Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[NH2:14])[C:7]([O:9][CH3:10])=[O:8].N[C:16](N)=[O:17].Cl>O>[O:17]=[C:16]1[NH:3][C:4]2[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=[CH:12][C:13]=2[NH:14]1
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: NC(N)=O
Agent: Cl
Solvent: O
Product: COC(=O)c1ccc2[nH]c(=O)[nH]c2c1
Temperature: 150 °C

Procedure:
Methyl 3,4-diaminobenzoate dihydrochloride (20 g, 0.08 mol) was mixed with urea (6.54 g, 0.11 mol). Reaction mixture was heated at ˜150° C. for 7 hours. After cooling powder was suspended in water (400 ml) and pH of the last one was adjusted to 0.45 with hydrochloric acid. Precipitate was filtered and rinsed with water and hydrochloric acid (pH=1.5). Obtained filter cake was dried at ˜100° C. Yield 15.7 g (97%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[PH:13](=[O:20])([O:17]CC)[O:14][CH2:15][CH3:16].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([P:13](=[O:17])([OH:20])[O:14][CH2:15][CH3:16])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: CCO[PH](=O)OCC
Reactant: COc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN(C)C=O
Product: CCOP(=O)(O)c1ccc([N+](=O)[O-])c(OC)c1
Temperature: 130 °C
Reaction time: 4 h
Yield: 36 %

Procedure:
4-Chloro-2-methoxy-1-nitrobenzene (4.84 g, 25.8 mmol) and diethyl phosphonate (3.92 g, 28.4 mmol) were added in a 250 mL round-bottomed flask. DMF (100 mL) was added to give a yellow solution. Potassium phosphate (6.02 g, 28.4 mmol) and palladium (II) acetate (0.290 g, 1.29 mmol) were added. Nitrogen was bubbled through the solution for 20 min before xantphos (1.045 g, 1.81 mmol) was added. The reaction was heated to 130° C. and stirred at that temperature for 4 h. After it was cooled to RT, the solution was concentrated in vacuo to remove the solvent, and to the residue was added water (60 mL) and DCM (40 mL). After partition, the aqueous layer was washed with DCM (2×20 mL). The aqueous layer was acidified using 12 N HCl (10 mL), and DCM was added (50 mL). After partition and extraction with DCM (2×30 mL), the DCM solution was combined and concentrated to give the product without further purification (2.4 g, 36% yield).
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:10](OC)=[O:11]>CO.CO[Na]>[OH:11][N:10]=[C:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON=O
Reactant: N#CCc1ccccc1
Agent: CO[Na]
Solvent: CO
Product: N#CC(=NO)c1ccccc1

Procedure:
This compound is prepared from benzyl cyanide by reaction with methyl nitrite in CH3OH/CH3ONa in accordance with the method described in Org. Synthesis 59, 95 (1979). Colourless crystals with a melting point of 119°-121° C.
Reaction SMILES: [CH2:1](Br)C#C.CI.COC(N1CCC(N2CCC(N3C4C=CC=CC=4NC3=O)CC2)CC1)=O.[CH2:33]([O:35][C:36]([N:38]1[CH2:43][CH2:42][CH:41]([N:44]2[CH2:49][CH2:48][CH:47]([N:50]3[C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=4[NH:52][C:51]3=[O:59])[CH2:46][CH2:45]2)[CH2:40][CH2:39]1)=[O:37])[CH3:34]>>[CH2:33]([O:35][C:36]([N:38]1[CH2:43][CH2:42][CH:41]([N:44]2[CH2:45][CH2:46][CH:47]([N:50]3[C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=4[N:52]([CH3:1])[C:51]3=[O:59])[CH2:48][CH2:49]2)[CH2:40][CH2:39]1)=[O:37])[CH3:34]
Reactant: C#CCBr
Reactant: CCOC(=O)N1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Agent: COC(=O)N1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Solvent: CI
Product: CCOC(=O)N1CCC(N2CCC(n3c(=O)n(C)c4ccccc43)CC2)CC1

Procedure:
Example 1 was repeated except that the propargyl bromide was replaced with methyl iodide and 1-[1-(1-methoxycarbonylpiperidin-4-yl)-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one was replaced with 1-[1-(1-ethoxycarbonylpiperidin-4-yl-piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one which was synthesized by the method of Referential Example 16, and the title compound was obtained as a colorless oil.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][O:13][C:14](=[O:19])[CH:15]=[CH:16][CH:17]=[O:18].C([C@@H]1N[C@H](C(C)(C)C)N(C)C1=O)C1C=CC=CC=1>>[CH3:12][O:13][C:14](=[O:19])[C@@H:15]([C:4]1[CH:5]=[CH:6][C:1]([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:2][CH:3]=1)[CH2:16][CH:17]=[O:18]
Reactant: COC(=O)C=CC=O
Reactant: c1ccc(N2CCCC2)cc1
Agent: CN1C(=O)[C@H](Cc2ccccc2)N[C@@H]1C(C)(C)C
Product: COC(=O)[C@H](CC=O)c1ccc(N2CCCC2)cc1

Procedure:
This example describes a Friedel-Crafts alkylation reaction of 1-phenyl-pyrrolidine and 4-oxo-butenoic acid methyl ester, catalyzed by the hydrochloride salt of (1), to provide (R)-4-oxo-2-(4-pyrrolidin-1-yl-phenyl)-butyric acid methyl ester.
Reaction SMILES: S(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=1)(=O)(=O)C.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[K]>CN(C=O)C>[CH2:15]([C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][CH2:6][N:24]2[C:23](=[O:25])[C:22]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]3[C:20]2=[O:30])=[CH:10][CH:11]=1)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCCCc1ccc(CCCOS(C)(=O)=O)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: CCCCCc1ccc(CCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 0 °C
Yield: 82 %

Procedure:
A solution of 3-(4-pentylphenyl)propyl mesylate (42.4 g, 149 mmol) and potassium phthalimide (27.6 g, 149 mmol) in DMF (200 ml) was stirred at 80° C. for 3 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate anhydride, and the organic layer was concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give the object compound as an oily substance. 41.1 g, (yield 82%)
Reaction SMILES: [C:1]([Si:5]([CH3:23])([CH3:22])[O:6][C@@H:7]([CH3:21])[CH2:8][O:9][N:10]1C(=O)C2C(=CC=CC=2)C1=O)([CH3:4])([CH3:3])[CH3:2].CNN>C(Cl)Cl>[C:1]([Si:5]([CH3:23])([CH3:22])[O:6][C@@H:7]([CH3:21])[CH2:8][O:9][NH2:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: C[C@@H](CON1C(=O)c2ccccc2C1=O)O[Si](C)(C)C(C)(C)C
Agent: CNN
Solvent: ClCCl
Product: C[C@@H](CON)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cold solution of crude 2-[(S)-2-(tert-butyl-dimethyl-silanyloxy)-propoxy]-isoindole-1,3-dione (0.28 mol) in DCM (200 ml) at 0° C. was added methyl hydrazine (14.74 mol, 0.28 mol). The reaction mixture was stirred at 0° C. for 30 minutes then filtered and the filtrate concentrated in vacuo. The resultant residue was subjected to distillation (b.p. 108-112° C. at 2-10 mbar) to yield the title compound as a colourless oil. (42.63 g, 74% from ethyl lactate). 1H NMR (CDCl3, 400 MHz) 5.36 (2H, s), 3.95 (1H, m), 3.55-3.41 (2H, m), 1.04 (3H, d, J=6.28 Hz), 0.81 (9H, s), 0.02 (6H, m).
Reaction SMILES: [C:1]1([CH:7]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[S:22][C:21]3[CH:20]=[C:19]4[C:10]([S:11][C:12]5[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=5[CH:18]4[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:9][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>ClC1C=CC=CC=1Cl>[C:1]1([C:7]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[S:22][C:21]3[C:8]=2[CH:9]=[C:10]2[C:19]([CH:20]=3)=[C:18]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:11]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2c3ccccc3Sc3cc4c(cc32)Sc2ccccc2C4c2ccccc2)cc1
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: Clc1ccccc1Cl
Product: c1ccc(C2=c3cc4c(cc3Sc3ccccc32)=C(c2ccccc2)c2ccccc2S4)cc1
Temperature: 22 °C

Procedure:
A mixture of 8.0 g of 7,14-diphenyl-7,14-dihydro-5,12-dithia-pentacene and 3.1 grams of chloranil is heated in 70 ml ortho-dichlorobenzene to 150° C. for one hour. After cooling to 22° C., the product is filtered off and washed with 30 ml of ortho-dichlorobenzene, twice with 15 ml toluene and finally with 30 ml of ethanol. After drying 5.9 g of 7,14-Diphenyl-5,12-dithia-pentacene is obtained as dark violet crystals, mp=320° C. EI-MS: 468 (100%), 436 (7%), 391 (7%), 358 (8%), 234 (11%). The structure is confirmed by single crystal X-ray diffraction analysis: (space group: P-1; cell length: a 5.746(2); b 10.337(2); c 10.623(2); cell angles: α 116.620(11) β 104.914(13) γ 92.354(14)). FIG. 5 shows representations of the product calculated according to the above x-ray data (views other than along crystallographic axes).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH:6]=[CH:7][C:8]([OH:10])=[O:9]>[Pd]>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: O=C(O)C=Cc1cccc(C(F)(F)F)c1
Agent: [Pd]
Product: O=C(O)CCc1cccc(C(F)(F)F)c1

Procedure:
m-Trifluoromethyl cinnamic acid is hydrogenated at room temperature at 2 psi using palladium on carbon as catalyst to provide m-trifluoromethylbenzyl acetic acid. 21.8 Parts of this acid is dissolved in 200 parts by volume of ether. Then 100 parts by volume of 1.0 molar methyl lithium in ether is added dropwise over a 30-minute period at 0°. After the addition is complete the mixture is allowed to stir at room temperature for 3-4 hours. The mixture is poured into 1 N HCl, the organic layer is washed successively with water and 5% potassium carbonate, and then dried over anhydrous sodium sulfate. The solvent is removed to provide m-trifluoromethylbenzyl acetone. Following the procedure set out in Example 1, replacing benzyl acetone with m-trifluoromethyl benzylacetone provides racemic methyl 7-[3β-hydroxy-2β-(3(R)-hydroxy-3-methyl-5-m-trifluoromethylphenyl-1-pentyn-1-yl)-5-oxocyclopent-1α-yl]heptanoate: ##STR11## racemic methyl 7-[3β-hydroxy-2β-(3(S)-hydroxy-3-methyl-5-m-trifluoromethylphenyl-1-pentyn-1-yl)-5-oxocyclopent-1α-yl]heptanoate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([NH:21][S:22]([CH:25]2[CH2:27][CH:26]2[CH2:28][O:29]CC2C=CC=CC=2)(=[O:24])=[O:23])=[C:12]2[O:20][CH2:19][CH2:18][N:13]2[C:14](=[O:17])[C:15]=1[CH3:16].B(F)(F)F.C(S)C>C(OC(=O)C)C>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([NH:21][S:22]([CH:25]2[CH2:27][CH:26]2[CH2:28][OH:29])(=[O:24])=[O:23])=[C:12]2[O:20][CH2:19][CH2:18][N:13]2[C:14](=[O:17])[C:15]=1[CH3:16]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC2COCc2ccccc2)c2n(c1=O)CCO2
Agent: FB(F)F
Solvent: CCOC(C)=O
Solvent: CCS
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC2CO)c2n(c1=O)CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.5 %

Procedure:
2-Benzyloxymethyl-cyclopropanesulfonic acid [7-(2-fluoro-4-iodo-phenylamino)-6-methyl-5-oxo-2,3-dihydro-5H-oxazolo[3,2-a]pyridin-8-yl]-amide (0.05 g, 0.0001 mol) was added to a stirred solution of BF3.EtO2 (0.34 g, 0.002 mol) in ethane thiol (0.05 g, 0.001 mol) at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight. The reaction was monitored by TLC (100% ethylacetate). The reaction mixture was quenched with saturated NaHCO3 solution and extracted with ethylacetate. The organic layer was washed with water, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (2-3% MeOH in DCM) afforded 11 mg of the product (27% yield).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([B:6]2[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])([CH3:9])[O:7]2)[CH:3]=[N:2]1.[CH2:15](Br)[CH:16]=[CH2:17].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:17]([N:2]1[CH:3]=[C:4]([B:6]2[O:7][C:8]([CH3:9])([CH3:10])[C:11]([CH3:13])([CH3:12])[O:14]2)[CH:5]=[N:1]1)[CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 70 °C
Yield: 93.1 %

Procedure:
A mixture of 4-pyrazoleboronic acid pinacol ester (3.0 g, 15.6 mmol), allyl bromide (6.9 g, 77 mmol) and sodium bis(trimethylsilyl)amide (20.5 mL of a 1.5N solution in THF, 30.7 mmol) in THF (20 mL) was heated to 70° C. overnight. After cooling to r.t. the reaction was quenched with water (15 mL) and extracted with EtOAc (2×30 mL). The combined organic fractions were washed with brine (50 mL), dried (MgSO4) and concentrated in vacuo to give the title compound (3.4 g, 94%) as a yellow oil. δH (CDCl3) 1.20 (12H, s), 4.61-4.67 (2H, m), 5.06-5.24 (2H, m), 5.79-6.01 (1H, m), 7.60 (1H, s), 7.69 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:18]=[C:17]([C:19](O)=[O:20])[CH:16]=[CH:15][C:14]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:12][C:13]1[CH:18]=[C:17]([C:19]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[N:9]3)=[CH:4][CH:3]=2)=[O:20])[CH:16]=[CH:15][C:14]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccc2cccnc2c1
Reactant: Cc1cc(C(=O)O)ccc1-c1ccccc1
Product: Cc1cc(C(=O)Nc2ccc3cccnc3c2)ccc1-c1ccccc1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-aminoquinoline (D55) (30 mg, 0.21 mmol) and 2-methyl-1,1′-biphenyl-4-carboxylic acid (D60) (53 mg, 0.25 mmol) as a white solid. MS(ES): MH+ 339
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:26]2[CH2:31][CH2:30][S:29][CH2:28][CH2:27]2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1.[OH:32]OS([O-])=O.[K+].S(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:26]2[CH2:31][CH2:30][S:29](=[O:32])[CH2:28][CH2:27]2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1
Reactant: COc1cc(N2CCSCC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: O=S([O-])OO
Agent: O=C([O-])[O-]
Agent: O=S([O-])O
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COc1cc(N2CCS(=O)CC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Temperature: 60 °C
Reaction time: 8 h
Yield: 14.9 %

Procedure:
To a solution of 4-{3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-thiomorpholine (660 mg, 1.52 mmol) in dichloromethane (7 mL), methanol (7 mL) and water (0.1 mL) was added oxone (1.87 g, 3.04 mmol) and stirred for 8 h at 60° C. The reaction mixture was cooled to ambient temperature and aqueous sodium bisulfite (38%, 5 mL) was added and stirred for 1 h. After the addition of aqueous sodium carbonate (saturated, 30 mL) the mixture was extracted with dichloromethane (30 mL) and washed with aqueous sodium carbonate (half-saturated, 30 mL). Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane:methanol=40:40:20:0 to 0:75:20:5) afforded the title compound (102 mg, 15%) as an off-white solid. MS: m/e=451.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.CN(C=O)C.[H-].[Na+].CS(O[CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1)(=O)=O>O>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 29.1 %

Procedure:
A 1 L, 1-neck flask was charged with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (20.0 g, 103 mmol), and DMF (250 mL). The reaction mixture was cooled to 0° C. and NaH (2.73 g, 108 mmol) (95%) was added. The reaction mixture was stirred at 0° C. for 1 hour. tert-Butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (30.2 g, 108 mmol; prepared as in WO 06/021881) was added and the reaction mixture was heated at 100° C. overnight. The reaction mixture was cooled to ambient temperature and diluted with water. The reaction mixture was extracted with EtOAc, and the organic layer washed with brine, dried over sodium sulfate, filtered and concentrated. The crude material was purified on a Biotage 40S column eluting with EtOAc/Hexane 10% to 25% EtOAc. The product was isolated as a white solid (11.3 g, 29%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[CH:19](Br)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:29][C:30]1[CH:35]=[C:34]([C:36]([O:38][CH3:39])=[O:37])[CH:33]=[CH:32][N:31]=1>C(O)C>[CH3:39][O:38][C:36]([C:34]1[CH:33]=[CH:32][N:31]2[C:19]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[C:18]([C:15]3[CH:14]=[CH:13][C:12]([C:8]4([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:28])[CH2:11][CH2:10][CH2:9]4)=[CH:17][CH:16]=3)[N:29]=[C:30]2[CH:35]=1)=[O:37]
Reactant: COC(=O)c1ccnc(N)c1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Solvent: CCO
Product: COC(=O)c1ccn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2c1
Yield: 46.6 %

Procedure:
A mixture of {1-[4-(2-bromo-2-phenyl-acetyl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester [Int-1-A] (4.40 g, 9.91 mmol), methyl 2-aminopyridine-4-carboxylate (3.01 g, 19.8 mmol, 2 equiv) and powdered activated 3A sieves (10 g) in ethanol (37 mL) was heated for 4 h at the reflux temperature. The resulting solution was filtered through a pad of Celite with the aid of CH2Cl2. The resulting solution was separated between CH2Cl2 (50 mL) and a saturated aqueous NaHCO3 solution 50 mL). The organic phase was washed with a saturated aqueous NaCl solution, dried (Na2SO4 anh), and concentrated under reduced pressure. The remaining material was purified using MPLC (Biotage Isolera; 100 g SNAP cartridge: 100% hexane for 1.0 min., gradient to 80% hexane/20% EtOAc over 1.0 min., 80% hexane/20% EtOAc for 2.0 min., gradient to 75% hexane/25% EtOAc over 1.0 min., 75% hexane/25% EtOAc for 2.0 min, gradient to 50% hexane/50% EtOAc over 4.0 min., 50% hexane/50% EtOAc for 5.0 min., gradient to 25% hexane/75% EtOAc over 9.5 min.) to give 2-[4-(1-tert-butoxycarbonylamino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (2.3 g, 47%):
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[N:6]=[C:7]([C:11]2[CH:12]=[N:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)[O:8][C:9]=1[CH3:10].[OH-].[Na+:29]>CO.O1CCCC1>[CH3:26][S:23]([C:20]1[CH:19]=[CH:18][C:17]([C:14]2[N:13]=[CH:12][C:11]([C:7]3[O:8][C:9]([CH3:10])=[C:5]([CH2:4][C:3]([O-:27])=[O:2])[N:6]=3)=[CH:16][CH:15]=2)=[CH:22][CH:21]=1)(=[O:24])=[O:25].[Na+:29]
Reactant: COC(=O)Cc1nc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)oc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)nc1CC(=O)[O-]

Procedure:
To a stirring solution of {2-[6-(4-Methanesulfonyl-phenyl)-pyridin-3-yl]-5-methyl-oxazol-4-yl}-acetic acid methyl ester (See Intermediate 19) (1.0 mmol) in 1:1 methanol/tetrahydrofuran (0.10M), add 2N sodium hydroxide (1.2 mmol) and heat to reflux for 1 hour. After this time, concentrate the reaction in vacuo. Wash the resulting solid twice with dichloromethane to rinse away any impurities. MS (nme): 373.3 (M+1)
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(Cl)Cl.O>CCOCC>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[O:8][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccc(-c2cc3ccccc3o2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)c2c(-c3ccccc3)oc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3.9 g.(0.02 mol.) of 2-phenylbenzofuran and 6.2 g. (0.03 mol.) of 4-methoxybenzenesulfonyl chloride in 50 ml. of methylene chloride was added 3.5 ml. (7.83 g., 0.03 mol.) of stannic chloride. The reaction mixture was stirred at ambient temperature for about 12 hours then poured into 150 ml. of water. The layers were separated and the organic phase was extracted once with 10% aqueous sodium bicarbonate solution, three times with water and once with a saturated sodium chloride solution, dried (MgSO4) and evaporated to dryness to give a residue. Ether (ca. 35 ml.) was added to the residue and it was refluxed for 1 hour then filtered. The solid collected was recrystallized from benzene-hexane then chromatographed on a silica gel "dry column" with methylene chloride as eluant to give 3-(4-methoxyphenylsulfonyl)-2-phenylbenzofuran, m.p. 146°-148°.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:36])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[C:15]3C[CH2:20][N:19]([C:22]([O:24][C:25](C)(C)[CH3:26])=[O:23])[CH2:18][C:16]=3[N:17]=2)=[CH:8][CH:7]=1)[CH3:2].ClC1N=C(N2CCOC[C@@H]2C)C2CN(C(OCC)=O)CC=2N=1.CC1(C)C(C)(C)OB(C2C=CC(NC(=O)NCC[NH:78][C:79](=[O:81])[CH3:80])=CC=2)O1>Cl[Pd]Cl.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]>[C:79]([NH:78][CH2:2][CH2:1][NH:3][C:4](=[O:36])[NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:13]=[C:14]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[C:15]3[CH2:20][N:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][C:16]=3[N:17]=2)=[CH:10][CH:11]=1)(=[O:81])[CH3:80]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OC(C)(C)C)C3)cc1
Reactant: CC(=O)NCCNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CCOC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Product: CCOC(=O)N1Cc2nc(-c3ccc(NC(=O)NCCNC(C)=O)cc3)nc(N3CCOC[C@@H]3C)c2C1
Yield: 38 %

Procedure:
Method as described for intermediate 5 using (S)-ethyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 11) and N-(2-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ureido)ethyl)acetamide as starting materials and 1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) as catalyst. The mixture was filtered through a celite 545 pre-packed cartridge (2.5 g), washed with MeOH and solvent removed in vacuo. The residue was purified by prep HPLC (high pH) yielding the title compound (30 mg, 0.05 mmol, 38%).
Reaction SMILES: [CH3:1][N:2]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C@@H:3]([C:7]([O:9][CH3:10])=[O:8])[CH:4]([CH3:6])[CH3:5].O.O.[Sn](Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]([C:17]2[CH:16]=[CH:15][C:14]([S:11]([N:2]([CH3:1])[C@@H:3]([C:7]([O:9][CH3:10])=[O:8])[CH:4]([CH3:6])[CH3:5])(=[O:13])=[O:12])=[CH:19][CH:18]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)[C@@H](C(C)C)N(C)S(=O)(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](C(C)C)N(C)S(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To 0.22 g of methyl N-methyl-N-[(4′-nitro-1,1′-biphenyl-4-yl)sulfonyl]-D-valinate in 8 mL of ethyl acetate was added 1.21 g of tin (II) chloride dihydrate and the reaction was stirred at room temperature overnight. To the reaction was added ˜8 mL of 2N sodium carbonate to adjust the pH to ˜8-9. The reaction was then filtered through celite. The filtrate washed with water and brine, dried over Na2SO4, filtered, and concentrated to provide 0.19 g of as methyl N-[(4′-amino-1,1′-biphenyl-4-yl)sulfonyl]-N-methyl-D-valinate as an oil. Yield 95%. MS:377.2 (M+H)+.