Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:27]=[C:26]([CH3:28])[C:6]([O:7][C:8]2[C:13]([N+:14]([O-])=O)=[CH:12][N:11]=[C:10]([NH:17][C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)[N:9]=2)=[C:5]([CH3:29])[CH:4]=1)#[N:2]>O1CCCC1.[Pd]>[NH2:14][C:13]1[C:8]([O:7][C:6]2[C:26]([CH3:28])=[CH:27][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[CH3:29])=[N:9][C:10]([NH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)=[N:11][CH:12]=1
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)ncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)ncc1N
Yield: 84.2 %

Procedure:
A mixture of 4-[[4-(4-cyano-2,6-dimethylphenoxy)-5-nitro-2-pyrimidinyl]amino]-benzonitrile (0.0005 mol) in tetrahydrofuran (20 ml) was hydrogenated overnight with Pd/C 10% (0.100 g) as a catalyst. After uptake of H2 (3 equiv; 0.0015 mol), the catalyst was filtered off and the filtrate was concentrated by rotary evaporation and dried in vacuo over 16 hours at 40° C., yielding 0.15 g of 4-[[5-amino-4-(4-cyano-2,6-dimethylphenoxy)-2-pyrimidinyl]amino]benzonitrile (84%); mp. >300° C. (comp. 50).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([CH3:24])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH:10]=[CH:9]3)[CH2:6][CH2:5]1.C1C=CC=CC=1>C(Cl)Cl>[OH:1][CH2:2][C@@H:3]([CH3:24])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH:14]=[CH:15]2)[CH:10]=[CH:9]3)[CH2:6][CH2:5]1
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccccc1
Solvent: ClCCl
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A solution of 1.7 g. of (20S)-21-hydroxy-20-methylpregna-4,6-dien-3-one in 80 ml. of dry benzene was treated with 1.45 g. of dichlorodicyano and then heated under reflux for 10 hours. The resulting suspension was filtered under suction, the filtrate was washed with 5% sodium hydroxide, then with water and dried over sodium sulfate. The residue obtained by evaporation was taken up in methylene chloride and filtered through a column of 10 g. of aluminum oxide. From the filtrate, 1 g. of crude crystals were obtained, were recrystallized from ether to give (20S)-21-hydroxy-20-methylpregna-1,4,6-trien-3-one, m.p. 156°-157°. This was shown to be identical to the compound obtained in Example 8 according to its thin layer chromatogram mixture, melting point and infrared spectrum.
Reaction SMILES: [CH2:1]1[CH2:15][C@H:14]2[C@@H:4]([CH2:5][C:6]3[C:16]4[C:9](=[CH:10][CH:11]=[CH:12][C:13]2=4)[NH:8][CH:7]=3)[NH:3][CH2:2]1.C(#N)C.B(F)(F)F.CCOCC.S(Cl)([Cl:32])(=O)=O>C(Cl)Cl.[N+](C)([O-])=O>[Cl:32][C:7]1[NH:8][C:9]2[C:16]3[C:6]=1[CH2:5][C@@H:4]1[C@@H:14]([C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH2:15][CH2:1][CH2:2][NH:3]1
Reactant: c1cc2c3c(c[nH]c3c1)C[C@H]1NCCC[C@H]21
Reactant: O=S(=O)(Cl)Cl
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC#N
Solvent: ClCCl
Product: Clc1[nH]c2cccc3c2c1C[C@H]1NCCC[C@H]31

Procedure:
The above chlorination step is carried out by suspending or dissolving an ergoline according to Formula I wherein X is H in an inert solvent, as for example acetonitrile, nitromethane, methylene dichloride, etc. Ordinarily the suspension or solution is cooled to a temperature in the range -10° to 10° C. An excess (2--3 fold) of boron trifluoride etherate is then added, upon which addition the suspended ergoline, if not already in solution, dissolves. An excess (10 percent usually) of sulfuryl chloride in an inert solvent such as methylene dichloride is next added in dropwise fashion. The reaction mixture is stirred under cooling for about 15 minutes and the reaction is then quenched by dilution with an aqueous base such as 10 percent aqueous ammonium hydroxide. The 2-chloroergoline thus produced is then extracted into a water-immiscible organic solvent and the organic layer separated. The separated organic solution is then washed with, for example, a saturated aqueous sodium chloride solution or otherwise purified, separated again, and then dried. Evaporation of the solvent yields, as a residue, a 2-chloroegoline according to Formula I above (wherein X is chloro) formed in the above reaction. The 2-chloroergoline can be further purified by chromatography or crystallization. Yields of the chlorinated compound vary from 40 to 75 percent with a majority of runs giving in excess of 70 percent of the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[C:11]([C:13]1[C:14]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=1)#[N:12]>>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:14]3[N:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[C:11]#[N:12])[CH2:21][CH2:22]2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: Cc1cnc(N2CCNCC2)c(C#N)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C#N)c1
Yield: 79.2 %

Procedure:
Using 6-bromonicotinic acid (303 mg) and 4-(3-cyano-5-methylpyridin-2-yl)piperazine (303 mg) described in Preparation Example 107 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (458 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:14][CH3:15])[C:8](=[O:13])[CH2:9][CH2:10][NH:11][CH3:12])=[CH:5][N:4]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.N1C=CC=CC=1.[F:28][C:29]([F:35])([F:34])[CH2:30][C:31](Cl)=[O:32]>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[Cl:1][C:2]1[C:6]([N:7]([CH2:14][CH3:15])[C:8](=[O:13])[CH2:9][CH2:10][N:11]([CH3:12])[C:31](=[O:32])[CH2:30][C:29]([F:35])([F:34])[F:28])=[CH:5][N:4]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1
Reactant: O=C(Cl)CC(F)(F)F
Reactant: CCN(C(=O)CCNC)c1cn(-c2cccnc2)nc1Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCN(C(=O)CCN(C)C(=O)CC(F)(F)F)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-(methyl amino)propanamide (0.070 g, 0.23 mmol) in dry CH2Cl2 (0.76 mL) was cooled to a temperature of about 0° C. under N2. To the solution, DMAP (0.014 g, 0.11 mmol), pyridine (0.028 mL, 0.34 mmol), and 3,3,3-trifluoropropanoyl chloride (0.026 mL, 0.25 mmol) were added sequentially. The reaction was slowly warmed up to room temperature under N2, then stirred at room temperature overnight. The reaction was diluted with water (2 mL) and stirred for five minutes. Layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×2 mL). The combined organic extracts were dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0%-5% MeOH/CH2Cl2 to afford the title compound F102 as a white semi-solid (0.062 g, 63%).
Reaction SMILES: [CH3:1][C:2]([NH:6][CH3:7])([CH3:5])[CH2:3][OH:4].[CH2:8]1[O:18][C:17]2[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][C:10]=2[O:9]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][C:2]([N:6]([CH2:13][C:12]1[CH:15]=[CH:16][C:17]2[O:18][CH2:8][O:9][C:10]=2[CH:11]=1)[CH3:7])([CH3:5])[CH2:3][OH:4]
Reactant: CNC(C)(C)CO
Reactant: ClCc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(Cc1ccc2c(c1)OCO2)C(C)(C)CO
Yield: 58 %

Procedure:
A mixture of 2-methyl-2-methylaminopropanol (1.5 g), 3,4-methylenedioxybenzyl chloride (2.5 g) and potassium carbonate (2 g) in acetonitrile (50 ml) was heated under reflux for 4 hours and evaporated. The residue was partitioned between ether and 2M hydrochloric acid and the acidic layer was washed with methylene chloride, basified with 10% aqueous sodium carbonate solution and extracted into methylene chloride. The organic extract was dried over magnesium sulphate and evaporated to give essentially pure 2-methyl-2-[N-(3,4-methylenedioxybenzyl)-N-methylamino]propanol as a yellow oil (2.0 g, 58%) which was used directly in Example 34. A small portion of this product was dissolved in ether and the solution was treated with excess saturated ethereal hydrogen chloride and evaporated. The residue was triturated with acetone/ethyl acetate to give the title compound as a colourless solid, m.p. 157°-159°.
Reaction SMILES: C(OC(=O)[N:10]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[C:24]([CH:28]=2)=[N:25][O:26][N:27]=3)=[CH:16][CH:15]=1)[CH2:11][CH2:12][F:13])C1C=CC=CC=1>[Pd]>[N:27]1[O:26][N:25]=[C:24]2[CH:28]=[C:20]([C:17]3[CH:16]=[CH:15][C:14]([NH:10][CH2:11][CH2:12][F:13])=[CH:19][CH:18]=3)[CH:21]=[CH:22][C:23]=12
Reactant: O=C(OCc1ccccc1)N(CCF)c1ccc(-c2ccc3nonc3c2)cc1
Agent: [Pd]
Product: FCCNc1ccc(-c2ccc3nonc3c2)cc1

Procedure:
391 mg (1 mmol) (4-benzo[1,2,5]oxadiazol-5-yl-phenyl)-(2-fluoro-ethyl)-carbamic acid benzyl ester are hydrogenated in the presence of Pd/C, the reaction mixture filtered through celite and evaporated to dryness. The residues is column chromatographed (dichloromethane/petroleum ether 8:2) to yield the desired product as a yellow powder. MS(ES+): 258 (M+1).
Reaction SMILES: CO[C:3](=[O:26])[CH2:4][NH:5][C:6](=[O:25])[C@H:7]([CH3:24])[NH:8][C:9](=[O:23])[CH2:10][NH:11][C:12](=[O:22])[CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].O.[NH2:28][NH2:29]>CO>[C:18]([O:17][C:15]([NH:14][CH2:13][C:12]([NH:11][CH2:10][C:9]([NH:8][C@H:7]([C:6]([NH:5][CH2:4][C:3]([NH:28][NH2:29])=[O:26])=[O:25])[CH3:24])=[O:23])=[O:22])=[O:16])([CH3:19])([CH3:20])[CH3:21]
Reactant: COC(=O)CNC(=O)[C@H](C)NC(=O)CNC(=O)CNC(=O)OC(C)(C)C
Reactant: NN
Solvent: CO
Solvent: O
Product: C[C@H](NC(=O)CNC(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)NN
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a cooled (ice bath), stirred solution of Boc-Gly-Gly-Ala-Gly-OMe (2.5 g, 6.7 mmoles, described in Example 4) in methanol (50 ml) is added hydrazine hydrate (2.5 ml). The solution is stirred at 0° C for 3 hr and at room temperature overnight. The precipitate is separated by filtration, washed with methanol and dried to yield the title compound; amino acid analysis: Gly 3, Ala 0.99.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][CH2:19][CH:20]1[CH2:25][C:24]([F:27])([F:26])[CH2:23][CH2:22][CH:21]1[CH:28]([OH:43])[CH:29]([C:35]1[CH:40]=[CH:39][C:38]([S:41][CH3:42])=[CH:37][CH:36]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[CH2:11]([O:18][CH2:19][CH:20]1[CH2:25][C:24]([F:26])([F:27])[CH2:23][CH2:22][CH:21]1[C:28](=[O:43])[CH:29]([C:35]1[CH:36]=[CH:37][C:38]([S:41][CH3:42])=[CH:39][CH:40]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)C(c1ccc(SC)cc1)C(O)C1CCC(F)(F)CC1COCc1ccccc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C(=O)C1CCC(F)(F)CC1COCc1ccccc1)c1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Oxalyl chloride (2.9 mL, 34 mmol) was added dropwise to a −78° C. solution of dimethyl sulfoxide (2.9 mL, 41 mmol) in CH2Cl2 (40 mL). Stirring was continued at −78° C. for an additional 10 min prior to the slow introduction down the flask wall of a solution of ethyl 3-{2-[(benzyloxy)methyl]-4,4-difluorocyclohexyl}-3-hydroxy-2-[4-(methylthio)phenyl]propanoate (5.09 g, 10.6 mmol) and triethylamine (16 mL, 120 mmol) in CH2Cl2 (40 mL). The mixture was then held at −78° C. for 10 min followed by rapid warming to rt before being poured into 2 M HCl in a separatory funnel. The layers were shaken and separated, and the aqueous phase was extracted with an additional portion of CH2Cl2. The combined organics were washed with water, dried (Na2SO4) and concentrated. Flash chromatography of the residue on silica gel eluting with 1/4 ethyl acetate/hexanes afforded ethyl 3-{2-[(benzyloxy)methyl]-4,4-difluorocyclohexyl}-2-[4-(methylthio)phenyl]-3-oxopropanoate as a thick, tan colored syrup.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[S:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].ClC(Cl)(Cl)Cl.BrBr.C(O)C>C(#N)C>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH:11][C:12]2[S:13][C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(CNC(=S)Nc2ccccc2)CC1
Agent: BrBr
Solvent: CC#N
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)N1CCC(CNc2nc3ccccc3s2)CC1

Procedure:
To a stirred mixture of 5.8 parts of N-[(1-acetyl-4-piperidinyl)methyl]-N'-phenylthiourea and 160 parts of tetrachloromethane were added 3.7 parts of bromine. The whole was stirred and refluxed for 15 minutes. After the additions of 16 parts of ethanol and 16 parts of acetonitrile, the reaction mixture was cooled. The precipitated product was filtered off, washed with acetonitrile and dried. The hydrobromide salt was dissolved in methanol and water. This solution was alkalized with ammonium hydroxide. The precipitated product was filtered off, washed with water and dried, yielding 2.7 parts of 1-acetyl-N-(2-benzothiazolyl)-4-piperidinemethanamine; m.p. 138.1° C. (intermediate 29).
Reaction SMILES: CS(O[C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:7]=1[C:16]([CH3:19])([CH3:18])[CH3:17])(=O)=O.C([O-])=O.[Li+].CO>[Pd].[C].O>[C:12]([C:9]1[CH:10]=[CH:11][CH:6]=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:8]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1ccc(OS(C)(=O)=O)c(C(C)(C)C)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [Li+]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1cccc(C(C)(C)C)c1
Yield: 75.1 %

Procedure:
Using the thus-obtained, regenerated Pd/carbon (10 g), the same reaction as in Example II-1 was carried out in a nitrogen atmosphere under normal pressure at 25° C., in which, however, 2,4-di-tert-butylphenyl methanesulfonate (100 g, 0.35 mols), lithium formate (37 g, 0.70 mols) and methanol (600 g) were used. Water (20 mL) was added to the reaction liquid and Pd/carbon was collected through filtration, and heptane (100 g) was added to the filtrate. The organic layer obtained after extraction was concentrated under reduced pressure to give crude 1,3-di-tert-butylbenzene (50 g, yield 75% by mass).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:12]([N+:24]([O-])=O)=[C:13]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[CH:14]=[CH:15][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O1CCCC1.[OH-].[OH-].[Pd+2]>[C:1]1([S:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[C:12]=2[NH2:24])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN1CCN(c2cccc(CS(=O)(=O)c3ccccc3)c2[N+](=O)[O-])CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CCN(c2cccc(CS(=O)(=O)c3ccccc3)c2N)CC1
Temperature: 45 °C
Yield: 108.2 %

Procedure:
A solution of 1-(3-benzenesulfonylmethyl-2-nitro-phenyl)-4-methyl-piperazine (25 g) in tetrahydrofuran (500 mL) prepared by heating to 45° C. was added to a pre-hydrogenated suspension of Pearlman's catalyst (20% Pd(OH)2/C; 0.5 g) in tetrahydrofuran (20 mL). Stirring is continued under a hydrogen atmosphere at 45° C. until the reaction is complete (ca. 29 hours). After cooling, the catalyst is filtered off on Solkafloc™ (10 g) and washed with tetrahydrofuran (50 mL). The filtrate is concentrated under vacuum to give 24.9 g of 2-benzenesulfonylmethyl-6-(4-methyl-piperazin-1-yl)-phenylamine as a foam.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.F[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH:16]([C:15]1[CH:18]=[CH:19][C:12]([O:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=2)=[CH:13][CH:14]=1)=[O:17]
Reactant: O=Cc1ccc(F)cc1
Reactant: NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1ccc(Oc2ccc(C=O)cc2)cc1
Temperature: 140 °C
Reaction time: 8 h

Procedure:
3.1 g (23 mmol) of 4-hydroxybenzamide and 2.8 g (23 mmol) of 4-fluorobenzaldehyde were dissolved in DMSO, combined with 4.4 g (32 mmol) of K2CO3 and stirred overnight at 140° C., filtered through basic Alox, washed with DMF, concentrated by rotary evaporation and purified by chromatography (silica gel column, dichloromethane with a gradient of 10-20% methanol). As there was still some DMF present, the mixture was triturated with water, suction filtered and dried
Reaction SMILES: [CH3:1][N:2]1[CH:9]=[CH:8][C:6](=[O:7])[NH:5][C:3]1=[O:4].[CH2:10]([C:12]1[CH:13]=[CH:14][C:15]2[CH:25](O)[C:20]3[N:21]=[C:22]([CH3:24])[S:23][C:19]=3[CH:18]=[CH:17][C:16]=2[CH:27]=1)[CH3:11].FC(F)(F)C(O)=O>ClCCl>[CH2:10]([C:12]1[CH:13]=[CH:14][C:15]2[CH:25]([C:8]3[C:6](=[O:7])[NH:5][C:3](=[O:4])[N:2]([CH3:1])[CH:9]=3)[C:20]3[N:21]=[C:22]([CH3:24])[S:23][C:19]=3[CH:18]=[CH:17][C:16]=2[CH:27]=1)[CH3:11]
Reactant: CCc1ccc2c(c1)C=Cc1sc(C)nc1C2O
Reactant: Cn1ccc(=O)[nH]c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc2c(c1)C=Cc1sc(C)nc1C2c1cn(C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-Methyluracil (0.064 g) was added to a solution of the product from step (xi) (0.10 g) in dichloromethane (2 ml), followed by trifluoroacetic acid (1 ml). The orange solution was stirred at room temperature for 10 minutes before the solvent was removed under reduced pressure. The residue was azeotroped twice with acetonitrile, and the crude product purified by chromatography, eluting with 0-5% methanol in ethyl acetate.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH3:11])[CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]#N)[CH:5]=1.C1(C)C=CC=CC=1.CC(C[AlH]CC(C)C)C.CC[O:31]CC>CCCCCC>[CH3:1][C:2]([CH3:12])([CH3:11])[CH2:3][C:4]1[O:8][N:7]=[C:6]([CH:9]=[O:31])[CH:5]=1
Reactant: CC(C)(C)Cc1cc(C#N)no1
Reactant: CCOCC
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)Cc1cc(C=O)no1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 5-(2,2-dimethyl-propyl)-isoxazole-3-carbonitrile (821 mg, 5 mmol) in Et2O (15 mL) and n-hexane (50 mL) was added dropwise at −78° C. an 1.7M toluene solution of DIBAL (11.8 mL, 20 mmol) keeping the temperature below −70° C. The mixture was stirred at −78° C. for 1 h. The reaction was quenched with EtOAc (7.5 mL), allowed to warm to 0° C., then sat. NH4Cl solution (25 mL) and 1M HCl (50 mL) were added and the mixture stirred at room temperature for 2 h. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (cyclohexane to cyclohexane-EtOAc 80:20) to furnish title compound as a colorless oil: TLC (cyclohexane-EtOAc 80:20) Rf=0.44; ESIMS [M+H]+=168; 1H NMR (400 MHz, DMSO-d6): δ 10.06 (s, 1H), 6.66 (s, 1H), 2.74 (s, 2H), 0.92 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][NH:6][C:7]1[C:12]([CH2:13][NH:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[CH:11][CH:10]=[CH:9][N:8]=1.C1N=CN([C:39](N2C=NC=C2)=[O:40])C=1>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:12]=2[CH2:13][N:14]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[C:39]1=[O:40]
Reactant: COc1ccc(CNc2ncccc2CNC2CCN(C(=O)OC(C)(C)C)CC2)c(OC)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)N(C3CCN(C(=O)OC(C)(C)C)CC3)Cc3cccnc32)c(OC)c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 38.3 %

Procedure:
To a solution of tert-butyl 4-((2-(2,4-dimethoxybenzylamino)pyridin-3-yl)methylamino)piperidine-1-carboxylate (2.89 g, 6.33 mmol) in DMF (42 ml) was added CDI (1.23 g, 7.6 mmol) in portions and the reaction mixture was stirred at 120° C. for 2 hours. A further portion of CDI was added (0.82 g) was added and the reaction mixture stirred at 130° C. for 6 hours, followed by stirring at RT for 16 hours. The reaction was diluted with water and extracted with DCM. The organics were combined, dried (NaSO4) and evaporated to dryness. Purification by column chromatography (10 to 80% EtOAc in Hx) gave the desired product (1.17 g). LC/MS (10% to 99%): M/Z (M+H)+ (obs)=483; tR=3.58.
Reaction SMILES: C[Si]([Br:5])(C)C.[Cl:6][C:7]1[C:8]([C:15]2[S:16][C:17]3[C:18](Cl)=[N:19][CH:20]=[C:21]([F:24])[C:22]=3[N:23]=2)=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11].C(=O)(O)[O-].[Na+]>C(#N)CC>[Br:5][C:18]1[C:17]2[S:16][C:15]([C:8]3[C:7]([Cl:6])=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]#[N:11])=[N:23][C:22]=2[C:21]([F:24])=[CH:20][N:19]=1
Reactant: N#Cc1cccc(Cl)c1-c1nc2c(F)cnc(Cl)c2s1
Reactant: C[Si](C)(C)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC#N
Product: N#Cc1cccc(Cl)c1-c1nc2c(F)cnc(Br)c2s1
Temperature: 50 °C
Yield: 101.7 %

Procedure:
Trimethylsilyl bromide (1.8 mL, 13.2 mmol) was added to a suspension of 3-chloro-2-(4-chloro-7-fluorothiazolo[5,4-c]pyridin-2-yl)-benzonitrile (1.43 g, 4.40 mmol) in propionitrile (40 mL) at room temperature, under argon. The reaction mixture was heated at 50° C. for 7 hours. The reaction mixture was adjusted to pH 7 by careful addition of a saturated aqueous solution of sodium bicarbonate. The resultant mixture was extracted with DCM (×3) and the combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as an off-white solid (1.65 g, 100% yield). 1H NMR (300 MHz, CDCl3): δ 8.42 (d, J=1.8 Hz, 1H), 7.86-7.79 (m, 2H), 7.66 (t, J=8.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4](O)=[O:5].B.O1CCCC1.CO.Cl>O1CCCC1.C(OCC)(=O)C.C(OCC)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[CH2:4][OH:5]
Reactant: O=C(O)c1c(Cl)cccc1I
Agent: B
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: OCc1c(Cl)cccc1I
Temperature: 45 °C
Reaction time: 0.17 h
Yield: 18.1 %

Procedure:
To a solution of 47.5 g (168 mmol) 2-chloro-6-iodo-benzoic acid in 300 ml tetrahydrofuran was added dropwise 420 ml (420 mmol) borane-tetrahydrofuran complex (1 M solution in tetrahydrofuran) over 30 min and then the reaction mixture was heated at 45° C. for 16 hours. 40 ml Methanol was added dropwise and then 70 ml of 25% aqueous hydrochloric acid was added dropwise, and the reaction mixture was heated at reflux for 2 hours. After cooling to room temperature the mixture was diluted with ethyl acetate and washed sequentially with water, saturated brine, 2 N aqueous sodium hydroxide solution, water and saturated brine. The organic phases was separated and dried over Na2SO4, filtered and concentrated in vacuo to afford a brown oil. The residue was taken up in 300 ml diethyl ether and the mixture was stirred for 10 min at 0° C. before being filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography (silica gel, ethyl acetate/heptane 1:3) to afford 8.17 g (18%) of the title compound as an orange crystalline solid. MS (EI): 270.0 (30%) & 268.0 (100%) (M+).
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9](=[O:39])[CH2:10][C@@:11]1([C:26]2[S:27][C:28]([C:31]3[CH:36]=[CH:35][C:34]([CH2:37][CH3:38])=[CH:33][CH:32]=3)=[CH:29][CH:30]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][N:14]([S:20]([CH2:23][CH2:24][CH3:25])(=[O:22])=[O:21])[CH2:13][CH2:12]1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1>CO.C(Cl)(Cl)Cl>[OH:7][NH:8][C:9](=[O:39])[CH2:10][C@@:11]1([C:26]2[S:27][C:28]([C:31]3[CH:36]=[CH:35][C:34]([CH2:37][CH3:38])=[CH:33][CH:32]=3)=[CH:29][CH:30]=2)[S:17](=[O:18])(=[O:19])[CH2:16][CH2:15][N:14]([S:20]([CH2:23][CH2:24][CH3:25])(=[O:22])=[O:21])[CH2:13][CH2:12]1
Reactant: CCCS(=O)(=O)N1CC[C@](CC(=O)NOC2CCCCO2)(c2ccc(-c3ccc(CC)cc3)s2)S(=O)(=O)CC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: CCCS(=O)(=O)N1CC[C@](CC(=O)NO)(c2ccc(-c3ccc(CC)cc3)s2)S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 0.1 %

Procedure:
To a solution of N-(2-tetrahydropyranyloxy)-2-[(S)-7-(5-(4-ethylphenyl)-2-thienyl]-1,1-dioxoperhydro-4-propanesulfonyl-1,4-thiazepin-7-yl]acetamide (3.51 g) in methanol (8 ml) and chloroform (8 ml) was added toluenesulfonic acid monohydrate (112 mg). The resulting mixture was stirred for 4 hours at room temperature. The solvent was evaporated off to give a pale yellow solid. Silica gel column chromatography (eluent: methanol in chloroform from 0 to 4%) afforded N-hydroxy-2-[(S)-7-[5-(4-ethylphenyl)-2-thienyl]-1,1-dioxoperhydro-4-propanesulfonyl-1,4-thiazepin-7-yl]acetamide (2.41 mg) as a white solid.