Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH2:14])[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[C:21]=1[O:22][CH3:23].[NH2:24][C:25]1[C:30]([C:31]#[N:32])=[C:29](Cl)[N:28]=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:24][C:25]1[C:30]([C:31]#[N:32])=[C:29]([NH:14][C@H:12]([C:10]2[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]3[C:21]([O:22][CH3:23])=[C:4]([F:3])[CH:5]=[CH:6][C:7]=3[N:11]=2)[CH3:13])[N:28]=[CH:27][N:26]=1
Reactant: COc1c(F)ccc2nc([C@H](C)N)n(-c3ccccc3)c12
Reactant: N#Cc1c(N)ncnc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COc1c(F)ccc2nc([C@H](C)Nc3ncnc(N)c3C#N)n(-c3ccccc3)c12
Temperature: 90 °C
Yield: 67 %

Procedure:
To a solution of (S)-1-(6-fluoro-7-methoxy-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (160 mg, 0.44 mmol) in IPA (3 mL) was added 4-amino-6-chloropyrimidine-5-carbonitrile (72 mg, 0.47 mmol) and DIPEA (229 μL, 1.34 mmol) and the reaction mixture heated at 90° C. for 72 hours. The reaction mixture was concentrated in vacuo and the resultant residue purified by prep HPLC (C18 phenomenex column, 10-90% MeCN in water 0.1% formic acid, 20 min gradient) to give 339 as a white solid (119 mg, 66%). 1H NMR 400 MHz δ (d6-DMSO): 7.80 (1H, s), 7.58 (1H, d, J=7.3 Hz), 7.55-7.47 (2H, m), 7.47-7.40 (3H, m), 7.39 (1H, dd, J=8.8, 4.0 Hz), 7.14 (2H, br s), 7.10 (1H, dd, J=12.2, 8.8 Hz), 5.24 (1H, quin, J=6.9 Hz), 3.32 (3H, d, J=0.7 Hz), 1.43 (3H, d, J=6.8 Hz), LCMS (Method K): RT=3.86 min, [M+H]+=404
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:34](=[O:35])[N:6]2[C:7]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([S:19][CH3:20])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Cl:36]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.ClCCl>C1C=CC=CC=1.[Cl-].[Na+].O>[Cl:36][C:18]1[N:13]2[C:14]([S:15][C:11]([C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:34](=[O:35])[N:6]4[C:7]=3[C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=3)=[O:22])=[CH:12]2)=[C:16]([S:19][CH3:20])[N:17]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CSc1ncn2cc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Solvent: ClCCl
Product: CSc1nc(Cl)n2cc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Reaction time: 0.17 h
Yield: 27.5 %

Procedure:
4-Nitrobenzyl(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo-[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (109 mg) was dissolved in 10 ml of benzene at room temperature. N-Chlorosuccinimide (30 mg) and 5 mg of 2,2′-azobis(isobutyronitrile) were added to the solution. The mixture was stirred for 10 min. Dichloromethane (10 ml) and 10 ml of semisaturated brine were added thereto, followed by separation. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol=20:1) to give 32 mg of 4-nitrobenzyl(1S,5R,6S)-2-(5-chloro-7-methylthioimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [Br:1][C:2]1[C:3](O)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[N:13][CH:14]=2)=[N:6][CH:7]=1.C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:33])=O>>[Br:1][C:2]1[C:3]([Cl:33])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[N:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: NS(=O)(=O)c1ccc(Nc2ncc(Br)c(O)n2)cn1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: NS(=O)(=O)c1ccc(Nc2ncc(Br)c(Cl)n2)cn1
Reaction time: 0.5 h

Procedure:
175 mg (0.5 mmol) of 5-(5-bromo-4-hydroxy-pyrimidin-2-ylamino)-pyridine-2-sulfonic acid amide is refluxed with 20 mg of N,N-diethylaniline in 2 ml of phosphorus oxychloride for 3 hours. Then, it is cooled, poured onto ice and stirred for 30 minutes. The precipitated crystals are suctioned off, washed with water and acetonitrile and dried at 50° C. in a vacuum. Yield: 155 mg (85% of theory) of 5-(5-bromo-4-chloro-pyrimidin-2-ylamino)-pyridine-2-sulfonic acid amide.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[C:25]([C:27]4[CH:28]=[N:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=4)[CH:24]=[C:23]([CH3:37])[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH3:37][C:23]1[N:22]=[C:21]([C:17]2[CH:16]=[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:10]=3)[CH:20]=[CH:19][CH:18]=2)[CH:26]=[C:25]([C:27]2[CH:28]=[N:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=2)[CH:24]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)nc2)cc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)nc2)cc(-c2cccc(-c3cccc(S(N)(=O)=O)c3)c2)n1
Temperature: 23 °C
Reaction time: 16 h
Yield: 67.3 %

Procedure:
To 3′-(6′-methyl-6-trifluoromethyl-[3,4′]bipyridinyl-2′-yl)-biphenyl-3-sulfonic acid tert-butylamide (Example 31) (0.150 g, 0.285 mmol) was added TFA (2 mL) and the reaction mixture was stirred at 23° C. for 16 h. The mixture was partitioned between EtOAc and saturated NaHCO3 solution, the organic layer was dried over Na2SO4. Removal of the solvent in vacuum left a crude product which was triturated with diethyl ether to give the title compound as a white solid (0.090 g, 75%). MS (ISP) 470.1 [(M+H)+]; mp 227-232° C.
Reaction SMILES: [CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:65])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([O:51]C(=O)CCCCCCC(O)=O)[CH:47]([O:63][CH3:64])[CH2:46]2)[CH:8]([CH3:66])[CH:7]([OH:67])[CH2:6][C:5]1=[O:68])[CH:2]=[CH2:3].CCN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O.C(OC(=O)C)(=O)C.CN(C)C=O>C(Cl)Cl.CN1CCCC1=O.C1C=CC=CC=1>[CH3:32][C@H:27]1[CH2:28][C:29]([CH3:31])=[CH:30][C@@H:4]([CH2:1][CH:2]=[CH2:3])[C:5](=[O:68])[CH2:6][C@H:7]([OH:67])[C@@H:8]([CH3:66])[C@@H:9](/[C:43](/[CH3:65])=[CH:44]/[C@H:45]2[CH2:46][C@@H:47]([O:63][CH3:64])[C@H:48]([OH:51])[CH2:49][CH2:50]2)[O:10][C:11](=[O:42])[C@H:12]2[N:17]([CH2:16][CH2:15][CH2:14][CH2:13]2)[C:18](=[O:41])[C:19](=[O:40])[C@:20]2([OH:39])[O:35][C@@H:24]([C@@H:23]([O:36][CH3:37])[CH2:22][C@H:21]2[CH3:38])[C@@H:25]([O:33][CH3:34])[CH2:26]1
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OC(=O)CCCCCCC(=O)O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: C=CC[C@@H]1/C=C(\C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Agent: CCN=C=NCCCN(C)C
Agent: O=C1c2ccccc2C(=O)C1(O)O
Solvent: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CC[C@@H]1C=C(C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The syrup obtained in Example 1 was centrifuged with benzene and concentrated under reduced pressure, and dissolved in a mixed solvent of methylene chloride/N-methyl-2-pyrrolidone (4/1) (0.3 ml), and WSC (1.44 mg, 7.5 μmol) and 1-hydroxybenzotriazole (1.01 mg, 7.5 μmol) were added. This solution was added to 10 μl of TOYO-Pearl resin (TSKgel AF-amino; 0.01 mmol amine is present in 100 μl) and shaken at room temperature overnight. After completion of the reaction, the resin was thoroughly washed with a mixed solvent of methylene chloride/N-methyl-2-pyrrolidone (4/1), and DMF, and the percent condensation yield was determined by the ninhydrin test (about 29%). A mixed solution of acetic anhydride/DMF (1/4) (0.3 ml) was added to the resin obtained, and this was followed by shaking at room temperature for 30 minutes. After completion of the reaction, the resin was thoroughly washed with methylene chloride, dimethylformamide (DMF) and 20% aqueous ethanol, and this resin was used as the affinity resin in the subsequent experiments.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:11][O:12][C:13](=[O:43])[NH:14][CH:15]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([C:25](=[O:42])[CH2:26][C:27]([CH3:41])([CH3:40])[CH2:28][C@H:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:30]=O)[CH2:16]1.[Cl-].[NH4+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)C>[CH3:11][O:12][C:13](=[O:43])[NH:14][CH:15]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([C:25](=[O:42])[CH2:26][C:27]([CH3:41])([CH3:40])[CH2:28][C@H:29]([NH:32][C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[CH:30]=[CH2:1])[CH2:16]1
Reactant: COC(=O)NC1Cc2ccccc2N(C(=O)CC(C)(C)C[C@@H](C=O)NC(=O)OC(C)(C)C)C1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: CCOCC
Product: C=C[C@H](CC(C)(C)CC(=O)N1CC(NC(=O)OC)Cc2ccccc21)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4.60 g of methyltriphenylphosphonium bromide are added to a solution of 2.70 g of solid potassium bis(trimethylsilyl)amide in 60 ml of diethyl ether under argon at 0° and the mixture is stirred 30 minutes at 0° C. A solution of 1.98 g of [1-(5(S)-tert-butoxycarbonylamino-3,3-dimethyl-oxo-hexanoyl)-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl]-carbamic acid methyl ester in 20 ml of diethyl ether is added dropwise at 0° C. The mixture is stirred at 0° C. for 1 hour, then poured into saturated aqueous ammonium chloride solution and extracted with tert-butyl methyl ether (2×). The combined organic layers are washed with water and brine, dried over sodium sulphate, filtered and concentrated. The title compound is obtained as a white solid from the residue by means of flash chromatography (SiO2 60 F). Rf=0.28 (1:1 EtoAc-heptane); Rt=4.79 (gradient I).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](O)=[O:38])#[N:33].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:37](=[O:38])[C:36]1[CH:40]=[CH:41][CH:42]=[C:34]([C:32]#[N:33])[CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: N#Cc1cccc(C(=O)N2CC[C@H](N(Cc3ccnc4ccccc34)C(=O)C(F)(F)F)C[C@H]2Cc2ccccc2)c1
Yield: 96.2 %

Procedure:
200 mg (0.467 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 4a with 69 mg (0.514 mmol) of 3-cyanobenzoic acid, 143 mg (0.561 mmol) of bis-(2-oxo-3-oxazolidinyl)phosphinic chloride and 144 μl (1.03 mmol) of triethylamine. The title compound (250 mg, 96%) is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.53, FD-MS: M+ =556.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C:7]3[C:20]([C:21](=O)[C:22]=2[CH:23]=1)=[CH:19][C:18]1[CH2:17][C:16]2[C:11](=[CH:12][C:13]([CH3:25])=[CH:14][CH:15]=2)[C:10](=O)[C:9]=1[CH:8]=3>COCCOCCOC>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:22](=[CH:21][C:20]3[C:7]([CH:6]=2)=[CH:8][C:9]2[C:18](=[CH:17][C:16]4[C:11]([CH:10]=2)=[CH:12][C:13]([CH3:25])=[CH:14][CH:15]=4)[CH:19]=3)[CH:23]=1
Reactant: Cc1ccc2c(c1)C(=O)c1cc3c(cc1C2)C(=O)c1cc(C)ccc1C3
Solvent: COCCOCCOC
Product: Cc1ccc2cc3cc4cc5cc(C)ccc5cc4cc3cc2c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 24.6 grams of 7,14-dihydro-3,10-dimethylpentacene-5,12-dione in 250 mL of 2-methoxyethyl ether was stirred and flushed with nitrogen for 10 minutes. To this was added in small portions 16.5 grams of sodium borohydride and stirring was continued at room temperature overnight. To the reaction mixture was added slowly over 30 minutes 155 mL of methanol with the temperature maintained below 0° C. The resulting mixture was stirred for 1.5 hours at room temperature. To the mixture was added slowly 360 mL of glacial acetic acid over 10 minutes. The resulting mixture was heated to 60° C. for 1.5 hours. To the mixture was added 100 mL of concentrated hydrochloric acid. The resulting mixture was heated for one hour and cooled to room temperature. To the mixture was added 250 mL of water and stirring was continued for five minutes. The resulting solid was collected by filtration and washed with 3 L of water, 1 L of acetone, 1 L of tetrahydrofuran, and 1 L of acetone and dried to give 2,9-dimethylpentacene.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]#[N:14].O.[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[CH:17]=[CH2:18]>N1C=CC=CC=1>[NH2:1][C:2]1[N:6]([CH2:18][CH2:17][C:16]([O:20][CH2:21][CH3:22])=[O:19])[N:5]=[C:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]#[N:14]
Reactant: C=CC(=O)OCC
Reactant: N#Cc1c(-c2cccnc2)n[nH]c1N
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)CCn1nc(-c2cccnc2)c(C#N)c1N
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of 5-amino-3-(pyridine-3-yl)-1H-pyrazole-4-carbonitrile (300 mg, 1.62 mmol) in pyridine (4 mL)/H2O (1 mL) was added ethyl acrylate (325 mg, 3.24 mmol). The resulting mixture was stirred at 100° C. for 5 hours. After cooling to rt, the mixture was concentrated in vacuo. The residue was purified by preparative-TLC to afford the desired product: MS (m/z): 286.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[C:5]([C:13](=O)[CH3:14])=[CH:4][N:3]=1.Cl.[NH2:17][OH:18].CC([O-])=O.[Na+]>CO.O>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[C:5]([C:13](=[N:17][OH:18])[CH3:14])=[CH:4][N:3]=1
Reactant: NO
Reactant: CC(=O)c1cnc(N)c2ccc(F)cc12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=NO)c1cnc(N)c2ccc(F)cc12
Yield: 87.3 %

Procedure:
1-(1-amino-6-fluoro-isoquinolin-4-yl)-ethanone (0.8 g, 1 eq), hydroxylamine hydrochloride (1.36 g, 5 eq), and NaOAc (1.6 g. 5 eq) in MeOH (70 mL) and H2O (70 mL) is stirred at RT over 3-day, then concentrated to remove MeOH, poured into Sat'd NaHCO3 aq. (300 mL), extracted by dichloromethane (3×150 mL), dried over Na2SO4, filtered, concentrated to give product 1-(1-amino-6-fluoro-isoquinolin-4-yl)-ethanone oxime (0.75 g, 87%). LC/MS m/z=220 [M+H]+.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][CH:8]([NH:15][C:16]([C:18]1[S:19][C:20]([C:23](=[O:36])[NH:24][CH2:25][CH2:26][CH2:27][NH:28]C(OC(C)(C)C)=O)=[CH:21][CH:22]=1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(C)(C)C.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>ClCCl>[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[NH2:28][CH2:27][CH2:26][CH2:25][NH:24][C:23]([C:20]1[S:19][C:18]([C:16]([NH:15][CH:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:7][C:6]([OH:37])=[O:5])=[O:17])=[CH:22][CH:21]=1)=[O:36]
Reactant: CC(C)(C)OC(=O)CC(NC(=O)c1ccc(C(=O)NCCCNC(=O)OC(C)(C)C)s1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCNC(=O)c1ccc(C(=O)NC(CC(=O)O)c2ccccc2)s1
Temperature: 25 °C

Procedure:
With continued reference to Scheme G, preparation of compound VII was carried out using the procedure described for compound III. Compound VI: 3-{[5-(3-tert-Butoxycarbonylamino-propylcarbamoyl)-thiophene-2-carbonyl]-amino}-3-phenyl-propionic acid tert-butyl ester (200 mg, 0.704 mmol) was dissolved in 4.0 ml of anhydrous dichloromethane and 4.0 ml of anhydrous TFA. This reaction mixture was left stirring over night at room temperature. The solvents were evaporated under reduced pressure and the resulting residue was dissolved in anhydrous methanol (smallest amount possible). Diethyl ether was then added to precipitate the desired product, the supernatant was discarded and the solid washed with ether again then dried under reduced pressure to give 156 mg of the desired product as a white powder (Compound VII). 1H NMR (400 Mhz, DMSO-d6) 1.75 (m, 2H), 2.9 (m, 4H), 3.3 (m, 2H), 7.2-7.4 (m, 5H), 7.4 7.9 (bs, 3H), 7.65 (d, 1H), 7.8 (d, 1H), 8.75 (t, 1H), 9.05 (d, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[F:26][CH:27]([CH2:30][NH2:31])[CH2:28][NH2:29]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:29][CH2:28][CH:27]([F:26])[CH2:30][NH2:31])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: NCC(F)CN
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC(F)CN)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2-fluoropropane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 429, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (dd, J=7.83, 1.01 Hz, 1 H), 7.84 (d, J=7.58 Hz, 1 H), 7.65-7.57 (m, 2 H), 7.47-7.38 (m, 2 H), 7.29 (dd, J=8.59, 1.77 Hz, 1 H), 6.10 (s, 1 H), 5.14 (s, 2 H), 4.69 (s, 2 H), 3.64 (d, J=5.31 Hz, 1 H), 3.61-3.52 (m, 4 H), 3.04-2.91 (m, 2 H), 2.41 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]1[N:17]([CH3:18])[N:16]=[C:15]([S:19][CH3:20])[CH:14]=1.ClC1C=CC=C(C(OO)=[O:29])C=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[C:13]1[N:17]([CH3:18])[N:16]=[C:15]([S:19]([CH3:20])=[O:29])[CH:14]=1
Reactant: CSc1cc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n(C)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cn1nc(S(C)=O)cc1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 95.5 %

Procedure:
To a solution of 0.3 g of 5-(2,6-dichloro-4-trifluoromethylphenyl)-1-methyl-3-methylsulfenylpyrazole (compound 33) in 20 ml of anhydrous chloroform was slowly added 0.3 g of 70% m-chloroperbenzoic acid at -10° C. with stirring, followed by stirring for 3 hours. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution, and the organic layer was separated off and washed with a 5% aqueous sodium hydroxide solution and with brine. After drying the layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, giving 0.3 g of the desired compound in the form of white crystals (quantitative crude yield).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:37]=1[F:38]>>[CH:18]1([N:13]2[C:12]([C:35]3[CH:34]=[CH:33][C:32]([F:31])=[C:37]([F:38])[CH:36]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: Fc1ccc(-c2c3c(nn2C2CCCC2)CCNCC3)cc1F
Yield: 47.9 %

Procedure:
The title compound (70 mg) was prepared according to Example 180 using 209 mg of 2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 180, Step A) and 218 mg of 3,4-difluorophenylboronic acid. MS (ESI): exact mass calculated for C18H21F2N3, 317.17. found, m/z 318.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.50-7.45 (m, 1H), 7.36-7.32 (m, 1H), 7.18-7.17 (m, 1H), 4.49 (m, 1H), 3.43-3.41 (m, 2H), 3.21-3.19 (m, 2H), 2.80-2.78 (m, 2H), 2.15-1.87 (m, 6H), 1.66-1.61 (m, 2H).
Reaction SMILES: C(C1C=C(C(O)=O)SC=1C=O)C.[CH2:13]([C:15]1[CH:30]=[C:29]([C:31]2[N:35]=[C:34]([C:36]3[S:37][C:38]([CH:43]=[O:44])=[C:39]([CH3:42])[C:40]=3[CH3:41])[O:33][N:32]=2)[CH:28]=[C:27]([CH3:45])[C:16]=1[O:17][CH2:18][C@@H:19]([OH:26])[CH2:20][NH:21][C:22](=[O:25])[CH2:23][OH:24])[CH3:14]>>[CH2:13]([C:15]1[CH:30]=[C:29]([C:31]2[N:35]=[C:34]([C:36]3[S:37][C:38]([CH:43]=[O:44])=[C:39]([CH2:40][CH3:41])[CH:42]=3)[O:33][N:32]=2)[CH:28]=[C:27]([CH3:45])[C:16]=1[O:17][CH2:18][C@@H:19]([OH:26])[CH2:20][NH:21][C:22](=[O:25])[CH2:23][OH:24])[CH3:14]
Reactant: CCc1cc(-c2noc(-c3sc(C=O)c(C)c3C)n2)cc(C)c1OC[C@@H](O)CNC(=O)CO
Agent: CCc1cc(C(=O)O)sc1C=O
Product: CCc1cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(CC)c3)no2)sc1C=O

Procedure:
The title compound is prepared according to Method E starting from 4-ethyl-5-formyl-thiophene-2-carboxylic acid and N—((S)-3-{2-ethyl-4-[5-(5-formyl-3,4-dimethyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide; LC-MS: tR=0.73 min; [M+1]+=474.20.
Reaction SMILES: I[CH3:2].[CH3:3][O:4][CH:5]([O:13][CH3:14])[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([S-:12])[N:7]=1.[Na+]>CO>[CH3:14][O:13][CH:5]([O:4][CH3:3])[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([S:12][CH3:2])[N:7]=1
Reactant: CI
Reactant: COC(OC)c1ccnc([S-])n1
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1ccnc(SC)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Iodomethane (128 g, 902 mmol, 1.20 equiv.) was added carefully to the crude solution of sodium 4-(dimethoxymethyl)pyrimidine-2-thiolate (2) (156 g, 751 mmol) in methanol (700 mL, 1.1 M) while maintaining the reaction temperature below 28° C. using an ice-water bath for cooling. The resulting mixture was stirred at room temperature for 16 h. After removal of the solvent under reduced pressure, the residue was diluted with water (300 mL) and extracted with ethyl acetate (2×150 mL). The combined organic layer was concentrated under reduced pressure and the crude residue purified by passing through a short silica gel pad and washing with diethyl ether (200 mL) to afford 4-(dimethoxymethyl)-2-(methylthio)pyrimidine (3) as a brown oil (53.7 g, 150 g theoretical, 35.7%). LC-MS m/z 201 (M+1). Reference: WO 2006/0097341A1 (incorporated by reference), pg 67.
Reaction SMILES: [N:1]1[C:10]2[NH:9][C:8]3[CH:11]=[C:12]([CH2:15]O)[CH:13]=[CH:14][C:7]=3[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.CS([Cl:27])(=O)=O.C(Cl)Cl.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:27][CH2:15][C:12]1[CH:13]=[CH:14][C:7]2[S:6][C:5]3[N:4]=[CH:3][CH:2]=[N:1][C:10]=3[NH:9][C:8]=2[CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc2c(c1)Nc1nccnc1S2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: ClCc1ccc2c(c1)Nc1nccnc1S2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a solution of 7 g of 10H-pyrazino[2,3-b][1,4]benzothiazine-8-methanol and 6.1 ml of pyridine in N,N-dimethylformamide (50 ml) was added dropwise 5.9 ml of methanesulfonyl chloride at 0° C. After stirring at room temperature for 1 hour, the reaction mixture was poured into a pre-cooled aqueous solution of methylene chloride/sodium hydrogencarbonate, extracted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the crystals thus precipitated were diluted with a small amount of ethyl acetate, taken up by filtration and washed with diethyl ether. Thus 4.7 g of the title compound was obtained as a yellow powder.