Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][C:10]=1[CH3:17])([CH3:7])[CH3:6])[CH3:2].[CH3:19][O:20][CH2:21][CH2:22][C:23]1[C:28]([C:29](O)=[O:30])=[CH:27][N:26]=[C:25]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)[N:24]=1.COC(=O)CC(=O)CCOC>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:29]([C:28]2[C:23]([CH2:22][CH2:21][O:20][CH3:19])=[N:24][C:25]([C:32]3[CH:33]=[CH:34][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:36][CH:37]=3)=[N:26][CH:27]=2)=[O:30])=[CH:11][C:10]=1[CH3:17])([CH3:6])[CH3:7])[CH3:2]
Reactant: COCCc1nc(-c2ccc(C(F)(F)F)cc2)ncc1C(=O)O
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN)cc1C
Agent: COCCC(=O)CC(=O)OC
Product: CCOC(=O)C(C)(C)Oc1ccc(CNC(=O)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2CCOC)cc1C

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (example 97B]) was reacted with 4-(2-methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (prepared from 5-methoxy-3-oxo-pentanoic acid methyl ester, in analogy to the procedures described in examples 27C] and 27D] followed by saponification in analogy to the procedure described in example 53B]) to give 2-[4-({[4-(2-methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-methyl)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][OH:8])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[N+](C1C=CC([O:21][C:22]([N:24]2[C:33]3[C:28](=[CH:29][C:30]([C:34]([F:37])([F:36])[F:35])=[CH:31][CH:32]=3)[C@@H:27]([NH:38][C:39]3[N:44]=[CH:43][C:42]([N:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[CH:41][N:40]=3)[CH2:26][C@H:25]2[CH2:51][CH3:52])=O)=CC=1)([O-])=O.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([CH2:7][O:8][C:22]([N:24]1[C:33]2[C:28](=[CH:29][C:30]([C:34]([F:35])([F:37])[F:36])=[CH:31][CH:32]=2)[C@@H:27]([NH:38][C:39]2[N:44]=[CH:43][C:42]([N:45]3[CH2:46][CH2:47][O:48][CH2:49][CH2:50]3)=[CH:41][N:40]=2)[CH2:26][C@H:25]1[CH2:51][CH3:52])=[O:21])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CO
Reactant: CC[C@@H]1C[C@H](Nc2ncc(N3CCOCC3)cn2)c2cc(C(F)(F)F)ccc2N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC[C@@H]1C[C@H](Nc2ncc(N3CCOCC3)cn2)c2cc(C(F)(F)F)ccc2N1C(=O)OCC(=O)OC(C)(C)C
Temperature: 50 °C

Procedure:
Hydroxyacetic acid tert-butyl ester (70 mg) and sodium hydride (60%; 21 mg) were added to a solution of the compound obtained in Example 21 (1) above (200 mg) in tetrahydrofuran (3 ml) and the mixture was stirred at 50° C. for an hour. The reaction mixture was cooled to room temperature, a saturated sodium hydrogen carbonate aqueous solution and ethyl acetate were added and the organic layer was separated, washed with a saturated brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (NH-silica gel; hexane:ethyl acetate=9:1→3:2) to give the titled compound (183 mg). MS (m/z): 566 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])=[O:12]>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=[O:12])[CH:7]=1
Reactant: COc1ccccc1C(=O)CBr
Reactant: O=c1ncc(Cl)c[nH]1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccccc1C(=O)Cn1cc(Cl)cnc1=O
Yield: 30 %

Procedure:
A solution of 5-chloropyrimidin-2-one (541 mg) and 2-bromo-2'-methoxyacetophenone (954 mg) in triethylamine (1 ml) and ethanol (25 ml) was stirred at ambient temperature for 31/2 hours. After evaporation of solvents, the residue was dissolved in ethyl acetate (150 ml) and this solution was washed with water (50 ml) and brine (25 ml), dried (MgSO4) and evaporated to give a foam. This was purified by preparative thin-layer chromatography on silica, developed in chloroform, then chloroform-ethanol (25:1) before crystallisation from ethyl acetate to give the title pyrimidinone (347 mg,); m.p. 123°-125°; λmax 248.5 nm ε 12200), 317.5 nm (ε 6700), λinf 229.5 nm (ε 12440), 349 nm (ε 2640).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:21]=[N:22][C:23]([O:31][CH3:32])=[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=3)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][N:15]3S(C2C=CC=CC=2)(=O)=O)=[O:9])[N:7]=1.[CH3:42][CH:43]1[O:48][CH2:47][CH2:46][NH:45][CH2:44]1.[OH-].[Na+].Cl>CS(C)=O.CC(O)C>[CH3:42][CH:43]1[O:48][CH2:47][CH2:46][N:45]([CH2:2][C:3]2[S:4][CH:5]=[C:6]([C:8]([NH:10][C:11]3[CH:19]=[C:18]([C:20]4[CH:21]=[N:22][C:23]([O:31][CH3:32])=[C:24]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:25]=4)[CH:17]=[C:16]4[C:12]=3[CH:13]=[N:14][NH:15]4)=[O:9])[N:7]=2)[CH2:44]1
Reactant: COc1ncc(-c2cc(NC(=O)c3csc(CCl)n3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1NS(C)(=O)=O
Reactant: CC1CNCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CC(C)O
Product: COc1ncc(-c2cc(NC(=O)c3csc(CN4CCOC(C)C4)n3)c3cn[nH]c3c2)cc1NS(C)(=O)=O
Temperature: 90 °C
Reaction time: 30 h
Yield: 11.3 %

Procedure:
2-(Chloromethyl)-N-[6-{6-(methyloxy)-5-[(methylsulfonyl)amino]-3-pyridinyl}-1-(phenylsulfonyl)-1H-indazol-4-yl]-1,3-thiazole-4-carboxamide (50 mg, 0.079 mmol) was added to 2-methylmorpholine (0.5 ml, 0.079 mmol). The reaction mixture was heated in the microwave for 15 min at 90° C. The solvent was blown off under nitrogen. IPA (2 ml) and 2M NaOH (2 ml) were added to the mixture. The reaction mixture was stirred for 30 hours, then neutralised with 2M HCl aqueous to pH 7. The solvent was blown off under nitrogen. The mixture was dissolved in 2 ml of DMSO. Insoluble matter was removed by filtration and purification was carried out by MDAP (Method E) to afford the title compound (5 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:59])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:55]([CH3:58])[CH2:56][CH3:57])[C@H:25]([O:53][CH3:54])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:51][CH3:52])[C@@H:35]([CH3:50])[C:36]([NH:38][C@H:39]([C:47](O)=[O:48])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:37])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:60]([NH2:67])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1.C(N(CC)C(C)C)(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:59])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:55]([CH3:58])[CH2:56][CH3:57])[C@H:25]([O:53][CH3:54])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:51][CH3:52])[C@@H:35]([CH3:50])[C:36]([NH:38][C@@H:39]([CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:47]([NH:67][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:48])=[O:37])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:18])[CH3:19])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C
Reactant: NCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)NCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C

Procedure:
36 mg (43 μmol) of N-(tert.-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(1S)-1-carboxy-2-phenylethyl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (intermediate 39) and 4.6 mg (43 μmol) of benzyl amine were absorbed in 5 ml of DMF, mixed with 7.5 μl (88 μmol) of N,N-diisopropylethylamine, 10 mg (65 μmol) of HOBt as well as 10 mg (52 μmol) of EDC, and then stirred over night at RT. Then, the reaction composition was evaporated and the residue purified by means of preparative HPLC. This way, 29 mg (73% o. th.) of Fmoc protected intermediate of N-(tert.-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-(benzylamino)-1-oxo-3-phenylpropane-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide were obtained.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=O)[CH2:7][Cl:8])(=[O:3])[CH3:2].[NH2:10][C:11]([NH2:13])=[S:12]>C(O)C>[ClH:8].[C:1]([O:4][CH2:5][C:6]1[N:10]=[C:11]([NH2:13])[S:12][CH:7]=1)(=[O:3])[CH3:2]
Reactant: NC(N)=S
Reactant: CC(=O)OCC(=O)CCl
Solvent: CCO
Product: CC(=O)OCc1csc(N)n1
Product: Cl
Temperature: 25 °C
Yield: 51.1 %

Procedure:
A mixture of 3-chloro-2-oxopropyl acetate (5 g) and thiourea (2.5 g) in ethanol (25 ml) was refluxed for 4-hours. The reaction mixture was cooled to ambient temperature and the resulting crystalline precipitate was collected by filtration and washed with ethanol (20 ml) to give (2-amino-1,3-thiazol-4-yl)methyl acetate hydrochloride (3.5 g) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[C:11](O)(=[O:21])[C:12]1[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:14](O)=[O:15].C(OCC)C>O>[C:11]1(=[O:21])[N:1]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:4][N:3]=2)[C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12
Reactant: O=C(O)c1ccccc1C(=O)O
Reactant: Nc1n[nH]c2ccccc12
Solvent: O
Solvent: CCOCC
Product: O=C1c2ccccc2C(=O)N1c1n[nH]c2ccccc12
Temperature: 120 °C
Reaction time: 5 h
Yield: 87 %

Procedure:
5.0 g of the same 3-aminoindazole as Example 1 and 6.68 g of phthalic acid were added to 50 ml of dixoane, and the mixture was stirred for 5 hours at 120° C. The mixture was condensed under reduced pressure, 30 ml of diethyl ether was added and the mixture was stirred under cooling with ice and water for 30 minutes to separate crystals. The crystals were obtained by filtration and dried under reduced pressure to give 8.6 g of 3-phthalimidoindazole in a yield of 87%.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][CH:11]([C:15]1[O:16][C:17]2[C:22]([C:23](=[O:32])[C:24]=1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH:21][CH:20]=[C:19]([Cl:33])[CH:18]=2)[CH:12]([CH3:14])[CH3:13])(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[NH2:7][CH2:8][CH2:9][NH:10][CH:11]([C:15]1[O:16][C:17]2[C:22]([C:23](=[O:32])[C:24]=1[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[CH:21][CH:20]=[C:19]([Cl:33])[CH:18]=2)[CH:12]([CH3:13])[CH3:14]
Reactant: CC(C)C(NCCNC(=O)OC(C)(C)C)c1oc2cc(Cl)ccc2c(=O)c1Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(NCCN)c1oc2cc(Cl)ccc2c(=O)c1Cc1ccccc1
Yield: 90.9 %

Procedure:
A solution of {2-[1-(3-benzyl-7-chloro-4-oxo-4H-chromen-2-yl)-2-methyl-propylamino]-ethyl}-carbamic acid tert-butyl ester (5.7 g, 12 mmol) in 4:1 methylene chloride/trifluoroacetic acid (250 mL) was maintained at room temperature for 1.5 hours, at which time it was concentrated. The residue was dissolved in methylene chloride (200 mL), washed with 10% sodium carbonate, saturated sodium bicarbonate, and brine, dried over magnesium sulfate, and concentrated. The residue (4.2 g, 91% yield) was used without further purification.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[CH2:16][CH2:15][N:14]([CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(C)(C)C.[I-].[Na+].C(N(CC)CC)C.Cl[CH2:47][CH2:48][O:49][CH2:50][CH2:51][OH:52]>CN(C)C=O>[OH:52][CH2:51][CH2:50][O:49][CH2:48][CH2:47][N:11]1[CH2:10][CH2:9][N:8]([CH2:7][C:6]([OH:36])=[O:5])[CH2:19][CH2:18][N:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:16][CH2:15][N:14]([CH2:28][C:29]([OH:31])=[O:30])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Reactant: OCCOCCCl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)CN1CCN(CCOCCO)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1,4,7,10-Tetraazacyclododecane-4,7,10-triacetic acid tri-t-butyl-ester (515 mg, 1 mmol) was dissolved in dimethylformamide (3 ml). Sodium iodide (15 mg, 0.1 mmol), triethylamine (233 mg, 2.5 mmol) and 2(2-chloroethoxy)ethanol (313 mg, 3.5 mmol) were added to the stirred mixture at ambient temperature. The mixture was stirred for 18 hours at ambient temperature. The temperature was then raised to 100° C. and kept there for 1 hour. The solvent was then evaporated and the residue dissolved in a mixture of dichloromethane (4.5 ml) and trifluoroacetic acid (4.5 ml). The mixture was stirred for 2 hours at ambient temperature and the solvent was then evaporated. The residue was dissolved in water (8 ml), and this aqueous solution was washed with ether (6-4 ml). The aqueous solution was acidified and the title compound was isolated as a hygroscopic white powder after evaporation of the water. Yield 325 mg (75%), FAB MS: 435(M+1). The structure was confirmed by 1HNMR and 13C NMR.
Reaction SMILES: C([Cl:4])(=O)C.[C:5]([N:13]1[CH2:18][CH2:17][O:16][C:15]([CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][C:32]([NH:41]C(=O)OC(C)(C)C)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:31][CH2:30]2)([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)[CH2:14]1)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CO>[ClH:4].[ClH:4].[NH2:41][C:32]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:31][CH2:30][N:29]([CH2:28][CH2:27][C:15]2([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=3)[O:16][CH2:17][CH2:18][N:13]([C:5]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)=[O:12])[CH2:14]2)[CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccccc2)CCN(CCC2(c3ccc(F)c(F)c3)CN(C(=O)c3ccccc3)CCO2)CC1
Reactant: CC(=O)Cl
Solvent: CO
Product: Cl
Product: NC1(c2ccccc2)CCN(CCC2(c3ccc(F)c(F)c3)CN(C(=O)c3ccccc3)CCO2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
250 ml of methanol are cooled to −10° C., 25 ml of acetyl chloride are added rapidly and the solution is allowed to return to room temperature. The compound of formula (V) obtained in Example 2 is then added and is left stirring overnight at room temperature. The solvent is concentrated under vacuum at room temperature, the residue is taken up in 100 ml of methanol and the solvent is concentrated again under vacuum. The residue is taken up in 100 ml of ethyl acetate and the solvent is concentrated under vacuum, and this operation is repeated entirely three times. The residue is taken up in 150 ml of ethyl acetate and left stirring for two hours at room temperature, and the precipitate formed is spin-filtered off, washed with ethyl acetate and dried under vacuum. 32.4 g of the expected product are obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]([CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]([CH3:29])([OH:28])[CH3:27])[CH2:21][CH2:20]1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH3:31]>O1CCCC1.CN(C)C=O>[CH2:3]([N:10]([CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]([O:28][CH3:31])([CH3:29])[CH3:27])[CH2:21][CH2:20]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(O)CN1CCC(CN(Cc2ccccc2)Cc2ccccc2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(C)(C)CN1CCC(CN(Cc2ccccc2)Cc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 24.4 %

Procedure:
To a suspension of sodium hydride (abt. 60% in mineral oil, 342 mg, 8.6 mmol) in a mixture of tetrahydrofuran (20 mL) and N,N-dimethylformamide (10 mL) was added a solution of 1-{4-[(dibenzylamino)methyl]piperidin-1-yl}-2-methylpropan-2-ol (EXAMPLE 4, Step 4, 3.0 g, 8.2 mmol) in tetrahydrofuran (20 ml) at 0° C. Afer being stirred at the same temperature for 30 min, 0.53 mL (8.6 mmol) of iodomethane was added to the mixture. The mixture was stirred at ambient temperature for 3 days. The mixture was partitioned between ethyl acetate and water. After extraction with ethyl acetate, the combined organic phase was dried over magnesium sulfate, and concentrated. The residue was purified by flash column chromatography on amine gel eluting with hexane/ethyl acetate (100:1) to afford 0.76 g (24%) of the title compound as colorless amorphous.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])/[CH:4]=[CH:5]/[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[NH:8][CH:7]=1.[H][H]>[Pd].C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[NH:8][CH:7]=1
Reactant: [H][H]
Reactant: COC(=O)/C=C/c1c[nH]c2ccc(Cl)cc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCc1c[nH]c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a flask, (E)-3-(5-chloro-1H-indol-3-yl)-acrylic acid methyl ester (8, 3.4 g, 0.014 mol) and 10% palladium on carbon were combined and 140 mL of ethyl acetate was added. Vacuum was applied and the flask was back filled with hydrogen, repeated application of vacuum and hydrogen back fill for total of three times. The reaction was capped with a hydrogen filled balloon and the reaction stirred overnight at room temperature. TLC (20% ethyl acetatethexane) indicated absence of starting material and a major new spot. The reaction was filtered through celite and the filter rinsed generously with a total of 250 mL of ethyl acetate. The yellow filtrate solution was roto-evaporated to near dryness, silica was added, and the solvent fully removed. Column chromatography was performed, eluting with 2 to 30% ethyl acetate/hexane, then flushing with 40% ethyl acetate/hexane to provide the desired compound. 1H NMR consistent with structure.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:27]2[CH2:32][CH2:31][C:30]([CH3:34])([CH3:33])[CH2:29][CH2:28]2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[CH3:35][S:36](Cl)(=[O:38])=[O:37].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:27]2[CH2:28][CH2:29][C:30]([CH3:33])([CH3:34])[CH2:31][CH2:32]2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@@H:23]([O:26][S:36]([CH3:35])(=[O:38])=[O:37])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]1)=[O:12])=[O:4]
Reactant: COC(=O)c1sc(C2CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@@H](O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1sc(C2CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@@H](OS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-(4,4-Dimethyl-cyclohexyl)-3-[(cis-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (2.25 g, 4.60 mmol) in 23 ml of CH2Cl2 was added at 0° C. methanesulfonyl chloride (1.05 g, 9.20 mmol) followed by triethylamine (1.28 ml, 9.20 mmol). The reaction mixture was stirred at room temperature for 24 h and treated with water. The aqueous layer was extracted with ethyl acetate and the organic layer was washed with water and brine. The organic layer was dried with sodium sulfate, filtered and concentrated under reduce pressure to give 5-(4,4-Dimethyl-cyclohexyl)-3-[(cis-4-methanesulfonyloxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (2.56 g, 98%)
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:9][C@@H:10]2[CH2:14][C@H:13]([CH2:15][OH:16])[C@@H:12]([OH:17])[C@H:11]2[OH:18])=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].[CH:19]([O-])([O-])[O:20][CH2:21][CH3:22].[C:25]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>>[Cl:8][C:7]1[N:6]=[CH:5][N:4]=[C:3]2[C:2]=1[N:1]=[CH:25][N:9]2[C@H:10]1[C@@H:11]2[O:18][CH:19]([O:20][CH2:21][CH3:22])[O:17][C@@H:12]2[C@@H:13]([CH2:15][OH:16])[CH2:14]1
Reactant: CCOC([O-])[O-]
Reactant: Nc1c(Cl)ncnc1N[C@@H]1C[C@H](CO)[C@@H](O)[C@H]1O
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Product: CCOC1O[C@@H]2[C@@H](CO)C[C@@H](n3cnc4c(Cl)ncnc43)[C@@H]2O1
Reaction time: 5 h

Procedure:
The above crude (1R,2S,3R,5R)-3-((5-amino-6-chloropyrimidin-4-yl)amino)-5-(hydroxymethyl)cyclopentane-1,2-diol was treated with ethyl orthoformate (120 mL, 720 mmol) and 10-camphorsulfonic acid (8.11 g, 34.9 mmol). The heterogeneous brown mixture was stirred vigorously to afford a nearly homogeneous brown solution after 10 min. At 5 h, LC MS indicated the desired product as the major product and the reaction was quenched with saturated aqueous NaHCO3 (120 mL). The mixture was diluted with water (75 mL), extracted with CH2Cl2 (3×200 mL), and the combined organics were dried (Na2SO4) and concentrated in vacuo to afford the crude title compound as a dark brown liquid, which was carried on without further manipulation: MS (ESI+) for C14H17ClN4O4 m/z 341.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[N:10][N:9]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([CH2:20][C:21]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[CH2:27][CH2:28]2)=[O:22])[N:11]=[N:10][N:9]=1
Reactant: O=C(CCl)N1CCN(c2ccc(Cl)cc2)CC1
Reactant: Brc1ccccc1-c1nnn[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Cn1nnnc1-c1ccccc1Br)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-(2-Bromo-phenyl)-1H-tetrazole (0.374 g, 1.66 mmol) was taken in dry DMF (15 mL) and dry potassium carbonate (800 mg) and KI (20 mg) was added to it and stirred at rt for 1 h under nitrogen. 2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone (500 mg, 1.8 mmol) in DMF (5 mL) was then added to the mixture through a syringe. The reaction was then heated at 140° C. for 14 h, cooled and quenched with water and extracted with ethyl acetate. Drying of the organic layer with Na2SO4 followed by concentration afforded material that was further purified by flash column chromatography (ethyl acetate/pet ether): 1H NMR (300 MHz, CDCl3): δ 7.90 (d, 1H), 7.74 (d, 1H), 7.45 (t, 1H), 7.35 (t, 1H), 7.25 (d, 2H), 6.87 (d, 2H), 5.65 (s, 2H), 3.84 (m, 2H), 3.73 (m, 2H), 3.20 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].I[C:20]1[CH:30]=[CH:29][C:23]2[CH2:24][CH2:25][S:26](=[O:28])(=[O:27])[C:22]=2[CH:21]=1>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:30]=[CH:29][C:23]2[CH2:24][CH2:25][S:26](=[O:28])(=[O:27])[C:22]=2[CH:21]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: O=S1(=O)CCc2ccc(I)cc21
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1ccc2c(c1)S(=O)(=O)CC2

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 6-iodo-2,3-dihydro-1-benzothiophene 1,1-dioxide (Intermediate 234), the title compound was obtained as a beige solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.