Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](C=O)=[C:17]2[C:12]([C:13](=[O:31])[C:14]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[C:15]([CH:21]([CH3:23])[CH3:22])[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:40])C=1.[OH-].[K+]>C(Cl)Cl.CO.CCCCCC.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:18]([OH:40])=[C:17]2[C:12]([C:13](=[O:31])[C:14]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[C:15]([CH:21]([CH3:22])[CH3:23])[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)c1oc2c(C=O)c(OCc3ccccc3)ccc2c(=O)c1-c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: CC(C)c1oc2c(O)c(OCc3ccccc3)ccc2c(=O)c1-c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of 7-benzyloxy-3-(4-chlorophenyl)-2-isopropyl-4-oxo-4H-chromene-8-carbaldehyde (8.03 g, 18.6 mmol) in CH2Cl2 (200 ml) is added m-chloroperbenzoic acid (9.24 g, 53.5 mmol). The reaction mixture is stirred at 50° C. for 4 h, washed with saturated NaHCO3 solution, dried (MgSO4) and concentrated in vacuo to give a yellow oil. To a solution of the oil in methanol (350 ml) is added aqueous KOH solution (10%, 35 ml), and the mixture is stirred at room temperature overnight. The mixture is concentrated to a ca. 50 ml volume, ice/water is added, and the mixture is acidified with concentrated HCl. A solid is isolated by filtration, washed with water and taken up into CH2Cl2. The CH2Cl2 solution is dried (MgSO4), and the solvent is removed in vacuo to afford a dark brown solid. This is stirred in hot hexane/ethyl acetate and filtered to afford the title compound as a colourless solid. A further crop of the desired product can be isolated from the filtrate by concentrating the hot solution to a quarter of its original volume and allowing it to stand at room temperature.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[C:10]1[NH:19][C:18](=O)[C:17]2[C:12](=[CH:13][C:14]([CH3:21])=[CH:15][CH:16]=2)[N:11]=1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:33].C([O-])(O)=O.[Na+]>C1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:33][C:18]1[C:17]2[C:12](=[CH:13][C:14]([CH3:21])=[CH:15][CH:16]=2)[N:11]=[C:10]([C:4]2[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[N:19]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cccc(C)c1-c1nc2cc(C)ccc2c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Solvent: CN(C)c1ccccc1
Product: COc1cccc(C)c1-c1nc(Cl)c2ccc(C)cc2n1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
2-(2-Methoxy-6-methyl-phenyl)-7-methyl-3H-quinazolin-4-one (1.61 g, 5.74 mmol) was suspended in benzene after which was added N,N-dimethylaniline (1.1 mL, 8.62 mmol) and POCl3 (1.61 mL, 17.27 mmol). The reaction mixture was refluxed for 3 hours during which the color changed from yellow to dark red. The reaction mixture was cooled to room temperature, diluted with 40 mL toluene and poured onto ice. Saturated aq. NaHCO3 was carefully added until the pH remained constant at 7 and no more gas formed. The layers were separated, and the water layer was extracted with toluene. The organic layers were combined and washed with respectively 50 mL saturated aq. NaCl, 60 mL 0.5 N HCl, 40 mL 5% NaHCO3 and 50 mL saturated aq. NaCl. The solution was dried over Na2SO4 and evaporated to dryness to yield 1.7 g of the impure product. The product was filtered through silica gel and washed with CH2Cl2:heptane (2:1) to yield of 4-chloro-2-(2-methoxy-6-methyl-phenyl)-7-methyl-quinazoline (1.22 g, 71%).
Reaction SMILES: FC(F)(F)C(O)=O.ClCCl.[CH2:11]([O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([N:30](CC)CC)C>>[CH2:11]([O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH2:30])=[O:24])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1ccc(OCc2ccccc2)cc1

Procedure:
A solution of 3R-carboxylate-6-nitro-2H-3,4-dihydro-[2-1b]imidazopyran (Example 21, 1 eq.), triethylamine (1 eq.), diphenylphosphoryl azide (1 eq.) in toluene is heated at 80° C. for 4 h, cooled and t-butanol is added. The reaction is warmed to 70° C. for an additional 1 h. Workup in the standard fashion gives the Boc amine. Deprotection of the Boc group (trifluoroacetic acid:dichloromethane, 1:1) and addition of 4-benzyloxybenzoyl chloride and triethylamine gives the 4-benzyloxybenzamide of 3R-amino-6-nitro-2H-3,4-dihydro-[2-1b]imidazopyran.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH2:6][C:7]1[CH:8]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH2:39][CH3:40])([C:24]3[CH:29]=[CH:28][C:27](/[CH:30]=[CH:31]/[C:32]([CH2:36][CH3:37])([OH:35])[CH2:33][CH3:34])=[C:26]([CH3:38])[CH:25]=3)[CH2:22][CH3:23])=[CH:17][CH:16]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14].[Cl-].[NH4+]>CO.O1CCCC1>[CH2:22]([C:21]([C:18]1[CH:17]=[CH:16][C:15]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([CH2:6][C:5]([OH:41])=[O:4])[CH:8]=2)=[CH:20][CH:19]=1)([C:24]1[CH:29]=[CH:28][C:27](/[CH:30]=[CH:31]/[C:32]([CH2:33][CH3:34])([OH:35])[CH2:36][CH3:37])=[C:26]([CH3:38])[CH:25]=1)[CH2:39][CH3:40])[CH3:23]
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3ccc(OC)c(CC(=O)OC)c3)cc2)cc1C)CC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3ccc(OC)c(CC(=O)O)c3)cc2)cc1C)CC
Temperature: 60 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.200 mL, 0.200 mmol) was added to a solution of (4′-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propyl}-4-methoxy-biphenyl-3-yl)-acetic acid methyl ester (Example 180-(2); 35.2 mg, 0.067 mmol) in methanol-tetrahydrofuran (1:1, 4 mL), and the mixture was stirred at 60° C. for two hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=10:1) to give the target compound as a colorless oil (30.1 mg, 87%).
Reaction SMILES: [CH:1]1([NH:4][S:5]([C:8]2[CH:9]=[C:10]([CH:44]=[CH:45][CH:46]=2)[C:11]([NH:13][C:14]2[S:15][C:16]3[CH2:43][CH2:42][CH2:41][CH2:40][C:17]=3[C:18]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]3[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=3)=[CH:24][CH:23]=2)=[O:20])=[O:12])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[C:47]([O:50][CH2:51][CH2:52]Br)(=[O:49])[CH3:48].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH:1]1([N:4]([CH2:48][C:47]([O:50][CH2:51][CH3:52])=[O:49])[S:5]([C:8]2[CH:9]=[C:10]([CH:44]=[CH:45][CH:46]=2)[C:11]([NH:13][C:14]2[S:15][C:16]3[CH2:43][CH2:42][CH2:41][CH2:40][C:17]=3[C:18]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][CH:39]=3)=[CH:24][CH:23]=2)=[O:20])=[O:12])(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: CC(=O)OCCBr
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)NC5CC5)c4)sc4c3CCCC4)cc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(C1CC1)S(=O)(=O)c1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
A mixture of 250 mg of methyl 4-[2-(4-{[(2-{[3-(cyclopropylsulfamoyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 95 mg of bromoethyl acetate, 105 mg of potassium carbonate, and 2.5 mL of DMF was stirred at 80° C. overnight. To the reaction mixture was added an aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-chloroform) to obtain 218 mg of methyl 4-{2-[4-({[2-({3-[cyclopropyl(2-ethoxy-2-oxoethyl)sulfamoyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:15]Br.C(OCC)C>C(O)(=O)C>[Br:15][CH2:2][C:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(OCC(=O)O)cc1
Reactant: BrBr
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C(O)COc1ccc(C(=O)CBr)cc1
Reaction time: 48 h
Yield: 46 %

Procedure:
2-(4-acetylphenoxy)acetic acid (2.81 g, 14.5 mmol) was dissolved in acetic acid (100 mL) and treated with bromine (740 μL, 14.5 mmol) and stirred 48 hours. Bromine (370 mL, 7.25 mmol) was added and solution was stirred for an additional 16 hours. Volatiles were removed under reduced pressure to provide a brown solid which was titurated with diethyl ether to provide 2-(4-(2-bromoacetyl)phenoxy)acetic acid (1.82 g) as a light brown solid.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:32])[C@@H:15]([NH:24]C(OC(C)(C)C)=O)[CH2:16][CH2:17][C:18]2[N:22]([CH3:23])[N:21]=[N:20][N:19]=2)[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:32])[C@@H:15]([NH2:24])[CH2:16][CH2:17][C:18]2[N:22]([CH3:23])[N:21]=[N:20][N:19]=2)[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCc2nnnn2C)NC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CCc2nnnn2C)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 315 mg 4-[(S)-2-tert-Butoxycarbonylamino-4-(1-methyl-1H-tetrazol-5-yl)-butyryl]-piperazine-1-carboxylic acid butyl ester in 5 ml dichloromethane were added 0.5 ml TFA. After 12 h stirring at RT the solvents were removed and the residue was codistilled twice with toluene. Yield: 0.41 g.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:6]([CH3:17])[C:5](=[O:18])[N:4]2[CH2:19][CH2:20][S:21][C:3]=12.[CH2:22]([C:25]1([S:28](Cl)(=[O:30])=[O:29])[CH2:27][CH2:26]1)[CH:23]=[CH2:24]>N1C=CC=CC=1>[F:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:7]1[C:2]([NH:1][S:28]([C:25]2([CH2:22][CH:23]=[CH2:24])[CH2:27][CH2:26]2)(=[O:30])=[O:29])=[C:3]2[S:21][CH2:20][CH2:19][N:4]2[C:5](=[O:18])[C:6]=1[CH3:17]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCS2
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Solvent: c1ccncc1
Product: C=CCC1(S(=O)(=O)Nc2c(Nc3ccc(I)cc3F)c(C)c(=O)n3c2SCC3)CC1
Yield: 52 %

Procedure:
8-Amino-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-2,3-dihydro-thiazolo[3,2-a]pyridin-5-one (I-19f: 0.3 g, 0.719 mmol) in pyridine (3 mL) was reacted with 1-allyl-cyclopropane sulfonyl chloride (0.15 g, 0.863 mmol) to afford the crude product. Purification by column chromatography on silica gel (40% ethylacetate in hexane) afforded 0.21 g of the product (52% yield).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1.BrC1C=[C:14]([S:16]C)C=CN=1>>[I:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([S:16][CH3:14])[CH:7]=1
Reactant: Fc1cc(I)ccn1
Reactant: CSc1ccnc(Br)c1
Product: CSc1cc(I)ccn1

Procedure:
The title compound was prepared from 2-fluoro-4-iodo-pyridine following a procedure analogous to that described for 2-bromo-4-methylsulfanyl-pyridine in Example 184. Mass spectrum (ESI+): m/z=252 [M+H]+.
Reaction SMILES: [C:1]([C:9]1[CH:18]=[CH:17][C:12]2[N:13]=[CH:14][S:15](=[O:16])[C:11]=2[CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>>[CH2:1]([C:9]1[CH:18]=[CH:17][C:12]2[N:13]=[CH:14][S:15](=[O:16])[C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1ccc2c(c1)S(=O)C=N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=S1C=Nc2ccc(Cc3ccccc3)cc21
Temperature: 0 °C

Procedure:
10.2 g (0.04 mole) of 6-benzoylbenzothiazolinone are weighed into a 105-cm: flask. 45.6 g (0.4 mole) of trifluoroacetic acid are added via a dropping funnel equipped with a teflon tap. 10.5 g (0.09 mole) of triethylsilane are added dropwise with magnetic stirring and while cooling by means of a bath of ice-cold water. A calcium chloride guard tube is fitted and stirring is continued for fifteen hours at room temperature. The reaction mixture is poured with stirring into 500 cm3 of ice-cold water. The precipitate obtained is drained and washed with water until the washing liquors are neutral. The product is dried and recrystallized in toluene.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[C:10]([NH:12][NH:13][C:14]([C:16]1[O:17][CH:18]=[C:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:20]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:15])=[O:11].C(N(CC)CC)C.O1CCOCC1>C(OCC)(=O)C>[CH3:37][O:36][C:35]1[CH:34]=[CH:33][C:9]([C:10]([NH:12][NH:13][C:14]([C:16]2[O:17][CH:18]=[C:19]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:20]=2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:15])=[O:11])=[CH:8][C:7]=1[NH:6][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)cc1N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccc(C(=O)NNC(=O)c2occ(-c3ccccc3)c2-c2ccccc2)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methylsulfonyl chloride (0.28 ml) was added to a mixture of the compound of Example 41 (0.85 g), triethylamine (0.41 ml) and dioxane (30 ml) at 0° C., allowed to be warmed to 25° C. and stirred overnight. The reaction solution was diluted with ethyl acetate, washed with water and dried over MgSO4. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform), thereby giving 0.95 g of the desired compound. Melting point: 180-182° C. (Recrystallized from ethyl acetate/hexane).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[N:10]([CH3:22])[C:11](=[O:21])[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][N:16]=2)[N:14]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH:34]2[CH2:36][C@H:31]1[CH2:32][NH:33]2)=[O:29])([CH3:26])([CH3:25])[CH3:24].O>O1CCCC1>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH:34]2[CH2:36][C@H:31]1[CH2:32][N:33]2[C:9]1[N:10]([CH3:22])[C:11](=[O:21])[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][N:16]=2)[N:14]=1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Reactant: CC(C)(C)OC(=O)N1CC2C[C@H]1CN2
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1c(N2C[C@@H]3CC2CN3C(=O)OC(C)(C)C)nc(-c2ccncn2)cc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
A mixture containing 1.95 ml (14 mmol) of triethylamine, 2.45 g (11 mmol) of 2-chloro-1-methyl-1H-[4,4′]bipyrimidinyl-6-one, 2.58 g (13 mmol) of (1S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester in 100 ml of anhydrous tetrahydrofuran was stirred at room temperature for 2 h. Water was added to the cooled mixture and the resulting solution extracted with ethyl acetate. The combined extracts were washed with saturated aqueous ammonium chloride and evaporated. The crude product was purified by chromatography on silica gel eluting with a mixture of dichloromethane/methanol in the proportions 100/0 to 98/2 to afford 4.2 g of pure product as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([O:11][C:12]1[C:13]([F:21])=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1)[CH3:10]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH2:9][CH3:10])[C:13]=2[F:21])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CCOc1cccc(B(O)O)c1F
Product: CCOc1cccc(-c2ccc(Br)cn2)c1F
Yield: 47 %

Procedure:
Obtained (1.18 g, yield 47%) following the procedure described in Intermediate 27, starting with 2,5-dibromopyridine (8.44 mmol, 2.0 g), 3-ethoxy-2-fluorophenylboronic acid (8.43 mmol, 1.55 g).
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)=[O:7])(C)(C)C.[F:44][C:45]1[CH:53]=[CH:52][C:48](C(Cl)=O)=[CH:47][CH:46]=1>>[F:44][C:45]1[CH:53]=[CH:52][C:48]([C:6]([NH:8][C@H:9]2[CH2:13][C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@@H:11]([CH2:20][N:21]3[CH2:22][CH2:23][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=4)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:25][CH2:26]3)[CH2:10]2)=[O:7])=[CH:47][CH:46]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](NC(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](NC(=O)c3ccc(F)cc3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(S)-((t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 33 in Step A and 4-fluorobenzoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.Cl>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=2)(=[O:32])=[O:31])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)c1[nH]c2ccccc2c1-c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccccc2)c2ccccc2n1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.6 %

Procedure:
To a stirred solution of 3-phenyl-1H-indole-2-carboxylic acid ethyl ester (3.99 g, 15.0 mmol) in DMF (25 mL) cooled to 0° C. and under a nitrogen atmosphere was added NaH (60% in mineral oil, 720 mg, 18.0 mmol). After stirring for 10 min at RT, the reaction mixture was cooled to 0° C. and 4-methylbenzenesulfonyl chloride (3.44 g, 18.0 mmol) in DMF (15 mL) added. Stirring was continued for 16 h at RT then the mixture was poured into 1.0M HCl and extracted with EtOAc (×2). The combined organic fractions were washed with water, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 30-100% DCM in pentane) affording the title compound as a colourless oil (3.25 g, 52%). 1H NMR (CDCl3, 400 MHz): δ 8.08 (1H, d, J=8.43 Hz), 7.92 (2H, d, J=8.37 Hz), 7.53-7.36 (7H, m), 7.28-7.21 (3H, m), 4.35 (2H, q, J=7.15 Hz), 2.36 (3H, s), 1.25 (3H, t, J=7.14 Hz)
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-])=O)[CH3:2].[BH4-].[Na+].CO>O1CCCC1.[Pd]>[CH2:1]([NH:3][C:4]1[C:5]([NH2:10])=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCNc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCNc1ccccc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
To a solution of ethyl-(2-nitro-phenyl)-amine (12.5 g, 75 mmol) in anhydrous tetrahydrofuran (150 mL) was added sodium borohydride (5.8 g, 153 mmol), and 5% palladium on carbon (150 mg). Methanol (25 mL) was then added at room temperature under nitrogen in a dropwise manner. After addition, the reaction mixture was stirred at room temperature for about 30 minutes until the reaction was complete. The reaction mixture was then filtered through a pad of Celite. The filtrate was diluted with ethyl acetate (200 mL), washed with a saturated aqueous solution of ammonium chloride (80 mL), dried over sodium sulfite, and concentrated in vacuo to afford crude N-ethyl-benzene-1,2-diamine (8.4 g, 62 mmol) which was used in next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[C:20]3[N:19]=[C:18]([CH2:21][C:22]4[NH:26][N:25]=[N:24][N:23]=4)[NH:17][C:16]=3[C:15](=[O:27])[N:14]([CH2:28][CH2:29][CH3:30])[C:13]2=[O:31])=[CH:6][CH:5]=1)([O-])=O.O.NN.[H][H]>[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[C:20]3[N:19]=[C:18]([CH2:21][C:22]4[NH:26][N:25]=[N:24][N:23]=4)[NH:17][C:16]=3[C:15](=[O:27])[N:14]([CH2:28][CH2:29][CH3:30])[C:13]2=[O:31])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CCCn1c(=O)c2[nH]c(Cc3nnn[nH]3)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Agent: [Pd]
Agent: NN
Solvent: O
Product: CCCn1c(=O)c2[nH]c(Cc3nnn[nH]3)nc2n(CCc2ccc(N)cc2)c1=O

Procedure:
By the method of Example 2, 1H-tetrazole-5-acetic acid is reacted with 5,6-diamino-1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield 3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(1H-tetrazol-5-yl)methyl]xanthine. By methods well known in the art, 3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(1H-tetrazol-5-yl)methyl]xanthine is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-1-propyl-8-[(1H-tetrazol-5-yl)methyl]xanthine.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][OH:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13](Cl)(=[O:15])[CH3:14]>>[C:13]([O:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])(=[O:15])[CH3:14]
Reactant: O=C(NO)OCc1ccccc1
Reactant: CC(=O)Cl
Product: CC(=O)ONC(=O)OCc1ccccc1

Procedure:
[(Benzyloxy)carbonyl]amino acetate is prepared from N-(benzyloxycarbonyl) hydroxylamine and acetyl chloride according to Scheme 1. (1.24 g, 33%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.18 (1H, br. s.), 7.32-7.45 (5H, m), 5.22 (2H, s), 2.22 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:24][CH:23]=1.C(N(CC)CC)C.[I-].C[N+]1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C@H:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:26][CH:27]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CCCC[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(=O)O
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCC[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(=O)Nc1ccc(CC(=O)OCC)cc1
Yield: 87 %

Procedure:
The procedure described in Example 177 was repeated, except that (R)-2-(4-chlorobenzenesulfonylamino)hexanoic acid (3 g) and ethyl 4-aminophenylacetate hydrochloride (1.9 g) were condensed in chloroform (100 ml) in the presence of triethylamine (5.4 ml) and 1-methyl-2-chloropyridinium iodide (3.01 g) to obtain as a colorless oily substance (R)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)hexanamide (3.58 g).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[C:5]([N:7]1[CH2:11][C:10]2[CH2:12][N:13]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[CH2:14][C:9]=2[CH2:8]1)=[O:6].[CH3:30][NH:31][CH2:32][C:33]1[S:34][CH:35]=[CH:36][N:37]=1>>[CH3:30][N:31]([CH2:32][C:33]1[S:34][CH:35]=[CH:36][N:37]=1)[C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([N:13]2[CH2:14][C:9]3[CH2:8][N:7]([C:5](=[O:6])[C:4]4[CH:24]=[CH:25][CH:26]=[CH:27][C:3]=4[C:2]([F:1])([F:29])[F:28])[CH2:11][C:10]=3[CH2:12]2)=[N:16][CH:17]=1
Reactant: O=C(O)c1ccc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)nc1
Reactant: CNCc1nccs1
Product: CN(Cc1nccs1)C(=O)c1ccc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)nc1
Yield: 52 %

Procedure:
6-[5-(2-Trifluoromethylbenzoyl)-3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]nicotinic acid (54 mg, 0.134 mmol) was reacted with methylthiazol-2-ylmethylamine analogously to example 3d. Yield: 52%, M+H+: 514.30.