Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:10]=1)[CH3:2].[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][Br:24])=[C:11]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:10]=1)[CH3:2]
Reactant: BrCCCCCBr
Reactant: CCOC(=O)CCCCc1ccc(O)c(CCC(=O)OCC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCCCc1ccc(OCCCCCBr)c(CCC(=O)OCC)c1
Temperature: 92 °C
Reaction time: 22 h
Yield: 84 %

Procedure:
A mixture of 0.655 g (2.03 mmol) of 3-(3-ethoxy-3-oxopropyl)-4-hydroxybenzenepentanoic acid ethyl ester from the preceding example, 2.80 g (12.2 mmol) of 1,5-dibromopentane, 1.12 g (8.12 mmol) of anhydrous granular potassium carbonate, and 35 mL of 2-butanone was stirred at 92° C. for 22 hr. After being cooled to room temperature, the mixture was filtered through anhydrous magnesium sulfate and the solids were washed thoroughly with ethyl acetate and ether. The filtrate and washes were combined and concentrated in vacuo and the crude product was purified by flash chromatography on 80 g of silica gel, eluting with hexane-ethyl acetate (4:1). There was obtained 0.804 g (83.9%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].C(Cl)(=O)C(Cl)=O.[F:33][C:34]([F:43])([F:42])[C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=1)[NH2:38].C(N(CC)CC)C>ClCCl.CN(C)C=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:15]=[CH:16][C:17]([C:18](=[O:19])[NH:38][C:37]3[CH:39]=[CH:40][CH:41]=[C:35]([C:34]([F:33])([F:42])[F:43])[CH:36]=3)=[CH:21][CH:22]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(C(F)(F)F)c4)cc3)c(C#N)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a solution of 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (0.050 g, 0.1415 mmol) in dichloromethane (0.7 ml) and N,N-dimethylformamide (1 drop) was added oxalyl dichloride (0.01358 ml, 0.1557 mmol), and the reaction was stirred at ambient temperature for 30 minutes. 3-(Trifluoromethyl)aniline (0.01944 ml, 0.1557 mmol) and triethylamine (0.04339 ml, 0.3113 mmol) were added, and the reaction was stirred at ambient temperature for 3 days. The reaction mixture was diluted with ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was diluted with dichloromethane and stirred with excess amine-3 functionalized silica gel for 30 minutes, then filtered and concentrated. The crude material was purified by preparative thin layer chromatography eluting with 25% EtOAc in hexanes to yield 19 mg of the title compound (27% yield).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23](OC)=[O:24])[N:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[CH2:28]([NH2:31])[CH2:29][CH3:30]>>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:27])=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:22][C:23](=[O:24])[NH:31][CH2:28][CH2:29][CH3:30])[N:17]=[CH:16]4)[CH:12]=2)[CH2:2][CH2:3]1
Reactant: CCCN
Reactant: COC(=O)Cn1ncc2cc(-c3cc(C(=O)NC4CC4)ccc3C)ccc21
Product: CCCNC(=O)Cn1ncc2cc(-c3cc(C(=O)NC4CC4)ccc3C)ccc21

Procedure:
Example 128 was prepared by General Method D using methyl (5-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-1H-indazol-1-yl)acetate (Example 117) and 1-propylamine to give the title compound (0.011 g).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]([OH:14])=[C:8]([C:11](=[O:13])[CH3:12])[C:9]=1[OH:10])(=[O:3])[CH3:2].[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1>N1CCCCC1.C(Cl)(Cl)Cl>[C:11]([C:8]1[C:7](=[O:14])[O:6][C:5](=[O:15])[CH:4]([C:1](=[O:3])[CH:2]=[CH:16][C:17]2[CH:24]=[CH:23][C:20]([CH3:21])=[CH:19][CH:18]=2)[C:9]=1[OH:10])(=[O:13])[CH3:12]
Reactant: Cc1ccc(C=O)cc1
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Solvent: C1CCNCC1
Solvent: ClC(Cl)Cl
Product: CC(=O)C1=C(O)C(C(=O)C=Cc2ccc(C)cc2)C(=O)OC1=O

Procedure:
Following the procedure of Example 1, a mixture of 8.48 g. (0.04 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one, 4.8 g. (0.04 m.) of p-methylbenzaldehyde in 100 ml. of chloroform and 20 drops of piperidine is refluxed for 10 hours, concentrated and filtered to yield 5-acetyl-4-hydroxy-3-(p-methylcinnamoyl)-2H-pyran-2,6(3H)-dione, m.p. 188°-190° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([OH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:12]1[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]1[O:14][C:15](=[O:17])[CH3:16].[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38]Br)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[N:10]=[C:9]([O:11][CH2:38][CH2:37][C:34]2[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:12]1[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]1[O:14][C:15](=[O:17])[CH3:16]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(O)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Clc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(OCCc4ccc(Cl)cc4)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 32 h
Yield: 64 %

Procedure:
To a mixture of 6-chloro-2-hydroxy-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine (Example 2, Step C) and 2-(4-chlorophenyl)ethyl bromide (300.1 g, 1.36 mol) in dimethylformamide (7,280 mL), cesium carbonate (665 g, 2.04 mol) was added. The reaction was allowed to stir under inert atmosphere for 32 hours. The reaction was concentrated under reduced pressure and partitioned between dichloromethane and water. The organic layer was dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography eluting with ethyl acetate/heptanes to yield a yellow solid of 6-chloro-2-[2-(4-chlorophenyl)ethoxy]-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine Typical Yield: 64%
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[C:27]([O:39][CH3:40])=[N:28][CH:29]=[C:30]([C:32]5[C:33]([CH3:38])=[N:34][NH:35][C:36]=5[CH3:37])[CH:31]=4)=[CH:24][N:23]=[C:22]([N:41]4[CH2:44][CH:43]([F:45])[CH2:42]4)[N:21]=3)[C@H:14]2[CH3:46])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].I[CH2:52][CH2:53][CH3:54]>C1COCC1>[F:48][C:2]([F:47])([F:1])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[C:27]([O:39][CH3:40])=[N:28][CH:29]=[C:30]([C:32]5[C:33]([CH3:38])=[N:34][N:35]([CH2:52][CH2:53][CH3:54])[C:36]=5[CH3:37])[CH:31]=4)=[CH:24][N:23]=[C:22]([N:41]4[CH2:44][CH:43]([F:45])[CH2:42]4)[N:21]=3)[C@H:14]2[CH3:46])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CCCI
Reactant: COc1ncc(-c2c(C)n[nH]c2C)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCn1nc(C)c(-c2cnc(OC)c(-c3cnc(N4CC(F)C4)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-({5-[5-(3,5-dimethyl-1H-pyrazol-4-yl)-2-methoxypyridin-3-yl]-2-(3-fluoroazetidin-1-yl)pyrimidin-4-yl}methyl)-4-methyl-1,3-oxazolidin-2-one (EXAMPLE 17, 0.020 g, 0.029 mmol) in THF (2 mL) was added sodium hydride (0.011 g, 0.29 mmol) at 0° C. The resulting mixture was stirred for 10 minutes at room temperature, after which iodopropane (0.075 g, 0.044 mmol) was added. The resulting mixture was stirred for 24 hours at room temperature until the starting material was consumed completely. Water (1 mL) was added to quench the reaction. The aqueous layer was extracted with Ethyl acetate (2×2 mL), the combined organic layer was concentrated in vacuum and the residue was dissolved in 1 mL of DMSO and filtered. This clear DMSO filtrate was purified by preparative HPLC (reverse phase, Waters SunFire Prep C18 OBD5 um 19×100 mm) eluting with acetonitrile/water+0.14% HCOOH (30% to 100% organic in 5 minutes, 25 mL/minutes). Related fractions were pooled and evaporated under reduced pressure to afford a fluffy white solid of 2.8 mg as the titled compound. LCMS (M+H)+: 722.4. 1H NMR (DMSO-d6, 500 MHz): δ 8.24 (s, 1H), 8.16-8.14 (d, J=8.5 Hz, 2H), 7.92 (s, 2H), 7.62 (s, 1H), 5.87 (d, J=8.5 Hz, 1H), 5.60 (s, 1H), 5.42 (s, 1H), 4.53-3.98 (br m, 4H), 3.84 (s, 3H), 2.52 (s, 3H), 2.10 (m, 3H), 2.04 (m, 2H), 1.68 (m, 1H), 1.60-1.44 (m, 2H), 0.83 (t, J=6.5 Hz, 3H), 0.54 (d, J=6.5 Hz, 3H). RTA IC50: 12 nM
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:3][CH:2]=1.Br[C:22]1[S:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC(O)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[C:8]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:22]2[S:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)=[CH:16][CH:15]=1
Reactant: Nc1ccc(Oc2ncccc2-c2ccncc2)cc1
Reactant: Brc1nc2ccccc2s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: c1cnc(Oc2ccc(Nc3nc4ccccc4s3)cc2)c(-c2ccncc2)c1
Temperature: 25 °C

Procedure:
A 25 ml round bottomed flask was charged with 4-(3-(pyridin-4-yl)pyridin-2-yloxy)benzenamine (0.1531 g, 0.58 mmol), 2-bromobenzo[d]thiazole (0.1874 g, 0.88 mmol), Palladium acetate (0.0264 g, 0.12 mmol), 2-(dicyclohexylphosphino)biphenyl (0.0878 g, 0.23 mmol), and cesium carbonate (0.077 ml, 0.81 mmol) in toluene/t-BuOH (5/1) at 100° C. overnight. Upon completion, the reaction was allowed to cool to room temperature. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (25M), eluting with a gradient of 1% to 5% MeOH in DCM. Further purification was performed by reverse-phase preparative HPLC using a Phenomenex Gemini column, 5 micron, 150×30 mm, 0.1% TFA in ACN/H2O, gradient 10% to 100% over 15 min. The product peak fractions were collected and organic solvents were removed. The aqueous solution was diluted with water (5 mL) and sodium bicarbonate was added until the pH˜10. The solution was extracted with DCM. The organic extract was washed with water, brine, dried with magnesium sulfate, filtered, and concentrated to provide N-(4-(3,4′-bipyridin-2-yloxy)phenyl)benzo[d]thiazol-2-amine. MS (ESI, pos. ion) m/z: 397.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [CH3:1][C:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:21])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([S:18][C:19]#[N:20])[C:13](OCC)=[O:14])=[CH:7][CH:6]=1.Cl.[OH2:29]>C(O)C>[CH3:21][C:2]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([CH3:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]2[S:18][C:19](=[O:29])[NH:20][C:13]2=[O:14])=[CH:7][CH:6]=1
Reactant: CCOC(=O)C(Cc1ccc(OCC(C)(C)c2ccccc2)cc1)SC#N
Reactant: O
Agent: Cl
Solvent: CCO
Product: CC(C)(COc1ccc(CC2SC(=O)NC2=O)cc1)c1ccccc1

Procedure:
1.9 g Of ethyl 3-[4-(2-methyl-2-phenylpropyloxy)phenyl]-2-thiocyanatopropionate is dissolved in 20 ml of ethanol and to the solution 20 ml of 6 N--hydrochloric acid is added. The mixture is refluxed for 24 hours. After cooling, water is added to the mixture. The mixture is subjected to extraction with ether. The extract is washed with water and then dried. After distilling off ether, the residue is crystallized from ether-n-hexane, whereby 730 mg of 5-[4-(2-methyl-2-phenylpropyloxy)benzyl]thiazolidine-2,4-dione is obtained.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[N:3]1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:27]=[C:28]([CH:45]=[CH:46][CH:47]=1)[O:29][C:30]1[CH:31]=[CH:32][C:33]2[N:34]([N:36]=[C:37]([NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[N:38]=2)[CH:35]=1>CN(C)C=O.CN(C)C(=O)C>[CH:42]1([C:40]([NH:39][C:37]2[N:38]=[C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]4[CH:27]=[C:26]([NH:25][C:11]([C:4]5[C:5]6[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=6)[N:2]([CH3:1])[N:3]=5)=[O:13])[CH:47]=[CH:46][CH:45]=4)=[CH:35][N:34]3[N:36]=2)=[O:41])[CH2:43][CH2:44]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: Cn1nc(C(=O)O)c2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1nc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)c2ccccc21
Yield: 28.1 %

Procedure:
In the same manner as in Example 18-4 and using 1-methyl-1H-indazole-3-carboxylic acid (300 mg, 1.70 mmol), tetrahydrofuran (10 mL), oxalyl chloride (222 μL, 2.55 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.647 mmol), N,N-dimethylformamide (2 drops) and N,N-dimethylacetamide (10 mL) as starting materials, the title compound (85.0 mg, 28%) was obtained as a white solid.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:7][CH2:8][C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[N:16]([C:31]3[C:32]4[C@H:39]([CH3:40])[CH2:38][CH2:37][C:33]=4[N:34]=[CH:35][N:36]=3)[CH2:17][C:18]3([CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:10]=12.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[Cl:15][C:14]1[C:9]([CH2:8][NH:7][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:10]2[C:18]3([CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[CH2:17][N:16]([C:31]3[C:32]4[C@H:39]([CH3:40])[CH2:38][CH2:37][C:33]=4[N:34]=[CH:35][N:36]=3)[C:11]2=[CH:12][CH:13]=1
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4c3ccc(Cl)c4CN)c21
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4c3ccc(Cl)c4CNC3CCCC3)c21
Reaction time: 8 h
Yield: 57.4 %

Procedure:
Cyclopentanone (17.4 mg, 0.207 mmol) was added to a solution of (R)-tert-butyl 4-(aminomethyl)-5-chloro-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (20 mg, 0.041 mmol) in DCE (2 mL). The reaction was allowed to stir at room temperature for 15 minutes, at which point Na(OAc)3BH (22 mg, 0.103 mmol) was added. The reaction was allowed to stir overnight. The reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO3 solution and brine, dried with MgSO4 and concentrated. The residue was purified by column chromatography (15:1, DCM:MeOH) to give (R)-tert-butyl 5-chloro-4-((cyclopentylamino)methyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (13 mg, 54%) as an oil. LCMS (APCI+) m/z 552/554 [M+H]+; Rt=4.79 min This material was taken up into DCM (2 mL), and 2N HCl in ether was added (1 mL). The reaction was allowed to stir for 1 hour, at which point it was concentrated to give (R)-N-((5-chloro-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl)propan-2-amine trihydrochloride salt (12 mg, 52%) as a solid. 1H NMR (D2O, 400 MHz) δ 8.53 (s, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 4.55-4.39 (m, 3H), 4.17-4.15 (m, 1H), 3.84-3.38 (m, 7H), 3.17-2.97 (m, 4H), 2.44-1.67 (m, 14H). LCMS (APCI+) m/z 452/454 [M+H]+; Rt=2.52 min.
Reaction SMILES: [NH2:1][C@H:2]([C:24]([NH:26][C@H:27]([C:35]([NH:37][C@H:38]([C:46]([NH:48][C@H:49]([C:56]([NH:58][C@H:59]([C:64]([NH:66][C@H:67]([C:89]([NH:91][C@H:92]([C:99]([NH:101][C@H:102]([C:107]([OH:109])=[O:108])[CH2:103][CH:104]([CH3:106])[CH3:105])=[O:100])[CH2:93][O:94][C:95]([CH3:98])([CH3:97])[CH3:96])=[O:90])[CH2:68][S:69]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:65])[C@H:60]([CH2:62][CH3:63])[CH3:61])=[O:57])[CH2:50][O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:47])[C@@H:39]([CH3:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:36])[CH2:28][S:29][CH2:30][NH:31][C:32]([CH3:34])=[O:33])=[O:25])[CH2:3][S:4]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.II.O=C1O[C@H]([C@H](CO)O)C(O)=C1O.N>C(O)C(F)(F)F.O.C([O-])(=O)C.[NH4+].C(Cl)Cl>[NH2:1][C@H:2]([C:24]([NH:26][C@H:27]([C:35]([NH:37][C@H:38]([C:46]([NH:48][C@H:49]([C:56]([NH:58][C@H:59]([C:64]([NH:66][C@H:67]([C:89]([NH:91][C@H:92]([C:99]([NH:101][C@H:102]([C:107]([OH:109])=[O:108])[CH2:103][CH:104]([CH3:106])[CH3:105])=[O:100])[CH2:93][O:94][C:95]([CH3:98])([CH3:97])[CH3:96])=[O:90])[CH2:68][SH:69])=[O:65])[C@H:60]([CH2:62][CH3:63])[CH3:61])=[O:57])[CH2:50][O:51][C:52]([CH3:53])([CH3:54])[CH3:55])=[O:47])[C@@H:39]([CH3:45])[O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:36])[CH2:28][S:29][CH2:30][NH:31][C:32]([CH3:34])=[O:33])=[O:25])[CH2:3][SH:4]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](COC(C)(C)C)NC(=O)[C@@H](NC(=O)[C@H](CSCNC(C)=O)NC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H](C)OC(C)(C)C)C(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)O
Agent: CC(=O)[O-]
Agent: II
Agent: N
Solvent: OCC(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC[C@H](C)[C@H](NC(=O)[C@H](COC(C)(C)C)NC(=O)[C@@H](NC(=O)[C@H](CSCNC(C)=O)NC(=O)[C@@H](N)CS)[C@@H](C)OC(C)(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)O

Procedure:
0.47 g of H-Cys(Trt)-Cys(Acm)-Thr(But)-Ser(But)-Ile-Cys(Trt)-Ser(But)-Leu-OH in 15 ml of trifluoroethanol are added over the course of 10 minutes to a vigorously stirred mixture of 18 ml of methylene chloride, saturated with iodine, and 180 ml of trifluoroethanol. 2 minutes after completion of the addition, a solution of 3.2 g of ascorbic acid in 60 ml of water and 30 ml of 1 M ammonium acetate are added, the solution is brought to pH 5.6 with dilute ammonia and the trifluoroethanol is very largely removed under reduced pressure. The mixture is then taken up in 100 ml of chloroform-methanol (95:5) and the organic phase is twice washed with water. After drying over sodium sulphate, the mixture is evaporated and the product shown in the title is purified by gel filtration on Sephadex-LH 20 (column: 2 × 100 cm). Eluant: chloroform-methanol (1:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:15]3[C:11]([CH2:12][CH2:13][CH2:14]3)=[C:10]([C:16](OCC)=[O:17])[C:9]=2[C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.C1COCC1>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:15]3[C:11]([CH2:12][CH2:13][CH2:14]3)=[C:10]([CH2:16][OH:17])[C:9]=2[C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(-c2ccncc2)c(-c2ccc(F)cc2)n2c1CCC2
Solvent: C1CCOC1
Solvent: O
Product: OCc1c(-c2ccncc2)c(-c2ccc(F)cc2)n2c1CCC2
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Ethyl 3-(4-fluorophenyl)-2-(4-pyridyl)-6,7-dihydro-5H-pyrrolizine-1-carboxylate (example 1A, 4.56 g, 13 mmol) is dissolved in abs. THF (100 ml) under argon and Na bismethoxyethoxyaluminum hydride (VitrideR) is added dropwise through a septum via the cannula of a syringe (20 min). The mixture is stirred at 50° C. for 2 h, whereupon starting material is no longer detectable by tlc (Al2O3—ethyl acetate/n-hexane 3:7), then it is allowed to cool. H2O (25 ml) is cautiously added dropwise to the reaction solution, then it is concentrated in vacuo (THF evaporates), and the aqueous organic residue is treated with ethyl acetate (100 ml). The phases are separated. The organic phase is washed 2 times with water (40 ml), dried over Na2SO4 sicc. and concentrated in vacuo (5.0 g). The reddish brown-colored, resinous residue is crystallized from diethyl ether (10 ml). The crystals are washed with ethyl acetate (5 ml) and ether (5 ml) and dried. 3.67 g of the compound sought remain
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:13])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[N:6]1.[C:14](=O)(OC1C=CC=CN=1)[O:15]C1C=CC=CN=1>ClCCl>[N+:10]([C:7]1[CH:8]=[CH:9][N:5]([CH2:4][C@H:3]2[O:13][C:14](=[O:15])[NH:1][CH2:2]2)[N:6]=1)([O-:12])=[O:11]
Reactant: NC[C@H](O)Cn1ccc([N+](=O)[O-])n1
Reactant: O=C(Oc1ccccn1)Oc1ccccn1
Solvent: ClCCl
Product: O=C1NC[C@@H](Cn2ccc([N+](=O)[O-])n2)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.6 %

Procedure:
To a solution of (S)-1-amino-3-(3-nitro-pyrazole-1-yl)-propan-2-ol (0.65 g, 3.49 mmol) in dichloromethane (15 mL) was added di-2-pyridyl carbonate (0.76 g, 3.49 mmol). The reaction mixture was stirred at room temperature for 2 h and then diluted with dichloromethane. The organic layer was washed with a saturated sodium chloride solution and dried over magnesium sulfate. The crude product obtained after concentration, was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% to 10% methanol/dichloromethane) to afford (S)-5-(3-nitro-pyrazol-1-ylmethyl)-oxazolidin-2-one (0.36 g, 49%) as a clear colorless oil: HR-ES-MS m/z calculated for C7H8N4O4 [M]+ 212, observed 213 [M+H]+.
Reaction SMILES: [C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[Cl:9][C:10](Cl)=[CH:11][C:12]1([CH2:17][CH3:18])[CH2:16][CH2:15][CH2:14][CH2:13]1>CN1CCCC1=O.C(Cl)Cl>[Cl:9][CH:10]=[C:11]([C:12]1([CH2:17][CH3:18])[CH2:16][CH2:15][CH2:14][CH2:13]1)[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC1(C=C(Cl)Cl)CCCC1
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CCC1(C(=CCl)Oc2ccccc2)CCCC1
Temperature: 210 °C
Yield: 87.7 %

Procedure:
140 g (4.2 mol) of sodium phenolate in 500 ml of N-methylpyrrolidone were heated to 200° C. 116 g (0.6 mol) of 1-(2,2-dichlorovinyl)-1-ethyl-cyclopentane were added dropwise so slowly that the reaction temperature did not fall below 195° C. The mixture was then stirred for a further hour at 210° C. After the mixture had cooled, it was diluted with methylene chloride and extracted several times by shaking with 2N sodium hydroxide solution. The organic phase, which had been dried over sodium sulphate, was concentrated in vacuo, and the residue was fractionated. 132 g (88% of theory) of 1-chloro-2-(1-ethylcyclopentyl)-2-phenoxy-ethylene of boiling point 115° to 125° C./0.1 mm Hg were obtained. ##STR17##
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[C:9]([CH3:21])[N:10]2[CH2:15][C:16]([O:18]CC)=[O:17])([O-:5])=[O:4].Cl>C(O)C>[CH3:21][C:9]1[N:10]([CH2:15][C:16]([OH:18])=[O:17])[C:11]2[C:7]([CH:8]=1)=[C:6]([N+:3]([O-:5])=[O:4])[CH:14]=[CH:13][CH:12]=2
Reactant: CCOC(=O)Cn1c(C)cc2c([N+](=O)[O-])cccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc2c([N+](=O)[O-])cccc2n1CC(=O)O
Temperature: 40 °C
Reaction time: 1.17 h

Procedure:
Aqueous sodium hydroxide (1 M, 25 ml) was added to a solution of (4-nitro-2-methyl-1H-indol-1-yl)acetic acid, ethyl ester (5.0 g, 18.9 mmol) in ethanol (25 ml) and the mixture warmed to 40° C. After stirring for 70 mins at this temperature, the mixture was allowed to cool back to ambient temperature and aqueous hydrochloric acid (1 M, 27.5 ml) added causing precipitation of a solid. This was collected by filtration, washed with water (2×25 ml) then dried in a vacuum oven at 50° C. overnight to leave (2-methyl-4-nitro-1H-indol-1-yl)acetic acid as a yellow solid, 4.18 g (94%).