=CC=2)COC1=O)=[O:29])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][C:15]3[N:16]=[C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[O:18][C:19]=3[CH3:20])=[CH:11][C:10]=2[CH:27]=1)[CH3:2].[OH-:43].[Li+]>O1CCCC1>[CH2:1]([O:3][C@@H:4]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][C:15]3[N:16]=[C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[O:18][C:19]=3[CH3:20])=[CH:11][C:10]=2[CH:27]=1)[C:28]([OH:29])=[O:43])[CH3:2]
Reactant: [OH-]
Reactant: CCO[C@@H](Cc1ccc2oc(Cc3nc(-c4ccccc4)oc3C)cc2c1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: [Li+]
Solvent: C1CCOC1
Product: CCO[C@@H](Cc1ccc2oc(Cc3nc(-c4ccccc4)oc3C)cc2c1)C(=O)O
Temperature: 0 °C

Procedure:
5-((S)-2-Ethoxy-3[(S)-4-benzyl-2-oxo-3-oxazolidinyl]-3-oxopropyl}-2-[(5-methyl-2-phenyl-4-oxazolyl)methyl]benzofuran (0.15 g, 0.26 mmol) was dissolved in tetrahydrofuran (5 ml). The solution was cooled to 0° C. and 0.5N lithium hydroxide (1.1 ml, 0.52 mmol) was added. After 15 minutes the bulk of the ethanol was removed, the residue was acidified with 1N HCl, diluted with water and extracted with ethyl acetate (3×). The combined extracts were washed with brine, dried over sodium sulfate and concentrated. The product was purified by flash chromatography (hexanes/ethyl acetate/acetic acid, 10:10:1) then recrystallized from hexanes/ethyl acetate and obtained as a white solid (48 mg, m.p. 129° C., [α]D =-12.5° (c 0.99, CDCl3)):
Reaction SMILES: B#B.[CH3:3][CH:4]([CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1)[CH:5]=[CH2:6].[Br:15]Br.C[O-].[Na+]>O1CCCC1.CO.O>[Br:15][CH2:6][CH2:5][CH:4]([CH3:3])[CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1
Reactant: C=CC(C)COC1CCCCO1
Reactant: BrBr
Agent: B#B
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(CCBr)COC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65741.3 %

Procedure:
Diborane in tetrahydrofuran (125 ml, 0.150 m) at 0° C. under nitrogen is added to a mixture of 3-methyl-4-(tetrahydropyran-2-yloxy)-1-butene (72 g, 0.423 m) and tetrahydrofuran (150 ml). After the addition is complete, the mixture is allowed to warm to room temperature and then stirred for 1 hour. The reaction mixture is cooled to 0° C. and bromine (24 ml, 0.43 mmole) and sodium methoxide (0.565 m) in methanol (300 ml) are added slowly simultaneously. After the addition is complete, the mixture is allowed to warm to room temperature and stirred for thirty minutes. The mixture is then treated with water (100 ml) and extracted with petroleum ether (2×200 ml). The organic layer is washed with 5% sodium bicarbonate (100 ml), water (2×100 ml) and dried (Na2SO4). The solvent is removed in vacuo to give a colorless liquid. This crude product is purified by column chromatography on silica gel (500 g, 1% ether in petroleum ether) to give 1-bromo-3-methyl-4-(tetrahydropyran-2-yloxy)-butane (71 g, 65%) as a colorless liquid. NMR (CDCl3)δ: 1.0 (d, J=6 Hz, 3H, ##STR22## 4.59 (br, 1H, ##STR23##
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([NH:15][C:16]3[CH:17]=[N:18][C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[C:20]([CH3:22])[CH:21]=3)=[C:8]([CH:14]=2)[C:9]([O:11]CC)=[O:10])[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C.O.CO.N>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([NH:15][C:16]3[CH:17]=[N:18][C:19]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[C:20]([CH3:22])[CH:21]=3)=[C:8]([CH:14]=2)[C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cc(C2CC2)ccc1Nc1cnc(-c2ccccc2)c(C)c1
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CO
Product: Cc1cc(Nc2ccc(C3CC3)cc2C(=O)O)cnc1-c1ccccc1
Temperature: 60 °C
Yield: 29 %

Procedure:
The solid residue obtained in step A was dissolved in ethanol (5 ml) and aqueous solution 2N NaOH (0.67 ml) was added. The mixture was heated at 60° C. for 2 hours, the solvent was evaporated and the solid obtained was suspended in water. The pH was taken to 6.5 and extracted with CHCl3. The crude mixture was purified over a SCX cartridge eluting with MeOH/NH3 10:1 affording 0.070 g (yield 29%) of the expected product.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:21])O1.[CH:23]1([S:28]([NH2:31])(=[O:30])=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:10]([O:11][CH3:12])[C:8](=[O:9])[CH:7]=[C:5]([OH:6])[C:4]([NH:31][S:28]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)(=[O:30])=[O:29])=[O:21])=[CH:19][CH:18]=1
Reactant: CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Reactant: NS(=O)(=O)C1CCCC1
Product: CON(Cc1ccc(F)cc1)C(=O)C=C(O)C(=O)NS(=O)(=O)C1CCCC1

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-methoxy-acetamide was treated with cyclopentanesulfonic acid amide as described in the preparation of compound 1 to yield the title compound. 1H NMR (500 MHz, CDCl3) δ: 1.66 (m, 2), 1.83 (m, 2), 2.08 (overlapping m, 4), 3.69 (s, 3), 4.10 (p, 1, J=8), 4.79 (s, 2), 6.53 (s, 1), 7.01 (m, 2), 7.29 (m, 2), 8.84 (s, 1). 13C NMR (125 MHz, CDCl3) δ: 20.55, 22.24, 42.90, 57.27, 57.80, 87.06, 110.29, 110.46, 124.85, 124.91, 125.66, 153.94, 154.50, 156.29, 158.25, 165.53.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=2[Cl:17])=[O:9])=[CH:4][CH:3]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([C:2]2[N:7]=[CH:6][C:5]([C:8]([C:10]3[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=3[Cl:17])=[O:9])=[CH:4][CH:3]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(c1ccc(Br)nc1)c1cc(Br)ccc1Cl
Reactant: OB(O)c1ccccc1
Product: O=C(c1ccc(-c2ccccc2)nc1)c1cc(Br)ccc1Cl

Procedure:
The above 5-bromo-2-chlorophenyl 6-bromo-3-pyridyl ketone and phenylboronic acid were treated in a manner similar to Reference Example 20-(1) to give 5-bromo-2-chlorophenyl 6-phenyl-3-pyridyl ketone as yellow crystals. APCI-Mass m/Z 372/374 (M+H).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([O:15]C(C2C=CC=CC=2)C2C=CC=CC=2)[CH:12]=[CH:11][C:10]=1[O:29][CH2:30][CH:31]([CH3:33])[CH3:32])(=O)=O.[Cl:34][C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[NH:40][CH:39]=[C:38]2[CH2:44][C:45]([NH2:48])([CH3:47])[CH3:46].N1C2C(=CC=CC=2)C(CC(N)(C)C)=C1>>[ClH:34].[NH:40]1[C:41]2[C:37](=[CH:36][CH:35]=[CH:43][CH:42]=2)[C:38]([CH2:44][C:45]([NH:48][CH2:6][CH2:7][O:8][C:9]2[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=2[O:29][CH2:30][CH:31]([CH3:32])[CH3:33])([CH3:46])[CH3:47])=[CH:39]1
Reactant: CC(C)(N)Cc1c[nH]c2ccc(Cl)cc12
Reactant: CC(C)COc1ccc(OC(c2ccccc2)c2ccccc2)cc1OCCOS(C)(=O)=O
Agent: CC(C)(N)Cc1c[nH]c2ccccc12
Product: CC(C)COc1ccc(O)cc1OCCNC(C)(C)Cc1c[nH]c2ccccc12
Product: Cl

Procedure:
Proceeding as in Example 3, but replacing 2-[2-(cyclopropylmethyloxy)phenoxy]ethyl methanesulfonate with 2- [5-diphenylmethyloxy-2-(2-methylprop-1-yloxy)phenoxy]ethyl methanesulfonate and [2-(5-chloro-1H-indol-3-yl)-1,1-dimethylethyl]amine with [2-(1H-indol-3-yl)-1,1-dimethylethyl]amine and then removing the protective group, gave [2-(1H-indol-3-yl)-1,1-dimethylethyl]{2-[5-hydroxy-2-(2-methylprop-1-yloxy)phenoxy]ethyl}amine hydrochloride.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]([CH3:41])([CH3:40])[C:13]([NH:15][C:16]1[N:21]=[C:20]([F:22])[C:19]([CH:23]([OH:39])[CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)=[CH:18][CH:17]=1)=[O:14].C(N(CC)CC)C>ClCCl>[CH3:11][C:12]([CH3:41])([CH3:40])[C:13]([NH:15][C:16]1[N:21]=[C:20]([F:22])[C:19]([C:23](=[O:39])[CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)=[CH:18][CH:17]=1)=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(O)c2ccc(NC(=O)C(C)(C)C)nc2F)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCC(=O)c2ccc(NC(=O)C(C)(C)C)nc2F)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.9 %

Procedure:
To a solution of oxalyl chloride (0.11 ml, 1.25 mmol) in dichloromethane (10 ml) was added dropwise dimethylsulfoxide (0.18 ml, 2.51 mmol) at −78° C. After stirring for 10 min, a solution of 1,1-dimethylethyl 4-(3-{6-[(2,2-dimethylpropanoyl)amino]-2-fluoro-3-pyridinyl}-3-hydroxypropyl)-1-piperidinecarboxylate (step 1, 500 mg, 1.14 mmol) in dichloromethane (5 ml) was added to the mixture at −78° C. After 15 min, triethylamine (0.79 ml, 5.70 mmol) was added at the same temperature and the resulting mixture was allowed to warm up to room temperature and stirred for 18 h. The mixture was quenched with 1N aqueous hydrochloric acid (100 ml) and extracted with dichloromethane (150 ml). The organic layer was washed with water (50 ml) and dried over magnesium sulfate. Removal of solvent gave a pale yellow solid, which was chromatographed on a column of silica gel eluting with ethyl acetate/hexane (4:1 ) to afford 362 mg (73%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10](=[O:12])[NH:9][C@H:8]3[CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][C@@H:7]3[C:6]=2[CH:5]=[C:4]([CH3:23])[CH:3]=1.ClC1C=C(C)C=CC=1C(N(CC)CC)=O>>[ClH:1].[Cl:1][C:2]1[C:11]2[C:10](=[O:12])[NH:9][C@H:8]3[CH2:13][NH:14][CH2:15][C@@H:7]3[C:6]=2[CH:5]=[C:4]([CH3:23])[CH:3]=1
Reactant: Cc1cc(Cl)c2c(c1)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1NC2=O
Agent: CCN(CC)C(=O)c1ccc(C)cc1Cl
Product: Cc1cc(Cl)c2c(c1)[C@H]1CNC[C@@H]1NC2=O
Product: Cl

Procedure:
Following the procedure described in Example 23, Part K, (3aR,9bS)-tert-butyl 6-chloro-5-oxo-8-methyl-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate, the first eluting compound from Part C above, was converted into the title compound of Example 37 as an off-white solid. 1H NMR (CD3OD): δ 7.26 (s, 1H), 6.93 (s, 1H), 4.06-4.02 (m, 1H), 3.73-3.67 (m, 2H), 3.40-3.34 (m, 2H), 3.30-3.25 (m, 1H), 2.39 (s, 3H). LRMS (ESI): 237.1/239.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[CH:13]=2)=[CH:5][CH:4]=1.Cl.[CH2:19]([N:21]([CH2:34][CH3:35])[CH2:22][CH2:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)[CH3:20].C(Cl)Cl>O>[CH2:34]([N:21]([CH2:19][CH3:20])[CH2:22][CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([C:29]([C:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[O:10][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:30])=[CH:32][CH:33]=1)[CH3:35]
Reactant: CCN(CC)CCOc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(-c2cc3ccccc3o2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCN(CC)CCOc1ccc(C(=O)c2c(-c3ccc(OC)cc3)oc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 11.2 g. (0.05 mol.) of 2-(4-methoxyphenyl)benzofuran and 14.6 g. (0.05 mol.) of 4-(2-diethylaminoethoxy)benzoyl chloride hydrochloride in 100 ml. of methylene chloride is added 39.1 g. (0.15 mol.) of stannic chloride. The reaction mixture is stirred for 1.5 hours at ambient temperature then poured into water. The layers are separated and the organic phase is washed with aqueous sodium carbonate until basic and water, dried (MgSO4) and concentrated to give the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[NH2:5].Cl[C:24]1[N:25]=[CH:26][C:27]([C:30]([O:32][CH3:33])=[O:31])=[N:28][CH:29]=1.C(N(C(C)C)CC)(C)C>CC(O)C>[CH3:1][CH:2]([CH3:22])[CH2:3][CH:4]([NH:5][C:24]1[N:25]=[CH:26][C:27]([C:30]([O:32][CH3:33])=[O:31])=[N:28][CH:29]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: CC(C)CC(N)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COC(=O)c1cnc(NC(CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cn1
Temperature: 25 °C
Yield: 52 %

Procedure:
A solution of 3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butan-1-amine (0.200 g, 0.651 mmol), methyl 5-chloropyrazine-2-carboxylate (124 mg, 0.716 mmol), and diisopropylethylamine (168 mg, 1.30 mmol) in 2-propanol (5 mL) was heated in a microwave reactor at 100° C. for 2 h. The mixture was cooled to room temperature and concentrated. The mixture was concentrated and purified by column chromatography to give methyl 5-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butylamino)pyrazine-2-carboxylate (150 mg, 52%). 1H NMR (400 MHz, CDCl3, δ): 8.75 (s, 1H), 7.87 (s, 1H), 7.68 (d, J=8.8 Hz, 2H), 7.64 (d, J=8.8 Hz, 2H), 7.55 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 5.46 (s, 1H), 5.04 (t, 1H), 4.12 (s, 3H), 1.87-1.80 (m, 1H), 1.80-1.60 (m, 2H), 1.02 (d, J=6.4 Hz, 3H), 0.98 (d, J=6.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]([Cl:15])=[CH:3][CH:4]([CH3:14])[CH:5]([CH:11]([CH3:13])[CH3:12])[C:6]([O:8]CC)=[O:7].[OH-].[Na+].O>C(O)C>[Cl:1][C:2]([Cl:15])=[CH:3][CH:4]([CH3:14])[CH:5]([CH:11]([CH3:12])[CH3:13])[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(C(C)C)C(C)C=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)C(C(=O)O)C(C)C=C(Cl)Cl
Yield: 82.1 %

Procedure:
A solution of 23.41 g (0.0925 mol) of ethyl 5,5-dichloro-3-methyl-2-isopropyl-4-pentenoate, 11.10 g (0.278 mol) of sodium hydroxide, 40 ml of water, and 40 ml of ethanol was refluxed for 3 days under N2, the solvent was concentrated on the rotary evaporator, the residue taken up in 300 ml of water and extracted 2× with ether. The aqueous layer was acidified with conc. HCl, then extracted 3× with 150 ml of ether. The combined ether extracts were washed with water, dried (MgSO4), and stripped to give 17.09 g (82% yield) of the desired acid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:18][CH3:19])[C:4](=[O:17])[CH:5]=[CH:6][C:7]1[S:11][C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:9][CH:8]=1.[BH4-].[Na+].C(OCC)(=O)C.O>O1CCCC1>[CH3:19][O:18][CH:3]([O:2][CH3:1])[CH:4]([OH:17])[CH:5]=[CH:6][C:7]1[S:11][C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:9][CH:8]=1
Reactant: COC(OC)C(=O)C=Cc1ccc(-c2cccs2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(OC)C(O)C=Cc1ccc(-c2cccs2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-(4,4-dimethoxy-3-oxo-1-butenyl)-2,2'-bithiophene (50 mg) in tetrahydrofuran (2.5 ml) was added sodium borohydride (10 mg). The reaction mixture was stirred at room temperature for 1 hour. Ethyl acetate and water was added for partition. The organic layer was dried over anhydrous magnesium sulfate, concentrated and separated by silica gel chromatography. Light greenish oily product was obtained.
Reaction SMILES: C(OC([N:8]([CH3:18])[C@@H:9]([CH2:13][C:14]([CH3:17])([CH3:16])C)[C:10]([OH:12])=O)=O)(C)(C)C.[F:19][C:20]([F:38])([F:37])[O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:32][C@@H:31]3[C@@H:33]([NH2:36])[CH2:34][CH2:35][C@@H:30]3[CH2:29]2)=[CH:24][CH:23]=1.FC(F)(F)C1N=C(N2C[C@@H]3[C@@H](N)CC[C@@H]3C2)C=CC=1>>[CH:14]1([CH2:13][C@@H:9]([C:10]([NH:36][C@@H:33]2[C@@H:31]3[C@@H:30]([CH2:29][N:28]([C:25]4[CH:24]=[CH:23][C:22]([O:21][C:20]([F:38])([F:19])[F:37])=[CH:27][CH:26]=4)[CH2:32]3)[CH2:35][CH2:34]2)=[O:12])[NH:8][CH3:18])[CH2:16][CH2:17]1
Reactant: N[C@H]1CC[C@@H]2CN(c3ccc(OC(F)(F)F)cc3)C[C@@H]21
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CC(C)(C)C)C(=O)O
Agent: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Product: CN[C@@H](CC1CC1)C(=O)N[C@H]1CC[C@@H]2CN(c3ccc(OC(F)(F)F)cc3)C[C@@H]21

Procedure:
The title compound was prepared by substituting 3-cyclopropyl-N-(tert-butoxycarbonyl)-N-methyl-L-alanine for (S)-2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoic acid and (3aR,4S,6aS)-2-(4-(trifluoromethoxy)phenyl)octahydrocyclopenta[c]pyrrol-4-amine from Example 716 Step 1 for (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 587: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.28 (d, J=7.6, 1H), 7.22 (s, 2H), 6.65-6.54 (m, 2H), 4.46-4.36 (m, 1H), 3.55 (dd, J=9.9, 2.7, 1H), 3.35-3.24 (m, 2H), 3.15 (dd, J=9.5, 7.8, 1H), 3.02 (dd, J=9.6, 3.3, 1H), 2.79-2.67 (m, 2H), 2.46 (d, J=9.2, 3H), 2.17-2.05 (m, 1H), 2.02-1.91 (m, 1H), 1.84 (dd, J=30.5, 23.8, 1H), 1.83-1.62 (m, 3H), 1.45-1.35 (m, 1H), 0.99-0.86 (m, 1H), 0.53-0.38 (m, 2H), 0.19-0.07 (m, 2H); MS (ESI+) m/z 412 (M+H)+.