Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[NH:5][C:4](=[O:10])[C:3]=1[N:11]=O.OS([O-])=O.[Na+].[NH2:18]C1C(=O)NC(=O)N(C)C=1N.N([O-])=O.[Na+]>O.C(O)(=O)C>[CH3:8][N:7]1[C:2]2[NH:1][N:18]=[N:11][C:3]=2[C:4](=[O:10])[NH:5][C:6]1=[O:9]
Reactant: Cn1c(N)c(N=O)c(=O)[nH]c1=O
Reactant: Cn1c(N)c(N)c(=O)[nH]c1=O
Agent: O=N[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(=O)[nH]c(=O)c2nn[nH]c21
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a suspersion of 2.42 g (14.3 mmol) of the 6-amino-1-methyl-5-nitrosouracil in water heated to 90° C., was added 30 mL of a 38% solution of NaHSO3 over 10 minutes and the reaction allowed to continue until the reaction mixture was completely decolourized. After cooling the reaction mixture to 0° C., 5,6-diamino-1-methyluracil crystallized from the medium. After filtering off, washing with water, ethanol and diethylether and drying 2.14 g (80%) of the intermediate 5,6-diamino-1-methyluracil was isolated. 8.71 g (55.8 mmol) of 5,6-diamino-1-methyluracil was dissolved in 100 mL water and 50 mL acetic acid upon heating. After cooling to room temperature, a solution of 3.86 g (55.9 mmol) NaNO2 in 17 mL water was added over 5 minutes. The mixture was stirred for 5 minutes and then refluxed for a short time. After standing for two days at room temperature, 3-methyl-8-aza-9H-xanthine crystallized from the mixture. After filtering off, drying, recrystallization from water/ethanol 1:1 and drying 3.57 g (38%) of 3-methyl-8-aza-9H-xanthine was obtained (m.p. 313–320° C.).
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20](OC)(OC)[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1.[CH3:31][C@H:32]([OH:36])[C@@H:33]([OH:35])[CH3:34].CC1C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>CC1C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1([CH2:21][N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)[O:36][C@@H:32]([CH3:31])[C@H:33]([CH3:34])[O:35]1
Reactant: C[C@H](O)[C@H](C)O
Reactant: COC(Cn1cncn1)(OC)c1ccc(Cl)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C[C@@H]1OC(Cn2cncn2)(c2ccc(Cl)cc2Cl)O[C@H]1C
Yield: 31 %

Procedure:
A mixture of 7.1 parts of 1-[2-(2,4-dichlorophenyl)-2,2-dimethoxyethyl]-1H-1,2,4-triazole 4-methylbenzenesulfonate, 1.5 parts of (2S,3S)-(+)-2,3-butanediol, 0.7 parts of 4-methylbenzenesulfonic acid and 68 parts of methylbenzene is stirred and refluxed for 3 days. The reaction mixture is cooled and alkalized with a sodium hydroxide solution 20%. The whole is poured onto water and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using ethyl acetate as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2,2'-oxybispropane and petroleumether (1:1 by volume). The product is filtered off and dried, yielding 1.5 parts (31%) of (+)-(4S,trans)-1-[2-(2,4-dichlorophenyl)-4,5-dimethyl-1,3-dioxolan-2-ylmethyl]-1H-1,2,4-triazole; mp. 82.7° C.; [α]D =+30.47° (c=0.5 % CHCl3).
Reaction SMILES: O=P(Cl)(Cl)Cl.[F:6][C:7]([C:17]([F:20])([F:19])[F:18])([C:13]([F:16])([F:15])[F:14])[CH2:8][CH:9](I)[CH2:10]O>N1C=CC=CC=1>[F:6][C:7]([C:17]([F:18])([F:19])[F:20])([C:13]([F:14])([F:15])[F:16])[CH2:8][CH:9]=[CH2:10]
Reactant: OCC(I)CC(F)(C(F)(F)F)C(F)(F)F
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: C=CCC(F)(C(F)(F)F)C(F)(F)F

Procedure:
According to another embodiment, the reducing agent can include POCl3, pyridine, and/or a mixture of POCl3 and pyridine. For example, the RF-intermediate 4,5,5,5-tetrafluoro-4-(trifluoromethyl)-2-iodopentan-1-ol can be reacted to form the RF-intermediate 4,5,5,5-tetrafluoro-4-(trifluoromethyl)pent-1-ene in the presence of a mixture of POCl3 and pyridine. This reaction can be performed while maintaining the temperature of the mixture between from about 0° C. to about 5° C., for example.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([C:10](=O)[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2.B>O1CCCC1>[CH:1]1[CH:2]=[C:3]([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2
Reactant: CCOC(=O)CCC(=O)c1ccc2ccccn12
Agent: B
Solvent: C1CCOC1
Product: CCOC(=O)CCCc1ccc2ccccn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.1 %

Procedure:
To a solution of ethyl 4-(3-indolizinyl)-4-oxobutyrate (556 mg) in tetrahydrofuran (5 ml) was added borane in tetrahydrofuran (1M solution, 3.6 ml) at 0° C. After stirring at room temperature for 10 minutes, the reaction was quenched by aqueous potassium dihydrogen phosphate at 0° C., and the resulting mixture was extracted with ether. The organic layers were washed with water, aqueous sodium bicarbonate and brine, dried over sodium sulfate. After evaporation of the solvent, the residue was chromatographed on alumina (Hexane-methylene chloride=1:1) to give ethyl 4-(3-indolizinyl)butyrate (294 mg).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH:8]2[CH2:16][CH2:15][CH2:14][C:13]3[NH:12][CH:11]=[CH:10][C:9]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.O=P(Cl)(Cl)Cl.CN([CH:25]=[O:26])C>>[N:1]1([CH2:6][CH2:7][CH:8]2[CH2:16][CH2:15][CH2:14][C:13]3[NH:12][C:11]([CH:25]=[O:26])=[CH:10][C:9]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1cc2c([nH]1)CCCC2CCN1CCCC1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cc2c([nH]1)CCCC2CCN1CCCC1

Procedure:
4-(2-Pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-indole (475 mg, 2.2 mmol) was formylated with POCl3 (0.25 mL, 1.2 eq.) and DMF (2 ml) using standard Vilsmierer condition to give 250 mg of 4-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde as a light yellow solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH:5]([CH:7]([N:24]2[C:28](=[O:29])[C:27]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]3[C:25]2=[O:34])[C:8]([O:10][CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[O:4][NH:3]1.[N+](=[CH2:37])=[N-].CCOCC>C(Cl)Cl>[CH3:37][O:1][C:2]1[CH2:6][CH:5]([CH:7]([N:24]2[C:25](=[O:34])[C:26]3=[CH:33][CH:32]=[CH:31][CH:30]=[C:27]3[C:28]2=[O:29])[C:8]([O:10][CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])[O:4][N:3]=1
Reactant: C=[N+]=[N-]
Reactant: O=C1CC(C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)c3ccccc3C2=O)ON1
Solvent: CCOCC
Solvent: ClCCl
Product: COC1=NOC(C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)c3ccccc3C2=O)C1

Procedure:
To 90 mg. (0.2 mmole) of 3-oxo-α-phthalimido 5-isoxazolidine acetic acid, benzhydryl ester (IIa) in 5 ml of methylene chloride is added a 50% molar excess of a standard etheral diazomethane solution. A 5 μl. amount of βF3.Et2O is added and, after 30 minutes, the reaction is concentrated and the residue chromatographed on preparative TLC (AIX eluent) to yield (45 mg.) of 3-methoxy-4,5-dihydro-α-phthalimido-5-isoxazole acetic acid, benzhydryl ester.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][C@@H:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH3:19])=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28](F)[CH:27]=2)[N:3]=1.CCO.CCN(C(C)C)C(C)C.[NH2:47][NH2:48]>O.CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][C@@H:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH3:19])=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:26]2[CH:27]=[C:28]3[C:29]([C:32]([NH2:33])=[N:47][NH:48]3)=[CH:30][CH:31]=2)[N:3]=1
Reactant: NN
Reactant: C[C@@H]1CC[C@H](C(=O)N[C@H](C)C2CCCCC2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: C[C@@H]1CC[C@H](C(=O)N[C@H](C)C2CCCCC2)CN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 110 °C
Yield: 50.8 %

Procedure:
Into a microwave tube, (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-[(1R)-1-cyclohexylethyl]-6-methyl-3-piperidinecarboxamide (195.6 mg, 0.421 mmol), 5 mL of EtOH, Hunig's base (0.294 mL, 1.684 mmol), and hydrazine anhydrous (0.079 mL, 2.53 mmol) were added, and the yellow suspension mixture was heated overnight at 110° C. in an oil bath. LCMS showed mainly product. CH3OH (5 mL) was added to the solution. The black solid and the yellow solution were carefully separated due to the black solid is heavier than yellow solution. Water (20 mL) was added to the yellow solution, and a solid formed. The solid was filtered, washed by water and dried in vacuum. The solid was recrystallized using CH3CN, and the solid in the solvent was filtered, washed by EtOAc and CH3CN, and dried in vacuum to afford the title compound (102 mg) as a light yellow solid. LC-MS (ES) m/z=477 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.83-1.36 (m, 12H), 1.55-1.85 (m, 9H), 2.20-2.37 (m, 1H), 2.92 (m, 1H), 3.56-3.71 (m, 1H), 5.38 (s, 2H), 6.07 (s, 2H), 6.57 (s, 1H), 7.54-7.61 (m, 1H), 7.66-7.78 (m, 2H), 7.94 (s, 1H), 11.50 (s, 1H).
Reaction SMILES: CC([O-])=O.[K+].Cl[CH2:7][C:8](=[O:24])[CH:9]([N:15]=[N:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])[C:10]([O:12][CH2:13][CH3:14])=[O:11]>CCO.CCOC(C)=O>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:16]1[CH:7]=[C:8]([OH:24])[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:15]1
Reactant: CCOC(=O)C(N=Nc1ccccc1F)C(=O)CCl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1nn(-c2ccccc2F)cc1O
Temperature: 25 °C
Yield: 102.9 %

Procedure:
KOAc (1.14 g) was added portionwise to a solution of ethyl 4-chloro-2-(2-fluoro-phenylazo)-3-oxobutanoate (2.75 g) in EtOH (30 mL), and the mixture was refluxed for 1 hour. After being cooled to room temperature, the mixture was diluted with EtOAc and washed with H2O (twice) and brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to yield 2.47 g of the title compound. KOAc means potassium acetate.
Reaction SMILES: [Li].[C:2](#[N:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CC(O)(C)C.[CH2:15]([O:22][C:23](=[O:26])[CH2:24]Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>N.C1COCC1>[CH2:15]([O:22][C:23](=[O:26])[CH2:24][C:3]1([C:2]#[N:9])[CH:8]=[CH:7][CH2:6][CH:5]=[CH:4]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: N#Cc1ccccc1
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: N#CC1(CC(=O)OCc2ccccc2)C=CCC=C1
Reaction time: 0.25 h
Yield: 72.9 %

Procedure:
Lithium (0.17 g, 24 mmol) was added in portions to a stirred solution of benzonitrile (0.99 mL, 1.0 g, 9.7 mmol) and t-BuOH (0.93 mL. 0.72 g, 9.7 mmol) in NH3 (50 mL) and THF (10 mL) under N2 at −78° C. After stirring for 15 minutes, benzyl-2-bromoacetate (3.1 mL, 4.5 g, 20 mmol) was added dropwise. After 1 hour, ammonium chloride (4.0 g, 75 mmol) was added in portions. The reaction mixture was slowly warmed to room temperature while the NH3 was removed with a stream of N2. Water (25 mL) was added, and the mixture extracted with EtOAc (3×5 mL). The combined organic extracts were washed with brine (50 mL), dried (MgSO4), and concentrated under reduced pressure. Flash chromatography (SiO2, 1:1-3:1 CH2Cl2:hexane) afforded 1.79 g (73%) of product as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:39])[C:5]([CH3:38])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:34]C(=O)C)=[C:17]([CH:33]=2)[C:18]([NH:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:39])[C:5]([CH3:38])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:34])=[C:17]([CH:33]=2)[C:18]([NH:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cc(OC)c(OC)c(OC)c3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3cc(OC)c(OC)c(OC)c3)c2)=C(C)C1=O
Yield: 54.6 %

Procedure:
N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-3,4,5-trimethoxyaniline (0.100 g, 0.185 mmol) was dissolved in methanol (6 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:2) and then recrystallized from ether to obtain the titled compound (0.050 g, 0.101 mmol, 55%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH:16]([C:19]1[N:20]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:21](=[O:29])[C:22]2[C:27]([CH3:28])=[N:26][S:25][C:23]=2[N:24]=1)[CH2:17][CH3:18])[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:51][C:52]([CH3:54])=O>C(O)(=O)C>[CH2:30]([N:20]1[C:21](=[O:29])[C:22]2[C:27]([CH3:28])=[N:26][S:25][C:23]=2[N:24]=[C:19]1[CH:16]([N:6]([CH2:5][CH2:4][CH2:3][NH:2][CH:52]([CH3:54])[CH3:51])[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[CH2:17][CH3:18])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCC(c1nc2snc(C)c2c(=O)n1Cc1ccccc1)N(CCCN)C(=O)c1ccc(C)cc1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CCC(c1nc2snc(C)c2c(=O)n1Cc1ccccc1)N(CCCNC(C)C)C(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-(3-amino-propyl)-N-[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-propyl]-4-methyl-benzamide hydrogen chloride (method 13g) (1.24 g, 2.54 mmol), in the presence of molecular sieves (2 g,) was added acetone (1 mL) and the mixture was stirred at room temperature for 2 h. Analysis of the reaction mixture by MS showed the completion of the schiff's base formation. To this mixture was added two drops of acetic acid followed by sodium triacetoxyborohydride (220 mg) and the mixture was stirred overnight. The reaction mixture was filtered and the filtrate was washed with water, dried (Na2SO4) and concentrated to get the crude product which was purified by column chromatography (silica gel) using 0-30 % EtOAc in hexanes. N-[1-(5-Benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-propyl]-N-(3-isopropylamino-propyl)-4-methyl-benzamide was isolated as a white foam. Yield 0.206 g (15%). m/z 532 (MH+); 1H NMR (DMSO-d6, 96° C.) δ: 0.65 (t, 3H), 1.05 (d, 6H), 1.26-1.48 (m, 1H), 1.65-1.70 (m, 1H), 1.80-1.98 (m, 1H), 2.00-2.17 (m, 1H), 2.35 (s, 3H), 2.63 (b, 2H), 2.80 (s, 3H), 3.05 (b, 1H), 3.40 (t, 2H), 4.90 (d, 1H), 5.50 (bs, 1H), 5.80 (d, 1H), 7.35-7.00 (m, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:22][CH2:21][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([O:18]CC)=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([O:41][CH:42]([CH3:44])[CH3:43])=[CH:37][CH:36]=3)=[CH:31][C:30]=2[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:25]([F:28])([F:27])[F:26])[N:3]=1.[Li+].[OH-]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:21][CH2:22]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:36]=[CH:37][C:38]([O:41][CH:42]([CH3:43])[CH3:44])=[CH:39][CH:40]=3)=[CH:31][C:30]=2[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:25]([F:27])([F:28])[F:26])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(-c5ccc(OC(C)C)cc5)cc4-c4ccccc4)C(F)(F)F)nc(N)n3)CC2)CN1
Agent: [Li+]
Agent: [OH-]
Product: CC(C)Oc1ccc(-c2ccc([C@@H](Oc3cc(N4CCC5(CC4)CN[C@H](C(=O)O)C5)nc(N)n3)C(F)(F)F)c(-c3ccccc3)c2)cc1

Procedure:
Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-isopropoxy-[1,1′:3′,1″-terphenyl]-4′-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the LiOH general method provided the title compound as an off-white solid.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[C@H:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:9]1([CH3:22])[CH3:21])=O)CCC.[H-].C([Al+]CC(C)C)C(C)C.Cl>ClCCl>[F:18][C:17]([F:19])([F:20])[C:13]1[CH:12]=[C:11]([C@H:10]2[C@H:8]([CH2:6][OH:5])[C:9]2([CH3:21])[CH3:22])[CH:16]=[CH:15][CH:14]=1
Reactant: CCCCOC(=O)[C@H]1[C@H](c2cccc(C(F)(F)F)c2)C1(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Product: CC1(C)[C@@H](CO)[C@@H]1c1cccc(C(F)(F)F)c1
Reaction time: 18 h
Yield: 51.1 %

Procedure:
The above ester (0.78 g) was dissolved in dichloromethane (12 ml) under nitrogen and cooled to -20°. Diisobutylaluminium hydride (7.4 ml) was added dropwise and the solution stirred at 25° for 18 hours. Careful addition of dilute hydrochloric acid was followed by work up in the usual manner to give (±)-[trans-3-(3-trifluoromethylphenyl)-2,2-dimethylcyclopropyl]methanol (0.31 g). NMR 1H: 7.5(4H,m), 3.65(2H,d), 2.55(1H,bs), 1.62(1H,d), 1.14(1H,m), 1.15(3H,s). 0.90(3H,s).
Reaction SMILES: [N:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1O)=[O:2].[CH:14]([NH2:17])([CH3:16])[CH3:15]>>[CH:14]([NH:17][C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[N:1]=[O:2])([CH3:16])[CH3:15]
Reactant: O=Nc1c(O)ccc2ccccc12
Reactant: CC(C)N
Product: CC(C)Nc1ccc2ccccc2c1N=O

Procedure:
The starting N-isopropyl-1-nitroso-2-naphthaleneamine is prepared through reaction of 1-nitroso-2-naphthol with isopropylamine according to the method described in J. Am. Chem. Soc. 70, 2415 (1948).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:30])=[C:5]([C:26]([O:28][CH3:29])=[O:27])[CH:6]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][NH2:16])=[O:9].[C:31]1([O:37][CH2:38][CH:39]2[O:41][CH2:40]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(O)C>[CH3:1][C:2]1[NH:3][C:4]([CH3:30])=[C:5]([C:26]([O:28][CH3:29])=[O:27])[CH:6]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][NH:16][CH2:40][CH:39]([OH:41])[CH2:38][O:37][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOCCN)C1c1cccc([N+](=O)[O-])c1
Reactant: c1ccc(OCC2CO2)cc1
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOCCNCC(O)COc2ccccc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 35.8 %

Procedure:
In 20 ml of ethanol were dissolved 1.8 g of 2-(2-aminoethoxy)ethyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and 0.64 g of glycidyl phenyl ether, and the solution was stirred at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography. The product was eluted with chloroform-methanol (95:5 v/v), and 0.87 g of 2-[2-(2-hydroxy-3-phenoxypropylamino)ethoxy]ethyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate was obtained. The product was treated with an ethanol solution of hydrochloric acid to provide 0.8 g of hydrochloric acid salt as amorphous powder.
Reaction SMILES: [C:1]([NH:20][C@@H:21]([CH2:24][CH3:25])[CH:22]=[O:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([Mg]Br)[CH3:27].O>CCOCC>[C:1]([NH:20][C@@H:21]([CH2:24][CH3:25])[CH:22]([OH:23])[CH2:26][CH3:27])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC[Mg]Br
Solvent: CCOCC
Solvent: O
Product: CCC(O)[C@H](CC)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-2-(trityl-amino)-butyraldehyde (1.5 g, 1 eq, 4.53 mmol) in ether (150 mL) under an argon atmosphere at −78° C., was added ethylmagnesium bromide (3 M in ether, 1.51 mL, 1 eq, 4.53 mmol) dropwise. The solution was stirred at −78° C. for 2 h, then allowed to warm to room temperature over 16 h. The mixture was re-cooled to 0° C., H2O (150 mL) added, and the organic phase separated. The aqueous phase was extracted with more ether (2×50 mL), and the combined organic phase washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by silica gel column chromatography, eluted with hexane:ether (90:10) to afford the title compound as a light yellow oil; Yield: 1.19 g (73%). (65% de 3R,4S: 35% de 3S,4S) 1H-NMR(d6-DMSO, 250 MHz): δ 0.46+0.69 (t+m, 6H, J=7.34 Hz, —NHCH(CH2CH3)CH(CH2CH3)OH), 1.13-1.29 (m, 4H, —NHCH(CH2CH3)CH(CH2CH3)OH), 2.17 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 2.55 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 3.20-3.39 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 4.29+4.39 (2×d, 1H, J=4.74+5.53 Hz, —NHCH(CH2CH3)CH(CH2CH3)OH), 7.15-7.52 (m, 15H, 3×Bz).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][C:22]=1[OH:23])[CH2:8][C@@H:9]([C:11]([N-:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[O:12])[NH2:10])([CH3:4])([CH3:3])[CH3:2].[C:24]([N:34]([CH3:42])[C@H:35]([C:39](O)=[O:40])[CH:36]([CH3:38])[CH3:37])([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25].O>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([CH2:8][CH:9]([NH:10][C:39](=[O:40])[CH:35]([N:34]([C:24]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:25])[CH3:42])[CH:36]([CH3:38])[CH3:37])[C:11](=[O:12])[NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:20]=[CH:21][C:22]=1[OH:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(C[C@H](N)C(=O)[N-]c2ccccn2)ccc1O
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)C(=O)Nc1ccccn1)N(C)C(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 65.6 %

Procedure:
To a solution of 3-tert-butyl-4-hydroxyphenylalanyl (2-pyridyl)amide (1.48 g, 4.73 mmol), Z-N-Me-Val-OH (1.63 g, 6.15 mmol) and CMPI (1.57 g, 6.15 mmol) in THF 30 ml, TEA (1.5 ml, 10.88 mmol) was added under cooling with ice and stirred for 3 hours under cooling with ice. The mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:2), giving the titled compound (1.74 g, 65%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9](B(O)O)[S:8][C:7]=2[CH:14]=1.Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[NH:26][C:25]([CH3:32])([CH3:31])[CH2:24]2)[N:17]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:20]3[CH:21]=[CH:16][N:17]=[C:18]([NH:22][CH:23]4[CH2:28][C:27]([CH3:30])([CH3:29])[NH:26][C:25]([CH3:32])([CH3:31])[CH2:24]4)[N:19]=3)[S:8][C:7]=2[CH:14]=1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: COc1ccc2cc(B(O)O)sc2c1
Product: COc1ccc2cc(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)sc2c1

Procedure:
The title compound was prepared analogous to Method C, starting 6-methoxy-benzo[b]thiophen-2-boronic acid and (4-Chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine.