Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(P(C(C)(C)C)C1N(C2C=CC=CC=2)C=CC=1)(C)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:30]1[CH:35]=[CH:34][C:33]([C:36]2[N:41]=[C:40]3[N:42]=[C:43]([O:53][C@H:54]4[C@H:58]5[O:59][CH2:60][C@@H:61]([OH:62])[C@H:57]5[O:56][CH2:55]4)[N:44]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:39]3=[CH:38][C:37]=2[Cl:63])=[CH:32][CH:31]=1.[OH:64][C@H:65]1[CH2:69][CH2:68][NH:67][CH2:66]1>O1CCOCC1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:62][C@@H:61]1[CH2:60][O:59][C@@H:58]2[C@H:54]([O:53][C:43]3[N:44]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:39]4[C:40]([N:42]=3)=[N:41][C:36]([C:33]3[CH:34]=[CH:35][C:30]([N:67]5[CH2:68][CH2:69][C@H:65]([OH:64])[CH2:66]5)=[CH:31][CH:32]=3)=[C:37]([Cl:63])[CH:38]=4)[CH2:55][O:56][C@H:57]12
Reactant: O[C@H]1CCNC1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(Br)cc3)c(Cl)cc21
Agent: [Pd]
Agent: CC(C)(C)P(c1cccn1-c1ccccc1)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(N4CC[C@H](O)C4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 17 h

Procedure:
2-(di-tert-butyl-phosphino)-1-phenyl-1H-pyrrole (21.2 mg, 0.074 mmol) and Pd2(dba)3 (62.3 mg, 0.068 mmol) were combined in a 40 ml vial, which was evacuated (3×) and placed under nitrogen. Dioxane (1.0 ml) was added to the vial to give a dark solution that was stirred at room temperature. Tripotassium phosphate (1.1 ml, 2.200 mmol) was added to a solution of (3R,3aR,6R,6aR)-6-[5-(4-bromophenyl)-6-chloro-1-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol and (S)-3-hydroxypyrrolidine (101.2 mg, 1.162 mmol) in dioxane (3.0 ml). This biphasic mixture was transferred to the catalyst solution via syringe after the catalyst solution had been stirred for 40 minutes. The reaction mixture was degassed (3×) and placed under nitrogen before being heated to 110° C. After 17 hours, the reaction mixture was cooled to room temperature. The reaction mixture was partitioned between EtOAc (100 ml) and water (100 ml). The aqueous layer was extracted with EtOAc (2×50 ml). The organic layers were combined, washed with brine (1×30 ml), dried over MgSO4, filtered, and evaporated under reduced pressure to give an amber residue. The residue was dissolved in EtOAc and loaded onto three 1000 micron 20 cm×20 cm silica gel plates, which were developed using 80% EtOAc/Hex. The silica containing the product band was collected and eluted with EtOAc (125 ml). The solvent was evaporated under reduced pressure to give the desired product as an amber residue. LC-MS: calculated for C28H37ClN4O6Si 588.22 observed m/e: 589.14 (M+H)+ (Rt 1.42/2 min).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1CO[C:14]([C@@H:16]2[C@:33]3([CH3:34])[C@H:19]([C@H:20]4[C@H:30]([C@@H:31]([O:35][C:36](=[O:45])[CH2:37][N:38]([CH2:42][CH2:43][CH3:44])[CH2:39][CH2:40][CH3:41])[CH2:32]3)[C@:28]3([CH3:29])[C@H:23]([CH2:24][C@H:25]([OH:46])[CH2:26][CH2:27]3)[CH2:22][CH2:21]4)[CH2:18][CH2:17]2)([CH3:15])[O:13]1.C(=O)(O)[O-].[Na+]>CC(C)=O>[OH:46][C@@H:25]1[CH2:26][CH2:27][C@@:28]2([CH3:29])[C@@H:23]([CH2:22][CH2:21][C@@H:20]3[C@@H:30]2[C@@H:31]([O:35][C:36](=[O:45])[CH2:37][N:38]([CH2:39][CH2:40][CH3:41])[CH2:42][CH2:43][CH3:44])[CH2:32][C@@:33]2([CH3:34])[C@H:19]3[CH2:18][CH2:17][C@@H:16]2[C:14](=[O:13])[CH3:15])[CH2:24]1
Reactant: CCCN(CCC)CC(=O)O[C@H]1C[C@]2(C)[C@@H](C3(C)OCCO3)CC[C@H]2[C@@H]2CC[C@H]3C[C@H](O)CC[C@]3(C)[C@H]21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCN(CCC)CC(=O)O[C@H]1C[C@]2(C)[C@@H](C(C)=O)CC[C@H]2[C@@H]2CC[C@H]3C[C@H](O)CC[C@]3(C)[C@H]21

Procedure:
Toluene-4-sulphonic acid (120 mg) was added to a solution of 20,20-ethylenedioxy-11β-dipropylaminoacetoxy-5α-pregnan-3α-ol (260 mg) in acetone (20 ml). The mixture was kept at room temperature until reaction was judged complete (TLC), when sodium bicarbonate solution was added and the precipitated material collected by filtration. Crystallization from ether-petroleum ether afforded title compound, m.p. 120°-122°, [α]D +92°.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10]O.S(Cl)([Cl:14])=O.O>C(Cl)(Cl)Cl.ClCCl>[Cl:14][CH2:10][C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: OCc1cc2ccccc2o1
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: ClCc1cc2ccccc2o1
Yield: 80 %

Procedure:
A three-necked flask is charged with 33.2 g of 2-benzofuranylmethanol dissolved in 450 ml of anhydrous chloroform, 48.8 ml of thionyl chloride are then introduced dropwise and the temperature is raised gently to reflux and maintained for 3 hours 30 minutes. The reaction medium is then cooled and poured into 1 1 of water, and is thereafter diluted with 500 ml of dichloromethane. After settling has taken place, the organic phase is washed to neutrality and dried over anhydrous magnesium sulfate, the solvent is evaporated off and the residue is distilled under vacuum to obtain the expected compound.
Reaction SMILES: [K].[F-].[C:3]([C:5]([C:27]#[N:28])=[C:6]1[C:10]([C:11]#[N:12])=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][Si](C)(C)C)=[CH:15][CH:14]=2)[C:8]([CH3:26])([CH3:25])[O:7]1)#[N:4].O>C1COCC1.CO>[C:11]([C:10]1[C:6](=[C:5]([C:3]#[N:4])[C:27]#[N:28])[O:7][C:8]([CH3:26])([CH3:25])[C:9]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=1)#[N:12]
Reactant: CC1(C)OC(=C(C#N)C#N)C(C#N)=C1c1ccc(C#C[Si](C)(C)C)cc1
Agent: [F-]
Agent: [K]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C#Cc1ccc(C2=C(C#N)C(=C(C#N)C#N)OC2(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(RS01039) Potassium) fluoride (260 mg, 4.5 mmol) was added to a solution of 2-dicyanomethylene-3-cyano-5,5-dimethyl-4-(4′-trimethylsilylethynylphenyl)-2,5-dihydrofuran (500 mg, 1.4 mmol) in degassed THF/methanol (1.5:1, 40 mL). The reaction mixture was stirred for 24 h at room temperature, poured into water, stirred for 1 hr, kept in the refrigerator overnight, filtered and air-dried. The product was recrystallized from dichloromethanel/1-propanol, Yield: 330 mg. (90%), mp: 225° C., 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J=8.8 Hz, 2H), 7.67 (d, J=8.8 Hz, 2H), 3.36 (s, 1H), 1.81 (s, 6H). 13C NMR (100 MHz, CDCl3) 176.24, 174.31, 133.32, 128.00, 126.93, 110.98, 110.06, 109.97, 102.50, 99.08, 82.29, 81.71, 26.13. IR (neat, cm−1 2965, 2226, 1623, 1614, 1534.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.CCN(CC)CC.[CH3:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>CN(C1C=CN=CC=1)C.COC(C)(C)C.CCOC(C)=O>[C:20]([O:8][CH2:7][CH:5]1[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]1)(=[O:21])[CH2:19][CH2:18][CH3:17]
Reactant: CCCC(=O)Cl
Reactant: CC1(C)OCC(CO)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: COC(C)(C)C
Product: CCCC(=O)OCC1COC(C)(C)O1
Temperature: 0 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
To a well-stirred solution of solketal (21, 62.6 ml, 500 mmol), Et3N (83.6 ml, 600 mmol) and DMAP (5 g, 40.9 mmol) in tert-butyl methyl ether (11) at 0° C., n-butyryl chloride (52.4 mL, 500 mmol) was added dropwise over a 75 minute period. The mixture was stirred for an additional hour at 0° C. and then at room temperature for an additional 5 hours. The mixture was diluted with AcOEt (11), washed with water (11), dried (MgSO4), filtered and evaporated to afford 22 (104.6 g, 500 mmol, 100%) as an oil. The material was used in the next step without any further purification.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][N:8]([C@H:24]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:34]=[C:33]([C:35]#[N:36])[S:32][CH:31]=2)[C:25]1=[O:37])[S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:35]([C:33]1[S:32][CH:31]=[C:30]([CH2:29][N:26]2[CH2:27][CH2:28][C@H:24]([N:8]([S:9]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][CH:18]=4)[CH:13]=3)(=[O:11])=[O:10])[CH2:7][C:6]([OH:38])=[O:5])[C:25]2=[O:37])[CH:34]=1)#[N:36]
Reactant: COc1ccc2ccc(S(=O)(=O)N(CC(=O)OC(C)(C)C)[C@H]3CCN(Cc4csc(C#N)c4)C3=O)cc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2ccc(S(=O)(=O)N(CC(=O)O)[C@H]3CCN(Cc4csc(C#N)c4)C3=O)cc2c1
Reaction time: 2 h

Procedure:
To a solution of 2-[[1-(5-cyanothiophene-3-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-(7-methoxynaphthalene-2-sulfonyl)amino]acetic acid tert-butyl ester (0.40 g, 0.72 mmol) in 15 mL of CH2Cl2 is added 5 mL of TFA. After 2 hours, the solution is concentrated to give the title compound as a white foam.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:33])=[C:4]([N:8]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([OH:19])=O)=[O:11])[CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:46][S:47]([NH2:50])(=[O:49])=[O:48].C1CCN2C(=NCCC2)CC1.Cl>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:33])=[C:4]([N:8]([S:23]([C:26]2[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=2)(=[O:24])=[O:25])[CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([NH:50][S:47]([CH3:46])(=[O:49])=[O:48])=[O:19])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(=O)NCc2cccc(C(=O)O)c2)c2cccc(Cl)c2C)cc1
Reactant: CS(N)(=O)=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(S(=O)(=O)N(CC(=O)NCc2cccc(C(=O)NS(C)(=O)=O)c2)c2cccc(Cl)c2C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
182 mg of 3-[({N-(3-chloro-2-methylphenyl)-N-[(4-methylphenyl)sulfonyl]glycyl}amino)methyl]benzoic acid was dissolved in 0.50 mL of DMF, and 75 mg of 1,1′-carbonyldiimidazole was added thereto, followed by stirring at room temperature for 1 hour. To the reaction liquid were added 40 mg of methane sulfonamide and 66 mg of DBU, followed by stirring at 50° C. for 8 hours. The reaction liquid was acidified by addition of 2.50 mL of 1 M hydrochloric acid, and then extracted with a mixed solvent of chloroform/methanol (5/1), and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 95:5) to obtain 207 mg of 3-[({N-(3-chloro-2-methylphenyl)-N-[(4-methylphenyl)sulfonyl]glycyl}amino)methyl]-N-(methylsulfonyl)benzamide.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)=[CH:13][C:12]=3[CH2:25][CH2:26][CH3:27])=[N:9][O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:28].[C:29]([O:34]C)(=[O:33])[C@@H:30]([CH3:32])O>>[Cl:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)=[CH:13][C:12]=3[CH2:25][CH2:26][CH3:27])=[N:9][O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[O:28][C@@H:30]([CH3:32])[C:29]([OH:34])=[O:33]
Reactant: COC(=O)[C@@H](C)O
Reactant: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1noc2ccc(O)c(Cl)c12
Product: CCCc1cc(Oc2ccc(Cl)cc2)ccc1-c1noc2ccc(O[C@@H](C)C(=O)O)c(Cl)c12

Procedure:
The phenol product from Step 1 (0.38 g, 0.9 mmol) and methyl (R)-lactate (0.16 g, 1.5 mmol) was reacted according the general procedure described in Step 11 of Example 1 to give the title compound as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].[C-:12]#[N:13].[K+].Cl>C(O)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][C:12]#[N:13])=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 5.9 %

Procedure:
To a stirred suspension of 2.5 g (11.5 mmol) 2-bromo-1-(4-fluoro-phenyl)-ethanone (the preparation of which is described in example . . . ) in 40 ml ethanol was added a solution of 0.90 g (23 mmol) potassium cyanide in 9 ml water. The mixture was then stirred at RT for 2 h, then acidified to ph=5-6 with aqueous HCl 1M and then extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 6:1) afforded 0.11 g (6%) 3-(4-fluoro-phenyl)-3-oxo-propionitrile as a yellow solid.
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CC(C)=O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].S(=O)(=O)(O)O>O>[CH:1]#[C:2][C:3](=[O:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C#CC(O)CCCCC
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C#CC(=O)CCCCC
Reaction time: 0.5 h

Procedure:
A 1500-mL reactor is loaded with 25.24 g (200 mmoles) i.e. 29.1 mL of 1-octyn-3-ol, 600 mL of acetone and 90 mL of water. Accompanied by vigorous stirring a solution of 29.4 g (100 mmoles) of potassium dichromate of (RN 7778-50-9) in 300 mL of water and 22 mL of sulphuric acid is added over 1 hour 30 minutes. The coloration changes from orange to green. At the end, stirring is continued for another 30 minutes then 1000 mL of water is added also over 30 minutes.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:18]2[CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[C:16]3[C:15](=[O:29])[NH:14][CH:13]=[CH:12][C:11]=3[NH:10][C:9]=2[CH:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2].F[B-](F)(F)F.[CH3:35][O+](C)C.C(=O)([O-])O.[K+]>ClCCCl>[CH:1]([O:4][C:5]1[N:6]=[CH:7][CH:8]=[C:9]2[C:18]=1[CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26])[C:16]1[C:15]([O:29][CH3:35])=[N:14][CH:13]=[CH:12][C:11]=1[NH:10]2)([CH3:3])[CH3:2]
Reactant: C[O+](C)C
Reactant: CC(C)Oc1nccc2c1C(c1ccccc1C(F)(F)F)c1c(cc[nH]c1=O)N2
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCCl
Product: COc1nccc2c1C(c1ccccc1C(F)(F)F)c1c(ccnc1OC(C)C)N2

Procedure:
7.5 g (18.7 mMole) (±)-1,2,5,10-tetrahydro-9-isopropoxy-1-oxo-10-(2-trifluoromethylphenyl)-pyrido[4,3-b][1,6]naphthyridine (see Example 2) and 5.0 g (34 mMole) trimethyloxonium tetrafluoroborate are stirred for 24 hours at ambient temperature in 200 ml 1,2-dichloroethane under an atmosphere of nitrogen. The reaction mixture is then shaken with a saturated aqueous solution of potassium hydrogen carbonate and the organic phase is separated off, washed with water and dried over anhydrous sodium sulphate. The residue obtained after evaporation in a vacuum is chromatographed on silica gel with toluene/ethyl acetate (3:1 v/v). The fraction with the Rf of 0.2 is isolated and recrystallized from n-hexane/diisopropyl ether. There is obtained (±)-5,10-dihydro-1-isopropoxy-9-methoxy-10-(2-trifluoromethylphenyl)-pyrido[4,3-b][1,6]naphthyridine in the form of colorless crystals; mp 183°-185° C.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][O:12][CH2:13][CH2:14][CH2:15][C:16]1[N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:19]2[CH:29]=[CH:30][CH:31]=[C:32]([C:33](OC)=[O:34])[C:18]=2[N:17]=1>O1CCCC1>[CH3:11][O:12][CH2:13][CH2:14][CH2:15][C:16]1[N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])[C:19]2[CH:29]=[CH:30][CH:31]=[C:32]([CH2:33][OH:34])[C:18]=2[N:17]=1
Reactant: COCCCc1nc2c(C(=O)OC)cccc2n1COCC[Si](C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: COCCCc1nc2c(CO)cccc2n1COCC[Si](C)(C)C
Temperature: -10 °C
Reaction time: 1 h

Procedure:
35 ml of diisobutylaluminium hydride (1.5M in toluene) are added dropwise at −70° C. to a solution of 4.95 g of methyl 2-(3-methoxypropyl)-1-(2-trimethylsilanylethoxymethyl)-1H-benzoimidazol-4-carboxylate in 200 ml of tetrahydrofuran. The reaction mixture is then stirred at −10° C. for 1 hour and subsequently partitioned between tert-butyl methyl ether and 2:1 water/1N potassium bisulphate solution—the organic phase is washed with saturated aqueous sodium bicarbonate solution and water, dried over sodium sulphate and concentrated by evaporation. The combined aqueous phases are reextracted with ethyl acetate (3×)—the combined organic phases are washed with saturated aqueous sodium bicarbonate solution and water, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow oil from the residues by means of flash chromatography (SiO2 60F). Rf=021 (95:5 ethyl acetate-methanol), Rt=3.91.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[CH3:8][C:9]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[NH:11][CH:10]=1>C(O)=O>[CH:5]([N:11]1[C:12]2[N:13]([N:14]=[CH:15][CH:16]=2)[C:9]([CH3:8])=[CH:10]1)=[O:7]
Reactant: Cc1c[nH]c2ccnn12
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: Cc1cn(C=O)c2ccnn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of acetic anhydride (4.83 ml) and formic acid (3.86 ml) was stirred at room temperature for 1 hour. The solution was cooled at ice-bath and 3-methyl-1H-imidazo[1,2-b]pyrazole (3.1 g) was added thereto. The mixture was stirred at the same condition for 1 hour. The reaction mixture was evaporated and the residue was subjected to column chromatography on silica gel using ethyl acetate as an eluent. Fractions containing the object compound were combined and the solvent was evaporated to give 1-formyl-3-methyl-1H-imidazo[1,2-b]pyrazole (2.99 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH:16]1[O:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]3[N:28]=[C:27]([CH3:29])[O:26][C:23]3=2)[O:18][CH2:17]1.[CH:30](=O)[CH3:31].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:30]([N:14]([CH2:13][CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[NH:7][CH:6]=1)[CH2:15][CH:16]1[CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]3[N:28]=[C:27]([CH3:29])[O:26][C:23]=3[C:24]=2[O:25]1)[CH3:31]
Reactant: CC=O
Reactant: Cc1nc2ccc3c(c2o1)OC(CNCCCc1c[nH]c2ccc(F)cc12)CO3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCN(CCCc1c[nH]c2ccc(F)cc12)CC1COc2ccc3nc(C)oc3c2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [3-(5-fluoro-1H-indol-3-yl)-propyl]-(2-methyl-7,8-dihydro-1,6,9trioxa-3-aza-cyclopenta[a]napthalen-8-ylmethyl)-amine (0.13 g, 0.32 mmol) and acetaldehyde (0.18 mL, 3.2 mmol) in methanol (20 mL) was added sodium cyanoborohydride (0.07 g, 0.57 mmol) and acetic acid (0.04 mL, 0.32 mmol) at room temperature. The mixture was stirred at room temperature under nitrogen overnight, then quenched with 1N NaOH (5 mL). The mixture was extracted with methylene chloride (3×50 mL). The organic layer was washed with water (3×50 mL), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. The crude oil was column chromatographed on silica gel (5% methanol-methylene chloride). The product-containing fractions were concentrated in vacuum to give 145 mg of the (S)-enantiomer of the title compound as a yellow oil. The dihydrochloride salt was prepared in ethyl acetate as a white solid, m.p. 115° C. d.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C(N(CC)CC)C.[S:21](Cl)([CH3:24])(=[O:23])=[O:22].O>C(Cl)Cl>[CH3:24][S:21]([O:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)(=[O:23])=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.6 %

Procedure:
To a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (Aldrich; 7.42 g, 39.6 mmol), in DCM (20 mL) was added, at 0° C., triethylamine (8.44 mL; 48.5 mmol) and then mesylchloride (3.13 mL; 40 mmol). The mixture was stirred for 18 hours at RT and then water was added and the product was extracted with DCM (3×20 mL). The combined organic fractions were dried (MgSO4), filtered and the solvent removed in vacuo to give tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate (8.26 g; 77%) as a brown oil. 1H NMR: (CDCl3, 400 MHz) δ 5.27-5.20 (1 H, m), 3.70-3.49 (4 H, m), 3.04 (3 H, s), 2.90-2.05 (2 H, m), 1.46 (9 H, s).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[N+:13]([C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20])([O-:15])=[O:14]>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][CH:24]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=1
Reactant: COCCN
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCNC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 2-methoxyethylamine (0.9 ml) in dichloromethane (20 ml) was added triethylamine (2.1 ml), and the mixture was cooled in an ice-cooling bath. A solution of 3-nitrobenzoyl chloride (1.8 g) in dichloromethane (10 ml) was dropwise added thereto and the resulting mixture was stirred for 1.5 hours at the same temperature. The mixture was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate. After filtration, the solvent was removed in vacuo to afford N-(2-methoxyethyl)-3-nitrobenzamide (2.7 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([NH2:23])[C:17]3[O:21][N:20]=[C:19]([CH3:22])[N:18]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=2)=[CH:29][C:28]=1[C:47](O)=[O:48])[CH3:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C@@H:16]([NH:23][C:47]([C:28]3[CH:29]=[C:30]([C:33]4[CH:34]=[C:35]([C:43]([F:44])([F:45])[F:46])[CH:36]=[C:37]([C:39]([F:40])([F:42])[F:41])[CH:38]=4)[CH:31]=[CH:32][C:27]=3[O:26][CH2:24][CH3:25])=[O:48])[C:17]3[O:21][N:20]=[C:19]([CH3:22])[N:18]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOc1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C(=O)O
Reactant: Cc1noc([C@H](N)Cc2ccc(-c3ccc(F)c(Cl)c3)cc2)n1
Product: CCOc1ccc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C(=O)N[C@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)c1nc(C)no1
Yield: 82.4 %

Procedure:
4-Ethoxy-3′,5′-bis-trifluoromethyl-biphenyl-3-carboxylic acid [2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide (57 mg) was prepared from 2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine (33 mg, 0.10 mmol) and 4-Ethoxy-3′,5′-bis-trifluoromethyl-biphenyl-3-carboxylic acid (37 mg, 0.1 mmol) following the general procedure A.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH2:13])=[O:12])[CH:9]=2)[N:4]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[N:3]=1.[NH2:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[NH2:20][C:21]1[CH:26]=[C:25]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH2:13])=[O:12])[CH:9]=3)[N:4]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][O:15]3)[N:3]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: NC(=O)c1ccc2c(c1)c(Br)nn2C1CCCCO1
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Product: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Yield: 88 %

Procedure:
To a solution of 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (0.500 g, 1.54 mmol) in 15 mL of ethylene glycol dimethyl ether, was added 3-aminophenyl boronic acid (0.358 g, 2.31 mmol), [1,1′-bis(diphenylphosphino)-ferrocene] complex with dichloromethane (1:1) (0.178 g, 0.098 mmol), and potassium phosphate (1.63 g, 7.7 mmol). The reaction mixture was heated to reflux temperature of the solvent for 18 hours. The solvent was then removed under reduced pressure and the crude was partitioned between ethyl acetate and water. The title compound was purified by column chromatography (SiO2, 6% MeOH in CH2Cl2) (0.457 g, 88% yield): ES-MS (m/z) 337 [M+H]+.