Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH3:9][C:10]([CH3:22])([CH3:21])[C:11](=[O:20])[CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1.O>CS(C)=O>[C:10]([C:11]1([CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH2:4][O:20]1)([CH3:22])([CH3:21])[CH3:9]
Reactant: C[S+](C)(C)=O
Reactant: CC(C)(C)C(=O)COC1CCCCO1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)C1(COC2CCCCO2)CO1
Temperature: 10 °C
Yield: 93.1 %

Procedure:
880 ml of absolute dimethylsulphoxide are added dropwise to a mixture of 38.2 g (1.27 mols) of sodium hydride (80% strength) and 271.5 g (1.23 mols) tri-methyl-oxosulphonium iodide at 10° C. under a nitrogen atmosphere, with stirring. The mixture is subsequently stirred for a further hour at room temperature and is then cooled to 10° C., and a solution of 219 g (1.1 mols) of 3,3-dimethyl-1-(tetrahydro-2H-pyran-2-yloxy)-butan-2-one in 250 ml of absolute dimethylsulphoxide is added dropwise at this temperature. The reaction mixture is stirred at room temperature for 48 hours and then poured into water. The mixture is extracted with ethyl acetate and the combined organic phases are washed with water, dried over sodium sulphate and concentrated by stripping off the diluent under reduced pressure. 219.4 g (94% of theory) of 2-tert.-butyl-2-(tetrahydro-2H-pyran-2-yloxymethyl) oxirane are obtained in this manner.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9])[CH:3]=1.[N:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.CCO.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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.C(Cl)Cl>[F:12][C:11]([F:14])([F:13])[S:8]([C:4]1[CH:3]=[C:2]([C:18]2[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][CH:5]=1)(=[O:10])=[O:9]
Reactant: OB(O)c1ccncc1
Reactant: O=S(=O)(c1cccc(Br)c1)C(F)(F)F
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: CCO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=S(=O)(c1cccc(-c2ccncc2)c1)C(F)(F)F
Temperature: 90 °C

Procedure:
1-Bromo-3-trifluoromethylsulfonyl benzene (580 mg) and 4-pyridine-boronic acid (275 mg) was dissolved in toluene (5 ml) and abs EtOH (5 ml). To the mixture was then added Na2CO3 (424 mg) and Pd(PPh3)4 (119 mg) under an atmosphere of Argon. The resulting mixture was heated to 90° C. for 18 h. Then CH2Cl2 was added and the organic phase was washed with water and dried (MgSO4), filtered and evaporated to dryness. The residue was then used without any further purification. (MS m/z (rel. intensity, 70 eV) 287 (M+, 33), 218 (22), 154 (bp), 127 (56), 69 (27).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][C:13]1[NH:14][C:15]2[C:20]([C:21]=1[CH:22]=O)=[CH:19][CH:18]=[CH:17][CH:16]=2.Cl>C(O)C>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:22]/[C:21]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[NH:14][C:13]=3[CH3:12])/[O:8][C:4]=2[CH:3]=1
Reactant: O=C1COc2cc(O)ccc21
Reactant: Cc1[nH]c2ccccc2c1C=O
Agent: Cl
Solvent: CCO
Product: Cc1[nH]c2ccccc2c1/C=C1\Oc2cc(O)ccc2C1=O
Temperature: 75 °C
Reaction time: 2 h
Yield: 114.4 %

Procedure:
A solution of 6-hydroxybenzofuran-3(2H)-one (0.50 g, 3.3 mmol) and 2-methyl-1H-indole-3-carboxaldehyde (0.58 g, 3.6 mmol) in ethanol (10 mL) was added with concentrated hydrochloric acid (1.0 mL), and the mixture was stirred at 75° C. for 2 hours. The reaction mixture was cooled to room temperature, and then the solid was collected by filtration, and washed with methanol to obtain (Z)-6-hydroxy-2-[(2-methyl-1H-indol-3-yl)methylene]benzofuran-3(2H)-one (1.1 g, 95%).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[C:4](C)[CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]([F:28])[C:23]([C:26]#[CH:27])=[N:24][CH:25]=2)=[CH:16][CH:15]=1.C(N(CC)CC)C.CCOC(C)=O>C1COCC1.[Cu]I>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]([F:28])[C:23]([C:26]#[C:27][C:2]3[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:10][CH:11]=3)=[N:24][CH:25]=2)=[CH:16][CH:15]=1
Reactant: C#Cc1ncc(-c2ccc(Cl)cc2)cc1F
Reactant: Cc1cc(I)ccc1OCCO
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: OCCOc1ccc(C#Cc2ncc(-c3ccc(Cl)cc3)cc2F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Under an argon atmosphere 14.8 mg (0.078 mmol) of CuI was added to a solution of 0.82 g (3.11 mmol) of 2-(4-iodo-2-methylphenoxy)ethanol, 0.72 g (2.11 mmol) of 5-(4-chlorophenyl)-2-ethynyl-3-fluoropyridine, 57 mg (0.078 mmol) of [1,1′-bis(diphenylphosphine)ferrocene]palladium (II) chloride, and 0.86 mL (6.22 mmol) of triethylamine in 20 mL of THF and the mixture was stirred for 16 hours at RT. The reaction mixture was combined with EtOAc, and the precipitate was filtered off and washed with EtOAc. The filtrate and the organic washing solutions were washed with 5% aqueous ammonia and water, dried over magnesium sulfate and evaporated down in vacuo. The crude product was purified by column chromatography (silica gel, PE/EtOAc 1:1). Yield: 0.20 g (18% of theoretical); C21H15ClFNO2 (M=367.800); calc.: molpeak (M+H)+: 368/370 (Cl); found: molpeak (M+H)+: 368/370 (Cl); HPLC-MS: 5.94 minutes (method B).
Reaction SMILES: [CH:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[C:9]([F:17])[CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[C:5]=1[F:18])=[CH:2][CH3:3].C(O)C>[C].[Pd].C1(C)C=CC=CC=1>[CH2:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[C:9]([F:17])[CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[C:5]=1[F:18])[CH2:2][CH3:3]
Reactant: CC=Cc1ccc2c(c1F)Cc1c(F)cccc1-2
Agent: [Pd]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCc1ccc2c(c1F)Cc1c(F)cccc1-2
Reaction time: 8 h
Yield: 43.7 %

Procedure:
A mixture of 19.3 g of 2-(propen-1-yl)-1,8-difluorofluorene (K-3) (crude product), 1.5 g of 5% palladium-carbon, 80 ml of ethanol and 80 ml of toluene was hydrogenated over an 8 hour period at room temperature and under atmospheric pressure, with constant stirring. The palladium-carbon was removed by filtration, the solvent was removed from the filtrate by evaporation under reduced pressure, and the residue was then purified by silica gel column chromatography (hexane) to yield 8.5 g of 2-propyl-1,8-difluorofluorene (K-4).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:25](O)[C:26]1[O:30][CH:29]=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[O:30]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH2:25][N:20]1[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=[C:16]1[C:14]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:15]
Reactant: OCc1ccco1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3[nH]2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(c1nc2ccccc2n1Cc1ccco1)C1CCNCC1
Reaction time: 18 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazole-2-carbonyl)piperidine (1.16 mmol), furfuryl alcohol (0.10 mL, 1.16 mmol), and triphenylphosphine (0.33 g, 1.28 mmol) in tetrahydrofuran (5 mL). Add diethyl azodicarboxylate (0.20 mL, 1.28 mmol). After 18 hours, evaporate the reaction mixture in vacuo to give a residue. Partition the residue between ethyl acetate and water. Separate the organic layer and extract with water and saturated aqueous sodium chloride solution. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound. Chromatograph the residue on silica gel eluting with 5% acetone/dichloromethane to give 1-(t-butoxycarbonyl)-4-(1-(fur-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine. Cool 1-(t-butoxycarbonyl)-4-(1-(fur-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine (1.0 mmol), and dichloromethane (5 mL). Slowly add a cold solution of trifluoroacetic acid (1 mmol) in dichloromethane (2 mL). After 15 minutes, partition the reaction mixture between dichloromethane and saturated aqueous sodium bicarbonate solution. Separate the organic layer and extract with brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [F:1][CH:2]([F:19])[CH2:3][O:4][C:5]1[C:10]([C:11]2([F:15])[CH2:14][CH2:13][CH2:12]2)=[CH:9][N:8]=[C:7]([C:16]([OH:18])=O)[CH:6]=1.[NH2:20][C:21]1([CH2:27][C:28]([NH2:30])=[O:29])[CH2:24][S:23](=[O:26])(=[O:25])[CH2:22]1>>[NH2:30][C:28](=[O:29])[CH2:27][C:21]1([NH:20][C:16]([C:7]2[CH:6]=[C:5]([O:4][CH2:3][CH:2]([F:1])[F:19])[C:10]([C:11]3([F:15])[CH2:12][CH2:13][CH2:14]3)=[CH:9][N:8]=2)=[O:18])[CH2:22][S:23](=[O:25])(=[O:26])[CH2:24]1
Reactant: O=C(O)c1cc(OCC(F)F)c(C2(F)CCC2)cn1
Reactant: NC(=O)CC1(N)CS(=O)(=O)C1
Product: NC(=O)CC1(NC(=O)c2cc(OCC(F)F)c(C3(F)CCC3)cn2)CS(=O)(=O)C1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 4-(2,2-difluoroethoxy)-5-(1-fluorocyclobutyl)pyridine-2-carboxylic acid (example 308b) and 2-(3-amino-1,1-dioxo-thietan-3-yl)acetamide (example 160d) as starting materials and isolated (11.5 mg, 14%); MS (ESI, m/z): 436.3 (M+H+).
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]3([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].Cl[CH2:31][C:32]1N=CO[N:33]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:32]([CH2:31][N:27]1[CH2:28][CH2:29][C:22]2([S:21][C:20]([C:17]3[NH:18][C:19]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:2]([CH3:1])[S:3]([C:6]3[S:7][CH:8]=[CH:9][CH:10]=3)(=[O:4])=[O:5])=[N:24][CH2:23]2)[CH2:25][CH2:26]1)#[N:33]
Reactant: ClCc1ncon1
Reactant: CN(c1cccc2cc(C3=NCC4(CCNCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1cccc2cc(C3=NCC4(CCN(CC#N)CC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 50 °C
Reaction time: 16 h
Yield: 50.6 %

Procedure:
A mixture of N-Methyl-N-[2-(1-thia-3,8-diazaspiro[4.5]dec-2-en-2-yl)-1H-indol-7-yl]thiophene-2-sulfonamide (100 mg), 3-(chloromethyl)-1,2,4-oxadiazole (35 mg), potassium carbonate (44 mg) and N,N-dimethylformamide (5 mL) was stirred at 50° C. for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was purified by preparative HPLC to give the title compound (55 mg, yield 47%) as white crystals. melting point 211° C.
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[CH2:16][NH:17][C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][N:22]2[C@H:27]1[C@H:31]([OH:32])[C@H:30]([N:33]=[N+:34]=[N-:35])[C@@H:29]([C:36](=[O:39])[NH:37][CH3:38])[O:28]1)(C)(C)C.FC(F)(F)C(O)=O>>[N:33]([C@@H:30]1[C@@H:29]([C:36](=[O:39])[NH:37][CH3:38])[O:28][C@@H:27]([N:22]2[CH:21]=[N:20][C:19]3[C:23]2=[N:24][CH:25]=[N:26][C:18]=3[NH:17][CH2:16][C:10]2[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]([OH:40])=[O:5])[C@@H:31]1[OH:32])=[N+:34]=[N-:35]
Reactant: CNC(=O)[C@H]1O[C@@H](n2cnc3c(NCc4cc(Cl)ccc4OCC(=O)OC(C)(C)C)ncnc32)[C@H](O)[C@@H]1N=[N+]=[N-]
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@H]1O[C@@H](n2cnc3c(NCc4cc(Cl)ccc4OCC(=O)O)ncnc32)[C@H](O)[C@@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(2R,3R,4S,5S)(2-{[9-(4-Azido-3-hydroxy-5-methylcarbamoyl-tetrahydro-furan-2-yl)-9H-purin-6-ylamino]-methyl}-4-chloro-phenoxy)-acetic acid tert-butyl ester (1 g, 1.9 mmol) was added to trifluoroacetic acid (15 mL) and stirred at room temperature for 3 hours. The mixture was concentrated and the residue was reconcentrated from chloroform three times to afford the title compound as a foam. M.S. 518 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 8.5 (m, 2H); 7.38 (bs, 1H); 7.25 (d, 1H, J=8.0 Hz); 6.95 (d, 1H, J=8.0 Hz); 6.0 (d, 1H, J=4.0 Hz); 5.0 (m, 1H); 4.85 (m, 2H); 4.75 (s, 2H); 4.4 (m, 2H); 2.8 (s, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:22][CH2:23]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=O)C.[Cl-].C[Al+]C.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH2:38][CH2:39][NH2:40])[CH:35]=[CH:36][CH:37]=1>C1(C)C=CC=CC=1>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:3])[N:40]([CH2:39][CH2:38][C:34]3[CH:35]=[CH:36][CH:37]=[C:32]([O:31][CH3:30])[CH:33]=3)[CH2:23][CH2:22]2)[CH2:11][CH2:10]1)(=[O:14])=[O:13]
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Reactant: COc1cccc(CCN)c1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: COc1cccc(CCN2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)c1

Procedure:
This material was prepared in analogy to example 1 step D) from 1-(2-chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester, dimethylaluminium chloride in toluene and 2-(3-Methoxy-phenyl)-ethylamine. MS (ESI): 463.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([NH:29][CH2:30][C:31](O)=[O:32])=[O:28])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][CH:44]([CH2:47][NH2:48])[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]>>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][CH:44]([CH2:47][NH:48][C:31](=[O:32])[CH2:30][NH:29][C:27](=[O:28])[CH2:26][CH:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]2[S:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)(=[O:10])=[O:11])[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=C(O)CNC(=O)CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)CNC(=O)CC2c3ccccc3-c3ccccc3N2S(=O)(=O)c2ccc(Cl)c(Cl)c2)CC1

Procedure:
The title compound was prepared from {2-[5-(3,4-dichloro-benzenesulfonyl)-5,6-dihydro-phenanthridin-6-yl]-acetylamino}-acetic acid and 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester according to the method described in Example 1e.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].[Na].[OH-].[Ca+2:16].[OH-].[C:18]([OH:30])(=[O:29])[CH2:19][C:20]([CH2:25][C:26]([OH:28])=[O:27])([C:22]([OH:24])=[O:23])[OH:21].[Na]>O>[C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4].[Ca+2:16].[C:18]([O-:30])(=[O:29])[CH2:19][C:20]([CH2:25][C:26]([O-:28])=[O:27])([C:22]([O-:24])=[O:23])[OH:21].[Ca+2:16].[Ca+2:16]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Ca+2]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Temperature: 25 °C

Procedure:
To produce this product, 1920 g. of anhydrous citric acid was dissolved in 6000 ml. water. Sodium caseinate (143 g.) (Alanate 155, New Zealand Milk Products) was dissolved in 1500 ml. hot water; this solution was then cooled to room temperature and mixed with the citric acid solution. A slurry of 1110 g. of calcium hydroxide in 1870 ml water was added quickly with stirring to the citric acid-sodium caseinate solution. Within two minutes of mixing, the temperature of the mixture increased from 70° F. to 150° F. A coarse caseinate-coated calcium citrate suspension was obtained that was continually stirred for about 45 minutes. During this period, the temperature dropped to 100° F. The suspension was homogenized for 10 minutes using a Ross laboratory homogenizer followed by one pass through the Dyno-Mill as in Example 2. The homogenization step facilitated the even pumping of the suspension through the Micromill.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:31])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[N:9]=3)[CH2:2]1.Cl[C:33]([C:35]([O:38][C:39](=[O:41])[CH3:40])([CH3:37])[CH3:36])=[O:34].CCN(CC)CC>C1COCC1>[CH3:36][C:35]([O:38][C:39](=[O:41])[CH3:40])([CH3:37])[C:33]([N:1]1[CH2:2][CH:3]([CH2:5][C:6]2[N:7]([CH3:31])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[N:9]=3)[CH2:4]1)=[O:34]
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OC(C)(C)C(=O)N1CC(Cc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.8 %

Procedure:
A mixture of 8-azetidin-3-ylmethyl-2-(2-methylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (131 mg, 0.31 mmol), acetic acid 1-chlorocarbonyl-1-methylethyl ester (45 μL, 0.31 mmol) and NEt3 (40 μL, 0.31 mmol) in THF (3 mL) was allowed to stir at r.t. for 16 h then concentrated in vacuo. The resulting residue was partitioned between DCM and H2O, the organic phase dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-10%) affording the title compound as a white solid (125 mg, 73%). LCMS (method H): RT 2.50 min [M+H]+ 547.5
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12](=[CH2:31])[O:11][C@H:10]1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH3:48])=[CH:42][CH:41]=2)[CH:33]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:49]CCCCC.ICI>C(OCC)C.C([Zn]CC)C.O.C(=O)(O)[O-].[Na+]>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]2([CH2:49][CH2:31]2)[O:11][C@H:10]1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH3:48])=[CH:42][CH:41]=2)[CH:33]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCC
Reactant: C=C1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCC)cc3)c2)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: CC[Zn]CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ICI
Solvent: O
Product: CCOc1ccc(Cc2cc([C@@H]3OC4(CC4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
To a solution of (2S,3S,4R,5S)-3,4,5-tris-benzyloxy-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-methylene-tetrahydro-pyran (150 mg, 0.22 mmole) in dry diethyl ether (3 mL), 1.0M diethylzinc in hexane (1.2 mL, 1.2 mmole), diiodomethane (0.1 mL, 1.2 mmole) was added at room temperature and stirred at 40° C. in sealed vessel for 8 hours. The reaction mixture was diluted with water (20 mL) and saturated aqueous sodium bicarbonate (3 ml) and extracted with DCM (2×30 mL). The crude product was purified by silica gel column chromatography (2% ethyl acetate in hexane) to furnish 105 mg of (5S,6S,7R,8S)-6,7,8-tris-benzyloxy-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-4-oxa-spiro[2.5]octane.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][CH2:10]2)=[CH:6][C:5]=1[NH2:13])([O-])=[O:2].[N:14]#[C:15][NH2:16].[CH]Cl.[OH-].[Na+]>O.CCOCC>[N+:1]1([O-:2])[C:4]2[CH:12]=[C:11]3[C:7](=[CH:6][C:5]=2[N:13]=[C:15]([NH2:16])[N:14]=1)[CH2:8][CH2:9][CH2:10]3
Reactant: N#CN
Reactant: Nc1cc2c(cc1[N+](=O)[O-])CCC2
Agent: [CH]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: Nc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Temperature: 50 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
A mixture of amine 2 (21.67 g, 121.6 mmol), cyanamide (20.45 g, 486 mmol) and Et2O (10 mL) were mixed together at 80° C., cooled to ca. 50° C., cHCl (20 mL) added dropwise, during which a vigorous reaction occurred, and the mixture was heated at 80° C. for 1 h. The mixture was cooled to 50° C., 7.5 M NaOH solution added until the mixture was strongly basic and the mixture stirred at 100° C. for 8 h. The mixture was cooled, diluted with water (500 mL), and the yellow/green precipitate filtered. The precipitate was washed with water (3×50 mL), washed with ether (3×30 mL) and dried to give crude material (20.93 g, 85%), which can be used without further purification. The material was purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give 1-oxide 19 (16.72 g, 68%) as a yellow powder: mp (MeOH/DCM) 270-272° C.; 1H NMR [(CD3)2SO] δ 7.92 (s, 1H, H-9), 7.33 (s, 1 H, H-5), 7.11 (br s, 2H, NH2), 2.91-2.99 (m, 4H, H-6, H-8), 2.01-2.09 (m, 2H, H-7); 13C NMR [(CD3)2SO] δ 159.9, 154.0, 148.5, 142.5, 128.7, 119.8, 113.8, 32.4, 31.6, 25.2. Anal. calcd for C10H10N4O: C, 59.4; H, 5.0; N, 27.7. Found: C, 59.4; H, 5.1; N, 27.8%.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]1=[O:17].[H-].[Na+].[F:20]N(CC(C)(C)C)S(C1C=CC(C)=CC=1)(=O)=O.Cl>C1COCC1.ClCCl>[F:20][C:2]1([CH3:1])[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]1=[O:17]
Reactant: CC1C(=O)N(c2ccccc2)c2ncccc21
Reactant: Cc1ccc(S(=O)(=O)N(F)CC(C)(C)C)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC1(F)C(=O)N(c2ccccc2)c2ncccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add 1,3-dihydro-3-methyl-1-phenyl-2H-pyrrolo[2,3-b]-pyridin-2-one (H) (3.0 g, 0.013 mole) portionwise to sodium hydride (0.63 g of 60% NaH in oil, 0.015 mole, washed with hexane) in dry THF (35 mL) at 10° C. under a N2 atmosphere. Stir for 30 minutes at room temperature, and then recool to 10° C. Add N-fluoro-N-neopentyl-p-toluenesulfonamide (4.1 g, 0.015 mole) in dry THF (30 mL) dropwise over 10 minutes. Warm reaction mixture up to room temperature slowly, and stir for 16 hours. Pour onto ice/water (100 mL), and neutralize to pH=4 to 5 with 15% aqueous HCl. Separate layers. Dry organic solution with MgSO4, filter, and rotoevaporate to give an oil. Dissolve the oil in dichloromethane, and chromatograph on silica gel, eluting with 30% ethyl acetate-hexane. Combine the appropriate fractions, and concentrate under reduced pressure. Triturate with isopropyl ether-petroleum ether and filter to give the title compound AA as a white solid (1.1 g, m.p. 83°-85° C.).
Reaction SMILES: Br[C:2]1[C:3]([N:7]2[C:15]3[CH:14]=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=3[C:9]3[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]2=3)=[CH:4][S:5][CH:6]=1.N1C=CC(B(O)O)=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.O>[Cl:16][C:12]1[CH:13]=[CH:14][C:15]2[N:7]([C:3]3[CH:2]=[CH:6][S:5][CH:4]=3)[C:8]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][C:9]=3[C:10]=2[CH:11]=1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2-c2cscc2Br)C1
Agent: O=P([O-])([O-])[O-]
Agent: OB(O)c1ccncc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2-c2ccsc2)C1
Temperature: 95 °C
Yield: 43.9 %

Procedure:
To a de-aerated solution of 5-(4-bromo-thiophen-3-yl)-8-chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.263 mmol), 4-pyridinylboronic acid (48.5 mg, 0.394 mmol) and K3PO4 (139.39 mg, 0.657 mmol) in DMF-water (2:0.2 mL) was added dichlorobis(triphenylphosphine) palladium (II) (9.23 mg, 5 mol %). The reaction mixture was heated at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 8-chloro-2-methyl-5-thiophen-3-yl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (35 mg). 1H NMR (TFA salt, CD3OD) d (ppm): 7.7 (dd, 1H), 7.58 (m, 2H), 7.2 (m, 3H), 4.76 (d, 1H), 4.4 (d, 1H), 3.8 (m, 1H), 3.6 (m, 1H), 3.2 (m, 4H), 3.0 (m, 1H).