Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[CH2:4]([O:11][C:12]1[C:13]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:14][C:15]([N+:23]([O-])=O)=[C:16]([CH:22]=1)[CH:17]=[CH:18][N+]([O-])=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>[Fe].C(O)(=O)C>[CH2:4]([O:11][C:12]1[CH:22]=[C:16]2[C:15](=[CH:14][C:13]=1[O:26][CH2:27][CH2:28][CH2:29][CH3:30])[NH:23][CH:18]=[CH:17]2)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCCCOc1cc([N+](=O)[O-])c(C=C[N+](=O)[O-])cc1OCc1ccccc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCOc1cc2[nH]ccc2cc1OCc1ccccc1
Reaction time: 0.25 h
Yield: 40 %

Procedure:
8.6 g of activated iron are added at 60° C. to a solution of 28 ml of absolute ethanol and 14 ml of acetic acid. The mixture is kept for 15 minutes at 80° C. and 5-benzyloxy-4-butoxy-2,β-dinitrostyrene (1.6 g; 0.0043 mole) is added. The mixture is left at 80° C. for 1 hour, and the ferric sludge is filtered off and rinsed with 40 ml of ethanol and 40 ml of acetic acid. The filtrate is diluted with 100 ml of ice-cold water. After extraction of the solution with methylene chloride and drying of the organic phase over sodium sulphate, the organic phase is concentrated and chromatographed on silica 60 (eluent: toluene/CH2Cl2, 50:50). 0.5 g (40% yield) of the expected derivative is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:35][CH2:36][C:37](Br)=[O:38]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[C:37](=[O:38])[CH2:36][Br:35])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Reactant: O=C(Br)CBr
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N(Cc3ccc4ccc(C#N)cc4c3)C(=O)CBr)cc2)CC1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, bromoacetyl bromide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])/[CH:4]=[CH:5]\[C:6]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:7]=1[C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9].CO[CH2:25][N:26]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:27][Si](C)(C)C.FC(F)(F)C(O)=O>CCOC(C)=O.FC(F)(F)C(O)=O>[CH2:32]([N:26]1[CH2:27][C@H:5]([C:6]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:7]=2[C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[C@H:4]([C:3]([O:2][CH3:1])=[O:22])[CH2:25]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: COC(=O)/C=C\c1cccc(C(F)(F)F)c1C(=O)OC(C)C
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1c1cccc(C(F)(F)F)c1C(=O)OC(C)C
Temperature: 65 °C
Reaction time: 4 h
Yield: 92.9 %

Procedure:
To a solution of (Z)-isopropyl 2-(3-methoxy-3-oxoprop-1-enyl)-6-(trifluoromethyl)benzoate (2.5 g, 7.9 mmol) in 30 mL of EtOAc was added N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (2.34 g, 9.9 mmol) and trifluoroacetic acid (0.12 mL, 1.6 mmol). The solution was allowed to stir at 65° C. for 4 h. Starting material still remained by TLC analysis and so additional N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (1.0 g, 4.2 mmol) and trifluoroacetic acid (0.05 mL, 0.65 mmol) were added and the reaction was stirred at 65° C. for an additional 3 h. The reaction was allowed to cool and was diluted with EtOAc, washed with sat'd aq NaHCO3 and brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography (5:1 hexane/EtOAc) to afford 3.3 g (93%) of the title compound as an oil. LRMS (ES)+: 450.35 (M+H)+.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C@@H:8]([C@@H:17]1[C@@H:21]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)[CH2:20][N:19]([C:30]([C:32]2[CH:37]=C(C)N=[N:34][CH:33]=2)=[O:31])[CH2:18]1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)(C)(C)C.CC[CH2:43][CH2:44][N+:45](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)(=O)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C@H:8]([C@@H:17]2[C@@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=3)[CH2:20][N:19]([C:30]([C:32]3[CH:37]=[N:45][C:44]([CH3:43])=[N:34][CH:33]=3)=[O:31])[CH2:18]2)[CH2:7][OH:6])=[N:11][CH:12]=1
Reactant: Cc1cc(C(=O)N2C[C@H]([C@H](CO[Si](C)(C)C(C)(C)C)Oc3ccc(Cl)cn3)[C@@H](c3ccc(F)c(F)c3)C2)cnn1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ncc(C(=O)N2C[C@H]([C@H](CO)Oc3ccc(Cl)cn3)[C@@H](c3ccc(F)c(F)c3)C2)cn1
Temperature: 25 °C
Yield: 84 %

Procedure:
To a solution of [(3R,4S)-3-[(R)-2-(tert-butyl-dimethyl-silanyloxy)-1-(5-chloro-pyridin-2-yloxy)-ethyl]-4-(3,4-difluoro-phenyl)-pyrrolidin-1-yl]-(6-methyl-pyridazin-4-yl)-methanone (0.050 g, 0.085 mmol) dissolved in THF (4 mL) was added 0.10 mL of TBAF (1.0M in THF). The reaction mixture was stirred over night at room temperature. The mixture was diluted with ethyl acetate and washed with water and aq. sodium bicarbonate solution subsequently. The separated organic phase was dried over sodium sulfate and concentrated in vaccuo after filtration. The residue was purified by TLC (SiO2, MeOH/DCM, 1:10) yielded 40 mg (84%) of the title compound as a light yellow oil. ES-MS m/e: 475.1 (M+H+).
Reaction SMILES: Cl.Cl[C:3]1[N:4]=[CH:5][C:6]2[N:12]([CH3:13])[C:11](=[O:14])[C:10]3([CH2:16][CH2:15]3)[CH2:9][N:8]([C@@H:17]3[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18]3)[C:7]=2[N:24]=1.[NH2:25][C:26]1[CH:37]=[CH:36][C:29]([C:30]([NH:32][CH:33]2[CH2:35][CH2:34]2)=[O:31])=[CH:28][C:27]=1[O:38][CH3:39]>C(O)C.O>[CH:33]1([NH:32][C:30](=[O:31])[C:29]2[CH:36]=[CH:37][C:26]([NH:25][C:3]3[N:4]=[CH:5][C:6]4[N:12]([CH3:13])[C:11](=[O:14])[C:10]5([CH2:15][CH2:16]5)[CH2:9][N:8]([C@@H:17]5[CH2:21][CH2:20][C:19]([F:22])([F:23])[CH2:18]5)[C:7]=4[N:24]=3)=[C:27]([O:38][CH3:39])[CH:28]=2)[CH2:34][CH2:35]1
Reactant: CN1C(=O)C2(CC2)CN([C@@H]2CCC(F)(F)C2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)NC2CC2)ccc1N
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)NC2CC2)ccc1Nc1ncc2c(n1)N([C@@H]1CCC(F)(F)C1)CC1(CC1)C(=O)N2C
Temperature: 85 °C
Reaction time: 18 h
Yield: 33 %

Procedure:
Concentrated hydrochloric acid (45 μl) was added to a mixture of (R)-2′-chloro-9′-(3,3-difluorocyclopentyl)-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepin]-6′(5′H)-one (100 mg, 0.29 mmol) and 4-amino-N-cyclopropyl-3-methoxybenzamide (90 mg, 0.44 mmol) in ethanol (1.4 mL) and water (5.2 mL). The reaction mixture was heated to 85° C. and stirred for 18 hours. The reaction mixture was concentrated in vacuo. The residue was taken up with ethyl acetate, washed with an aqueous saturated solution of sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the desired compound as a white solid (49 mg, 33% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[CH:10]=[C:6]2[N:5]=[CH:4][CH:3]=1.[I:18]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.C(Cl)Cl>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:10]([I:18])=[C:6]2[N:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1ccccc1-c1cc2nccc(Cl)n2n1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Clc1ccccc1-c1nn2c(Cl)ccnc2c1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
To a solution of 7-chloro-2-(2-chlorophenyl)-pyrazolo[1,5-a]pyrimidine (I-1A-1c; 6.00 g, 22.7 mmol) in chloroform (23 ml) and methylene chloride (207 ml) cooled in an ice bath was added N-iodosuccinimide (7.67 g, 34.1 mmol), portionwise. The ice bath was removed and the reaction was stirred overnight at room temperature. After concentrating the red-brown reaction, in vacuo, an ethyl acetate solution of the residue was washed with saturated aqueous Na2S2O4 and brine. The solution was dried (MgSO4), concentrated, in vacuo, and the resulting solids repulped at room temperature from ethyl acetate (30 ml) to give product I-1A-1d as a solid (6.8 g, 77%): +APcI MS (M+1) 390.1; 1H NMR (400 MHz, CD2Cl2) δ 8.52 (d, J=4.6 Hz, 1H), 7.59–7.56 (m, 1H), 7.53–7.42 (m, 3H), 7.14 (d, J=4.6 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:10]=[N:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]3[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1.C[Si](Cl)(C)C.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.N>N1C=CC=CC=1.O>[C:25]([NH:1][C:2]1[C:3]2[N:10]=[N:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]3[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ncnc2c1nnn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: O=C(Cl)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: N
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1ncnc2c1nnn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
100 mg (0.37 mmol) of 7-amino-3-β-D-ribofuranosyl-3H-1,2,3-triazolo[4,5-d]pyrimidine are initially introduced in 5 ml of dry pyridine. 0.47 ml (3.7 mmol) of trimethylsilyl chloride is added dropwise to this solution under an argon atmosphere. After the mixture has been stirred at room temperature for half an hour (monitoring by TLC), 0.25 ml (2.0 mmol) of benzoyl chloride is added dropwise, and this reaction mixture is stirred at room temperature for 4 hours. It is then cooled down to 0-5° C. and 1 ml of water is added followed, 5 min later, by 2 ml of aqueous ammonia (25%); this mixture is then stirred for a further 30 min. The solvent is stripped off and the residue is then evaporated with toluene. The residue is taken up in 15 ml of a saturated solution of NaHCO3, and this mixture is extracted one with 25 ml of methylene chloride and several times with ethyl acetate. The combined organic phases are dried using Na2SO4.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:23][N:24]([CH3:27])C=O>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:4][CH2:5][C:6]4[CH:7]=[N:8][N:24]([CH3:27])[CH:23]=4)[CH2:13][CH2:12]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Clc1ccc2c(C3CCNCC3)c[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cn1cc(CCN2CCC(c3c[nH]c4cc(Cl)ccc34)CC2)cn1
Temperature: 25 °C
Yield: 59.8 %

Procedure:
To a mixture of 2.0 gm (8.5 mMol) 6-chloro-3-(piperidin-4-yl)-1H-indole and 2.25 gm (21 mMol) sodium carbonate in 20 mL dimethylformamide was added a solution of 1.74 gm (8.4 mMol) 1-methyl-4-(2-methanesulfonyloxy)ethyl-1H-pyrazole in a minimal volume of dimethylformamide. The resultant mixture was heated at 100° C. for 18 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between dichloromethane and water. The organic phase was separated and washed first with water and then with saturated aqueous sodium chloride. The remaining organics were dried over sodium sulfate and concentrated under reduced pressure to give a yellow oil. This residue was subjected to silica gel chromatography, eluting with dichloromethane containing 5% methanol. Fractions shown to contain product were combined and concentrated under reduced pressure to give 1.74 gm (59.8%) of 6-chloro-3-(1-(2-(1-methylpyrazol-4-yl)ethyl)piperidin-4-yl)-1H-indole as a yellow foam. The oxalate salt was formed and crystallized from methanol to provide the title compound as yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH:11][S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ccc([N+](=O)[O-])cc1NS(=O)(=O)c1ccccc1

Procedure:
A solution of 4-nitro 1,2-phenylene diamine(1.53 g, 10.0 mmol) in DMF was treated with phenyl sulfonyl chloride(1.76 g, 10.0 mmol) and triethyl amine(1.01 g) in DMF for 12 h at 23° C. The reaction mixture was partitioned between saturated NH4Cl and methylene chloride. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting solid was recrystallized (EtOH) to afford desired (0.275 g, 9%). 1H NMR(DMSO) 9.5(s, 1H, br), 7.83 (dd, 1H, J=10 Hz, 2 Hz), 7.74(d, 2H, J=8 Hz), 7.76(t, 1H, J=8 Hz), 7.56(t, 2H, J=8 Hz), 7.55(d,1H, J=2 Hz), 6.79 (d, 1H, J=8 Hz), 6.5(s, 2H, br).
Reaction SMILES: [I-].C[S+](C)C.[CH3:6]C(C)([O-])C.[K+].[C:12]([O:16][C:17]([N:19]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@H:20]([CH:28]=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>C(#N)C.O>[C:12]([O:16][C:17]([N:19]([C@@H:20]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C@@H:28]1[O:29][CH2:6]1)[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)[C@H](C=O)Cc1ccccc1
Agent: C[S+](C)C
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)[C@@H](Cc1ccccc1)[C@H]1CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a suspension of 0.90 g (4.42 mmoles) of trimethylsulfonium iodide in 18 mL of acetonitrile was added 0.495 g (4.42 mmoles) of potassium t-butoxide. A solution of 1.0 g (2.95 mmoles) of N-(t-butoxycarbonyl)-N-benzyl-L-phenylalaninal in 7 mL of acetonitrile was added and the mixture was stirred at room temperature for one hour. The mixture was diluted with 80 mL of water and extracted twice with 80 mL of ethyl acetate. The organic layers were combined and washed with 100 mL water, 30 mL brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 1.04 g of a yellow crude oil. The crude product was a mixture of the two diastereomers N,αS-bis(phenylmethyl)-N-(t-butoxycarbonyl)-2S-oxiranemethanamine and N,αS-bis(phenylmethyl)-N-(t-butoxycarbonyl)-2R-oxiranemethanamine.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:28])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:29][C:30]1[CH:35]=[C:34]([S:36][CH3:37])[CH:33]=[C:32]([F:38])[C:31]=1[C:39]1[N:44]=[C:43]([C:45](O)=[O:46])[CH:42]=[CH:41][C:40]=1[F:48].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:28][C:45]([C:43]3[CH:42]=[CH:41][C:40]([F:48])=[C:39]([C:31]4[C:30]([F:29])=[CH:35][C:34]([S:36][CH3:37])=[CH:33][C:32]=4[F:38])[N:44]=3)=[O:46])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CSc1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CSc1cc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3CCC[C@H](NC(=O)OC(C)(C)C)C3)CCC4OC(C)=O)ccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.3 %

Procedure:
A mixture of 3-amino-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (12.0 mg, 0.031 mmol), 6-[2,6-difluoro-4-(methylthio)phenyl]-5-fluoropyridine-2-carboxylic acid (11.0 mg, 0.037 mmol), HATU (29.2 mg, 0.077 mmol) in DMF (0.07 mL) and DIPEA (11.9 mg, 0.092 mmol) was stirred at room temperature for 16 h. The reaction mixture was filtered, concentrated and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as a colorless gum (6.3 mg, 30%). LCMS calc. for C33H37F3N5O5S (M+H)+: m/z=672.2. Found: 672.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[CH2:16]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([O:22][C:23]([NH:25][CH:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19].[O-]CC.[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=1[CH2:16][C:26]([NH:25][C:23]([O:22][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:24])([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1cc(I)ccc1OCc1ccccc1
Reactant: CCOC(=O)C(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(Cc1cc(I)ccc1OCc1ccccc1)(NC(=O)OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
41 g (101.7 mmol) of 1-benzyloxy-2-bromomethyl-4-iodobenzene (Example 4A) are added to a solution of 28 g (101.7 mmol) of diethyl 2-[N-(tert-butoxycarbonyl)amino]malonate and 7.9 ml (101.7 mmol) of sodium ethoxide in 300 ml of ethanol. After stirring at RT for 3 h, the precipitated product is collected by suction filtration. After drying in vacuo, 55 g (90% of theory) of product are isolated.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:24][CH2:25][CH2:26][O:27][C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(OCCN)cc1
Reactant: O=C(O)c1ccc(Br)cc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(OCCNC(=O)c2ccc(Br)cc2)cc1
Yield: 56.7 %

Procedure:
p-Bromobenzoic acid (6 g) and 3.35 g of triethylamine were dissolved in 80 ml of chloroform, the mixture was cooled at 0°-5° C. with stirring, and 3.26 g of ethyl chlorocarbonate was dropped thereinto. The mixture was stirred at the same temperature for 30 minutes, 5.86 g of methyl 4-(2-aminoethoxy)benzoate was added, and the mixture was stirred for 7 hours more. The reaction solution was washed with 10% hydrochloric acid, saturated potassium carbonate solution, and with water, dried with anhydrous magnesium sulphate, concentrated in vacuo, the residue was crystallised with n-hexane, and 8.5 g of crystals obtained were recrystallised from ethyl acetate to give 6.4 g of the product, m.p. 134°-136° C.
Reaction SMILES: [CH2:1]([C:12]#[N:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH3:14][CH:15](N)[CH2:16][OH:17]>C(O)CCC.O.O.C([O-])(=O)C.[Cd+2].C([O-])(=O)C>[CH3:14][CH:15]1[CH2:16][O:17][C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[N:13]1
Reactant: CCCCCCCCCCCC#N
Reactant: CC(N)CO
Agent: CC(=O)[O-]
Agent: [Cd+2]
Solvent: CCCCO
Solvent: O
Product: CCCCCCCCCCCC1=NC(C)CO1
Yield: 91.9 %

Procedure:
10.9 g (60 mmoles) of undecyl cyanide was treated with 5 g (66.6 mmoles) of DL-2-amino-1-propanol in presence of 400 mg (1.5 mmoles) of cadmium acetate dihydrate in 1-butanol as outlined under Example 1. 13.2 g (92%) of product was obtained on distillation at 115°-117° C./1-1.5 mm Hg.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6]/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10]>CN(C=O)C>[N:1]([CH2:6]/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10])=[N+:2]=[N-:3]
Reactant: COC(=O)/C=C/CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C/CN=[N+]=[N-]
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
To the solution of NaN3 (2.80 g, 43.01 mmol) in 100 ml of DMF at −20° C. was added methyl 4-bromocrotonate (5.00 ml, 85%, 36.10 mmol). After stirred at −20° C. for 30 min, the mixture was stirred at 0° C. for 4 h, evaporated, suspended with EtAc/Hexane (1:1), filtered, evaporated and chromatographic purification on SiO2 column eluted with EtAc/Hexane (1:25 to 1:10) to afford HRMS for 4.08 g (80%) of the title product. 1H NMR (CDCl3) 6.88 (m, 1H), 6.06 (ddd, 1H, J=1.7, 3.4, 15.6 Hz), 3.97 (dd, 2H, J=1.2, 4.96 Hz), 3.73 (s, 3H); 13C NMR 166.23, 140.86, 123.49, 51.95, 51.36; ESI MS m/z+182.5 (M+Na+H2O); HRMS m/z+(C5H7N3O2+H2O+Na) calcd 182.0542. found 182.0548.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][NH:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:36])[C:9]=2[F:37])=[O:6])[CH2:3][CH2:2]1.CO.C(Cl)Cl.[C:43](OC(=O)C)(=[O:45])[CH3:44]>>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:25]=[CH:26][C:27]([CH2:30][N:31]([CH2:32][CH2:33][O:34][CH3:35])[C:43](=[O:45])[CH3:44])=[CH:28][CH:29]=5)[S:23][C:16]=34)=[C:10]([F:36])[C:9]=2[F:37])[CH2:2][CH2:3]1
Reactant: CC(=O)OC(C)=O
Reactant: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)c(F)c4F)c3s2)nc1
Solvent: ClCCl
Solvent: CO
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)c(F)c4F)c3s2)nc1)C(C)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 38 %

Procedure:
A suspension of compound 25 (100 mg, 0.156 mmol, TFA salt) in acetic anhydride (1 mL) was stirred at RT for 2 days. The reaction mixture was quenched by addition of methanol and water. The fine suspension was collected by filtration, rinsed successively with water, 1N NaOH, water, and air-dried. The crude product was purified by Biotage (SNAP 25 g cartridge; MeOH/DCM: 0/100 to 10/90 over 20 CV, then 10/90 over 5 CV) to afford the title compound 26 (34 mg, 0.06 mmol, 38% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): mixture of rotamers, 8.57-8.44 (m, 3H), 8.38 and 8.34 (2s, 1H), 8.30 and 8.24 (2d, J=8.2 Hz, 1H), 8.04 (bt, J=8.3 Hz, 1H), 7.82-7.75 (m, 1H), 7.32-7.25 (m, 1H), 6.87 (bd, J=2.7 Hz, 1H), 6.79-6.74 (m, 1H), 4.71 and 4.59 (2s, 2H), 3.54-3.40 (m, 4H), 3.24 and 3.21 (2s, 3H), 2.61-2.53 (m, 1H), 2.13 and 2.05 (2s, 3H), 0.73-0.58 (m, 2H), 0.50-0.36 (m, 2H). MS (m/z): 568.6 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:35])[CH2:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:33]=[N:32][CH:31]=[CH:30][N:29]=2)[CH:23]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:29]1[CH:30]=[CH:31][N:32]=[CH:33][C:28]=1[C:24]1[CH:23]=[C:22]([C:21]2[CH2:20][C:19](=[O:35])[NH:18][C:9]3[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=3[N:7]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cnccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3cnccn3)c2)=Nc2ccc(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from {2-[3-oxo-3-(3-pyrazin-2-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M81) (0.33 g, 0.66 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (197 mg, 78%).