Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:6]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[C:7]2[C:14]3[CH2:15][CH2:16][CH2:17][C:13]=3[S:12][C:8]2=[N:9][C:10]=1[CH3:11].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:36]1[CH2:40]OC[CH2:37]1.ICCC>CN(C=O)C>[CH3:11][C:10]1[N:9]=[C:8]2[S:12][C:13]3[CH2:17][CH2:16][CH2:15][C:14]=3[C:7]2=[C:6]([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)[C:5]=1[CH:4]([CH2:37][CH2:36][CH3:40])[C:3]([O:2][CH3:1])=[O:25]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3
Yield: 58.6 %

Procedure:
This compound was prepared according to the procedure C from methyl[2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3yl]acetate (0.189 g; 0.538 mmol), LHMDS 1N in THF (0.594 mL; 0.594 mmol), 1-iodopropane (0.080 mL; 0.823 mmol) in DMF (8 mL) for 4 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-15%) in heptane furnished 0.124 g (59%) of the title compound as a yellow solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[CH:11]=[CH:10][C:9]([C@@H:12]([NH:14][C:15](=[O:17])[CH3:16])[CH3:13])=[CH:8][CH:7]=2)[CH2:3]1.[F:18][C:19]1[CH:24]=[C:23](F)[CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:18][C:19]1[CH:24]=[C:23]([O:1][CH:2]2[CH2:3][N:4]([C:6]3[CH:7]=[CH:8][C:9]([C@@H:12]([NH:14][C:15](=[O:17])[CH3:16])[CH3:13])=[CH:10][CH:11]=3)[CH2:5]2)[CH:22]=[CH:21][N:20]=1
Reactant: Fc1ccnc(F)c1
Reactant: CC(=O)N[C@@H](C)c1ccc(N2CC(O)C2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](C)c1ccc(N2CC(Oc3ccnc(F)c3)C2)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
1.0 g (4.3 mmol) (S)—N-{1-[4-(3-Hydroxy-azetidin-1-yl)-phenyl]-ethyl}-acetamide (V.1), 0.6 g (5.2 mmol) 2,4-difluoropyridine and 2.0 g (6.2 mmol) cesium carbonate are combined in 40 mL DMF and the mixture is stirred for 12 h at 80° C. Water is added and the mixture is extracted twice with ethylacetate. After concentration in vacuo the residue is purified by chromatography (silica; ethylacetate) to yield the desired product.
Reaction SMILES: CC1C(C2CCCC(C3C(C)=CC=CN=3)N2)=NC=CC=1.[CH3:21][O:22][C:23](=[O:35])[C:24]1[CH:29]=[CH:28][C:27](CBr)=[C:26]([N+:32]([O-:34])=[O:33])[CH:25]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:21][O:22][C:23](=[O:35])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N+:32]([O-:34])=[O:33])[CH:25]=1
Reactant: COC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Agent: Cc1cccnc1C1CCCC(c2ncccc2C)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cccc([N+](=O)[O-])c1

Procedure:
Using General Procedure A: A solution of 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (0.829 g, 3.10 mmol), 4-bromomethyl-3-nitrobenzoic acid methyl ester (1.26 g, 4.61 mmol), KI (115 mg, 0.69 mmol), and DIPEA (1.20 mL, 6.89 mmol) in DMF (16 mL) was heated at 60° C. for 18 hours. Purification of the crude material by column chromatography on silica gel (40:1:1 CH2Cl2—CH3OH—NH4OH) provided 1.40 g (98%) of 4-3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-3-nitro-benzoic acid methyl ester as a tan solid. To a solution of 4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-3-nitro-benzoic acid methyl ester (1.40 g,3.03 mmol) in MeOH (15 mL) and EtOAc (15 mL) was added palladium (50% wet with water), 10 wt. % on activated carbon (0.30 g). The resultant mixture was hydrogenated at 30 psi on a Parr shaker for 3 hours. The mixture was vacuum filtered through celite and the cake was washed with MeOH and EtOAc. The solvent was removed from the filtrate under reduced pressure and the thus obtained oil was purified by column chromatography on silica gel (40:1:1 CH2Cl2—CH3OH—NH4OH) and provided 0.90 g (69%) of 3-amino-4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzoic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:25])=[C:16]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH:17]=1)[N:5]=2.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:25][C:15]1[CH:14]=[CH:13][C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:29]([CH:26]4[CH2:28][CH2:27]4)=[O:30])=[N:10][C:9]3=[CH:8][CH:7]=2)=[CH:17][C:16]=1[NH:18][C:19](=[O:24])[C:20]([F:22])([F:21])[F:23]
Reactant: O=C(Cl)C1CC1
Reactant: Nc1nc2ccc(Oc3ccc(Cl)c(NC(=O)C(F)(F)F)c3)nc2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Nc1nc2ccc(Oc3ccc(Cl)c(NC(=O)C(F)(F)F)c3)nc2s1)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
N-{5-[(2-Amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2-chlorophenyl}-2,2,2-trifluoroacetamide (5.0 g, 12.9 mmol) was dissolved in pyridine (25 mL), cyclopropanecarbonyl chloride (1.28 ml, 14.2 mmol) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was treated with aqueous sodium hydrogen carbonate solution (100 mL), and diluted with ethyl acetate (100 mL). The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residual solid was crystallized from ethyl acetate (30 mL), collected by filtration, and dried to give the title compound (3.46 g, 59%) as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:20][O:21][CH2:22][C@H:23](O)[CH2:24][CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>C1COCC1>[CH3:20][O:21][CH2:22][C@@H:23]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH2:24][CH3:25]
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Reactant: CC[C@@H](O)COC
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC[C@@H](COC)Oc1cc(OCc2ccccc2)cc(C(=O)OC)c1
Temperature: 10 °C
Reaction time: 16 h
Yield: 68.6 %

Procedure:
A stirred solution of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (7.5 g, 29 mmol), (R)-1-methoxy-butan-2-ol (3.76 g, 36.25 mmol) and triphenylphosphine (9.5 g, 36.25 mmol) in dry THF (75 mL) was cooled in an ice-bath and a solution of 40% DEAD in toluene (15.8 mL, 36.25 mmol) was added dropwise over 30 minutes. The reaction mixture was allowed to warm slowly to 10° C. and stirred for 16 hours. The THF was evaporated. The residue was dissolved in 30% ethyl acetate in isohexane and cooled in ice. The resultant precipitate was removed by filtration and washed with 10% ethyl acetate in isohexane. The filtrate was evaporated and purified by column chromatography, eluting with 10% ethyl acetate in isohexane, to give the title compound as a colourless oil (6.85 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([OH:12])=[CH:5]2.O[CH:14]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]1.PPP.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([O:12][CH:18]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17]1)=[CH:5]2
Reactant: Oc1cnc2ccc(Br)cc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: PPP
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(Oc2cnc3ccc(Br)cc3c2)C1
Temperature: 50 °C
Reaction time: 6 h
Yield: 74 %

Procedure:
To a solution of 6-bromoquinolin-3-ol (500 mg, 2.232 mmol), tert-butyl 3-hydroxypyrrolidine-1-carboxylate (418 mg, 2.232 mmol) and triphosphine (875 mg, 3.35 mmol) in THF (10 ml) was added DEAD (0.424 ml, 2.68 mmol) at 0° C. Then the mixture was stirred at 50° C. for 6 h under N2. The mixture was diluted with ether and filtered. The filtrate was concentrated. The residue was purified by silica gel chromatography eluted with Hex/EA (from 100% to 95%) to afford the title compound (650 mg, 67% yield) as brown gel.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][S:11]([CH:14]2[CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:6][CH:5]=1)([O-])=O.[P].[S]>[Pd].C(O)C.CCOC(C)=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([O:10][S:11]([CH:14]2[CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(OS(=O)(=O)C2CC2)cc1
Agent: [Pd]
Agent: [P]
Agent: [S]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(OS(=O)(=O)C2CC2)cc1

Procedure:
This material was prepared from cyclopropanesulfonic acid 4-nitro-phenyl ester (J. F. King et al; Phosphorus, Sulfur and Silicon and the Related Elements; 1-4; 1993; p 445) (1.096 g) by hydrogenation over 10% Pd/C as catalyst, in ethanol/AcOEt as solvent (10 ml/15 ml) for 16 h, and at atmospheric pressure and RT. Yellow oil (0.55 g). MS (m/e): 214.2 [MH+].
Reaction SMILES: CC(C)CC([OH:6])C.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.[P:22](=[S:26])([OH:25])([OH:24])[SH:23].[O-2].[Zn+2:28]>O.C(O)(C)C>[P:22]([O-:25])([O-:24])([S-:26])=[S:23].[Zn+2:28].[P:22]([O-:25])([O-:24])([S-:26])=[S:23].[Zn+2:28].[Zn+2:28].[O-2:6].[Zn+2:28]
Reactant: OP(O)(=S)S
Reactant: CC(C)CC(C)O
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [O-2]
Agent: [Zn+2]
Solvent: CC(C)O
Solvent: O
Product: [O-]P([O-])(=S)[S-]
Reaction time: 4 h

Procedure:
Preparation 1. A mixture of 12 mole percent isopropanol and 88 mole percent 4-methyl-2-pentanol is reacted with phosphorus pentasulfide in approximately a 4.5:1 molar ratio at a maximum temperature of 80° C. The resulting dithiophosphoric acid mixture is reacted with a 12% molar excess of zinc oxide suspended in mineral oil at a temperature of 90° C. for four hours. After the reaction is complete, water of reaction and excess alcohols are distilled under a reduced pressure of 2.7 kPa (20 mm Hg) at 90° C. The product, containing about 9 percent by weight diluent oil, has a Total Base Number (TBN, ASTM D-2896) of 5.56 and includes about 14 percent basic zinc dithiophosphate by 31p NMR analysis. The product contains 8.70% P and 9.45% Zn. (The basic zinc salt is a known material which is formed during the zinc oxide reaction, from 3 moles of neutral zinc dithiophosphate and one mole of zinc oxide. The basic zinc salt is believed to be in the form of a tetrahedral complex that titrates with strong mineral acid, and it is believed to account for the TBN content of the product mixture.)
Reaction SMILES: C[Al](C)C.[CH2:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][NH:6]1.[C:15]1([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28](OCC)=[O:29])[CH2:24][CH2:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCCCCC.C1(C)C=CC=CC=1>[C:15]1([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([C:28]([N:6]3[CH2:7][CH2:8][C:9]4[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH2:5]3)=[O:29])[CH2:24][CH2:23]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Reactant: c1ccc2c(c1)CCNC2
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=C(C1CCN(Cc2ccccc2)CC1)N1CCc2ccccc2C1
Temperature: 50 °C
Yield: 90.8 %

Procedure:
251 ml (594 mmol) of trimethylaluminium (at a concentration of 25% in hexane) are introduced under an argon atmosphere into 400 ml of tolune. The solution is cooled in an ice bath and 81.5 g (612 mmol) of 1,2,3,4-tetrahydroisoquinoline, dissolved in 200 ml of toluene, are added. The mixture is heated to approximately 50° C. and 95 g (384 mmol) of ethyl 1phenylmethyl-4-piperidinecarboxylate, dissolved in 400 ml of toluene, are added. The mixture is heated under reflux for 2 h, approximately 250 ml of solvent being removed by means of a Dean and Stark apparatus. The mixture is cooled in an ice bath and hydrolysed by slowly adding 250 ml of water, and the insoluble material is filtered off, it being rinsed with ethyl acetate. The filtrate is washed three times with water, the organic phase dried over sodium sulphate, the solvent evaporated off and the residue recrystallized in cyclohexane. 116.6 g of product are obtained. Melting point: 98°-100° C.
Reaction SMILES: [CH3:1]O.S(Cl)(Cl)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:19]([CH3:20])=[CH:18][C:17](=[O:21])[C:16]([C:22]([OH:24])=[O:23])=[N:15]2)=[CH:10][CH:9]=1>O>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:19]([CH3:20])=[CH:18][C:17](=[O:21])[C:16]([C:22]([O:24][CH3:1])=[O:23])=[N:15]2)=[CH:10][CH:9]=1
Reactant: CO
Reactant: Cc1cc(=O)c(C(=O)O)nn1-c1ccc(Cl)cc1
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1nn(-c2ccc(Cl)cc2)c(C)cc1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 100 ml of methanol, cooled to -5° C., there is added dropwise 11.9 g (0.1 mol) of thionyl chloride. Upon completion of the addition 13.23 g (0.05 mol) of 1-(4-chlorophenyl)-1,4-dihydro-4-oxo-6-methylpyridazine-3-carboxylic Acid (see Example 12) is added. The suspension formed is vacuum filtered after stirring at room temperature for 3 hrs. to afford the product, mp 183°-193° C. decomp. Treatment of the product with water affords the Methyl 1-(4-chlorophenyl)-1,4-dihydro-4-oxo-6-methylpyridazine-3-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH2:18]([N:22]=[C:23]=[O:24])[CH2:19][CH2:20][CH3:21]>>[CH2:18]([NH:22][C:23]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:24])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCN=C=O
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CCCCNC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Yield: 78.5 %

Procedure:
Beginning with 0.15 gm (0.65 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.088 mL (0.78 mMol) butyl isocyanate, 0.168 gm (78%) of the title compound were recovered essentially by the procedure of Example 122. An analytical sample was crystallized from aqueous ethanol.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].[Cl:30][C:31]([Cl:35])([Cl:34])[CH2:32]O.C([C@@H](O)C1C=CC=C(OC2C=CC=CC=2)C=1)#N>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:29])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:9])[O:8][CH2:32][C:31]([Cl:35])([Cl:34])[Cl:30])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Reactant: OCC(Cl)(Cl)Cl
Agent: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Solvent: c1ccccc1
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OCC(Cl)(Cl)Cl

Procedure:
Using the procedure of Step F of Example 9, the ester of Step A after reaction with 2,2,2-trichloroethanol and (S)α-cyano-3-phenoxy-benzyl alcohol was reacted to obtain (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-(2,2,2-trichloroethoxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+42.5°±2° (c=0.5% in benzene).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:27][C:28]([F:39])([F:38])[C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>>[CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=2)[CH:12]=[C:13]([O:15][C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([C:28]([F:39])([F:38])[F:27])[CH:34]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)C(CC(C)C)c1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: COC(=O)C(CC(C)C)c1cc(Oc2cccc(C(F)(F)F)c2)cc(-c2ccc(C(F)(F)F)cc2)c1
Yield: 25 %

Procedure:
The title compound was prepared in 25% yield from 2-(5-hydroxy-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester and 3-trifluoromethylphenylboronic acid under the conditions described in Example 15, step (g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14](O)=[O:15])[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[NH2:29][C:30]1[CH:40]=[CH:39][C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:32][CH:31]=1>S(Cl)(Cl)=O.CN(C)C1C=CN=CC=1.ClCCl>[CH2:37]([O:36][C:34](=[O:35])[C:33]1[CH:39]=[CH:40][C:30]([NH:29][C:14](=[O:15])[CH:13]([N:12]2[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=[C:8]2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:31][CH:32]=1)[CH3:38]
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 63.6 %

Procedure:
The solution of 3.0 g (7.4 mmol) [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid in 5.4 ml thionylchloride was stirred under reflux. After 1 h the volatile components were removed at a rotary evaporator, the residue taken up in toluene and evaporated (three times). The remaining oil was dissolved in 30 ml dichloromethane, cooled to 0° C. and added dropwise on a solution of ethyl 4-aminobenzoate (1.35 g, 8.1 mmol) and 2.72 g (22.2 mmol) 4-dimethylaminopyridine dissolved in 30 ml dichloromethane. The cooling bath was removed and stirring was continued for another 4 h. The reaction was poured on 25% aqueous hydrochloric acid solution, the phases separated and the aqueous phase extracted with dichloromethane. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography on silica gel using heptane:ethyl acetate (1:0 to 1:1 v/v) as eluant to afford the title compound as a colorless solid (2.6 g, 62%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[NH:8][N:7]=[C:6]([NH:9][C:10]2[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[C:12]([NH:19][C@H:20]([C:22]3[N:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=3)[CH3:21])[N:11]=2)[CH:5]=1)[CH3:2].[CH2:29](O)C.C(OCC)(=O)C>[Cl-].[Na+].O.[Pd]>[CH2:1]([O:3][C:4]1[NH:8][N:7]=[C:6]([N:9]2[C:10]3=[N:11][C:12]([NH:19][C@H:20]([C:22]4[N:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=4)[CH3:21])=[CH:13][CH:14]=[C:15]3[N:16]=[CH:29]2)[CH:5]=1)[CH3:2]
Reactant: CCOc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)ccc2[N+](=O)[O-])n[nH]1
Reactant: CCO
Agent: [Pd]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1cc(-n2cnc3ccc(N[C@@H](C)c4ncc(F)cn4)nc32)n[nH]1
Temperature: 25 °C

Procedure:
N2-(5-Ethoxy-1H-pyrazol-3-yl)-N6-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-3-nitropyridine-2,6-diamine (Intermediate 28, 0.3 g) was dissolved into ethanol (20 mL) with Pd—C (90 mg) and a hydrogen inlet. The mixture was stirred at room temperature until no starting material was detected with TLC or LCMS. Formylamidine acetate (0.5 g) was added to the filtrate after the filtration of resulting mixture. The mixture was stirred at 85° C. for 4 hours. Ethyl acetate (40 mL) was added into the resulting mixture, and brine (10 mL×3) was used to wash the organic layer. The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Ethyl acetate/MeOH) to afford 0.034 g of the title compound. MS (electrospray): 369 (M+1) for C17H17FN8O. 1H NMR (300 MHz, CD3OD) δ ppm 8.70 (s, 2H) 8.30 (s, 1H) 7.80 (d, 1H) 6.80 (d, 1H) 6.30 (s, 1H) 5.40 (m, 1H) 4.30 (q, 2H) 1.70 (d, 3H) 1.55 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([Cl:12])=[CH:4][N:3]=1.[C:13]1([NH:19][C:20](=[O:28])[CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([N:25]2[CH2:26][CH2:27][N:22]([CH2:21][C:20]([NH:19][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:28])[CH2:23][CH2:24]2)[C:5]([Cl:12])=[CH:4][N:3]=1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Reactant: O=C(CN1CCNCC1)Nc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Nc1ncc(Cl)c(N2CCN(CC(=O)Nc3ccccc3)CC2)c1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
To a mixture of 2-amino-4,5-dichloro-3-nitropyridine (0.031 g, 0.15 mmol) and isopropanol (3.5 ml) was added N-phenyl-2-piperazin-1-yl-acetamide×2HCl salt (0.048 g, 0.16 mmol) followed by diisopropylethylamine (0.10 ml, 0.54 mmol). The reaction mixture was heated at 45° C. for 18 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 10% to 30% ethyl acetate in dichloromethane. The title compound was obtained as a yellow solid (0.041 g, 71%); 1H-NMR (500 MHz, DMSO-d6) 2.64 (br s, 4H, piperazine N(CH2)2), 3.13 (br s, 4H, piperazine N(CH2)2), 3.19 (s, 2H, NCH2CO), 7.00 (br s, 2H, 2-NH2), 7.06 (t, J=7.34 Hz, 1H, p-ArH), 7.31 (t, J=8.26 Hz, 2H, m-ArH), 7.63 (d, J=7.34 Hz, 2H, o-ArH), 8.07 (s, 1H, 6-H), 9.76 (s, 1H, CONH);
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7]C=O)=[N:4][C:3]=1[CH2:10][S:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18]C=O)=[CH:14][CH:13]=1.Cl.CO>O1CCCC1>[NH2:7][C:5]1[S:6][C:2]([Cl:1])=[C:3]([CH2:10][S:11][C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[N:4]=1
Reactant: O=CNc1ccc(SCc2nc(NC=O)sc2Cl)cc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(SCc2nc(N)sc2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.3 %

Procedure:
A solution of 5-chloro-2-formylamino-4-(4-formylaminophenylthiomethyl)thiazole (3.5 g) in a mixture of concentrated hydrochloric acid (9 ml), methanol (30 ml) and tetrahydrofuran (30 ml) was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water. The solution was adjusted to pH 8 using aqueous sodium bicarbonate with stirring under ice cooling. The precipitates were collected by filtration, washed with water and dried in vacuo to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 150 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-amino-4-(4-aminophenylthiomethyl)-5-chlorothiazole (2.3 g, yield: 79.3%). mp: 158°-163° C. (dec.)
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[C:18]([F:21])([F:20])[F:19]>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:13][C:12]=1[C:18]([F:19])([F:20])[F:21]
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=Cc1ccc(F)cc1
Product: O=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 4-fluorobenzaldehyde and 4-chloro-3-(trifluoromethyl)phenol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20]CC(O)=O)=[CH:16][CH:15]=3)[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=2)=[C:4]([O:31][CH2:32]C2CCCC2)[CH:3]=1.ClC1C=CC(C2N(CC3C=C(C=CC=3)C(O)=O)C3C=C(F)C(F)=CC=3[N:46]=2)=C(OCC2CCCC2)C=1.BrCC1C=CC(C#N)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]#[N:46])=[CH:16][CH:15]=3)[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=2)=[C:4]([O:31][CH3:32])[CH:3]=1
Reactant: O=C(O)c1cccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)c1
Reactant: O=C(O)CCc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1
Agent: N#Cc1ccc(CBr)cc1
Product: COc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1Cc1ccc(C#N)cc1

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(4-chloro-2-methoxy-phenyl)-5,6-difluoro-1H-benzoimidazole (Example 19, intermediate c) and 4-bromomethyl-benzonitrile (CAS Reg. No. 17201-43-3). Brown solid (48%). MS (Turbo Spray): m/z=410.3 (M+H).