Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:38])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[C:35]([CH3:36])=[CH:34][N:33]=[C:32]([CH3:37])[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:38])[CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[C:35]([CH3:36])=[CH:34][N:33]=[C:32]([CH3:37])[CH:31]=4)[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(Cl)cc3NC(=O)OC(C)(C)C)c2)c(C)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(Cl)c(C(F)(F)F)cc4NC(=O)C3)c2)c(C)cn1

Procedure:
The title compound was prepared from (5-chloro-2-{3-[3-(2,5-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M122) (0.24 g, 0.43 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (110 mg, 58%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8]=[C:9]1[O:13][C:11](=[O:12])[CH2:10]1>CO>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:11](=[O:12])[CH2:10][C:9](=[O:13])[CH3:8])[CH2:4][CH2:3]1
Reactant: C=C1CC(=O)O1
Reactant: OC1CCNCC1
Solvent: CO
Product: CC(=O)CC(=O)N1CCC(O)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A solution of 25.30 g (0.25 mol) 4-hydroxy-piperidin in 50 ml MeOH was added dropwise to a solution of 20.00 g (0.24) diketene in 50 ml MeOH at 0° C. After stirring for 1 hour at 0° C., no starting material was detected anymore by thin-layer chromatography. The reaction mixture was spun off and the residue was purified by means of column chromatography. 42.54 g (96% yield) of a slightly yellow oil was obtained.
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]([S:13][CH2:14][CH2:15][OH:16])([CH2:9][CH:10]([CH3:12])[CH3:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:23]([N:27]=[N:28][C:29]([C:36]#[N:37])([CH3:35])[CH2:30][CH2:31][C:32](Cl)=[O:33])([CH3:26])([CH3:25])[CH3:24].O>CCCCC>[C:23]([N:27]=[N:28][C:29]([C:36]#[N:37])([CH3:35])[CH2:30][CH2:31][C:32]([O:16][CH2:15][CH2:14][S:13][C:7]([N:6]=[N:5][C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:8])[CH2:9][CH:10]([CH3:11])[CH3:12])=[O:33])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)N=NC(C)(C#N)CCC(=O)Cl
Reactant: CC(C)CC(C)(N=NC(C)(C)C)SCCO
Solvent: c1ccncc1
Solvent: CCCCC
Solvent: O
Product: CC(C)CC(C)(N=NC(C)(C)C)SCCOC(=O)CCC(C)(C#N)N=NC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a solution of 6.5 grams (.0264 moles) of 2-t-butylazo-2-(β-hydroxyethylthio)-4-methylpentane and 2.5 grams (.031 moles) of pyridine in 50 ml of pentane in a beaker was added 5.75 grams (.025 moles) of 4-t-butylazo-4-cyanovaleryl chloride dropwise while holding the reaction temperature at 25° C ± 2° C. After the addition was complete, the reaction was stirred an additional 1/2 hour at 25° C, 50 ml of water added and the pentane layer separated. The pentane layer was successively washed with 25 ml of 10% HCl, 25 ml of water and 25 ml of 10% NaHCO3 solution, dried over anhydrous Na2SO4, filtered and the pentane evaporated under reduced pressure to leave a viscous tan liquid weighing 7.3 grams (66% yield). The product was purified by chromatographing it over alumina and eluting it with pentane. Evaporation of the pentane left a yellow viscous liquid whose infrared spectrum was in agreement with the structure of the desired product.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:14][C:13]([C:15]([OH:17])=[O:16])=[CH:12][C:9]=3[NH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(NC(=NC(C)C)O[C:24]([CH3:27])([CH3:26])[CH3:25])(C)C.NC(=N)O>C(Cl)Cl>[CH:1]1([C:7]2[C:8]3[S:14][C:13]([C:15]([O:17][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:16])=[CH:12][C:9]=3[NH:10][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)N=C(NC(C)C)OC(C)(C)C
Reactant: O=C(O)c1cc2[nH]cc(C3CCCCC3)c2s1
Agent: N=C(N)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc2[nH]cc(C3CCCCC3)c2s1
Reaction time: 16 h
Yield: 57 %

Procedure:
A suspension of 6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylic acid (1 eq., prepared as described in WO2005/023819) in dry CH2Cl2 (0.19 M) was treated with tert-butyl N,N′-diisopropylimidocarbamate (2 eq.). The resulting clear solution was heated to reflux for 20 h. Addition of a further equivalent of isourea was required after 16 h to drive the reaction to complete conversion. After cooling down the solvent was evaporated in vacuo giving a residue that was purified by flash chromatography (PE:EtOAc, 10:1) affording the title compound (57%). 1H-NMR (400 MHz, DMSO-d6, 300 K, δ) 11.12 (bs, 1H), 7.55 (s, 1H), 7.08 (s, 1H), 2.60-2.50 (m, 1H), 1.99-1.67 (m, 5H), 1.51 (s, 9H), 1.45-1.19 (m, 5H). MS (ES+) m/z: 306 [M+H]+.
Reaction SMILES: [Na].[C:2]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:3][C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:5].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19].C(O)(=O)C>C(O)C>[CH3:17][N:18]([CH:20]=[C:3]([C:4](=[O:5])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:2]([O:12][CH2:13][CH3:14])=[O:11])[CH3:19]
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Reactant: COC(OC)N(C)C
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)C(=CN(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.1 %

Procedure:
To a solution of diethyl oxalacetate sodium salt (100 g, 476 mmol) in ethanol (250.00 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (113 g, 952 mmol) and the reaction was stirred at room temperature for 30 min. Acetic acid (54.5 mL, 952 mmol) was added slowly over a period of 3 h and stirred at room temperature for 24 h. The volatile components were evaporated under reduced pressure and the oily residue was purified by silica gel chromatography (750 g REDISEP® column, eluting with 30% EtOAc in hexane). Fractions containing the product were combined and evaporated to afford Intermediate 104A (43 g, 30.8%). MS(ES): m/z=244 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 7.84 (s, 1H), 4.31 (q, J=7.2 Hz, 2H), 4.18 (q, J=5.4 Hz, 2H), 3.35 (s, 3H), 3.04 (s, 3H), 1.36 (t, J=7.2 Hz, 3H), 1.26 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10]Cl)=[N:5][N:4]=[N:3]1.[C:12]1([SH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.[I-].[K+]>[CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][S:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1SCCCCl
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1nnnc1SCCCSc1ccccc1
Yield: 95.2 %

Procedure:
1-Methyl-5-(3-chloropropyl)thio-1,2,3,4-tetrazole (1.9 g) and thiophenol (1.1 g) are dissolved in acetone (50 ml). To the mixture are added potassium carbonate (1.5 g) and potassium iodide (0.1 g), and the mixture is refluxed for 3 hours. After acetone is distilled off, water is added to the residue, and the mixture is extracted with ether. The ether solution is washed with diluted aqueous sodium hydroxide and saturated aqueous sodium chloride and dried over sodium sulfate. After ether is distilled off, the residue is purified by silica gel column chromatography (Kieselgel 60), followed by eluting with benzene-chloroform (3:2) to give 1-methyl-5-(3-phenylthiopropyl)thio-1,2,3,4-tetrazole (2.5 g) as colorless liquid, nD18 =1.6008.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]([C:10]#[N:11])[C:8]#[N:9])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:17][CH2:18][F:19]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]([CH2:17][CH2:18][F:19])([C:8]#[N:9])[C:10]#[N:11])=[CH:12][CH:13]=1
Reactant: N#CC(C#N)Cc1ccc(F)cc1
Reactant: FCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCF)Cc1ccc(F)cc1
Yield: 50.7 %

Procedure:
Using 0.37 g of (4-fluorobenzyl)malononitrile, 5 ml of N,N-dimethylformamide, 0.12 g of sodium hydride (60% in oil), and 0.25 g of 1-bromo-2-fluoroethane, and according to the process described in the Production Example 1, there was obtained 0.22 g of 2-(4-fluorobenzyl)-2-(2-fluoroethyl)malononitrile (the present compound (59)).
Reaction SMILES: [N:1]1([C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([C:24]5[C:25]([CH3:48])=[N:26][N:27]([C:29]([C:42]6[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=6)([C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)[C:30]6[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=6)[CH:28]=5)[CH:22]=4)[N:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[O:7])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:49]N(C)CCN>>[CH3:2][N:3]([CH3:49])[CH2:4][CH2:5][NH:1][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]4[C:25]([CH3:48])=[N:26][N:27]([C:29]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)([C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)[C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH:28]=4)[CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7]
Reactant: CN(C)CCN
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCN(C(=O)n4ccnc4)CC3)c2c1
Product: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCN(C(=O)NCCN(C)C)CC3)c2c1

Procedure:
60 mg 1H-1-imidazolyl{4-[6-(3-methyl-1-trityl-1H-pyrazolyl)-4-quinolyl]piperazin-1-yl)methanone obtained in Example 195 and 1 mL N,N-dimethylethylene diamine were reacted in the same manner as in Example 196, to give 29 mg of the title compound as a pale yellow oil.
Reaction SMILES: O.NN.[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)[N:11]=2)[CH:5]=1>C(O)C>[N:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[N:11]=2)[CH:5]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCn1ccc(-c2cccnc2)n1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCCn1ccc(-c2cccnc2)n1
Yield: 68.9 %

Procedure:
7 ml of hydrazine hydrate is added to a suspension containing 450 ml of ethanol and 22.33 g of the product of Stage A. The reaction medium is taken to reflux for 15 hours. The ethanol is evaporated off, the reaction mixture is agitated with 200 ml of ethyl acetate, washed with salt water, dried, filtered and concentrated. In this way 9.60 g of sought product is obtained.
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:24])[CH:7]([CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)C(OCC)=O)C.Cl>C(O)CO.O>[CH3:23][O:22][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][CH2:13][CH2:7][C:6]([OH:24])=[O:5])[CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C(CCCc1cccc(OC)c1)C(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: COc1cccc(CCCCC(=O)O)c1

Procedure:
KOH (7.0 g, 0.105 mol) was added slowly to a hot solution of the diester from Step C (14 g, 0.046 mol) in ethylene glycol (50 mL) with stirring under Ar. The reaction mixture was heated at reflux for 3 hr, cooled, acidified to pH=2 with HCl, diluted with H2O (150 mL), and extracted with benzene (3×50 mL). The organic layers were combined, washed with dilute NaHCO3 solution (2×100 mL), H2O (2×50 mL), dried, filtered, and concentrated to dryness to give the title compound after chromatography on SiO2 eluting with CHCl3:MeOH, 40:1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C:36]2[N:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][N:37]=2)[CH2:32][CH2:31]1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[CH:11]1([N:8]2[C:9]3[CH:10]=[C:2]([C:39]4[CH:38]=[N:37][C:36]([N:33]5[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]5)=[N:41][CH:40]=4)[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]4[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=4[CH3:26])=[O:17])[C:5]=3[CH:6]=[N:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CN1CCN(c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cnc(N4CCN(C)CC4)nc3)cc3c2cnn3C2CCCC2)c(=O)[nH]1

Procedure:
To a 2 mL microwave vial were added 6-bromo-1-cyclopentyl-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (150 mg, 0.338 mmol), 2-(4-methyl-1-piperazinyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (134 mg, 0.440 mmol), Na2CO3 (108 mg, 1.015 mmol), PdCl2(dppf)-CH2Cl2 adduct (27.6 mg, 0.034 mmol), 1,2-Dimethoxyethane (1269 μl) and water (423 μl). The contents were irradiated in a microwave reactor at 150° C. for 30 min. The reaction solution was filtered through a Whatman 0.45 μl Teflon syringless filter device and diluted with DMSO (6 mL). The DMSO solution was purified by HPLC reverse phase chromatography (phenomenex Gemini-NX, 30×100 5μ column, 5-30% acetonitrile/water 0.01% formic acid, 8 min gradient). The fractions containing the desired product were concentrated to dryness using a Genovac HT-4 instrument at 40° C. The title compound was obtained as a pale cream colored foam (28 mg, 14.83% yield). 1H NMR (400 MHz, CHLOROFORM-δ) δ 8.62 (s, 2H), 8.39 (s, 1H), 7.99 (t, J=5.56 Hz, 1H), 7.71 (s, 1H), 7.57 (s, 1H), 5.98 (s, 1H), 5.03 (quin, J=7.14 Hz, 1H), 4.66 (d, J=5.81 Hz, 2H), 3.97 (br. s., 4H), 2.64 (br. s., 4H), 2.44 (s, 6H), 2.12-2.25 (m, 7H), 1.89-2.07 (m, 2H), 1.67-1.85 (m, 2H). LCMS(ES) [M+H]+ 541.5.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][N:14]=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[CH:12]=[C:7]12.C([Sn](CCCC)(CCCC)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)CCC>O1CCOCC1.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>[CH3:25][O:24][C:20]1[CH:19]=[C:18]([C:13]2[CH:12]=[C:7]3[C:8]4[C:3]([CH2:4][CH2:5][N:6]3[C:16](=[O:17])[CH2:15][N:14]=2)=[C:2]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:11]=[CH:10][CH:9]=4)[CH:23]=[CH:22][CH:21]=1
Reactant: COc1cccc(C2=NCC(=O)N3CCc4c(I)cccc4C3=C2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COc1cccc(C2=NCC(=O)N3CCc4c(cccc4-c4ccccc4)C3=C2)c1
Temperature: 140 °C
Yield: 65.2 %

Procedure:
A mixture of 9-iodo-2-(3-methoxyphenyl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (Example 30) (250 mg, 0.56 mmol), tributyl(phenyl)stannane (202 μL, 1.10 mmol) and Pd(PPh3)4 (33 mg, 0.03 mmol) in 1,4-dioxane (4 mL) was heated in a microwave reactor at 140° C. for 1 h. The mixture was then filtered and concentrated in vacuo. The crude product obtained was purified by flash chromatography (SiO2, hexane to hexane/AcOEt 3:1) to give a yellow oil that was recrystallized from heptane to afford the title compound (144 mg) as white solid. UPLC-MS: MS 395.1 (M+H+); UPLC rt 1.20 min. 1H NMR (400 MHz, CHLOROFORM-d): δ ppm 2.90 (t, J=6.06 Hz, 2 H); 3.79 (t, J=6.26 Hz, 2 H); 3.86 (s, 3 H); 4.53 (br. s., 2 H); 6.97 (s, 1 H); 6.97-7.04 (m, 1 H); 7.28-7.37 (m, 3 H); 7.37-7.51 (m, 7 H); 7.68 (t, J=4.50 Hz, 1 H).
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-])=O)[CH2:5][C:6]([O:8][CH3:9])=[O:7]>CO.O=[Pt]=O>[CH3:9][O:8][C:6](=[O:7])[CH2:5][C@@H:4]1[C:3](=[O:2])[NH:17][C:12]2[C:11](=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:10]1
Reactant: COC(=O)C[C@@H](Nc1ccccc1[N+](=O)[O-])C(=O)OC
Agent: O=[Pt]=O
Solvent: CO
Product: COC(=O)C[C@H]1Nc2ccccc2NC1=O
Reaction time: 6 h

Procedure:
A mixture of 2-(R)-(2-nitrophenylamino)succinic acid dimethyl ester (2.15 g, 7.62 mmol) (prepared below), and PtO2 (210 mg) in methanol (35 mL) was shaken on a Parr apparatus at 48 psi for 6 hours. The reaction was filtered through celite, rinsed with methanol and was evaporated in vacuo to a very sticky oil as the title compound (1.69 g, 100%): 1H NMR (CDCl3) δ=8.23 (bs, 1H), 6.91 (dt, 1H, J=1.8, 7.5 Hz), 6.80-6.70 (m, 3H), 4.74 (bs, 1H), 4.34 (dt, 1H, J=2.4, 10.5 Hz), 3.75 (s, 3H), 3.14 (dd, 1H, J=2.4, 17.4 Hz), 2.75 (dd, 1H, J=10.5, 17.4 Hz).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[S:27]1[CH:31]=[C:30](B(O)O)[C:29]2[CH:35]=[CH:36][CH:37]=[CH:38][C:28]1=2.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[S:27]1[CH:31]=[C:30]([C:2]2[N:3]=[C:4]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)[C:29]2[CH:35]=[CH:36][CH:37]=[CH:38][C:28]1=2
Reactant: OB(O)c1csc2ccccc12
Reactant: CN(C)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CN(C)C1CCN(Cc2cc3nc(-c4csc5ccccc45)nc(N4CCOCC4)c3s2)CC1
Temperature: 140 °C
Yield: 48.1 %

Procedure:
A microwave vessel was charged with [1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-dimethyl-amine (0.400 g, 1.01 mmol), benzo[b]thien-3-ylboronic acid (197 mg, 1.11 mmol), 1 N sodium carbonate solution (2.5 mL), acetonitrile (7.5 mL) and Pd(dppf)Cl2 (82.4 mg. 0.100 mmol), then the mixture was degassed, sealed, and heated at 140° C. under microwave irradiation for 20 min. The reaction mixture was diluted with dichloromethane (100 mL) and 1 N sodium carbonate solution (10 mL) then the phases were separated. The organic phase was washed with saturated aqueous sodium bicarbonate solution (15 mL) then dried (MgSO4) and concentrated in vacuo. Purification by chromatography (silica, 0 to 15% of a 9.5:0.5 MeOH:NH4OH solution in dichloromethane) to afford 146 (240 mg, 48.2%) as a light brown solid. MS m/e 494 [M+H]+ 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.47-1.68 (m, 2 H) 1.81 (d, J=12.43 Hz, 2 H) 2.03-2.20 (m, 3 H) 2.28 (s, 6 H) 3.02 (d, J=12.06 Hz, 2 H) 3.80 (s, 2 H) 3.85-3.95 (m, 4 H) 3.99-4.10 (m, 4 H) 7.32 (s, 1 H) 7.34-7.42 (m, 1 H) 7.43-7.53 (m, 1 H) 7.89 (d, J=7.91 Hz, 1 H) 8.44 (s, 1 H) 9.00-9.15 (m, 1 H).
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:8]([NH:9][C:10]([C@@H:12]([NH:17][C:18]([C:20]2[O:28][C:27]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)=[O:19])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:11])[CH2:7][CH2:6][C@@H:5]([CH3:29])[N:4]([S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)(=[O:32])=[O:31])[CH2:3]1.C(N(CC)CC)C>CS(C)=O.O>[CH3:15][CH:14]([CH3:16])[CH2:13][C@H:12]([NH:17][C:18]([C:20]1[O:28][C:27]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)=[O:19])[C:10](=[O:11])[NH:9][C@H:8]1[CH2:7][CH2:6][C@@H:5]([CH3:29])[N:4]([S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)(=[O:32])=[O:31])[CH2:3][C:2]1=[O:1]
Reactant: CC(C)C[C@H](NC(=O)c1cc2ncccc2o1)C(=O)N[C@H]1CC[C@@H](C)N(S(=O)(=O)c2ccccn2)C[C@@H]1O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: CC(C)C[C@H](NC(=O)c1cc2ncccc2o1)C(=O)N[C@H]1CC[C@@H](C)N(S(=O)(=O)c2ccccn2)CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.4 %

Procedure:
Sulfur trioxide-pyridine complex (0.050 g, 0.31 mmol) was added to a solution of Furo[3,2-b]pyridine-2-carboxylic acid {(S)-1-[(3S,4S,7R)-3-hydroxy-7-methyl-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-amide (0.056 g, 0.103 mmol) in DMSO (1.0 ml) and triethylamine (0.085 ml, 0.6 mmol) was stirred at RT for 1 h. The reaction was incomplete; therefore, additional triethyl amine (0.04 ml, 0.3 mmol) and sulfur trioxide-pyridine complex (0.0.025 g, 0.15 mmol) was added ant the reaction was stirred an additional hour. The reaction mixture was diluted with water, then was extracted with EtOAc. Then, the organic layer was was extracted with brine. The combined organics were dried with magnesium sulfate, filtered, concentrated in vacuo, and purified by column chromatography (50% to 80% ethyl acetate/hexanes) gave the title compound (12.5 mg, 22%): 1H NMR: 1H NMR: 8.72 (1H, d), 8.66 (1H, d), 8.02 (1H, d), 7.93 (1H, dd), 7.85 (1H, d), 7.53 (1H, dd), 7.40 (1H, dd), 7.25 (d, 1H), 6.95 (1H, d), 5.15 (m, 1H), 4.77 (m, 2H), 3.72 (q, 1H), 2.20-2.08 (m, 2H), 1.78-1.50 (m, 5H), 1.22 (dd, 3H), 0.98 (m, 6H); Electrospray mass spec: M+H+=542.2
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:12](=[O:49])[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]([C:30]3[C:38]4[C:33](=[C:34]([F:44])[CH:35]=[CH:36][C:37]=4[O:39][C:40]([F:43])([F:42])[F:41])[N:32]([CH2:45][CH2:46][O:47][CH3:48])[CH:31]=3)=[O:29])[CH2:24][CH2:23]2)[CH:16]=1)[CH:9]([CH3:11])[CH3:10])(C)(C)C.[ClH:51]>CCOCC>[ClH:51].[NH2:7][C@@H:8]([CH:9]([CH3:11])[CH3:10])[C:12]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([CH:22]2[CH2:27][CH2:26][N:25]([C:28]([C:30]3[C:38]4[C:33](=[C:34]([F:44])[CH:35]=[CH:36][C:37]=4[O:39][C:40]([F:41])([F:42])[F:43])[N:32]([CH2:45][CH2:46][O:47][CH3:48])[CH:31]=3)=[O:29])[CH2:24][CH2:23]2)[CH:16]=1)=[O:49]
Reactant: COCCn1cc(C(=O)N2CCC(c3cc(CNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)ccc3F)CC2)c2c(OC(F)(F)F)ccc(F)c21
Agent: Cl
Solvent: CCOCC
Product: COCCn1cc(C(=O)N2CCC(c3cc(CNC(=O)[C@@H](N)C(C)C)ccc3F)CC2)c2c(OC(F)(F)F)ccc(F)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of [(S)-1-(4-fluoro-3-{1-[7-fluoro-1-(2-methoxy-ethyl)-4-trifluoromethoxy-1H-indole-3-carbonyl]-piperidin-4-yl}-benzylcarbamoyl)-2-methyl-propyl]-carbamic acid tert-butyl ester (0.35 g, 0.49 mmol) in ether (20 mL) was added 2M HCl in ether (10 mL, 20.0 mmol). The reaction mixture was stirred at rt overnight. The resulting precipitate was collected to give the titled compound (260 mg, 82%). 1H NMR (300 MHz, DMSO-d6) δ 9.0 (m, 1H), 8.3 (bs, 2H), 7.7 (s, 1H), 7.3-7.0 (m, 5H), 4.5 (m, 2H), 4.4-4.2 (m, 2H), 3.7-3.5 (m, 6H), 3.2 (s, 3H), 3.1-2.9 (m, 2H), 2.1 (m, 1H), 1.85-1.5 (m, 4H), 0.9 (m, 6H). MS m/z: [M+H]+=611.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][N:12]([CH2:28][CH2:29][CH2:30][CH3:31])[CH:13]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]4[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:21]=4[N:22]=3)[CH2:14]2)[CH:6]=1.[OH-].[Na+].O1CCCC1.Cl>CO>[CH2:28]([N:12]([CH2:11][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:32])=[O:2])[CH:10]=[CH:9][CH:8]=1)[CH:13]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]3[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:21]=3[N:22]=2)[CH2:14]1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCCN(Cc1cccc(CC(=O)OC)c1)C1CCN(c2nc3ccc(Cl)cc3s2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCN(Cc1cccc(CC(=O)O)c1)C1CCN(c2nc3ccc(Cl)cc3s2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
A mixture of [3-[[butyl[1-(6-chlorobenzothiazole-2-yl)pyrrolidine-3-yl]amino]methyl]phenyl]acetic acid methyl ester (28 mg), 2N sodium hydroxide (0.15 mL), tetrahydrofuran (1 mL) and methanol (0.5 mL) was stirred at room temperature for 1 hour. The mixture was neutralized with 2N hydrochloric acid and concentrated under reduced pressure. The solution was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate to give the title compound (19 mg). Yield: 68%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:15]([F:18])([F:17])[F:16])=[CH:5][C:6]([N+:12]([O-])=O)=[C:7]([CH2:9][C:10]#N)[CH:8]=1>C(O)C.O.C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][C:4]=1[C:15]([F:18])([F:17])[F:16])[NH:12][CH:10]=[CH:9]2
Reactant: COc1cc(CC#N)c([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2cc[nH]c2cc1C(F)(F)F
Yield: 96.1 %

Procedure:
(5-Methoxy-2-nitro-4-trifluoromethylphenyl)acetonitrile (D9) (85 g, 0.327 mol) in ethanol/water (9:1, 1.6 l) and glacial acetic acid (16 ml) was hydrogenated over 10% palladium on carbon (50 g) at 50 psi for 0.5 h at room temperature. The reaction mixture was filtered and evaporated in vacuo. The residue was partitioned between aqueous K2CO3 (1 l) and dichloromethane (2×1 l) and the combined organic extract was dried Na2SO4) and evaporated to afford the title indole (67.63 g, 96%) as a grey solid.