Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:24][C:25]1[CH:29]=[CH:28][S:27][CH:26]=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]([CH2:24][C:25]3[CH:29]=[CH:28][S:27][CH:26]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: BrCc1ccsc1
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccc(OC)cc23)CC1
Product: CCOC(=O)N1CCC(c2cn(Cc3ccsc3)c3ccc(OC)cc23)CC1
Reaction time: 15 h
Yield: 85.5 %

Procedure:
This compound was prepared following the procedure described in example 13 (part B) at room temperature for 15 hours, starting with 4 g (13.2 mmol) of 4-(5-methoxy-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester and 2.65 g (15 mmol) of 3-bromomethylthiophene. After standard work-up, 4.5 g (87% of yield) of 4-(5-methoxy-1-thiophen-3-ylmethyl-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C@H:8]2[CH2:10][C@H:9]2[C:11](O)=[O:12])=O)=[CH:4][CH:3]=1.O.[NH2:17][NH2:18]>C(O)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]2[CH:8]3[CH:9]([C:11](=[O:12])[NH:17][N:18]=2)[CH2:10]3)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)[C@H]1C[C@H]1C(=O)O
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=C1NN=C(c2ccc(Cl)cc2)C2CC12
Yield: 79.8 %

Procedure:
6.0 g (26.7 millimoles) of cis-2-(p-chlorobenzoyl)-cyclopropanecarboxylic acid, 1.47 g (29.4 millimoles) of hydrazine hydrate and 150 ml of ethanol are refluxed for 6 hours. The mixture is concentrated to about 20 ml and the product is filtered off at 0° C. and recrystallized from methanol. 4.7 g (80% of theory) of 2-(p-chlorophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one are obtained as colorless crystals, of melting point 199°-200° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH:25]3[CH2:30][CH2:29][CH2:28][N:27](CC4C=CC=CC=4)[CH2:26]3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[N:22]1([CH:25]2[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]2)[CH2:21][CH2:20][CH:19]([NH:18][C:10]2[N:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=2)[CH2:24][CH2:23]1
Reactant: Fc1ccc(Cn2c(NC3CCN(C4CCCN(Cc5ccccc5)C4)CC3)nc3ccccc32)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Fc1ccc(Cn2c(NC3CCN(C4CCCNC4)CC3)nc3ccccc32)cc1
Yield: 91.5 %

Procedure:
A mixture of 11.3 parts of 1-[(4-fluorophenyl)methyl]-N-[1'-(phenylmethyl)-[1,3'-bipiperidin]-4-yl]-1H-benzimidazol-2-amine and 200 parts of methanol was hydrogentated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered off and dried, yielding 8.5 parts (91.5%) of N-([1,3'-bipiperidin]-4-yl)-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine (intermediate 72).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[SH:35]>CCO>[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[CH:17][CH:18]=1
Reactant: Nc1ccccc1S
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C#N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N#Cc1ccc(CCSc2ccccc2N)cc1
Yield: 82.4 %

Procedure:
4-Toluenesulfonic acid, 2-(4-cyanophenyl)ethyl ester (1.9 g; 6.3 mmol; from Example 18(i) above) and K2CO3 (2.0 g) were added to a solution of 2-aminothiophenol (0.875 g; 7.0 mmol) in EtOH (20 mL). The mixture was heated to reflux for 48 hours, cooled, filtered and concentrated in vacuo to an oil which was dissolved in EtOAc (50 mL) and washed with water (25 mL). The organic portion was dried (MgSO4) and concentrated. The residue was purified by flash chromatography (SiO2; Et2O:hexane (1:1)) to obtain 1.32 g (78%) of the sub-title product as a viscous oil.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.[N:32]1(OC(N(C)C)=[N+](C)C)[C:36]2C=[CH:38][CH:39]=[CH:40][C:35]=2N=N1.N1CCCCC1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:32]3[CH2:38][CH2:39][CH2:40][CH2:35][CH2:36]3)=[O:25])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc2[nH]c(C(=O)N3CCCCC3)cc2c1)N1CCN(C2CCCC2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), piperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[F:12])#[N:2].Cl[C:14]1[N:19]=[C:18]([NH2:20])[N:17]=[C:16]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:15]=1.O1CCOCC1.C([O-])(O)=O.[Na+]>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.O>[NH2:20][C:18]1[N:19]=[C:14]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([F:12])[CH:5]=2)[CH:15]=[C:16]([NH:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:17]=1
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: Nc1nc(Cl)cc(NCc2ccccc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cc(NCc3ccccc3)nc(N)n2)cc1F
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To (4-cyano-3-fluorophenyl)boronic acid (190 mg, 1.15 mmol) and 6-chloro-N4-(phenylmethyl)-2,4-pyrimidinediamine (300 mg, 1.28 mmol) into a sealable flask were added 1,4-dioxane (6 mL) and saturated aqueous NaHCO3 (3 mL). The mixture was degassed with nitrogen gas for 10 minutes. Pd(Ph3P)4 (74 mg, 0.064 mmol) was added and the reaction mixture was stirred overnight at 100° C. The mixture was poured onto EtOAc and water. The organic layer was separated and the aqueous layer was further extracted with EtOAc. The combined organic layers were filtered, then washed with brine, dried (MgSO4), filtered and concentrated. The resulting residue was chromatographed on SiO2 (gradient: 99:1:0.1 CHCl3/CH3OH/NH4OH to 90:10:1 CHCl3/CH3OH/NH4OH). The material (367 mg) was carried on as is into the next reaction.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]#[N:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:12][OH:13].[OH-].[Na+]>CCO.O>[NH2:10][C:9]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:13][N:12]=1
Reactant: N#CC#Cc1ccccc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cc(-c2ccccc2)on1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 3-phenyl-2-propyne-nitrile (1.27 g, 0.01 mol, Step A) in EtOH (20 mL) was added at RT hydroxylamine hydrochloride (3.5 g, 0.05 mol) followed by 10% NaOH (28 mL). The exothermic reaction was stirred at RT 24 h, then diluted with H2O. The resulting precipitate was filtered off, washed with H2O and dried over P2O5 to afford 3-amino-5-phenylisoxazole as a white crystalline solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH:21]([CH3:25])[C:22](=O)[CH3:23])[CH:18]=2)[NH:13][C:12]=1[CH3:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH:21]([CH3:25])[CH:22]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH3:23])[CH:18]=2)[NH:13][C:12]=1[CH3:26])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C(C)Oc1ccc2[nH]c(C)c(C(=O)OCc3ccccc3)c2c1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: Cc1[nH]c2ccc(OC(C)C(C)N3CCCC3)cc2c1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.3 %

Procedure:
2-Methyl-5-(1-methyl-2-oxo-propoxy)-1H-indole-3-carboxylic acid benzyl ester (0.248 g, 0.707 mmol) and pyrrolidine (0.05 g, 0.706 mmol) were mixed together in dichloroethane and stirred under N2 at room temperature for 1 hour. The reaction was then cooled to 0° C. whereupon sodium triacetoxyborohydride (0.209 g, 0.988 mmol) was added. After 30 minutes, the reaction was then permitted to warm to rt and stirred for a further 2 hours. It was then stopped by the addition of 1N NaOH (10 mL). The mixture was then extracted with EtOAc and the combined organic layers washed with brine and dried over anhydrous Na2SO4 Purification on SiO2 (10% MeOH/CH2Cl2) gave 0.110 g (38%) of the desired compound, mp 94-98° C. 1HNMR (400 MHz, DMSO): 1.58 (d, J=6.10 Hz, 3H), 1.60 (b, 4H), 2.40 (b, 4H), 2.59 (s, 3H, ArCH3),3.35 (b, 1H), 4.43 (m, 1H), 5.26 (s, 2H), 6.69 (d, J=8.44 Hz, 1H), 7.19 (d, J=8.64 Hz, 1H), 7.28-7.44 (m, 6H), 11.72 (s, H, H). MS APCI+) m/z 407.2(MH+). Anal. Calcd for C25H30N2O3.0.20H2O: C, 3.21;H,7.47; N, 6.83. Found: C, 72.84: H, 7.57: N, 6.56 I (KBr): 3294, 2973, 1691, 1665, 1454, 1167, 1073 cm−1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[N:10]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][S:25][CH2:26][CH2:27][CH2:28][C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])[C:9]2=[O:36])=[CH:4][C:3]=1[CH3:37].[CH:38]([N:42]=[C:43]=[O:44])([CH2:40][CH3:41])[CH3:39].O>ClCCCl>[CH3:14][C:11]1([CH3:15])[C:12](=[O:13])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:43]([NH:42][CH:38]([CH3:39])[CH2:40][CH3:41])=[O:44])=[C:3]([CH3:37])[CH:4]=2)[C:9](=[O:36])[N:10]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][S:25][CH2:26][CH2:27][CH2:28][C:29]([F:35])([F:34])[C:30]([F:33])([F:31])[F:32]
Reactant: CCC(C)N=C=O
Reactant: Cc1cc(N2C(=O)N(CCCCCCCCCSCCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)ccc1N
Solvent: O
Solvent: ClCCCl
Product: CCC(C)NC(=O)Nc1ccc(N2C(=O)N(CCCCCCCCCSCCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)cc1C
Yield: 36 %

Procedure:
The compound of Example 25 (395 mg, 0.72 mmole) is dissolved in anhydrous 1,2-dichloroethane (10 ml) under an argon atmosphere, before the dropwise addition of sec-butylisocyanate (0.35 ml, 3 mmoles) at 23° C. The mixture is then heated under reflux for 24 hours. The reaction medium is then poured onto cold water and extracted using CH2Cl2. After decantation, the organic phase is washed with water and salt water. The organic solution is then dried over MgSO4, filtered, concentrated to dryness under vacuum and the evaporation residue is purified on a silica column (eluent: heptane/AcOEt: 1/0 to 4/6). The expected compound is obtained in the form of a colourless oil with a yield of 36%.
Reaction SMILES: Cl.C(OC(=O)[NH:8][CH:9]1[CH2:12][N:11]([C:13](=[O:56])[C@@H:14]2[CH2:18][C@@H:17]([OH:19])[CH2:16][N:15]2[C:20]2([C:47]3[CH:52]=[C:51]([CH3:53])[CH:50]=[CH:49][C:48]=3[O:54][CH3:55])[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([Cl:29])[CH:27]=3)[N:22]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=3[O:41][C:42]([F:45])([F:44])[F:43])(=[O:32])=[O:31])[C:21]2=[O:46])[CH2:10]1)(C)(C)C.C([O-])(O)=O.[Na+]>>[NH2:8][CH:9]1[CH2:10][N:11]([C:13]([C@@H:14]2[CH2:18][C@@H:17]([OH:19])[CH2:16][N:15]2[C:20]2([C:47]3[CH:52]=[C:51]([CH3:53])[CH:50]=[CH:49][C:48]=3[O:54][CH3:55])[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([Cl:29])[CH:27]=3)[N:22]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=3[O:41][C:42]([F:44])([F:45])[F:43])(=[O:31])=[O:32])[C:21]2=[O:46])=[O:56])[CH2:12]1
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(C)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N3CC(NC(=O)OC(C)(C)C)C3)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(C)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N3CC(N)C3)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Concentrated hydrochloric acid was added to 200 mg of compound obtained in Example 162, and the solution was stirred at room temperature for 30 minutes. The solution was poured into saturated NaHCO3 and the resulting mixture was extracted with EtOAc. The extract was dried over Na2SO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The title compound in the amount of 144 mg (colorless amorphous) was obtained.
Reaction SMILES: C([O:3][C:4](=[O:31])[C@@H:5]([NH:13][C:14](=[O:30])[CH:15]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.O1CCCC1.O.O.[OH-].[Li+].Cl>[Cl-].[Na+].O.O>[C:26]([O:25][C:23]([NH:22][CH:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:14]([NH:13][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:4]([OH:31])=[O:3])=[O:30])=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)C(NC(=O)OC(C)(C)C)c1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC(C(=O)N[C@@H](Cc1ccccc1)C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 102.4 %

Procedure:
To a solution of 2-(S)-(2-tert-butoxycarbonylamino-2-phenyl-acetylamino)-3-phenyl-propionic acid ethyl ester (≈20 mmol) in 3:1 v/v tetrahydrofuran/water (80 mL total) was added lithium hydroxide monohydrate (1.06 g, 25.3 mmol) and the mixture was stirred at ambient temperature for 5 hours. The reaction mixture was poured into water (300 mL), diluted with brine (100 mL), acidified with 1M aqueous hydrochloric acid (30 mL, 30 mmol) and extracted with ethyl acetate (3×100 mL). the combined organic extracts were washed with brine (2×100 mL), dried with sodium sulfate and concentrated in vacuo to give 2-(S)-(2-tert-butoxycarbonylamino-2-phenyl-acetylamino)-3-phenyl-propionic acid as a colorless solid (8.16 g, 100%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[C:9]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=2)=[O:23])=[CH:17][CH:16]=1)([O-])=O.[Sn](Cl)Cl>C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[C:9]2[O:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=2)=[O:23])=[CH:19][CH:20]=1
Reactant: O=C(Nc1ccc(Oc2ccnc3c([N+](=O)[O-])cccc23)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1cccc2c(Oc3ccc(NC(=O)Nc4ccc(Cl)c(C(F)(F)F)c4)cc3)ccnc12
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
1-[4-(8-Nitroquinolin-4-yloxy)phenyl]-3-(4-chloro-3-trifluoromethylphenyl)urea (12.0 mg, 0.027 mmol) and tin (II) chloride (25.9 mg, 0.11 mmol) were dissolved in ethanol (0.23 mL), and then refluxed with stirring for 30 minutes. When the reaction was completed, the solvent was removed by vacuum distillation, the resultant was extracted with ethyl acetate and saturated sodium bicarbonate. Combined organic layers were dried with anhydrous sodium sulfate, and then filtered. The solvent was removed and then filtered a brown solid product to obtain 8.1 mg of the desired compound (yield 75.0%).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:7][C@H:6]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:4].[OH-].[K+]>CO>[C:11]([O:10][C:8]([C@H:6]1[CH2:7][C@H:5]1[C:3]([OH:4])=[O:2])=[O:9])([CH3:14])([CH3:12])[CH3:13]
Reactant: COC(=O)[C@H]1C[C@H]1C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)[C@H]1C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.7 %

Procedure:
To 100 ml of a methanol solution of 9.49 g (47.4 mmol) of t-butyl cis-2-methoxycarbonylcyclopropanecarboxylate was added 40 ml of an aqueous solution of 4.06 g (61.5 mmol) of potassium hydroxide under cooling with ice, followed by stirring at room temperature for 24 hours. After completion of the reaction, the solvent was evaporated under reduced pressure. Water was added to the residue, and the mixture was washed with diethyl ether. The aqueous layer was adjusted to a pH of 2 to 3 with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 7.56 g (85.7%) of the title compound as a pale yellow solid.
Reaction SMILES: [F:1][CH:2]([F:32])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([O:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]3)[CH:9]=2)[C:6]2[CH:28]=[CH:29][CH:30]=[CH:31][C:5]=2[N:4]=1.[C:33]([O:37][C:38]([N:40]([CH3:49])[C@H:41]([C:46](O)=[O:47])[CH2:42][CH2:43][S:44][CH3:45])=[O:39])([CH3:36])([CH3:35])[CH3:34].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O>[F:32][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([O:20][C@H:21]3[CH2:22][CH2:23][C@H:24]([NH:27][C:46](=[O:47])[C@@H:41]([N:40]([CH3:49])[C:38](=[O:39])[O:37][C:33]([CH3:34])([CH3:36])[CH3:35])[CH2:42][CH2:43][S:44][CH3:45])[CH2:25][CH2:26]3)[CH:9]=2)[C:6]2[CH:28]=[CH:29][CH:30]=[CH:31][C:5]=2[N:4]=1
Reactant: N[C@H]1CC[C@H](Oc2cc(-n3c(C(F)F)nc4ccccc43)nc(N3CCOCC3)n2)CC1
Reactant: CSCC[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CSCC[C@@H](C(=O)N[C@H]1CC[C@H](Oc2cc(-n3c(C(F)F)nc4ccccc43)nc(N3CCOCC3)n2)CC1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexanamine (700 mg) and N,N-dimethylformamide (7.0 mL) were added N-(tert-butoxycarbonyl)-N-methyl-L-methionine (622 mg), 1H-benzotriazol-1-ol (319 mg), and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (452 mg), followed by stirring at room temperature overnight. After the completion of the reaction, water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=90:10-40:60) to obtain tert-butyl [(2S)-1-{[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]amino}-4-(methylsulfanyl)-1-oxobutan-2-yl]methylcarbamate (859 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([CH3:10])[CH:4]=1.C([N:13](CC)CC)C.C(OC(=O)C)(=O)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:8][CH:9]=1)[NH:7][N:13]=[CH:10]2
Reactant: COc1ccc(N)c(C)c1
Reactant: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: COc1ccc2[nH]ncc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 4-methoxy-2-methylaniline (2 ml) in dichloromethane (10 ml) was treated with triethylamine (3.27 ml). The mixture was cooled to 0° C. then treated with acetic anhydride (2.38 ml), then stirred at ambient temperature for 1 hour, then cooled to 0° C. when a pink solid precipitated. This solid was filtered, then washed with cold dichloromethane and then dissolved in acetic acid (55 ml) and concentrated hydrochloric acid (20 ml). This solution was cooled to −5° C., then treated with a solution of sodium nitrite (2.68 g) in water (20 ml), then stirred at that temperature for 1 hour and then treated with water (100 ml). This mixture was stirred vigorously at 0° C. for 10 minutes after which a yellow solid precipitated. This solid was filtered, then washed with water and then dissolved in toluene (13 ml). This solution was heated to 80° C. for 1.5 hours, then cooled and then washed with aqueous 1N sodium carbonate solution. The organic phase was extracted three times with aqueous 2N hydrochloric acid and the acid extracts chilled and then made alkaline by addition of aqueous 5N sodium hydroxide solution. The aqueous layers were extracted three times with ethyl acetate and the combined organic layers were dried over magnesium sulfate and then evaporated to yield 5-methoxy-1H-indazole (0.410 g) as a yellow solid. LC-MS (METHOD B): RT=1.32 minutes; 149 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[S:11])[CH:5]=[CH:6][C:7]=1[CH3:8].Cl.C([O:15][C:16](=O)[CH2:17][NH:18][CH3:19])C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:16](=[O:15])[CH2:17][N:18]([CH3:19])[C:10]2=[S:11])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(N=C=S)cc1Cl
Reactant: CCOC(=O)CNC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(N2C(=O)CN(C)C2=S)cc1Cl
Yield: 57.1 %

Procedure:
The title compound was prepared by the procedure described in Example 1 using 18.3 g of 3-chloro-4-methylphenyl-isothiocyanate, 15.3 g of sarcosine ethyl ester hydrochloride, 25 g of triethyl amine, and 300 mL of chloroform. Crystallization from ethyl acetate afforded the title compound (14.5 g) as an off-white solid, m.p. 178°-180° C. Anal. Calcd. for C11H11Cl N2O S: C, 51.87; H, 4.35; N,11.00. Found: C, 1.89; H, 4.20; N, 10.95. Mass spectrum (+FAB, [M+H]+) m/z 255/257.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].CCO[C:13]([S-])=[S:14].[K+]>CO>[F:8][C:7]1[C:2]2[N:1]=[C:13]([SH:14])[O:9][C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: Nc1c(O)cccc1F
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: CO
Product: Fc1cccc2oc(S)nc12
Temperature: 70 °C
Yield: 42.7 %

Procedure:
A mixture of 1 g (7.867 mmol) 2-amino-3-fluorophenol and 1.42 g (8.654 mmol) potassium ethylxanthogenate in 28 mL methanol was heated in a 70° C. oil bath for 3 h. The solvent was removed in vacuo. The residue was dissolved in 50 mL water. The aqueous layer was acidified with HCl 2N. The solid was filtered, washed with water and dried to provide 568 mg (42.7%) of the title compound as a light grey solid. MS(m/e): 168.0 (M−H+).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@@H:7]([CH2:22]C=C)[C@:8]([C:14]3[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1.[F:25][C:26]([F:48])([C:44]([F:47])([F:46])[F:45])[CH2:27][CH2:28][CH2:29][CH:30]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH:42]=[CH2:43])[C:31]([O:33]CC)=[O:32].ICCCC(F)(F)C(F)(F)F.C(OCC)(=O)CC(OCC)=O.ICCCCCCC=C>>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C@@H:7]([CH2:22][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH:30]([CH2:29][CH2:28][CH2:27][C:26]([F:25])([F:48])[C:44]([F:45])([F:46])[F:47])[C:31]([OH:33])=[O:32])[C@:8]([C:14]3[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=3)([CH3:13])[CH2:9][S:10]2)=[CH:5][CH:4]=1
Reactant: C=CC[C@@H]1c2ccc(OC)cc2SC[C@]1(C)c1ccc(OC)cc1
Reactant: C=CCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Agent: C=CCCCCCCI
Agent: FC(F)(F)C(F)(F)CCCI
Solvent: CCOC(=O)CC(=O)OCC
Product: C[C@]1(c2ccc(O)cc2)CSc2cc(O)ccc2[C@H]1CCCCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the (3S,4S)-7-methoxy-3-(4-methoxy-phenyl)-3-methyl-4-(2-propenyl)thiochroman prepared in Example 3 and ethyl 2-(4,4,5,5,5-pentafluoropentyl)-9-decenoate separately prepared from 1-iodo-4,4,5,5,5-pentafluoropentane, diethyl malonate and 1-iodo-7-octene, a procedure analogous to that as shown in Example 2 or 3 was repeated to give 11-[(3S,4S)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(4,4,5,5,5-pentafluoropentyl)undecanoic acid.