Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:14]=2)[N:5]=[C:4]([NH:24][C:25]2[NH:29][N:28]=[C:27]([CH3:30])[CH:26]=2)[CH:3]=1.[C:31]([O:35][C:36]([N:38]1[CH2:41][C:40]2([CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>O1CCOCC1>[C:31]([O:35][C:36]([N:38]1[CH2:41][C:40]2([CH2:46][CH2:45][N:44]([C:2]3[N:7]=[C:6]([N:8]4[CH2:12][CH2:11][CH2:10][CH:9]4[C:13]4[O:17][N:16]=[C:15]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=5)[CH:14]=4)[N:5]=[C:4]([NH:24][C:25]4[CH:26]=[C:27]([CH3:30])[NH:28][N:29]=4)[CH:3]=3)[CH2:43][CH2:42]2)[CH2:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CC2(CCNCC2)C1
Reactant: Cc1cc(Nc2cc(Cl)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)[nH]n1
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(N3CCC4(CC3)CN(C(=O)OC(C)(C)C)C4)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Temperature: 160 °C
Yield: 54.8 %

Procedure:
A mixture of 6-chloro-N-(3-methyl-1H-pyrazol-5-yl)-2-[2-(3-pyridin-2-ylisoxazol-5-yl)pyrrolidin-1-yl]pyrimidin-4-amine (Example 17) (300 mg, 0.7 mmol) and 2-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]nonane (949 mg, 4.2 mmol) in 1,4-dioxane (8 ml) was heated at 160° C. in a sealed vessel under microwave irradiation for 120 minutes. The mixture was allowed to cool and the volatiles removed by evaporation. The residue was purified by column chromatography on silica gel eluting with DCM/methanol/aqueous ammonia (100:0:0 increasing in polarity to 90:10:1) to give the product (235 mg, 55%) as a mauve solid.
Reaction SMILES: [N:1]1([S:6](Cl)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C@H:10]1([NH:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH2:30])[CH:26]=3)[N:21]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1>>[C@H:10]1([NH:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH:30][S:6]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)(=[O:8])=[O:7])[CH:26]=3)[N:21]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1
Reactant: O=S(=O)(Cl)N1CCCC1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Product: O=S(=O)(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)N1CCCC1

Procedure:
The title compound was prepared in accordance with the general method described in example 66 from pyrrolidine-1-sulfonyl chloride and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=409.6 (M+H+).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][NH:6][NH2:7])[CH3:2].[CH3:11][N:12]=[C:13]=[S:14]>C(O)C>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][N:6]([C:13]([NH:12][CH3:11])=[S:14])[NH2:7])[CH3:2]
Reactant: CN=C=S
Reactant: CCOC(CNN)OCC
Solvent: CCO
Product: CCOC(CN(N)C(=S)NC)OCC

Procedure:
A mixture of 4 g of hydrazino-acetaldehyd diethylacetal in 40 ml of ethanol is stirred with 1.97 g of methylisothiocyanate for ca. 4 hours at room temperature, the solvent is evaporated off and 2-(2,2-diethoxy-ethyl)-4-methyl-thiosemicarbazide is obtained in crystalline form.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]([NH:13][C:14]1[C:15]([C:19]2[CH:32]=[CH:31][C:22]([CH2:23][S:24][CH2:25][CH2:26][C:27]([O:29]C)=[O:28])=[CH:21][CH:20]=2)=[N:16][O:17][CH:18]=1)=[O:12])[CH3:9].[C:33]([NH:36][C@H](C(O)=O)CS)(=[O:35])[CH3:34]>>[C:33]([NH:36][C@H:26]([C:27]([OH:29])=[O:28])[CH2:25][S:24][CH2:23][C:22]1[CH:21]=[CH:20][C:19]([C:15]2[C:14]([NH:13][C:11]([O:10][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:12])=[CH:18][O:17][N:16]=2)=[CH:32][CH:31]=1)(=[O:35])[CH3:34]
Reactant: COC(=O)CCSCc1ccc(-c2nocc2NC(=O)OC(C)c2ccccc2Cl)cc1
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Product: CC(=O)N[C@@H](CSCc1ccc(-c2nocc2NC(=O)OC(C)c2ccccc2Cl)cc1)C(=O)O

Procedure:
Reaction similar to that of Step B-7 of Example 1 was carried out using Compound 1 and N-acetyl-L-cysteine to give the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C@@H:5]([NH:9]C(OC(C)(C)C)=O)[C:6]([OH:8])=[O:7])[CH3:3].[CH2:17]1[CH:21]2[CH:22]3C(=O)N(O)C(=O)[CH:23]3[CH:18]1[CH:19]=[CH:20]2.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.CCOC(C)=O>[NH2:9][C@H:5]([C:6]([O:8][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:7])[CH2:4][CH:2]([CH3:1])[CH3:3]
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C1C2C3C=CC(C3)C2C(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
pTos (21.6 g) was dissolved in DMF (100 ml), and the solution was cooled with ice. TEA (7.7 ml) and Boc-D-Leu-ONB (prepared from Boc-D-Leu--OH. H2O (12.5 g), HONB (9.86 g) and DCC (11.4 g) were added thereto, followed by stirring overnight. The resulting DCU was separated by filtration, and the filtrate was concentrated to obtain a residue. The residue was dissolved in AcOEt, and the resulting solution was washed with 4% aqueous NaHCO3 and 10% aqueous citric acid. After washing with water, the solution was dried with Na2SO4 and concentrated. Ether was added to the resulting residue to separate out a precipitate, which was collected by filtration.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([O:16]CC)=O)=[N:11][N:10]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:13][C:12]([C:14]([NH:32][CH:29]2[CH2:28][CH2:27][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:31][CH2:30]2)=[O:16])=[N:11][N:10]=1
Reactant: CCOC(=O)c1nnc(Nc2ccccc2F)o1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2nnc(Nc3ccccc3F)o2)CC1
Yield: 74 %

Procedure:
(intermediate 40) (102 mg, 0.41 mmol) and tert-butyl-4-aminopiperidine-1-carboxylate (81 mg, 0.41 mmol) was heated to 85° C. for 18 hours. Upon cooling the solid was filtered and washed with EtOH (10 mL), Et2O (10 mL) then hexane (10 mL) to leave the title compound (123 mg, 74%) as a white solid; 1H NMR δ 1.41 (9H, s), 1.46-1.54 (2H, m), 1.73-1.76 (2H, m), 2.81 (2H, s), 3.93-3.96 (3H, m), 7.13-7.17 (1H, m), 7.23-7.32 (2H, m), 7.99-8.04 (1H, m), 9.02 (1H, d), 10.63 (1H, s); MS m/e (M−H)− 404.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[CH:14]=[C:13]3[O:18][CH2:19][O:20][C:12]3=[CH:11][C:10]=2[NH:9][CH:8]=1)=[O:6].[H-].[Na+].Br.Br[CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[CH:14]=[C:13]3[O:18][CH2:19][O:20][C:12]3=[CH:11][C:10]=2[N:9]([CH2:29][C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[CH:8]=1)=[O:6]
Reactant: BrCc1ccncc1
Reactant: Cc1ccc(C(=O)c2c[nH]c3cc4c(cc3c2=O)OCO4)cc1C
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cn(Cc3ccncc3)c3cc4c(cc3c2=O)OCO4)cc1C

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 71 mg (0.22 mmol) of 7-(3,4-dimethyl-benzoyl)-5H-[1,3]dioxolo[4,5-g]quinolin-8-one, 23 mg of 60% sodium hydride, 72 mg of 4-bromomethylpyridine hydrobromide and 1.3 mL of N,N-dimethylformamide. Yield: 61 mg of a white solid: LC-MSD, m/z for C25H20N2O4 [M+H]+=413.5; HPLC retention time: 1.2 min.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:21][CH2:22][C@H:23]([OH:25])[CH3:24]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:13]1([C:8]2[CH:7]=[C:6]3[C:11]([CH2:12][C:4]4[CH:3]=[CH:2][N:21]([CH2:22][C@H:23]([OH:25])[CH3:24])[C:5]=43)=[CH:10][CH:9]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C[C@@H](O)CN
Reactant: O=CCC1Cc2ccc(-c3ccccc3)cc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H](O)Cn1ccc2c1-c1cc(-c3ccccc3)ccc1C2
Reaction time: 0.75 h
Yield: 51.9 %

Procedure:
A solution of 2.5 g of (RS)-2-(2-oxoethyl)-6-phenyl-1-indanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (diethyl ether/hexane 7:3). 1.5 g (52%) of (R)-1-(7-phenyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]([CH:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:8][CH:7]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:6]1)=[O:4].[CH3:24][C:25]1[CH:26]=[C:27]([NH:31][C:32](=[O:38])[NH:33][CH2:34][C:35](O)=[O:36])[CH:28]=[CH:29][CH:30]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[CH3:1][N:2]([CH3:23])[C:3]([CH:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:8]([C:35](=[O:36])[CH2:34][NH:33][C:32]([NH:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([CH3:24])[CH:26]=2)=[O:38])[CH:7]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:6]1)=[O:4]
Reactant: CN(C)C(=O)C1CC(C(=O)OC(C)(C)C)NC1c1ccccc1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: Cc1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CC(C(=O)N(C)C)C2c2ccccc2)c1
Yield: 81 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 2B but from 1.7 g of tert-butyl (2RS,4RS,5SR)-4-dimethylcarbamoyl-5-phenylpyrrolidine-2-carboxylate, 1.15 g of 2-[3-(3-methylphenyl)ureido]acetic acid and 1.15 g of N,N'-dicyclohexylcarbodiimide in 50 cm3 of acetonitrile. After treatment, there are obtained 2.2 g of tert-butyl (2RS,4RS,5SR)-4-dimethylcarbamoyl-1-{2-[3-(3-methylphenyl)ureido]acetyl}-5-phenylpyrrolidine-2-carboxylate, melting at 199° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH:17]=O)=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.[O:20]([NH2:22])[CH3:21].C(=O)(O)[O-].[Na+]>C(O)C>[CH3:21][O:20][N:22]=[CH:17][C:15]1[CH:14]=[CH:13][C:12]2[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[CH:9]=[N:10][C:11]=2[CH:16]=1
Reactant: CON
Reactant: O=Cc1ccc2c(c1)ncn2-c1cccc(Br)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CON=Cc1ccc2c(c1)ncn2-c1cccc(Br)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a suspension of 28 from Example 7 (2.95 g, 9.8 mmol) in abs. ethanol (100 ml) is added methoxylamine hydrochloride (1.23 g, 14.7 mmol) and the mixture is heated to 70° C. Sodium bicarbonate (1.23 g, 14.7 mmol) is added in portions over 20 min. Following the addition the mixture is stirred at 70° C. for additionally 2 hours. After cooling the solvent is removed under reduced pressure. Water is added to the residue and the product is filtered off, washed with water and dried. Yield: 2.77 g (86%). Mp 119-120° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][O:5][C:6](=O)[O:7]C1C=CC([N+]([O-])=O)=CC=1.CCN(C(C)C)C(C)C.[F:29][C:30]1[CH:35]=[C:34]([CH3:36])[C:33]([NH2:37])=[CH:32][C:31]=1[NH2:38]>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:1][Si:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][O:5][C:6](=[O:7])[NH:37][C:33]1[CH:32]=[C:31]([NH2:38])[C:30]([F:29])=[CH:35][C:34]=1[CH3:36]
Reactant: Cc1cc(F)c(N)cc1N
Reactant: C[Si](C)(C)CCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(F)c(N)cc1NC(=O)OCC[Si](C)(C)C
Temperature: 50 °C
Yield: 28 %

Procedure:
Example 48(a) was prepared in a similar manner as Example 41(a) from the starting material described below. 1H NMR (300 MHz, CD3OD) δ 8.54 (d, 1H, J=4.8 Hz), 7.95 (d, 1H, J=9.49 Hz), 7.84 (td, 1H, 1=7.71 Hz, =1.78 Hz), 7.70 (d, 1H, J=7.95 Hz), 7.53 (d, 1H, J=16.59 Hz), 7.40 (d, 1H, J=7.92 Hz), 7.29 (qd, 1H, 1=7.45 Hz, J=1.07 Hz), 7.11 (d, 1H, 1=11.8), 7.03-7.06 (m, 2H), 6.71 (s, 1H), 4.50 (q, 2H, J=7.16 Hz), 2.27 (s, 3H), 2.26 (s, 3H), 1.38 (t, 3H, 1=7.11 Hz). MS (ESI+) [M+H]/z Calc'd 496, found 496. Anal. Calc'd: C, 67.86; H, 5.29; N, 19.79. Found: C, 66.24; H, 5.50; N, 18.61. The starting material was prepared as follows: A mixture of 1-fluoro-5-methyl-2,4-dinitro-benzene (1.0 g, 5 mmol) and 10% Pd/C (200 mg) in MEOH (20 ml) was hydrogenated at 23° C. for 24 h. The reaction mixture was filtered through celite and concentrated. Purification by silica gel chromatography (1:1 ethyl acetate-hexane) gave 4-fluoro-6-methyl-benzene-1,3-diamine (613 mg, 87%). To a solution of carbonic acid 4-nitro-phenyl ester 2-trimethylsilanyl-ethyl ester (566 mg, 2 mmol) in DMF (4 ml) at 23° C. under an atmosphere of argon was added DMAP (12 mg. 0.1 mmol), DIEA (0.35 ml, 2 mmol) and 4-fluoro-6-methyl-benzene-1,3-diamine. The resulting solution was heated to 50° C. for 48 h. The reaction mixture was quenched with saturated NaHCO3 (aq), extracted with EtOAc (3×20 ml). The EtOAc was removed in-vacuo, and the residue was re-dissolved in Et2O then washed with 3 N NaOH (aq), water, brine, dried with Na2SO4, filtered and concentrated. Purification by silica gel chromatography (2:8-7:3 ethyl acetate-hexane) gave (5-amino-4-fluoro-2-methyl-phenyl)carbamic acid 2-trimethylsilanyl-ethyl ester (160 mg, 28%). MS (ESI+) [M+H]/z Calc'd 634, found 634.
Reaction SMILES: N1C=CC=CC=1S[C:8](=[O:21])[CH2:9][CH:10]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH2:12][CH2:11]1.N1C=CC=CC=1SC(=O)CC[C:32]1[CH2:37][CH2:36][CH2:35][CH2:34]C=1>>[CH:34]1([C:8](=[O:21])[CH2:9][CH:10]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)[CH2:35][CH2:36][CH2:37][CH2:32]1
Reactant: COc1ccc2c(c1)CCC2CC(=O)Sc1ccccn1
Reactant: O=C(CCC1=CCCCC1)Sc1ccccn1
Product: COc1ccc2c(c1)CCC2CC(=O)C1CCCC1

Procedure:
The title compound was prepared as described in Step 4 of Example A(13), where (5-Methoxy-indan-1-yl)-thioacetic acid S-pyridin-2-yl ester (from Step 3) was substituted in place of 3-Cyclohex-1-enyl-thiopropionic acid S-pyridin-2-yl ester. 1H NMR (CDCl3): δ 1.55-1.85 (br m, 9H), 2.39 (m, 1H), 2.60 (dd, 1H, J=17.2, 8.6 Hz), 2.80-2.92 (m, 4H), 3.59 (m, 1H), 3.78 (s, 3H), 6.70 (d, 1H, J=8.3 Hz), 6.77 (s, 1H), 7.02 (d, 1H, J=8.3 Hz).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([C:51]([F:54])([F:53])[F:52])=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][CH:12]3[CH2:15][CH:14]([CH2:16][N:17]([CH2:21][C@@H:22]4[C@H:26]5[O:27]C(C)(C)[O:29][C@H:25]5[C@H:24]([N:32]5[C:36]6[N:37]=[CH:38][N:39]=[C:40]([NH2:41])[C:35]=6[CH:34]=[CH:33]5)[CH2:23]4)[CH:18]([CH3:20])[CH3:19])[CH2:13]3)[N:8](COCC[Si](C)(C)C)[C:7]=2[CH:50]=1>CO>[NH2:41][C:40]1[C:35]2[CH:34]=[CH:33][N:32]([C@@H:24]3[CH2:23][C@H:22]([CH2:21][N:17]([CH2:16][CH:14]4[CH2:15][CH:12]([CH2:11][C:9]5[NH:8][C:7]6[CH:50]=[C:3]([Cl:2])[C:4]([C:51]([F:53])([F:52])[F:54])=[CH:5][C:6]=6[N:10]=5)[CH2:13]4)[CH:18]([CH3:20])[CH3:19])[C@@H:26]([OH:27])[C@H:25]3[OH:29])[C:36]=2[N:37]=[CH:38][N:39]=1
Reactant: CC(C)N(CC1CC(Cc2nc3cc(C(F)(F)F)c(Cl)cc3n2COCC[Si](C)(C)C)C1)C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Agent: Cl
Solvent: CO
Product: CC(C)N(CC1CC(Cc2nc3cc(C(F)(F)F)c(Cl)cc3[nH]2)C1)C[C@H]1C[C@@H](n2ccc3c(N)ncnc32)[C@H](O)[C@@H]1O
Temperature: 40 °C
Reaction time: 6 h
Yield: 27 %

Procedure:
12N HCl (1.5 ml) was added slowly to a solution of 7-[(3aS,4R,6R,6aR)-6-({[(3-{[6-chloro-5-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl]methyl}cyclobutyl)methyl](propan-2-yl)amino]methyl)-2,2-dimethyl-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (174 mg, 0.22 mmol) in MeOH (1.5 ml) and stirred at 40° C. for 6 h. The reaction was monitored by LCMS, no starting material seen after 2.5 h. The reaction mixture was concentrated in vacuo, then basified with 7N NH3 in MeOH (5 ml). This was then evaporated to dryness. Purification by silica gel column chromatography, eluting with 7N NH3 in MeOH:DCM (1:9) gave the desired product (36 mg, 27%) as a white solid; MS (ESI+) for C29H35ClF3N7O2 m/z 606.30 [M+H]+; HPLC purity 100% (ret. time, 2.59 min); 1H NMR (500 MHz, MeOD) δH ppm 0.93-1.09 (6H, m), 1.41-1.64 (2H, m), 1.76-2.06 (1H, m), 2.15-2.65 (9H, m), 2.65-2.88 (1H, m), 2.91-3.13 (3H, m), 3.80-4.09 (1H, m), 4.19-4.46 (1H, m), 4.88-4.94 (1H, m), 6.46-6.77 (1H, m), 7.19 (1H, d, J=3.63 Hz), 7.69 (1H, s), 7.89 (1H, s), 8.06 (1H, s)
Reaction SMILES: C(N(C(C)C)C(C)C)C.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]([C@@H:21]2[CH2:25][CH2:24][C:23]([CH3:27])([CH3:26])[N:22]2[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:18](O)=[O:19])=[CH:13][C:12]=1[F:35].Cl.Cl.[CH3:38][C@H:39]1[C:47]2[C:46]([N:48]3[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]3)=[N:45][CH:44]=[N:43][C:42]=2[C@@H:41]([OH:54])[CH2:40]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C@@H:17]([C@H:21]2[N:22]([C:28]([O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:29])[C:23]([CH3:26])([CH3:27])[CH2:24][CH2:25]2)[C:18]([N:51]2[CH2:52][CH2:53][N:48]([C:46]3[C:47]4[C@H:39]([CH3:38])[CH2:40][C@@H:41]([OH:54])[C:42]=4[N:43]=[CH:44][N:45]=3)[CH2:49][CH2:50]2)=[O:19])=[CH:13][C:12]=1[F:35]
Reactant: C[C@@H]1C[C@H](O)c2ncnc(N3CCNCC3)c21
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)O)c2ccc(Br)c(F)c2)CCC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Br)c(F)c4)[C@@H]4CCC(C)(C)N4C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
N-Ethyl-N-isopropylpropan-2-amine (0.045 mL, 0.26 mmol) was added to a solution of (S)-2-(4-bromo-3-fluorophenyl)-2-((S)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)acetic acid (0.035 g, 0.081 mmol; prepared analogously to that described in Example B), (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (0.025 g, 0.081 mmol; see Example 3, Step 12), and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.031 g, 0.081 mmol) in DCM (5 mL). The reaction was stirred overnight at room temperature. The reaction was then quenched with H2O, washed with H2O (3×30 mL), dried with MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography to give (S)-tert-butyl 5-((S)-1-(4-bromo-3-fluorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (23% yield). LCMS (APCI+) 648.2 m/z [M+H]+; Retention time=4.28 minutes.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][C:10]=1[C:18]1[CH:19]=[CH:20][C:21]([C:41]([O:43][CH3:44])=[O:42])=[N:22][C:23]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([O:31]CC2C=CC(OC)=CC=2)[CH:25]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][C:10]=1[C:18]1[CH:19]=[CH:20][C:21]([C:41]([O:43][CH3:44])=[O:42])=[N:22][C:23]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([OH:31])[CH:25]=1
Reactant: CCOc1ccc(Cl)c(-c2ccc(C(=O)OC)nc2-c2ccc(Cl)c(OCc3ccc(OC)cc3)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(Cl)c(-c2ccc(C(=O)OC)nc2-c2ccc(Cl)c(O)c2)c1
Temperature: 0 °C
Yield: 96.4 %

Procedure:
Add 1 mL (13 mmol) of trifluoroacetic acid to a solution of 700 mg (1.3 mmol) of methyl 5-(2-chloro-5-ethoxyphenyl)-6-{4-chloro-3-[(4-methoxybenzyl)oxy]phenyl}pyridine-2-carboxylate in 10 mL of DCM stirred at 0° C. Stir the reaction mixture for 2 h at 20° C. then concentrate under reduced pressure. Take up the residue in 50 mL of DCM and wash with 50 mL of a saturated aqueous solution of NaHCO3. Dry the organic phase over Na2SO4 and concentrate under reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a cyclohexane/EtOAc gradient from 0 to 30% of EtOAc. After concentration under reduced pressure, we obtain 524 mg of methyl 5-(2-chloro-5-ethoxyphenyl)-6-(4-chloro-3-hydroxyphenyl)pyridine-2-carboxylate in the form of oil.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].[C:13](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:13]([O:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][O:12][C:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[OH:10])[OH:8])[OH:6])=[O:4])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(COC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H](O)[C@H](O)[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 48 h
Yield: 29.8 %

Procedure:
To a solution of D-fructose (10 g, 55.5 mmole) in pyridine (40 ML) and chloroform (25 mL) was added trityl-chloride (35 g, 126.3 mmole) and the mixture was stirred at 25° for 2 days, another 5 g of trityl chloride was added and stirring was continued for 2 days. Solvent was removed under reduced pressure and the residue was extracted with chloroform, washed with aqueous saturated cupric sulfate solution, brine, dried over anhydrous sodium sulfate and concentrated. Column chromatography [chlorofm-methanol (100:1)] gave 1,6-Di-O-trityl-D-fructose (11 g, 30%). This compound was identified by its specific rotation and by NMR and Mass spectrometry.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH2:22]([O:24][C:25]([C@@H:27]1[CH2:31][CH2:30][CH2:29][C@@H:28]1[NH:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][N:35]=1)=[O:26])[CH3:23].C1(N=C=NC2CCCCC2)CCCCC1.ClCCl>CN(C)C=O>[CH2:22]([O:24][C:25]([C@@H:27]1[CH2:31][CH2:30][CH2:29][C@@H:28]1[N:32]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][N:35]=1)[C:17](=[O:19])[CH2:16][C:11]1[NH:10][C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[S:13](=[O:14])(=[O:15])[N:12]=1)=[O:26])[CH3:23]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1NCc1ccc(F)cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CCC[C@@H]1N(Cc1ccc(F)cn1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 6 h
Yield: 48.7 %

Procedure:
A solution of (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.100 g, 0.300 mmol) and cis-2-[(5-fluoro-pyridin-2-ylmethyl)-amino]-cyclopentanecarboxylic acid ethyl ester (0.080 g, 0.300 mmol) in N,N-dimethylformamide (1.5 mL) was treated with a 1.0 M solution of N,N′-dicyclohexylcarbodiimide in dichloromethane (0.315 mL, 0.315 mmol). The reaction was stirred for 6 h at 25° C., the urea byproduct was filtered off and the crude material was purified by prep-HPLC [Column Luna 5μ C18 (2) 100 Å AXIA 50×21.2 mm, 5 micron, 30%-90% in 7 min @ 30 mL/min flow rate, 0.05% trifluoroacetic acid in acetonitrile/0.05% trifluoroacetic acid in water] to afford the desired product, cis-2-{(5-fluoro-pyridin-2-ylmethyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclopentanecarboxylic acid ethyl ester (0.085 g, 0.146 mmol, 48.7%), as a white solid. LC-MS (ESI) calcd for C24H28FN5O7S2 581.14, found 582.2 [M+H+].