Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH3:6])[CH:4]=O)[CH3:2].[C:7]([C:11]1[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=1)[O:14][C:15]1[N:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=1[CH3:22])([CH3:10])([CH3:9])[CH3:8].[OH-].[Na+]>ClCCl>[C:7]([C:11]1[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=1)[O:14][C:15]1[N:20]=[CH:19][C:18]([N:21]=[CH:4][N:3]([CH2:1][CH3:2])[CH3:6])=[CH:17][C:16]=1[CH3:22])([CH3:10])([CH3:8])[CH3:9]
Reactant: Cc1cc(N)cnc1Oc1cccc(C(C)(C)C)c1
Reactant: CCN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCN(C)C=Nc1cnc(Oc2cccc(C(C)(C)C)c2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
In a 25 ml single-necked round-bottomed flask, ethylmethylformamide (350 mg) is solubilized in dry dichloromethane (4 ml) at ambient temperature (colourless solution). Under stirring phosphorous oxide chloride (0.4 ml) is added dropwise by syringe. Stirring at ambient temperature is continued for 0.5 hour, whereupon a pink-orange solution is obtained. To this solution, 6-(3-tert-butyl-phenoxy)-5-methyl-pyridin-3-ylamine (0.51 g) dissolved in 5.0 ml of dry dichloromethane is added dropwise by syringe, giving a yellow solution. Stirring is continued at an ambient temperature for 2 hours. The mixture is then poured into ice/water (pH=2, water phase). 2 M aqueous NaOH is then added to get a pH of about 11 and stirring is continued for 10 minutes. The mixture is then extracted with dichloromethane (2×50 ml). The combined organic phases are then dried over sodium sulfate, filtered and the solvent is removed in vacuo. Purification of this gum by flash chromatography over silica gel with ethyl acetate gives 0.56 g of the compound as a brown oil.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[S:3]([N:6]1[C:10]2[CH:11]=[C:12]([C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH2:23])(=[O:5])=[O:4].[CH:25]([Mg]Cl)([CH3:27])[CH3:26]>O1CCCC1>[CH3:1][N:2]([CH3:24])[S:3]([N:6]1[C:10]2[CH:11]=[C:12]([C:15]([CH:25]([CH3:27])[CH3:26])([OH:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH2:23])(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)n1c(N)nc2ccc(C(=O)c3ccccc3)cc21
Reactant: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)C(O)(c1ccccc1)c1ccc2nc(N)n(S(=O)(=O)N(C)C)c2c1
Yield: 65 %

Procedure:
When the procedure of Example 71 was repeated using 4.1 g. (12 mmole) of 1-dimethylaminosulfonyl-2-amino-6-benzoylbenzimidazole in 180 ml. of tetrahydrofuran, 100 ml. tetrahydrofuran, and 28.6 ml. (60 mmole) of isopropyl magnesium chloride in 100 ml. of tetrahydrofuran, there was obtained 1-dimethylaminosulfonyl-2-amino-6-(α-isopropyl-α-hydroxybenzyl)benzimidazole, yield 65%.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]=1)#[N:2].O.[CH3:13]O>ClCCl.CN(C)C1C=CN=CC=1>[CH3:13][O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[N:4][CH:5]=1
Reactant: CO
Reactant: N#Cc1ccc(C(=O)O)cn1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(C#N)nc1
Reaction time: 0.17 h

Procedure:
6-Cyanonicotinic acid (500 mg) was dissolved in dichloromethane (25 ml), water-soluble carbodiimide (776 mg), methanol (0.164 ml) and 4-dimethylaminopyridine (49 mg) were added thereto, and the mixture was stirred for 2 hr 10 min. The reaction mixture was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated, and the obtained residue was purified by column chromatography (Yamazen HI-FLASH™ COLUMN size 2 L, elution solvent: hexane/ethyl acetate) to give the title compound. The same reactions were repeated using 6-cyanonicotinic acid (547 mg) to give the title compound (total 951 mg).
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:6][N:7]([CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=1[C:30]1[CH:35]=[C:34]([CH:36]([CH3:38])[CH3:37])[CH:33]=[CH:32][C:31]=1[O:39][CH3:40])[C:8]1[N:13]=[CH:12][C:11]([C:14]([O:16]CC)=[O:15])=[CH:10][N:9]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[F:47][C:44]([F:45])([F:46])[C:42]1[CH:41]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:48])[F:49])[CH:43]=1)[CH2:6][N:7]([CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=1[C:30]1[CH:35]=[C:34]([CH:36]([CH3:37])[CH3:38])[CH:33]=[CH:32][C:31]=1[O:39][CH3:40])[C:8]1[N:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[CH:12][N:13]=1
Reactant: CCOC(=O)c1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2-c2cc(C(C)C)ccc2OC)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(C(=O)O)cn1
Temperature: 50 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
Ethyl 2-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidine-5-carboxylate (1.1 g) is dissolved in a mixed solvent of ethanol (18 ml) and tetrahydrofuran (20 ml) and thereto is added a 2M-aqueous sodium hydroxide solution (3 ml), and the mixture is stirred at 50° C. for 1 hour and a half. The reaction solution is concentrated under reduced pressure and thereto is added a 1N-hydrochloric acid and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=25:1) to give 2-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidine-5-carboxylic acid (700 mg). MS (m/z): 672 [M+H]+
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:4]=1[Cl:13].[C:14]([O-:17])(=[O:16])[CH3:15].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[C:14]([O:17][CH2:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:4]=1[Cl:13])(=[O:16])[CH3:15]
Reactant: O=[N+]([O-])c1ccc(Cl)c(CBr)c1Cl
Reactant: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)OCc1c(Cl)ccc([N+](=O)[O-])c1Cl
Yield: 50 %

Procedure:
A rapidly stirred solution of the mixture from Step A, 20.6 grams (0.21 mole) of potassium acetate and 3.0 grams of tetrabutylammonium bromide in 250 ml of acetonitrile was heated under reflux for 24 hours. The reaction mixture was cooled and filtered. The filtrate was washed with two portions of an aqueous solution saturated with sodium chloride. The organic layer was slurried with magnesium sulfate, decolorizing carbon, and 500 grams of silica gel. The mixture was filtered and the filtrate concentrated under reduced pressure to give 28.7 grams of 50% 2,6-dichloro-3-nitrophenylmethyl acetate and 50% 2,6-dichloro-3-nitrotoluene. The nmr and the ir spectra were consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:27]=1>ClCCl.C(N(CC)CC)C>[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([S:32]([N:21]2[C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=[C:17]2[S:15]([CH2:14][C:3]2[C:2]([CH3:1])=[C:7]([O:8][CH2:9][C:10]([F:13])([F:11])[F:12])[CH:6]=[CH:5][N:4]=2)=[O:16])(=[O:34])=[O:33])[CH:27]=1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reactant: O=S(=O)(Cl)c1cccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2n1S(=O)(=O)c1cccnc1
Reaction time: 5 h
Yield: 68 %

Procedure:
2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (370 mg) was dissolved in 20 ml of dichloromethane and 1 ml of triethylamine. Pyridine-3-sulfonyl chloride (195 mg) was added and stirred in ice-bath for 5 hr. Dichloromethane layer was washed with an aqueous solution composed of 0.1M NaCl and 0.1M sodium bicarbonate. Dichloromethane layer was dried over anhydrous magnesium sulfate. Solvent was removed under reduced pressure. Residual material was precipitated by dichloromethane-ethyl ether-heptane to provide 348 mg of 1-(pyridine-3-sulfonyl)-2-[(3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl)methylsulfinyl]-1H-benzimidazole.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4](Cl)[N:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1
Reactant: C1COCCN1
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc(N2CCOCC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1

Procedure:
A solution of (±)-cis-4-(-2-Amino-6-chloro-9H-purin-9-yl)-2-cyclopentene-1-methanol (0.531 g, 2.00 mmol) from Example 4 and morpholine (0.526 g, 6.04 mmol) in ethanol (6 mL) was stirred at reflux for 1 hour. The reaction mixture was allowed to cool to room temperature before the addition of 2 mL of 1.0 N NaOH. Concentration of the mixture afforded the crude product which was purified by elution from a silica gel column using 5% methanol in chloroform (0.62 g, 98%). Crystallization of such a sample from ethanol-water gave a white powder; m.p. 165-167° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)=[CH:8][C:7]([OH:18])=[CH:6][CH:5]=2.[CH2:19]([O:21][C:22](=[O:27])[C:23](Br)([CH3:25])[CH3:24])[CH3:20]>>[CH2:19]([O:21][C:22](=[O:27])[C:23]([CH3:25])([O:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2]([CH3:1])=[C:10]2[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[CH3:24])[CH3:20]
Reactant: Cc1ccc(-c2c(C)[nH]c3ccc(O)cc23)cc1
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1ccc2[nH]c(C)c(-c3ccc(C)cc3)c2c1

Procedure:
The above compound was prepared from 2-methyl-3-(4-methyl-phenyl)-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[O:11][C:12]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:13]=2[CH:14]=1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][CH2:9][C:10]1[O:11][C:12]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:13]=2[CH:14]=1
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2o1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc2oc(CBr)cc2c1
Yield: 52.3 %

Procedure:
N-Bromosuccinimide (1.1 g. 6.2 mmole) was added portionwise to a solution of 2-methyl-5-nitrobenzofuran (1.0 g, 5.6 mmole) and benzoyl peroxide (50 mg) in carbon tetrachloride (50 ml) and the reaction mixture was heated at reflux temperature for 6 hours in the presence of bright light. The reaction mixture was then cooled, filtered and the filtrate evaporated to dryness. The residue was recrystallised from petroleum ether to give the title compound yield 0.75 g, m.p. 96°-98°.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:27])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)=[CH:14][C:13]=2[Cl:26])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].[CH2:28]([OH:32])[CH2:29][C:30]#[CH:31]>>[Cl:26][C:13]1[CH:14]=[C:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH:16]=[CH:17][C:12]=1[C:10]([C:8]1[CH:9]=[C:4]([N:1]2[CH:31]=[C:30]([CH2:29][CH2:28][OH:32])[N:3]=[N:2]2)[CH:5]=[CH:6][C:7]=1[CH3:27])=[O:11]
Reactant: C#CCCO
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2cccc(Cl)c2)cc1Cl
Product: Cc1ccc(-n2cc(CCO)nn2)cc1C(=O)c1ccc(Nc2cccc(Cl)c2)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 116, using compound 462 (0.23 mmol) and but-3-yn-1-ol (0.28 mmol). The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 6:1 as the eluent to afford the title compound as light yellow foam. 13C NMR (CDCl3) δ 194.9, 147.7, 146.3, 141.4, 140.7, 138.3, 135.4, 135.3, 134.8, 133.8, 132.6, 130.7, 128.7, 123.8, 122.4, 120.9, 120.7, 120.0, 118.8, 117.1, 113.6, 61.6, 28.7, 20.0
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([NH:8][C:9](=[O:14])[C:10]2([CH3:13])[O:12][CH2:11]2)=[CH:6][C:5]=1[C:17]([F:20])([F:19])[F:18])([O-:3])=[O:2].[NH3:21]>CO>[N+:1]([C:4]1[CH:16]=[CH:15][C:7]([NH:8][C:9](=[O:14])[C:10]([OH:12])([CH3:13])[CH2:11][NH2:21])=[CH:6][C:5]=1[C:17]([F:20])([F:19])[F:18])([O-:3])=[O:2]
Reactant: CC1(C(=O)Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CO1
Reactant: N
Solvent: CO
Product: CC(O)(CN)C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: -70 °C
Reaction time: 14 h
Yield: 58 %

Procedure:
A pressure reactor was charged with 4-nitro-3-trifluoromethyl-N-[2,3-epoxy-2-methyl propionyl]aniline, BP-33, (10.0 g, 34.46 mmol) and methanol (100 mL). After cooling to −70° C., ammonia in excess was condensed into the reactor which was sealed and stirred 14 hours. Following evaporation, the crude solid was washed with cold CH2Cl2 (5 mL). Filtration and drying gave 6.1 g BP-34 (58% yield).
Reaction SMILES: [C:1]1([O:11][CH2:12][CH:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1([O:24][C:25]([O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=O)C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]1([O:11][CH2:12][CH:13]2[CH2:17][CH2:16][N:15]([C:25]([O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:24])[CH2:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)COC(=O)Oc1ccccc1
Reactant: c1ccc2c(OCC3CCNC3)cccc2c1
Solvent: Cc1ccccc1
Product: CCOC(=O)COC(=O)N1CCC(COc2cccc3ccccc23)C1
Temperature: 60 °C

Procedure:
A solution of 0.20 g (0.88 mmol) of 3-[(1-naphthalenyloxy)methyl]pyrrolidine, prepared in Step 12.2, and 0.35 g (1.5 mmol) of ethyl [(phenyloxycarbonyl)oxy]acetate, prepared in accordance with Example 1.1, in 6 ml of toluene is heated at 60° C. overnight. It is evaporated to dryness and the residue is taken up in a mixture of water, dichloromethane and saturated aqueous sodium hydrogen carbonate solution. The organic phase is decanted, dried over sodium sulfate and evaporated to dryness. The residue is purified by chromatography on a silica gel column, eluting with dichloromethane and then with a 99/1 mixture of dichloromethane and methanol. This gives 0.24 g of product in oil form, which is used as it is in the following step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][O:23]CCO)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:27]([Li])CCC.C(=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]([OH:23])[CH3:27])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(COCCO)nc3N21
Reactant: [Li]CCCC
Agent: CC=O
Solvent: C1CCOC1
Product: CC(O)c1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of (4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (Example 5, intermediate b) (2 g) in THF (24 ml) at −78° C. was added n-butyllithium (2.72 ml, 2.5 M in hexanes) dropwise. The solution was stirred at −78° C. for 45 mins and acetaldehyde (604 μl) in THF (2 ml) was added dropwise. The solution was stirred for a further 2 hours, allowed to warm to room temperature slowly and stirred for a further 4.5 hours. The reaction was quenched with aqueous ammonium chloride (20 ml), diluted with ethyl acetate and the phases separated. The organics were washed successively with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography [SiO2; isohexane-ethyl acetate (3:2)] to afford (4R,9aR)-6-(1-hydroxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (742 mg) as a yellow oil: 1H NMR (400 MHz, CDCl3) 7.16 (1H, d, J 7 Hz), 6.35 (1H, d, J 7 Hz), 4.37–4.31 (1H, br s), 4.31–4.19 (1H, br s), 4.09–3.95 (1H, m), 3.95–3.85 (1H, m), 3.13–2.94 (2H, m), 2.79–2.55 (1H, br s), 2.54 (1H, dd, J 6 and 16 Hz), 1.48 (9H, s), 1.44 (3H, d, J 6.5 Hz), 1.25 (1.5H, R epimer, d, J 6.5 Hz) and 1.24 (1.5H, S epimer, d, J 6.5 HZ); MS (ES) 334.3 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([C:16]([O:18][CH3:19])=[O:17])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.C([BH3-])#N.[Na+]>CO>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:1][CH2:2][C:3]2([C:16]([O:18][CH3:19])=[O:17])[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:7][CH2:8]2)=[CH:24][CH:23]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COC(=O)C1(CN)CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(CNCc2ccc(OC)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 45 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
Commercial available 1-tert-butyl 4-methyl 4-(aminomethyl)piperidine-1,4-dicarboxylate (10.10 mmol, 2.75 g) and 4-methoxybenzaldehyde (15.15 mmol, 2.062 g) in anhydrous MeOH (40 mL) were stirred for 2 h at rt. After addition of sodium cyanoborohydride (20.19 mmol, 1.269 g) the reaction was stirred overnight at 45° C. The mixture was evaporated in vacuo, and solved in EtOAc and sat. aq. bicarb. After separation of the organic phase, the aq. phase was extracted with EtOAc. The combined organic phase was dried over MgSO4 and evaporated in vacuo. The crude was purified by flash chromatography (heptane/EtOAc: 10 to 100%) yielding 2.3 g oil (58%). 1H NMR (400 MHz, CDCl3, 300K): δ=1.40 (2H, s), 1.45 (9H, s), 2.07 (2H, dt, J=13.3 Hz, J=3.4 Hz), 2.66 (2H, m), 2.94 (2H, m), 3.68 (2H, s), 3.70 (3H, s), 3.76 (2H, m), 3.79 (3H, s), 6.85 (2H, d, J=8.3 Hz), 7.19 (2H, d, J=8.3 Hz). 13C NMR (100 MHz, CDCl3, 300K): δ=28.8, 31.9, 47.3, 52.3, 53.9, 55.7, 57.3, 79.8, 114.0, 129.4, 132.8, 155.2, 159.0, 176.1. MS (ES) C21H32N2O5 requires: 392. found: 393.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2([C:14]1[C:22](O)=[CH:21][C:17]2[O:18][CH2:19][O:20][C:16]=2[CH:15]=1)[CH2:12][OH:13].C(P(CCCC)CCCC)CCC.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]12[C:14]2=[CH:15][C:16]3[O:20][CH2:19][O:18][C:17]=3[CH:21]=[C:22]2[O:13][CH2:12]1
Reactant: O=C1Nc2c(Br)cccc2C1(CO)c1cc2c(cc1O)OCO2
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: O=C1Nc2c(Br)cccc2C12COc1cc3c(cc12)OCO3
Temperature: 0 °C
Reaction time: 16 h
Yield: 53.7 %

Procedure:
To a suspended mixture of 7-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one (4.70 g, 12.4 mmol) in anhydrous tetrahydrofuran (120 mL) was added tributylphosphine (3.8 mL, 15.5 mmol), followed by additional of di-tert-butyl azodicarboxylate (3.58 g, 15.5 mmol) in anhydrous tetrahydrofuran (25 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h and at ambient temperature for 16 h. The reaction was quenched by addition of saturated aqueous ammonium chloride solution (150 mL) and extracted with ethyl acetate (3×200 mL). The combined organic solution was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography with ethyl acetate in hexanes (10% to 30% gradient) to give 7′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (2.4 g, 53%) as a colorless solid: mp 240° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ10.88 (s, 1H), 7.34 (dd, J=8.1, 1.0 Hz, 1H), 7.10 (d, J=7.2 Hz, 1H), 6.93 (dd, J=8.1, 7.5 Hz, 1H), 6.68 (s, 1H), 6.36 (s, 1H), 5.93 (dd, J=2.9, 0.8 Hz, 2H), 4.77 (d, J=9.4 Hz, 1H), 4.65 (d, J=9.4 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 178.1, 155.3, 148.2, 141.6, 141.1, 134.2, 131.4, 123.8, 122.8, 119.4, 103.1, 102.0, 101.3, 93.1, 79.9, 58.8; MS (ES+) m/z 360.2 (M+1), 362.2 (M+1); MS (ES−) m/z 358.2 (M−1), 360.2 (M−1).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:18]2[CH:23]=[C:22]([C:24](=O)[C:25]#[CH:26])[CH:21]=[CH:20][C:19]=2[CH3:28])[C:5]([CH3:17])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.Cl.[OH:31][C:32]([CH3:37])([CH3:36])[C:33]([NH2:35])=[NH:34].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:18]2[CH:23]=[C:22]([C:24]3[CH:25]=[CH:26][N:35]=[C:33]([C:32]([OH:31])([CH3:37])[CH3:36])[N:34]=3)[CH:21]=[CH:20][C:19]=2[CH3:28])[C:5]([CH3:17])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1
Reactant: CC(C)(O)C(=N)N
Reactant: C#CC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3)c(Cl)c2=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(-c2ccnc(C(C)(C)O)n2)cc1-n1c(C)nc(OCc2ccc(F)cc2)c(Cl)c1=O
Temperature: 75 °C
Yield: 29.3 %

Procedure:
To a solution of 5-chloro-6-(4-fluoro-benzyloxy)-2-methyl-3-(2-methyl-5-propynoyl-phenyl)-3H-pyrimidin-4-one of Step C (10 mg, 0.02 mmol) in acetonitrile (1 mL) was added 2-hydroxy-2-methylpropionamidine HCl (5 mg, 0.03 mmol) and potassium carbonate (10 mg, 0.08 mmol) and the slurry was heated at 75° C. for eighteen hours. After cooling to room temperature the reaction was filtered to remove excess salts. The filtrate was concentrated and purified via normal phase chromatography (ethyl acetate/heptane) to provide the title compound as a yellow oil (2.9 mg, 24% yield). MS (M+H): 495
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([Cl:11])[CH:3]=1.[Cl:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([Cl:20])[C:14]=1[O:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]I)=[CH:27][CH:26]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][CH2:23][CH2:22][O:21][C:14]3[C:15]([Cl:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[Cl:12])=[CH:26][CH:27]=2)[C:9]#[N:10])=[C:4]([Cl:11])[CH:3]=1
Reactant: N#CCc1ccc(Br)cc1Cl
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CI)cc2)c(Cl)c1
Product: Cc1cc(Cl)c(OCCOc2ccc(CC(C#N)c3ccc(Br)cc3Cl)cc2)c(Cl)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 1, step 4 using (4-bromo-2-chlorophenyl)acetonitrile (III.3) and 1,3-dichloro-2-{2-[4-(iodomethyl)phenoxy]ethoxy}-5-methylbenzene (II.1) as starting materials. Purification by column chromatography on silica gel, eluting with Hex/Tol (50 to 75%), afforded the desired compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:28])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])=[O:16])[C:7]2=[O:27].Cl.[O:31]=[C:32]1[CH2:36][C:35]2([CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:34][NH:33]1.C(N(CC)C(C)C)(C)C>CS(C)=O>[Cl:1][C:2]1[C:3]([N:39]2[CH2:38][CH2:37][C:35]3([CH2:34][NH:33][C:32](=[O:31])[CH2:36]3)[CH2:41][CH2:40]2)=[C:4]([F:28])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])=[O:16])[C:7]2=[O:27]
Reactant: O=C(NCc1ccc(Cl)cc1Cl)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: O=C1CC2(CCNCC2)CN1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CC2(CCN(c3c(F)cc4c(=O)c(C(=O)NCc5ccc(Cl)cc5Cl)cn(C5CC5)c4c3Cl)CC2)CN1

Procedure:
60 mg (0.13 mmol) of the compound of Example 70A and 37 mg (0.20 mmol) of 3-oxo-2,8-diazaspiro[4,5]decane hydrochloride (Example 13A) are stirred with 91 μl (0.52 mmol) of N,N-diisopropylethylamine in 2 ml of DMSO at 120° C. for 2 days. After cooling, the entire reaction mixture is separated by preparative HPLC (method 5). Concentration of the appropriate fractions on a rotary evaporator and drying under high vacuum give 20 mg (26% of theory) of the title compound.