Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:3]=1[O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2.Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:18]([O:17][C:15]([N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][CH:13]=[CH:14][C:5]=2[O:4][C:3]2[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:2]=2[NH:1][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:10]1)=[O:16])([CH3:20])([CH3:21])[CH3:19]
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)(C)OC(=O)N1CCc2c(cccc2Oc2cc(Cl)ccc2N)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCNc1ccc(Cl)cc1Oc1cccc2c1CCN(C(=O)OC(C)(C)C)C2
Temperature: 60 °C
Reaction time: 3 h
Yield: 64.8 %

Procedure:
A mixture of 5-(2-amino-5-chlorophenoxy)-2-tert-butoxycarbonyl-1,2,3,4-tetrahydroisoquinoline (2.92 g, 7.8 mmols), ethyl 4-bromobutyrate (2.2 ml, 15.6 mmols), potassium carbonate (1.08 g, 10 mmols) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 3 hours. The reaction mixture was cooled, then poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography to give an oil of ethyl 4-[2-[2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yloxy]-4-chlorophenyl]aminobutyrate (2.47 g, 64.8%).
Reaction SMILES: C(OC(C1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH:14](N)[C:15]2=[O:18])=[CH:10][CH:9]=1)=O)(C)(C)C.[H-].[Na+].IC.C(OCC)(=O)C.CCCCCC.[CH3:36][N:37]([CH:39]=O)[CH3:38]>>[CH3:38][N:37]([CH3:36])[C:39]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH2:14][C:15]2=[O:18])=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)c1ccc2c(c1)C(=O)C(N)CC2
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CN(C)c1ccc2c(c1)C(=O)CCC2

Procedure:
7-Dimethylaminotetralone was prepared by treating 7-tert-butoxycarbonyl amino-1-tetralone (2.0 g, 7.6 mmol) with sodium hydride (337 mg of a 60% dispersion in oil) and iodomethane (0.48 ml, 7.6 mmol) in DMF (15 ml) at 100° for 3 h. The solvent was removed under reduced pressure to give an oil which was subjected to column chromatography (silica gel, 30% ethyl acetate/hexane) to give the desired product as a buff solid (137 mg) m.p. 107°. MS (ES+) 190 (MH+. 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C@@H:11]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:12]([OH:25])[CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O)[CH:6]=[C:5]2[CH3:32].[OH-].[NH4+:34]>CO>[NH2:34][CH2:13][CH:12]([OH:25])[CH:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[C:5]([CH3:32])=[CH:6]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](O)[C@H](c2ccccc2)n2cc(C)c3cc(F)ccc32)cc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: Cc1cn(C(c2ccccc2)C(O)CN)c2ccc(F)cc12
Reaction time: 12 h

Procedure:
To a solution of (2S,3S)-toluene-4 sulfonic acid 3-(5-fluoro-3-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester (Intermediate in EXAMPLE 117, step 6, 0.15 g, 0.33 mmol) in methanol (10 mL) was added concentrated ammonium hydroxide (20 mL), and the reaction was stirred for 12 hours. Upon completion, the reaction was partitioned between water (25 mL) and ethyl acetate (25 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Biotage chromatography (FlasH40i, silica, 25% MeOH/dichloromethane) to give (1SR,2RS)-3-amino-1-(5-fluoro-3-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol as a clear oil. The free base was dissolved in a minimum amount of ethanol and treated with a 4N solution of hydrochloric acid in dioxane and stirred for 1 hour s. The ethanol was removed in vacuo and the clear oil was triturated with ether/dichloromethane to give (1SR,2RS)-3-amino-1-(5-fluoro-3-methyl-1H-indol-1-yl)-1-phenylpropan-2-ol hydrochloride as a white solid. MS (ES) m/z 299.0
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=O.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>C(Cl)Cl>[CH2:21]([N:23]([CH2:24][CH3:25])[C:7]([C:6]1[CH:5]=[CH:4][O:3][C:2]=1[CH3:1])=[O:9])[CH3:22]
Reactant: Cc1occc1C(=O)O
Reactant: CCNCC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1ccoc1C
Temperature: 0 °C
Yield: 83.4 %

Procedure:
To a solution of 2-methyl-3-furoic acid (34.75 g, 0.3469 mol) in dry methylene chloride (200 ml) under an argon atmosphere, were added a catalytic amount of dimethylformamide followed by dropwise addition of oxalyl chloride (45.5 ml, 0.5216 mol). After the addition the reaction mixture was allowed to stir until the effervescence had subsided (4.0 hours). The excess oxalyl chloride/methylene chloride was evaporated and the residue was dissolved in methylene chloride (200 ml). The solution was cooled (ice/acetone) and diethylamine (75.0 ml, 0.725 mol) in methylene chloride (100 ml) was added dropwise. After the addition (1.0 hour) the reaction was poured into ice/water and the solution was acidified to a pH of 3.0. The mixture was extracted with diethyl ether (4×200 ml). The combined extracts were washed with saturated sodium carbonate solution (2×50 ml), water (4×50 ml), brine (2×25 ml), and dried (MgSO4). Solvent evaporation gave 59.75 g of crude product. The oil was distilled to give 52.45 g (83% yield) of product which crystallized upon standing (bp: 91° C./1.2 mmHg; mp 32°-34° C.).
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[NH2:9][C:10]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]>O1CCOCC1>[F:19][C:16]1[CH:17]=[CH:18][C:10]2[NH:9][C:2](=[O:3])[O:13][C:12](=[O:14])[C:11]=2[CH:15]=1
Reactant: Nc1ccc(F)cc1C(=O)O
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: O=c1[nH]c2ccc(F)cc2c(=O)o1
Yield: 95.1 %

Procedure:
Trichloromethyl chloroformate (7.01 mL, 58.13 mmol) was added to a stirred solution of Compound 34 (8.2 g, 52.85 mmol) in dry dioxane at room temperature and the solution was refluxed for 4 h. The solution was cooled in an ice bath and the solids formed were filtered. The solids were washed by ether and dried under vacuum at room temperature to yield 9.1 g (96%) of white solids. M.P. 240° C. 1H NMR (DMSO-d6): δ 7.19 (dd, J=4.2, 8.9 Hz, 1H), 7.63-7.71 (m, 1H), 11.77 (s, 1H). EIMS (neg. mode) m/z 180 (M=1). Anal. (C8H4FNO3) C, H, N.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][N:35]=[C:9]23)[CH2:4][CH2:3]1.[N+](=[CH:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[N-]>C([O-])(=O)C.[Rh+].C(Cl)Cl>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:12]2[C:13](=[O:14])[N:8]([C@H:5]3[CH2:6][CH2:7][C@H:2]([O:1][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:3][CH2:4]3)[C:9]3[N:10]([N:33]=[CH:34][N:35]=3)[C:11]=2[CH2:30][CH2:31][CH3:32])=[CH:17][CH:18]=1)#[N:29]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ncnn12
Agent: [Rh+]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ncnn12
Reaction time: 1 h

Procedure:
To a mixture of 4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1 g), rhodium(I) acetate (0.023 g) and methylene chloride (10 mL) was added dropwise ethyl diazoacetate (0.64 mL) at room temperature, and the mixture was stirred for 1 hr. The reaction mixture was concentrated, and the obtained residue was subjected to silica gel column chromatography to give the title compound as a colorless solid (0.68 g, 59%).
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](Cl)(=[O:20])=[O:19].[CH2:22]1[O:32][C:31]2[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][C:24]=2[O:23]1.C(N(CC)CC)C>C(O)(C)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:17])[CH2:13][S:12][C:11](=[N:14][CH3:15])[N:10]2[CH3:16])=[CH:5][C:4]=1[S:18](=[O:20])(=[O:19])[NH:28][CH2:27][C:26]1[CH:29]=[CH:30][C:31]2[O:32][CH2:22][O:23][C:24]=2[CH:25]=1
Reactant: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)Cl)c2)N1C
Reactant: NCc1ccc2c(c1)OCO2
Agent: Br
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)NCc3ccc4c(c3)OCO4)c2)N1C

Procedure:
6.5 g of 4-(4-chloro-3-chlorosulfonylphenyl)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol-hydrobromide were reacted as prescribed in Example 76 with 2.4 g of 3,4-methylenedioxybenzyl amine and 3.5 g of triethyl amine and worked up. Colorless crystals from isopropanol, melting point: 131°-132° C. (decomposition).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:15][C:16]#[N:17])=[O:5])C.O[Li].O.Cl>C1COCC1.CCO.O>[C:16]([CH2:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]2)#[N:17]
Reactant: CCOC(=O)c1cc2cccc(CC#N)c2[nH]1
Agent: Cl
Agent: [Li]O
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: N#CCc1cccc2cc(C(=O)O)[nH]c12
Temperature: 45 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a solution of 100 mg (0.46 mmol) of 7-cyanomethyl-1H-indole-2-carboxylic acid ethyl ester (the preparation of which is described in Chem. Pharm. Bull. 1996, 44, 55) in THF/EtOH/H2O (5 ml) at RT was added 50 mg of LiOH.H2O. The reaction mixture was stirred at 45° C. for one hour and then acidified with aqueous HCl 1M. The product was extracted with EtOAc and concentrated under vacuo to afford 80 mg (85%) of 7-Cyanomethyl-1H-indole-2-carboxylic acid as a white solid. ES-MS m/e (%): 199.6 (M−H+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CI.[F:9][C:10]1C=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:11]=1N.O.[CH3:21][N:22]([CH3:25])[CH:23]=O>>[F:9][C:10]1[CH:11]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][C:23]=1[N:22]([CH3:25])[CH3:21]
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: CN(C)c1cc([N+](=O)[O-])ccc1F
Temperature: 100 °C
Reaction time: 6 h

Procedure:
Potassium carbonate (4.15 g, 30 mmol) and methyl iodide (1.49 mL, 24.0 mmol) were added to a solution of 2-fluoro-5-nitroaniline (1.56 g, 10.0 mmol) in N,N-dimethylformamide (30 mL) at room temperature and the mixture was stirred at 100° C. for 6 hr. After cooling to room temperature, water was added to the reaction mixture and the mixture was extracted three times with ethyl acetate. The organic layer was washed with 1 mol/L hydrochloric acid and brine and dried over anhydrous magnesium sulfate and then the desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to afford 2-fluoro-N,N-dimethyl-5-nitroaniline as a pale yellow oil (290 mg).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH:11]([CH2:12][O:13][CH3:14])[CH2:10][CH2:9][CH:8]1[CH2:15][O:16][Si](C(C)(C)C)(C)C)=[O:6])[CH:2]=[CH2:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>O1CCCC1>[CH2:1]([O:4][C:5]([N:7]1[CH:11]([CH2:12][O:13][CH3:14])[CH2:10][CH2:9][CH:8]1[CH2:15][OH:16])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C(COC)CCC1CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)N1C(CO)CCC1COC
Temperature: 25 °C
Yield: 86.8 %

Procedure:
To a solution of 1-allyloxycarbonyl-2-t-butyldimethylsilyloxymethyl-5-methoxymethylpyrrolidine (9.67 g) in tetrahydrofuran (97 ml) was added dropwise a solution of tetrabutylammonium fluoride in tetrahydrofuran (31 ml) at 0° C. The mixture was allowed to warm to room temperature and stirred for an hour. The mixture was poured into water and ethyl acetate, and the aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layer was washed twice with 1N hydrochloric acid, and with saturated aqueous sodium bicarbonate, water and brine successively, dried over magnesium sulfate and evaporated under reduced pressure to give 1-allyloxycarbonyl-2-hydroxymethyl-5-methoxymethylpyrrolidine (5.60 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:13][NH:14][O:15][CH3:16]>>[CH3:13][N:14]([C:4]([C:3]1[CH:7]=[CH:8][C:9]([I:11])=[CH:10][C:2]=1[F:1])=[O:5])[O:15][CH3:16]
Reactant: O=C(O)c1ccc(I)cc1F
Reactant: CNOC
Agent: Cl
Product: CON(C)C(=O)c1ccc(I)cc1F

Procedure:
The product was prepared from 2-fluoro-4-iodo-benzoic acid (EP-A-0327190) and N,O-dimethylhydroxylamine hydrochloride by a similar method to Preparation 30, as a yellow oil, b.p. 120-122° C. (0.5 mmHg), which was characterised by NMR. 1H-NMR (300OMHz, CDCl3): δ=3.44(s,3H), 3.53(s,3H), 7.14(t,1H), 7.51(d,1H), 7.56(dd,1H) ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:19][S:18][C:17]([NH2:20])=[N:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[C:10](F)[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:23][C:24]1[C:29](B(O)O)=[CH:28][CH:27]=[CH:26][N:25]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[F:23][C:24]1[C:29]([C:2]2[CH:3]=[C:4]3[C@@:15]4([CH2:19][S:18][C:17]([NH2:20])=[N:16]4)[C:14]4[CH:13]=[C:12]([N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)[N:11]=[CH:10][C:9]=4[O:8][C:5]3=[CH:6][CH:7]=2)=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: C1COCCN1
Reactant: NC1=N[C@@]2(CS1)c1cc(Br)ccc1Oc1c2cc(Cl)nc1F
Reactant: OB(O)c1cccnc1F
Product: NC1=N[C@@]2(CS1)c1cc(-c3cccnc3F)ccc1Oc1cnc(N3CCOCC3)cc12

Procedure:
The titled compound was synthesized by steps analogous to those described in Method CC10 above, but using (S)-7-bromo-3-chloro-1-fluoro-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-thiazol]-2′-amine (prepared as described in Method BB26 but using 7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-one), 2-fluoropyridin-3-ylboronic acid and morpholine. MS m/z=450.1 [M+H]+. Calculated for C23H20FN5O2S: 449.13.
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].[O:6]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][NH2:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>C1(C)C=CC=CC=1>[CH:1](=[N:17][CH2:16][C:15]1[CH:18]=[CH:19][CH:20]=[C:13]([O:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:14]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: NCc1cccc(Oc2ccccc2)c1
Reactant: CC(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)C=NCc1cccc(Oc2ccccc2)c1
Reaction time: 0.33 h
Yield: 98 %

Procedure:
38 g (0.528 mol) of isobutyraldehyde is added dropwise within 30 minutes, with stirring, to a solution of 99.5 g (0.5 mol) of 3-phenoxybenzylamine in 100 ml of toluene. After completion of the dropwise addition, stirring is continued for 20 minutes at room temperature, and the water which has formed (about 8.5 g) is separated in a separating funnel. The toluene with the unreacted isobutyraldehyde and residual water is then removed by rotation in a water-jet vacuum, and the residue is distilled in an oil-pump vacuum to yield 124 g (0.49 mol) of N-isobutylidene-(3-phenoxybenzylamine) as a colourless, mobile liquid, corresponding to a yield of 97.8% of theory; b.p. 85° C./4 Pa; nD20 =1.5666.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:23]=[C:22](Cl)[C:21]([N+:25]([O-:27])=[O:26])=[CH:20][N:19]=1>O.O1CCOCC1>[ClH:17].[Cl:17][C:18]1[CH:23]=[C:22]([NH:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]2)[C:21]([N+:25]([O-:27])=[O:26])=[CH:20][N:19]=1
Reactant: N[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cl
Product: O=C(O)[C@H]1CC[C@H](Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
trans-4-Aminocyclohexanecarboxylic acid (5.01 g, 35.0 mmol) and potassium carbonate (4.83 g, 35.0 mmol) were dissolved in water (20 mL). 2,4-Dichloro-5-nitropyridine (6.75 g, 35.0 mmol) was added as a solution in dioxane (40 mL), and the reaction was stirred at 80° C. for 8 hours. The dioxane solvent was removed under vacuum. The remaining aqueous solution was acidified with aqueous 2N HCl (approx. pH 2-3), and the resulting precipitate was collected and washed with water, and then DCM. The solid was dried under high vacuum to yield trans-4-(2-chloro-5-nitropyridin-4-ylamino)cyclohexanecarboxylic acid hydrochloride as a yellow solid (8.79 g, 74.8% yield). MS m/z=300.0 [M+H], calc 299.71 for C12H14ClN3O4.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][C:15]2([C:25]3[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[CH:24]=3)[NH:19][CH2:18]2)[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C>ClCCl>[C:5]([O:9][C:10]([N:12]1[CH2:13][CH2:14][C:15]2([C:25]3[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[CH:24]=3)[N:19]([C:1](=[O:3])[CH3:2])[CH2:18]2)[CH2:16][CH2:17]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNc1ccc(Cl)cc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CC2(CCN(C(=O)OC(C)(C)C)CC2)c2cc(Cl)ccc21
Reaction time: 1 h
Yield: 87 %

Procedure:
Acetyl chloride (2.8 ml) was added dropwise to a stirred solution of 5-chlorospiro[indoline-3,4′-piperidine]-1′-carboxylic acid tert-butyl ester (9.8 g) and triethylamine (15 ml) in anhydrous dichloromethane (400 ml) under an atmosphere of nitrogen. The reaction was stirred for 1 h and was then quenched with saturated sodium bicarbonate solution (200 ml). The organic layer was dried over anhydrous sodium sulphate and concentrated in vacuo to yield 9.8 g (87%) of the desired amide as an off-white solid. M.p. 64-66° C. 1H NMR (400 MHz, CDCl3) δ 6:1 mixture of rotamers. Major rotamer 1.5 (9H, s), 1.70 (m, 2H), 1.85 (m, 2H), 2.25 (s, 3H), 2.85 (m, 2H), 3.90 (s, 2H), 4.2 (m, 2H), 6.97 (d, J=1 Hz, 1H), 7.20 (dd, J=7 & 1 Hz, 1H), 8.15 (d, J=7 Hz, 1H). Minor rotamer 1.5 (9H, s), 1.70 (m, 2H), 1.85 (m, 2H), 2.45 (s, 3H), 2.85 (m, 2H), 4.05 (s, 2H), 4.2 (m, 2H), 7.2 (d, J=1 Hz, 1H), 7.25 (dd, J=7 & 1 Hz, 1H), 7.48 (d, J=7 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[CH:3]1[C:9](O)=[O:10].S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[CH:3]1[C:9]([Cl:15])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)CCC(C)(C)C1C(=O)O
Solvent: Cc1ccccc1
Product: CC1(C)CCC(C)(C)C1C(=O)Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
2.51 g of 2,2,5,5-tetramethylcyclopentanecarboxylic acid was dissolved in 10 ml of toluene, and 2.5 ml of thionyl chloride was added thereto. The mixture was stirred at 80° C. for 3 hours. The reaction solution was concentrated and then distilled under reduced pressure, whereby 2.0 g of 2,2,5,5-tetramethylcyclopentanecarbonyl chloride was obtained. Yield 69%. (b.p. 110°-120° C./60 mmHg)
Reaction SMILES: [N:1](=[C:3]1[C:8](=[O:9])[NH:7][CH2:6][CH2:5][S:4]1)[OH:2].[CH3:10][N:11]=[C:12]=[O:13].C(OCC)C.CCCCCC.[CH3:25][N:26]([CH:28]=[O:29])C>C(N(CC)CC)C>[CH3:10][NH:11][C:12]([N:7]1[CH2:6][CH2:5][S:4][C:3](=[N:1][O:2][C:28](=[O:29])[NH:26][CH3:25])[C:8]1=[O:9])=[O:13]
Reactant: CN=C=O
Reactant: CN(C)C=O
Reactant: O=C1NCCSC1=NO
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CNC(=O)ON=C1SCCN(C(=O)NC)C1=O

Procedure:
To a solution of 4 g. (0.027 mole) of the oxime of Example I in 50 ml of DMF was added 3 g. (0.053 mole) of methyl isocyanate and 3 drops of triethylamine. This mixture was left in a pressure bottle over night at room temperature after which it was added with stirring to a 50:50 ethyl ether:hexane mixture (about 200 ml.). The resulting white solid was collected, washed thoroughly with ethyl ether and air dried. Recrystallization from acetonitrile produced 4 g. (57 per cent) of product, m.p. 187°-189° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([O:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]2[S:17][C:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=3[C:3]=12.C(=O)([O-])[O-].[K+].[K+].[C:30]1([CH3:39])[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(OCC)(=O)C>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][C:6]1[N:5]=[C:4]2[S:17][C:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=3[C:3]2=[C:2]([C:33]2[CH:34]=[CH:35][C:30]([CH3:39])=[CH:31][CH:32]=2)[C:7]=1[CH:8]([O:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10]
Reactant: CCOC(C(=O)OC)c1c(C)nc2sc3c(c2c1Cl)CCCC3
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CCOC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
To a solution of methyl 2-[4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-ethoxyacetate (0.040 g; 0.113 mmol) in a mixture of DME-water (3:1) (0.48 mL) were added potassium carbonate (0.062 g; 0.452 mmol), tetrakis(triphenylphosphine)palladium(0) (0.0065 g; 0.0056 mmol) and 4-tolylboronic acid (0.031 g; 0.226 mmol). The solution was stirred for 30 min at 140° C. under microwave irradiation. Ethyl acetate was added to the reaction mixture and the solution was washed with brine. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethylacetate (5-40%) in heptane furnished 0.025 g (54%) of the title compound as a solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][C:11]([NH:13][C:14]3[S:15][C:16]([C:20]([NH:22][C@@H:23]([CH2:27][NH:28][C:29]([C:31]4[S:32][CH:33]=[CH:34][CH:35]=4)=[O:30])[C:24]([OH:26])=[O:25])=[O:21])=[C:17]([CH3:19])[N:18]=3)=[O:12])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl[CH:37]([O:39][C:40](=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42])[CH3:38].C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[CH3:42][C:41]([CH3:44])([CH3:43])[C:40]([O:39][CH:37]([O:25][C:24](=[O:26])[C@@H:23]([NH:22][C:20]([C:16]1[S:15][C:14]([NH:13][C:11](=[O:12])[CH2:10][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH:3]=[N:2][NH:1]3)=[N:18][C:17]=1[CH3:19])=[O:21])[CH2:27][NH:28][C:29]([C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)=[O:30])[CH3:38])=[O:45]
Reactant: Cc1nc(NC(=O)Cc2cccc3[nH]ncc23)sc1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)O
Reactant: CC(Cl)OC(=O)C(C)(C)C
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(NC(=O)Cc2cccc3[nH]ncc23)sc1C(=O)N[C@@H](CNC(=O)c1cccs1)C(=O)OC(C)OC(=O)C(C)(C)C

Procedure:
A solution of (S)-2-{[2-(2-1H-Indazol-4-yl-acetylamino)-4-methyl-thiazole-5-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]-propionic acid (70.2 mg, 0.137 mmol), 2,2-Dimethyl-propionic acid 1-chloro-ethyl ester (51 mg, 0.310 mmol), triethylamine (22 mg, 0.217 mmol) and sodium iodide (15 mg, 0.10 mmol) in anhydrous DMF (2.5 mL) was microwaved at 150° C. for 10 min and then concentrated at reduced pressure to remove most of the DMF. The residue was diluted with ethyl acetate (40 mL), washed with water (10 mL), brine (10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting crude compound was purified by flash chromatography (50% to 80% EtOAc in hexanes) to give(S)-2-{[2-(2-1H-Indazol-4-yl-acetylamino)-4-methyl-thiazole-5-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]-propionic acid 1-(2,2-dimethyl-propionyloxy)-ethyl ester (25.4 mg, 28.9%) as a yellow solid. MS m/e 641.7 (M+H+).