Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH:21]=O)[CH:9]=2)=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[CH:28][C:29]=1[Cl:30].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][N:34]([CH2:21][CH2:20][CH2:19][C:10]3[CH:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[N:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:11]=3)[CH2:33][CH2:32]2)[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: O=CCCc1cc(-c2ccc(F)cc2)n(-c2ccccc2)n1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(-c2cc(CCCN3CCN(c4ccc(Cl)c(Cl)c4)CC3)nn2-c2ccccc2)cc1

Procedure:
90 mg (61%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (80 mg, 0.272 mmol), 1-(3,4-dichlorophenyl)piperazine (63 mg, 0.272 mmol), DIPEA (0.071 mL, 0.408 mmol) and NaBH(OAc)3 (173 mg, 0.816 mmol).
Reaction SMILES: CN(C)C([N:5]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][O:13][Si](C)(C)C)[N:7]=[CH:6]1)=O.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=1>C(#N)C.Cl>[C:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:7]2[C:8]([CH2:10][CH2:11][CH2:12][OH:13])=[CH:9][N:5]=[CH:6]2)=[CH:22][CH:23]=1)#[N:28]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CN(C)C(=O)n1cnc(CCCO[Si](C)(C)C)c1
Agent: Cl
Solvent: CC#N
Product: N#Cc1ccc(Cn2cncc2CCCO)cc1
Reaction time: 0.25 h

Procedure:
A solution of 97.0 g of 1-dimethylcarbamoyl-4-(3-trimethylsilyloxypropyl) -1H-imidazole and 72.0 g of 1-bromomethyl-4-cyanobenzene in 500 ml of acetonitrile is refluxed for 10 h. The solution is cooled to 0° in an ice bath and ammonia gas is bubbled in for a few minutes. The mixture is then evaporated in vacuo to give a semisolid which is dissolved in 500 ml of 1N hydrochloric acid. The solution is allowed to stand at room temperature for 15 min and then is extracted with ether. The pH of the aqueous phase is adjusted to 9 with 50% sodium hydroxide solution and the mixture is then extracted with methylene chloride. The methylene chloride extracts are washed with water, dried over sodium sulfate and evaporated to give a semi-solid which is triturated with cold acetone to yield the title compound (b) as a white solid, m.p. 121°-123°.
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17](=[O:26])[C:18]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])=[CH:9]1.Cl[C:28]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[C:29]([C:32]#[N:33])[C:30]#[N:31]>CCO>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17](=[O:26])[C:18]([N:20]2[CH2:21][CH2:22][N:23]([C:28]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[C:29]([C:32]#[N:33])[C:30]#[N:31])[CH2:24][CH2:25]2)=[O:19])=[CH:9]1
Reactant: O=C(C(=O)N1CCNCC1)c1c[nH]c2ccccc12
Reactant: N#CC(C#N)=C(Cl)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: N#CC(C#N)=C(c1ccccc1)N1CCN(C(=O)C(=O)c2c[nH]c3ccccc23)CC1
Reaction time: 16 h

Procedure:
Triethyl amine (1 ml) was added into a solution of 1-(1H-indol-3-yl)-2-(piperazin-1-yl)ethane-1,2-dione (150 mg) and 2-(chloro(phenyl)methylene)malononitrile (110 mg) in EtOH (20 ml). After 16 hours at 115° C., the reaction mixture was cooled down. Then the solvents were removed to offer a residue which was purified using Shimadzu automated preparative HPLC System to afford 2-((4-(2-(1H-indol-3-yl)-2-oxoacetyl)piperazin-1-yl)(phenyl)methylene)malononitrile.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH3:27])[C:9]([NH:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([C:19]#[C:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:13]=1)=[O:10])(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH:8]([CH3:27])[C:9]([NH:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([C:19]#[C:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:13]=1)=[O:10]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc(Cl)cc(C#Cc2ccccc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(N)C(=O)Nc1cc(Cl)cc(C#Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of tert-butylN-[1-[[4-chloro-6-(2-phenylethynyl)pyridin-2-yl]amino]-1-oxopropan-2-yl]carbamate D3a (20 mg, 0.05 mmol) and DCM:TFA (9:1, 1.8 ml) is stirred at RT for 90 minutes. The mixture is diluted with DCM and extracted with a saturated aqueous solution of NaHCO3. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 14 mg (93%). HPLC-MS: M+H=300; tR=1.92 min (*Method—1).
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:33]=[CH:32][C:7]([CH2:8][NH:9][C:10]2[CH:11]=[C:12]([CH:29]=[CH:30][CH:31]=2)[C:13]([NH:15][CH:16]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH2:17][C:18]([O:20]CC)=[O:19])=[O:14])=[CH:6][CH:5]=1.[OH-].[Li+]>CO>[NH2:1][N:2]=[CH:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]2[CH:11]=[C:12]([CH:29]=[CH:30][CH:31]=2)[C:13]([NH:15][CH:16]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH2:17][C:18]([OH:20])=[O:19])=[O:14])=[CH:32][CH:33]=1
Reactant: CCOC(=O)CC(NC(=O)c1cccc(NCc2ccc(C=NN)cc2)c1)c1cccnc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: NN=Cc1ccc(CNc2cccc(C(=O)NC(CC(=O)O)c3cccnc3)c2)cc1
Yield: 86.8 %

Procedure:
Ethyl β-[[3-[4-(aminoiminomethyl)benzyl]aminobenzoyl]amino]3-pyridine-propanoate (0.35 g; 0.8 mmoles) was treated with 1N lithium hydroxide and methanol (1:1; 20 ml) for 5 min. Methanol was removed under reduced pressure and the residue was purified by HPLC using acetonitrile/water/trifluoroacetic acid system. The desired fractions were collected and lyophilized to give 290 mg of white material. FAB-MS: MH+ =418.0.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([NH:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][C@@H:23]1[NH2:27])[N:15]=[CH:14]2.[C:28](O)(=[O:31])[C:29]#[CH:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([NH:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][C@@H:23]1[NH:27][C:28](=[O:31])[C:29]#[CH:30])[N:15]=[CH:14]2
Reactant: C#CC(=O)O
Reactant: COc1ccc(F)c(-c2ccc3nc(N[C@@H]4CCC[C@@H]4N)ncc3c2)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#CC(=O)N[C@H]1CCC[C@H]1Nc1ncc2cc(-c3c(F)ccc(OC)c3F)ccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
A mixture of (1R,2S)—N1-(6-(2,6-difluoro-3-methoxyphenyl)quinazolin-2-yl)cyclopentane-1,2-diamine (0.045 mmol), propiolic acid (0.004 mL, 0.067 mmol), HATU (25 mg, 0.067 mmol) and DIEA (0.023 mL, 0.135 mmol) in dichloromethane (1 mL) was stirred at room temperature for 60 minutes. LC-MS indicated complete consumption of SM. The reaction mixture was purified by silica gel chromatography to yield N-((1S,2R)-2-((6-(2,6-difluoro-3-methoxyphenyl)quinazolin-2-yl)amino)cyclopentyl)propiolamide (Compound 2) (13 mg, 68%). MS (ES+) C27H27N5O3 requires: 422, found: 423 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@@H:3]1[O:15][CH3:16].[Cl:17][C:18]1[N:19]=[C:20]([C:25](O)=[O:26])[NH:21][C:22]=1[CH2:23][CH3:24].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:17][C:18]1[N:19]=[C:20]([C:25]([NH:1][C@@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@@H:3]2[O:15][CH3:16])=[O:26])[NH:21][C:22]=1[CH2:23][CH3:24]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CO[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OC)nc1Cl
Yield: 72 %

Procedure:
The same operation as in Example (1g) was performed using tert-butyl (3S,4R)-4-amino-3-methoxypiperidine-1-carboxylate obtained in Example (56a) (224.4 mg, 0.96 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid synthesized by the method described in Example (1d) (140 mg, 0.80 mmol), WSC hydrochloride (440 mg, 2.29 mmol) and HOBT (110 mg, 0.81 mmol), to obtain 222.4 mg of the title compound as a white solid (72%).
Reaction SMILES: Cl.O.[C:3]([O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:12]=[CH:11][C:10]=1[C:18]1([NH:32][C:33](=[O:37])[CH2:34][CH2:35][CH3:36])[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[N+:28]([O-])=O)[C:19]1=[O:31])(=[O:7])[CH2:4][CH2:5][CH3:6]>C(O)C.[Fe]>[C:3]([O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:16])[CH3:17])[CH:12]=[CH:11][C:10]=1[C:18]1([NH:32][C:33](=[O:37])[CH2:34][CH2:35][CH3:36])[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[NH2:28])[C:19]1=[O:31])(=[O:7])[CH2:4][CH2:5][CH3:6]
Reactant: CCCC(=O)NC1(c2ccc(C(C)C)cc2OC(=O)CCC)C(=O)c2cccc([N+](=O)[O-])c2C1=O
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCCC(=O)NC1(c2ccc(C(C)C)cc2OC(=O)CCC)C(=O)c2cccc(N)c2C1=O
Yield: 86.3 %

Procedure:
Iron powder (0.07 g, 1.3 mmol), conc. HCl (0.05 ml), and water (1 ml) were added in that order to a solution of 2-(2-butyramido-4-nitro-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl butyrate (90 mg, 0.18 mmol) in ethanol (5 ml). The reaction mixture was heated for 1 hrs under reflux. After filtration at high temperature, the filtrate was concentrated in a vacuum and purified using column chromatography (ethylacetate:hexane=1:4 to 1:2) to afford the title compound (70 mg, 83%).
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:11][CH:12]([CH2:30][CH2:31][CH2:32][CH:33]([CH3:40])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:13][CH2:14][O:15][C:16]1[CH:28]=[CH:27][C:26]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19](=[O:29])[C:18]=2[CH:17]=1>C1COCC1>[CH3:11][CH:12]([CH2:30][CH2:31][CH2:32][CH:33]([CH3:40])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:13][CH2:14][O:15][C:16]1[CH:28]=[CH:27][C:26]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)([OH:29])[C:18]=2[CH:17]=1
Reactant: Brc1ccccc1
Reactant: CC(C)CCCC(C)CCCC(C)CCOc1ccc2c(c1)C(=O)c1ccccc1-2
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)CCCC(C)CCCC(C)CCOc1ccc2c(c1)C(O)(c1ccccc1)c1ccccc1-2
Temperature: 40 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
Under a nitrogen atmosphere, magnesium (280 mg, 11.5 mmol) was suspended in dehydrated THF (2 ml), iodine (45 mg, 0.18 mmol) was added, bromobenzene (390 μl, 3.70 mmol) was slowly added dropwise, and the suspension was stirred at 40° C. for 4 hr. To the reaction mixture was added the aforementioned 2-(3′,7′,11′-trimethyldodecyloxy)-9-fluorenone (300 mg, 0.74 mmol), and the mixture was stirred at 50° C. overnight. The reaction mixture was cooled to room temperature, and the reaction was quenched with 1N hydrochloric acid (30 ml). The mixture was extracted with chloroform (40 ml), and the extract was washed three times with 1N hydrochloric acid (20 ml), three times with 5% aqueous sodium hydrogen carbonate solution (20 ml), and once with 20% brine (20 ml). The solvent of the organic layer was evaporated, and the obtained residue was purified and separated by silica gel column chromatography (hexane:ethyl acetate=10:1) to give 2-(3′,7′,11′-trimethyldodecyloxy)-9-phenylfluoren-9-ol (181 mg, 0.37 mmol, yield 51%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH:30]1[CH:34]=[CH:33][C:32]([C:35](O)=[O:36])=[N:31]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:35]([C:32]4[CH:33]=[CH:34][NH:30][N:31]=4)=[O:36])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc[nH]n1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2cc[nH]n2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and 1H-pyrazole-3-carboxylic acid (17 mg, 0.15 mmol).
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[N:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH2:44][C:45](O)=[O:46]>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[C:25]([C:33]([F:36])([F:34])[F:35])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:45](=[O:46])[CH2:44][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][N:38]=2)[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Reactant: O=C(O)Cc1ccccn1
Agent: Cl
Product: O=C(Cc1ccccn1)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (31.8 mg) obtained in Example 25 and 2-pyridineacetic acid hydrochloride (20.8 mg) were reacted and treated in the same manner as in the method described in Example.32 to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:11]([O:15][C:16](=[O:19])[CH:17]=[CH2:18])([CH3:14])([CH3:13])[CH3:12]>C(O)C>[C:11]([O:15][C:16](=[O:19])[CH2:17][CH2:18][NH:10][C@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH3:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: C[C@H](N)c1cccc(Br)c1
Reactant: C=CC(=O)OC(C)(C)C
Solvent: CCO
Product: C[C@H](NCCC(=O)OC(C)(C)C)c1cccc(Br)c1

Procedure:
A solution of (S)-1-(3-bromo-phenyl)-ethylamine (0.3 g, 1.5 mmol) and acrylic acid tert-butyl ester (0.19 g, 1.50 mmol) in ethanol (1.3 mL) was stirred at 55° C. for 2.5 hours. The solvent was concentrated and the crude residue was purified by chromatography on silica gel (heptane/EtOAc).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:27])([F:26])[F:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[O:29]1[CH:33]=[CH:32][CH:31]=[CH:30]1>>[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:25])([F:26])[F:27])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5]
Reactant: c1ccoc1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1
Product: O=C(c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1)c1ccco1

Procedure:
This compound is prepared by method C using compound 12f and furane
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:16]([C:17]3[C:18](=O)[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:11]3[N:12]=[C:13]([CH3:15])[S:14][C:10]=3[CH:9]=[CH:8][C:7]=2[CH:26]=1)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>O1CCOCC1>[CH3:23][N:21]1[CH:22]=[C:17]([CH:16]2[C:11]3[N:12]=[C:13]([CH3:15])[S:14][C:10]=3[CH:9]=[CH:8][C:7]3[CH:26]=[C:3]([CH2:1][CH3:2])[CH:4]=[CH:5][C:6]2=3)[C:18](=[S:36])[NH:19][C:20]1=[O:24]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCc1ccc2c(c1)C=Cc1sc(C)nc1C2c1cn(C)c(=O)[nH]c1=O
Solvent: C1COCCO1
Product: CCc1ccc2c(c1)C=Cc1sc(C)nc1C2c1cn(C)c(=O)[nH]c1=S

Procedure:
A mixture of the product of step (xii) (0.070 g) and Lawesson's reagent (0.077 g) in 1,4-dioxane (5 ml) was heated at reflux for 16 hours. The solvent was evaporated under reduced pressure. Purification was by chromatography eluting with 2% ethanol in dichloromethane to give the title compound.
Reaction SMILES: [O:1]=[C:2]([CH3:42])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:25]2[CH2:29][CH2:28][C@H:27]([C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)[O:26]2)[CH:10]=[C:11]([O:17]CC2C=CC=CC=2)[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5]>C(O)(=O)C.C(OCC)(=O)C>[O:1]=[C:2]([CH3:42])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:25]2[CH2:29][CH2:28][C@H:27]([C:30]3[CH:31]=[C:32]([O:40][CH3:41])[C:33]([O:38][CH3:39])=[C:34]([O:36][CH3:37])[CH:35]=3)[O:26]2)[CH:10]=[C:11]([OH:17])[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:5])=[O:6]
Reactant: CCCOc1c(OCc2ccccc2)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCOc1c(O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)=O
Reaction time: 0.75 h

Procedure:
A mixture of 1.2 g of 2-[3-(2-oxopropylsulfonyl)-4-n-propoxy-5-benzyloxyphenyl]-5-(3,4,5-trimethoxyphenyl) tetrahydrofuran (STEP J), 400 mg 10% PD/C, 1-2 drops of acetic acid in 100 mL of ethyl acetate was stirred under H2 at 40 psi for 45 minutes. The reaction mixture was filtered over a bed of celite and evaporated in vacuo to yield the title compound: NMR (200 MHz, CDCl3) δ 1.10 (t, CH2CH2CH3), 1.92 (m, CH2CH2CH3), 1.9-2.6 (m, 3-CH2 δ 4-CH2), 2.40 (s, CH3C(O)CH2), 3.86 (s, OCH3), 3.90 (s, 2 OCH3), 4.12 (t, CH2CH2CH3), 4.42 (s, CH3C(O)CH2), 5.10-5.28 (m, 2-CH δ 5-CH), 6.64 (s, 5-ArH), 7.35 δ 7.47 (2 d, 2-ArH).
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]=1.O>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:16][C:14]1[CH:13]=[CH:12][N:11]=[C:10]([C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:15]=1
Reactant: Cc1ccnc(Br)c1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccnc(C#Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phenylacetylene (15.4 mL) is added to a mixture of 2-bromo-4-methyl-pyridine (20.0 g), CuI (2.2 g), and Pd(PPh3)2Cl2 (4.1 g) in triethylamine (600 mL) kept under argon atmosphere. The mixture is stirred at ambient temperature overnight. Then, water is added and the resulting mixture is extracted with diethyl ether. The combined organic extracts are washed with brine and dried (MgSO4). The solvent is removed under reduced pressure and the residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 9:1→4:1) to give the product as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:36])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([S:30][CH2:31][CH3:32])=[CH:26][C:25]=3[O:33][CH2:34][CH3:35])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:39][S:40]([CH2:43][CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)(=[O:42])=[O:41]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:36])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:49]3[CH2:50][CH2:51][N:46]([CH2:45][CH2:44][CH2:43][S:40]([CH3:39])(=[O:41])=[O:42])[CH2:47][CH2:48]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([S:30][CH2:31][CH3:32])=[CH:26][C:25]=3[O:33][CH2:34][CH3:35])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)CCCN1CCNCC1
Reactant: CCOc1cc(SCC)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(SCC)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-ethylsulfanyl-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% methanol in carbon dioxide) gave the title compound. HR-MS (ES, m/z) calculated for C36H45N4O4S2Cl2 [(M+H)+] 731.2254, observed 731.2259.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][NH:12][CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[Cl:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)Cl>[Cl:23][CH2:24][C:25]([N:12]([CH2:11][CH2:10][C:5]1[CH:6]=[CH:7][C:8]([F:9])=[C:3]([C:1]#[N:2])[CH:4]=1)[CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:26]
Reactant: CC(C)(C)OC(=O)NCCNCCc1ccc(F)c(C#N)c1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCN(CCc1ccc(F)c(C#N)c1)C(=O)CCl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of tert-Butyl (2-{[2-(3-cyano-4-fluorophenyl)ethyl]amino}ethyl)carbamate (0.9 g, 3.1 mmol) and TEA (0.4 g, 3.7 mmol) in 10 mL of anhydrous DCM was added chloroacetyl chloride (0.4 g, 3.7 mmol) dropwise at 0° C. The mixture was stirred at 0° C. for 1 h, and then the solvent was evaporated. The residue was partitioned between EtOAc and water. The organic layer was dried and evaporated. The residue was purified with prep-TLC to give tert-Butyl (2-{(chloroacetyl) [2-(3-cyano-4-fluorophenyl)ethyl]amino}ethyl)carbamate.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[CH:6][CH:5]=1.Cl.[CH3:20][NH:21][O:22][CH3:23].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH3:23][O:22][N:21]([CH3:20])[C:14](=[O:16])[CH2:13][CH2:12][C:11]#[C:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:18])[F:17])=[CH:9][CH:8]=1
Reactant: O=C(O)CCC#Cc1ccc(OC(F)(F)F)cc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)CCC#Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A solution of 1.00 g (3.87 mmol) of 5-(4-trifluoromethoxy-phenyl)-pent-4-ynoic acid (example 29D]) in 50 ml CH2Cl2 was treated with 0.45 g (4.65 mmol) N,O-dimethylhydroxylamine hydrochloride, 0.55 ml (5.03 mmol) N-methylmorpholine and at 0° C. with 0.97 g (5.03 mmol) N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI). The reaction was naturally warmed to ambient temperature over night and partitioned between aqueous 10% KHSO4/ether (three times). The organic phases were washed with aqueous saturated NaHCO3, 10% NaCl and dried (Na2SO4) to give 1.165 g of the title compound as brown oil.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[C:8]([NH2:10])[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:11]N1C(=O)CCC1=O>CC#N>[Br:11][C:5]1[CH:6]=[CH:7][C:8]([NH2:10])=[N:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cccc([N+](=O)[O-])n1
Solvent: CC#N
Product: Nc1ccc(Br)c([N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a stirred solution of 6-nitro-pyridin-2-ylamine (9) (5.1 g, 18.4 mmol) in MeCN (125 mL) under nitrogen atmosphere, N-bromosuccinimide (3.43 g, 19.3 mmol) was added at 0° C. After 1 hour, another portion of N-bromosuccinimide (3.57 g, 20.1 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirring was continued overnight. The product was precipitated by addition of water (125 mL). The slurry was cooled to 0° C. and precipitated product was isolated by filtration, washed with premixed MeCN:water (1:1) and dried under vacuum at 40° C. to afford 3.8 g of 5-bromo-6-nitro-pyridin-2-ylamine (2).