Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].C(C[P+](C)(C)C)#N.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26](O)[CH3:27].[F:29][C:30]1([F:58])[CH2:35][CH2:34][N:33]([C:36]([C:38]2[NH:39][C:40]3[C:45]([CH:46]=2)=[CH:44][C:43]([C:47]([N:49]2[CH2:54][CH2:53][N:52]([CH:55]([CH3:57])[CH3:56])[CH2:51][CH2:50]2)=[O:48])=[CH:42][CH:41]=3)=[O:37])[CH2:32][CH2:31]1>C1(C)C=CC=CC=1>[F:58][C:30]1([F:29])[CH2:35][CH2:34][N:33]([C:36]([C:38]2[N:39]([CH:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[F:19])[CH3:27])[C:40]3[C:45]([CH:46]=2)=[CH:44][C:43]([C:47]([N:49]2[CH2:50][CH2:51][N:52]([CH:55]([CH3:56])[CH3:57])[CH2:53][CH2:54]2)=[O:48])=[CH:42][CH:41]=3)=[O:37])[CH2:32][CH2:31]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: CC(O)c1ccccc1F
Agent: C[P+](C)(C)CC#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3C(C)c2ccccc2F)CC1
Yield: 15 %

Procedure:
The title compound was synthesized in analogy to example 74, from (cyanomethyl)-trimethylphosphonium chloride (prepared according to Tetrahedron Lett. 1996, 37 (14), 2459-62), potassium bis(trimethylsilyl)amide, 1-(2-fluorophenyl)ethanol and (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32) in toluene, to give the desired product as a light brown foam (15%).
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5]>CO>[OH:1][C@@H:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: CCC(=O)CC(=O)OC
Solvent: CO
Product: CC[C@H](O)CC(=O)OC
Temperature: 80 °C
Reaction time: 66 h
Yield: 90 %

Procedure:
To a solution of 6.22 mg (48 mmol) of methyl 3-ketovalerate in 48 ml methanol, 36 mg (0.004 mmol) RuCl2(S)-binap was added and stirred in an autoclave under a hydrogen pressure of 30 atm at 80° C. for 66 hours. After concentration and distillation, 5.71 g (43.2 mmol, 97% ee) of methyl (S)-3-hydroxyvalerate was obtained. The condition of chiral HPLC is the following. Column, CHIRALPAK OD manufactured by Daicel Chemical Industries, Ltd.; Eluate, Hexane:2-propanol=95:5; flow rate, 1.0 mL/min; Wavelength of detection, 210 nm; Temperature, 25° C.; Retention time, 15 min (R) and 27 min (S).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:7]=[CH:8][C:9]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:10][CH:11]=1)CCC.C[O:28][C:29](=[O:43])[C:30]([C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35](Br)=[CH:34][CH:33]=1)=[O:31].[F-].[K+]>C1CCOCO1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:13]1([CH2:12][C:9]2[N:10]=[CH:11][C:6]([C:35]3[C:36]4[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:32]([C:30](=[O:31])[C:29]([OH:43])=[O:28])=[CH:33][CH:34]=3)=[CH:7][CH:8]=2)[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: COC(=O)C(=O)c1ccc(Br)c2ccccc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(CN2CCOCC2)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C1COCOC1
Agent: [F-]
Solvent: CCOC(C)=O
Product: O=C(O)C(=O)c1ccc(-c2ccc(CN3CCOCC3)nc2)c2ccccc12
Temperature: 150 °C
Yield: 54 %

Procedure:
4-(5-Tri-butylstannanyl-pyridin-2-ylmethyl)-morpholine (0.47 g, 1.59 mmol) and (4-Bromo-naphthalen-1-yl)-oxo-acetic acid methyl ester (18) (0.6 g, 1.3 mmol) and catalytic tetrakis(triphenylphosphine)palladium (0) were dissolved in 2 mL anhydrous 2,4-dioxane under nitrogen atmosphere. The tube was heated under microwave irradiation for 10 minutes at 150° C. After cooling to room temperature the mixture was diluted with EtOAc, and a solution of KF 40% was added. The organic phase was separated and the aqueous layer was evaporated and purified by LC-MS to afford the target product in 54% yield. Calculated mass=376. Observed mass=376.
Reaction SMILES: [CH2:1]([C:12](C)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(O)(=[O:17])C>>[C:12]([OH:13])(=[O:17])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CC(=O)O
Reactant: CCCCCCCCCCCC(C)=O
Product: CCCCCCCCCCCC(=O)O
Yield: 85 %

Procedure:
There is also reported, in Japanese Patent Application (Laid-Open) No. 175951/1989, a process for production of ketone from higher aliphatic carboxylic acid and lower aliphatic carboxylic acid using cerium oxide-on-alumina catalyst. According to the literature, methyl n-undecyl ketone, for example, is produced from lauric acid and acetic acid and the yield is 85%. In the process, however, GHSV (gas phase space velocity) is as low as 171 hr-1 ; consequently, the productivity is low and a large reactor is necessary, which are not advantageous industrially.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8](=O)[CH:9]([O:20][C:21](=O)[CH3:22])[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:29]>C(O)(=O)C>[CH3:22][C:21]1[O:20][C:9]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)[N:29]=1
Reactant: [NH4+]
Reactant: CC(=O)OC(C(=O)c1cccc(C)n1)c1ccc2ncccc2c1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: Cc1cccc(-c2nc(C)oc2-c2ccc3ncccc3c2)n1

Procedure:
A solution of acetic acid 2-(6-methyl-pyridin-2-yl)-2-oxo-1-quinolin-6-yl-ethyl ester (83 mg, 0.26 mmol), ammonium acetate (200 mg, 2.6 mmol, 10 equiv) in acetic acid (4 mL) is heated to 105° C. for 3 hours. The resulting reaction mixture is concentrated in vacuo, and reverse phase high pressure liquid chromatography (a gradient from 5-30% acetonitrile in 0.1% aqueous formic acid) provides 6-[2-Methyl-4-(6-methyl-pyridin-2-yl)-oxazol-5-yl]-quinoline.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:4]=2[S:3]1.[CH2:14]1[C@H:23]2[C@H:18]([CH2:19][CH2:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=32)[NH:17][CH2:16][CH2:15]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:14]1[C@H:23]2[C@H:18]([CH2:19][CH2:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=32)[N:17]([C:11]([C:9]2[CH:8]=[CH:7][C:5]3[NH:6][C:2](=[O:1])[S:3][C:4]=3[CH:10]=2)=[O:13])[CH2:16][CH2:15]1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1ccc2[nH]c(=O)sc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2[nH]c(=O)sc2c1)N1CCC[C@@H]2c3ccccc3CC[C@@H]21
Yield: 56 %

Procedure:
The title compound is prepared from 2-oxo-2,3-dihydro-benzothiazole-6-carboxylic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 56% of theory; LC (method 3): tR=2.32 min; Mass spectrum (ESI+): m/z=365 [M+H]+.
Reaction SMILES: Br.[CH2:2]([C:4]1[S:8][C:7](=[NH:9])[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[N:5]=1)[CH3:3].C[Sn]([N:29]=[N+:30]=[N-:31])(C)C.Cl>C1(C)C=CC=CC=1>[CH2:2]([C:4]1[S:8][C:7](=[NH:9])[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:31][N:30]=[N:29][N:24]=3)=[CH:13][CH:12]=2)[N:5]=1)[CH3:3]
Reactant: CCc1nn(Cc2ccc(-c3ccccc3C#N)cc2)c(=N)s1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Agent: Br
Agent: Cl
Solvent: Cc1ccccc1
Product: CCc1nn(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=N)s1
Yield: 3.1 %

Procedure:
In 20 ml of toluene, 2.0 g of 5-ethyl-2-imino-3-(2'-cyanobiphenyl-4-yl)methyl-1,3,4-thiadiazoline.hydrobromide and 1.1 g of trimethyltin azide were suspended, followed by heating under reflux for 6 hours. After cooling, the reaction mixture was subjected to column chromatography on a silica gel and eluted using chloroform:methanol (20:1)→chloroform:methanol:acetic acid (20:10:1). The eluate fraction thus obtained were then distilled off under reduced pressure. To the residue, 40 ml of 2N sodium hydroxide and 40 ml of ethyl acetate were added. The aqueous layer so obtained was neutralized with 12N hydrochloric acid and powders so precipitated were collected by filtration. The powders were washed successively with water, ethanol and then diethyl ether and then dried, whereby 56 mg of the title compound was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:3]=1.[NH2:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17]>C(O)(C)C>[Cl:8][C:6]1[N:7]=[C:2]([NH:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[N:3]=[C:4]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=1
Reactant: CC(C)(C)Nc1cc(Cl)nc(Cl)n1
Reactant: CC(C)(C)CN
Solvent: CC(C)O
Product: CC(C)(C)CNc1nc(Cl)cc(NC(C)(C)C)n1

Procedure:
After dissolving 5.0 g of 2,4-dichloro-6-(1,1-dimethylethylamino)pyrimidine in 25 ml of isopropanol and adding 5 ml of 1-amino-2,2-dimethylpropane, the reaction mixture is boiled under reflux for 20 hours. Subsequently, the reaction mixture is evaporated and the residue is distributed between 80 ml of chloroform and 15 ml of 10% sodium hydroxide solution. After separation the organic phase is washed 4 times with 20 ml of water each, then dried and evaporated. The evaporation residue is purified by chromatography on a silica gel column by using a 9:1 mixture of hexane/ethyl acetate as eluent. After recrystallizing the eluted product from hexane, the title product is obtained in a yield of 4.05 g (65.9%), m.p.: 115°-119° C.
Reaction SMILES: [C:1]1(=[O:4])[CH2:3][CH2:2]1.[CH2:5]([O:12][C@H:13]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C:15](=[CH:16][CH2:17][C@@H:18]3[C@@H:27]2[CH2:26][CH2:25][C@@:23]2([CH3:24])[C@H:19]3[CH2:20][CH2:21][C@@H:22]2[SH:32])[CH2:14]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>ClCCl>[CH2:5]([O:12][C@H:13]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C:15](=[CH:16][CH2:17][C@@H:18]3[C@@H:27]2[CH2:26][CH2:25][C@@:23]2([CH3:24])[C@H:19]3[CH2:20][CH2:21][C@@H:22]2[S:32][C:1]2([OH:4])[CH2:3][CH2:2]2)[CH2:14]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C1CC1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](OCc5ccccc5)CC[C@@]43C)[C@@H]1CC[C@@H]2S
Solvent: ClCCl
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](OCc5ccccc5)CC[C@@]43C)[C@@H]1CC[C@@H]2SC1(O)CC1
Reaction time: 16 h

Procedure:
3β-Benzyloxyandrost-5-en-17β-thiol is obtained starting from dehydroepiandrosterone. The dehydroepiandrosterone is reacted with one equivalent of sodium hydride and benzyl chloride by standard procedures for making benzyl ethers to give 3-benzyloxyandrost-5-en-17-one. This benzyloxy compound is then reacted with Lawesson's reagent (4-methoxyphenylthiophosphine sulfide dimer) according to the procedure described in M. Feiser, "Feiser and Feiser's Reagents for Organic Synthesis", John Wiley & Sons, New York, 1980, p. 327; also B. S. Pedersen et al., Bull. Soc. Chim. Belg., 87, 223 (1978). This gives 3β-benzyloxyandrost-5-ene-17-thione and this thione is then reduced with lithium aluminum hydride by standard procedures to give the desired 17β-thiol. Then, to a solution of cyclopropanone in dichloromethane under nitrogen at -50° C., there is added rapidly 1.1 equivalent of the above thiol in dichloromethane. The temperature is allowed to rise to -30° C. and, after 16 hours, most of the solvent is evaporated. Dry ether is added to precipitate by-product polyketene. The by-product is removed by filtration, the solvent is distilled from the filtrate, and the residue is purified by flash chromatography to give 3β-benzyloxy-17β-(1-hydroxycyclopropylthio)androst-5-ene.
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]1[C:13]([CH3:14])=[C:12]([CH3:15])[C:11]([O:16][CH3:17])=[C:10]([CH3:18])[C:9]=1[CH:19]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:20][CH2:21][CH2:22]O.C(N(CC)CC)C.[I-:37].[Na+]>ClCCl.O>[I:37][CH2:22][CH2:21][CH2:20][CH:19]([C:9]1[C:10]([CH3:18])=[C:11]([O:16][CH3:17])[C:12]([CH3:15])=[C:13]([CH3:14])[C:8]=1[O:7][CH3:6])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1c(C)c(C)c(OC)c(C(CCCO)c2ccccc2)c1C
Reactant: [I-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1c(C)c(C)c(OC)c(C(CCCI)c2ccccc2)c1C
Reaction time: 0.33 h
Yield: 309.5 %

Procedure:
A solution of 1.37 g (10×1.2 mmole) of methanesulfonyl chloride in dichloromethane (10 ml) was added dropwise to 3.28 g (10.0 mmole) of 4-(2,5-dimethoxy-3,4,6-trimethylphenyl)-4-phenylbutan -1-ol and 2.10 ml (10×1.5 mmole) of triethylamine dissolved in dichloromethane (30 ml) at -5° C. over the period of 30 minutes, and the reaction was continued for 20 minutes under stirring, with ice cooling. The reaction was stopped by adding cold water to the reaction solution, and the dichloromethane layer was separated out, washed with cold dilute hydrochloric acid and aqueous sodium chloride solution successively, dried (magnesium sulfate) and evaporated. The residue was dissolved in acetone (50 ml), and 4.5 g (10×3 mmole) of sodium iodide was added to the solution, followed by stirring at 50° C. for 2 hours. The acetone was distilled off, and isopropyl ether and water were added to the residue to extract the product. The isopropyl ether layer was separated out, washed with aqueous sodium chloride solution, and evaporated, and the residual solution was chromatographed on a silica gel column to perform purification (elution with hexane/isopropyl ether) to thereby give 4.07 g (93%) of 1-iodo-4-(2,5-dimethoxy-3,4,6-trimethylphenyl)-4-phenylbutane. Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 14.
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](Cl)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:12]([N:8]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:11][N:10]=[N:9]1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(-c2nnn[nH]2)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: c1ccc(-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
The Compound of the formula 11 is prepared from 5-phenyl tetrazole of the formula 14 by reacting with trityl chloride to get N-trityl-5-phenyl tetrazole of the formula 13, which on reaction with butyl lithium and triisopropyl borate followed by hydrolysis to give compound of the formula 11. This process is shown in the Scheme 7
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](O)=[O:9])([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:21])=O>>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([Cl:21])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Product: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O

Procedure:
3,5-Di-t-butyl-4-hydroxybenzoic acid is refluxed with thionyl chloride as described in the procedure of Example 27 to give 3,5-di-t-butyl-4-hydroxybenzoyl chloride.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4]>[Cr]([O-])([O-])=O.[Cu+2].C(O)C(C)C>[CH2:3]([CH:2]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:1][OH:5])[CH3:4]
Reactant: CCCCO
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Solvent: CC(C)CO
Product: CCCCC(CC)CO
Yield: 12.1 %

Procedure:
The mixture is then hydrogenated continuously on a copper chromite catalyst under 300 bars and at 180° C. 865 g of n-butanol, 98 g of iso-butanol and 92 g of 2-ethyl-hexanol are obtained.
Reaction SMILES: C([O:5][C:6]([C:8]1([NH:11][C:12]([C:14]2[N:18]3[C@@:19]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=4)([CH3:31])[C:20](=[O:30])[N:21]([C:22]4[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=4)[C:17]3=[N:16][CH:15]=2)=[O:13])[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:39]([C:36]1[CH:37]=[CH:38][C:33]([CH2:32][C@@:19]2([CH3:31])[N:18]3[C:14]([C:12]([NH:11][C:8]4([C:6]([OH:7])=[O:5])[CH2:9][CH2:10]4)=[O:13])=[CH:15][N:16]=[C:17]3[N:21]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)[C:20]2=[O:30])=[CH:34][CH:35]=1)#[N:40]
Reactant: CC(C)(C)OC(=O)C1(NC(=O)c2cnc3n2[C@](C)(Cc2ccc(C#N)cc2)C(=O)N3c2cc(Cl)cc(Cl)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)O)CC3)n21
Reaction time: 8 h
Yield: 98.9 %

Procedure:
1-{[(R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarboxylic acid tert-butyl ester (3.8 g, 6.55 mmol) was dissolved in CH2Cl2 (100 mL), and. TFA (20 mL) was then added dropwise to the solution. The mixture was stirred overnight. After evaporation of the solvent in vacuo, the residue was purified by flash chromatography on silica gel (5% MeOH/CH2Cl2) to give 1-{[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-α]imidazole-3-carbonyl]-amino}-cyclopropane-carboxylic acid (3.4 g, 6.48 mmol, 99.0%) as a white solid, m/z 524.3 [M+1]+.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:20]=[CH:19][C:6]([CH2:7][NH:8][C:9](=[O:18])[NH:10][CH2:11][CH2:12][CH2:13][C:14](NO)=O)=[CH:5][CH:4]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O:40][C:41](=[O:49])[CH2:42][CH2:43]CCCCN)C1C=CC=CC=1>>[CH3:1][N:2]([CH3:21])[C:3]1[CH:20]=[CH:19][C:6]([CH2:7][NH:8][C:9](=[O:18])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:43][CH2:42][C:41]([OH:49])=[O:40])=[CH:5][CH:4]=1
Reactant: NCCCCCCC(=O)OCc1ccccc1
Reactant: CN(C)c1ccc(CNC(=O)NCCCC(=O)NO)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CN(C)c1ccc(CNC(=O)NCCCCCCC(=O)O)cc1

Procedure:
Compound 5 was prepared using the methodology described for the preparation of compound 2, by substituting 4-amino-butyric acid benzyl ester toluene-4-sulfonic acid with 7-amino-heptanoic acid benzyl ester toluene-4-sulfonic acid. 1H NMR (300 MHz, DMSO-d6) δ (ppm) 10.33 (br, s, 1H), 8.66 (br s, 1H), 7.05 (d, J=8.7 Hz, 2H), 6.67 (d, J=8.7 Hz, 2H), 6.04 (t, J=5.7 Hz, 1H), 5.79 (t, J=5.7 Hz, 1H), 4.05 (d, J=6.0 Hz, 2H), 2.97 (dt, J=6.6, 6.6 Hz, 2H), 2.84 (s, 6H), 1.93 (t, J=7.5 Hz, 2H), 1.47 (m, 2H), 1.34 (m, 2H), 1.22 (m, 4H)
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.CC1(C)[C@]2(CS(O)(=O)=O)C(C[C@H]1CC2)=O.Cl[C:35]1[N:40]=[C:39]([NH:41][C@H:42]2[C@H:47]3[CH2:48][C@H:44]([CH2:45][CH2:46]3)[C@H:43]2[C:49]([NH2:51])=[O:50])[C:38]([Cl:52])=[CH:37][N:36]=1>>[Cl:52][C:38]1[C:39]([NH:41][C@H:42]2[C@H:47]3[CH2:48][C@H:44]([CH2:45][CH2:46]3)[C@H:43]2[C:49]([NH2:51])=[O:50])=[N:40][C:35]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][CH:5]([NH:4][CH2:3][C:2]([F:17])([F:18])[F:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:36][CH:37]=1
Reactant: Nc1ccc2c(c1)CCC(NCC(F)(F)F)CC2
Reactant: NC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Product: NC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1Nc1nc(Nc2ccc3c(c2)CCC(NCC(F)(F)F)CC3)ncc1Cl
Yield: 29.7 %

Procedure:
In an analogous procedure to Example 651, part c, N*7*-(2,2,2-Trifluoro-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine (75 mg, 0.290 mmol) was combined with DL-10-camphorsulfonic acid (101 mg, 0.436 mmol) and (1S,2R,3S,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid amide (86.9 mg, 0.290 mmol) to prepare (1S,2R,3S,4R)-3-{5-Chloro-2-[7-(2,2,2-trifluoro-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino}-bicyclo[2.2.1]heptane-2-carboxylic acid amide (45.07 mg, 30% yield) as a white powder. Product was purified on a 12 g Isco cartridge using methelene chloride/methanol as the eluent. 1H-NMR (CDCl3) δ 7.86 (s, 1H), 7.40 (d, J=8.2 Hz, 1H), 7.28 (s, 1H), 7.03 (d, J=8.1 Hz, 1H), 6.84 (m, 2H), 6.33 (m, 2H), 5.54 (br s, 1H), 5.32 (br s, 1H), 4.36 (t, J=7.8 Hz, 1H), 3.24 (q, J=18.9, 9.5 Hz, 2H), 3.06 (s, 1 h), 2.80 (m, 4H), 2.68 (m, 2H), 2.47 (d, J=8.5 Hz, 1H), 2.22 (d, J=9.5 Hz, 1H), 2.08 (m, 2H), 1.64 (m, 1H), 1.34 (m, 2H), 0.88 (m, 1H). LC/MS (ESI+)=521 (M+H). MP=217.5-218.5° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[OH-].[K+].[I:14]I.[O-]S([O-])(=S)=O.[Na+].[Na+]>CN(C=O)C.O>[I:14][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[CH:5]=2)[NH:1][N:2]=1
Reactant: II
Reactant: O=Cc1ccc2[nH]ncc2c1
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc2[nH]nc(I)c2c1
Temperature: 25 °C

Procedure:
To an ice-cooled solution of 1H-indazol-5-carbaldehyde (34 mmol) and KOH (37 mmol) in DMF (50 mL) was added I2 (37 mmol) portionwise over 30 min. The mixture was allowed to warm to rt for 6 h. Water was added and then sat. Na2S2O3 solution was added to quench excess I2. The aqueous solution was extracted with EtOAc and the organic layer was dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (EtOAc/hexane) to afford 3-iodo-1H-indazol-5-carbaldehyde.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[OH-].[Na+].N(C(OC(C)(C)C)=O)[C@H](C(O)=O)CC1C=CC(O)=CC=1>>[NH2:2][CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:1])[CH:7]=1)[OH:5]
Reactant: Cl
Reactant: NCC(O)c1ccccc1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: NC[C@H](O)c1cccc(Cl)c1

Procedure:
To 15 ml of 1N aqueous solution of hydrochloric acid was added 3.38 g of the concentrate of the reaction products containing 15.0 mmol of 2-amino-1-phenylethanol obtained in the same manner as in Example 295. The resultant solution was added with 7.5 ml of 1N sodium hydroxide solution containing 2.10 g of Boc-L-Tyr (7.5 mmol) with stirring slowly to precipitate or crystallize crystals. The crystals were isolated by filtration to give 2.49 g (5.5 mmol) of (R)-2-amino-1-(3-chlorophenyl)ethanol.Boc-L-Tyr salt. The yield relative to (R)-2-amino-1-(3-chlorophenyl)ethanol in the concentrate was 73.4%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CC(C)=O>[CH2:29]([O:22][C:18]1[CH:17]=[C:16]([CH2:15][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:21]=[CH:20][CH:19]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)C(Cc1cccc(O)c1)NC(=O)OC(C)(C)C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(Cc1cccc(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 88 %

Procedure:
158 (760 mg, 1 equivalent) was dissolved in 15 ml of acetone, then potassium carbonate (373 mg, 1.1 equivalent) and benzylbromide (1.1équivalent, 323 μl) were added successively. The reaction mixture was let overnight at room temperature. The reaction mixture is concentrated and 50 ml of AcOEt are added. The organic phase are washed with 10% citric acid, saturated NaHCO3 and brine then dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (AcOEt/Hexane 2/8) to afford 159 as white solid (860 mg, 88%). 1H NMR (CDCl3): δ 1.38 (t, 3H, J=7.4 Hz), 1.69 (s, 9H), 3.22 (m, 2H), 4.31 (q, 2H, J=7.4 Hz), 4.71 (s, 2H), 5.13 (m, 1H), 5.20 (s, 2H), 6.90 (d, 1H, J=7.1 Hz), 6.94 (s, 1H), 7.01 (d, 1H, J=8.2 Hz), 7.36 (t, 1H, J=7.7 Hz), 7.49 (m, 1H), 7.56 (m, 4H).