Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:66][CH:67]([CH2:70][OH:71])[CH2:68][OH:69]>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:66][CH:67]([CH2:70][OH:71])[CH2:68][OH:69])=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cn3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reactant: NC(CO)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NC(CO)CO)cn3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reaction time: 0.08 h
Yield: 24.67 %

Procedure:
To a flask charged with 6-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)nicotinic acid (for a preparation see Intermediate 7) (90 mg, 0.211 mmol) and HATU (96 mg, 0.253 mmol) was added DMF (3 mL) and the resulting mixture was treated with DIPEA (0.110 mL, 0.632 mmol). After stirring for 5 min, the mixture was treated with 2-aminopropane-1,3-diol (38.4 mg, 0.421 mmol). After stirring for 3 min, the solution was partitioned between EtOAc and saturated aqueous NaHCO3 solution and the layers were separated. The aqueous phase was extracted with EtOAc (×2) and the combined organic layers were washed with saturated aqueous NaHCO3 solution (×3), then dried over MgSO4 and concentrated in vacuo. The residue was purified by MDAP (HpH). The appropriate fractions were collected and concentrated in vacuo. The residue was subsequently dissolved in MeOH and dried (hydrophobic frit). The solvent was removed and the residue triturated in Et2O to give 6-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-N-(1,3-dihydroxypropan-2-yl)nicotinamide (26 mg, 0.052 mmol, 24.67% yield) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][NH:11][C:10]2[N:15]=[CH:16][C:17](I)=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1>>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][NH:11][C:10]2[N:15]=[CH:16][C:17]([C:22]3[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=3)=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CNc2ncc(I)cc2N1Cc1ccccc1
Reactant: OB(O)c1cccnc1
Product: O=C1CNc2ncc(-c3cccnc3)cc2N1Cc1ccccc1
Yield: 60 %

Procedure:
1-Benzyl-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (100 mg) was reacted with 3-pyridine boronic acid as in General Procedure 4A to give the title compound as a light yellow solid (60% yield). M.p. 58° C., LCMS: m/z=317.16 (M+H+), 1H-NMR (CD3OD, 400 MHz) δ 4.42 (s, 2H), 7.22-7.31 (m, 2H), 7.32-7.38 (m, 4H), 7.50 (s, 1H), 7.85-7.92 (m, 1H), 8.02 (s, 1H), 8.39 (d, J=8.1 Hz, 1H), 8.65-8.75 (m, 1H), 8.75-8.90 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[C:8]([CH3:13])=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:5].N1C=CC=CC=1.[F:27][CH2:28][C:29](Cl)=[O:30]>O1CCCC1>[F:27][CH2:28][C:29]([NH:1][C:2]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[C:8]([CH3:13])=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:5])=[O:30]
Reactant: O=C(Cl)CF
Reactant: Cc1ccccc1NC(=O)c1cc([N+](=O)[O-])ccc1N
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1ccccc1NC(=O)c1cc([N+](=O)[O-])ccc1NC(=O)CF
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
14.4 g(0.053 mol) of N-(2-amino-5-nitrobenzoyl)-o-toluidine and 6.3 g(0.08 mol) of pyridine are dissolved in 300 ml of tetrahydrofuran. 12.2 g(0.126 mol) of fluoroacetyl chloride are added to the solution for 10 minutes under ice-cooling. The solution is stirred at the same temperature for 30 minutes and then at room temperature for 2.5 hours. The reaction solution is allowed to stand at room temperature overnight. The crystalline precipitate is collected by filtration, washed with water and then dried. 16.4 g of N-(2-fluoroacetamido-5-nitrobenzoyl)-o-toluidine are obtained.
Reaction SMILES: [F:1][C:2]([F:23])([CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][CH2:4][C@@H:5]1[C@@H:12]2[C@@H:8]([O:9][C:10](=[O:13])[CH2:11]2)[CH2:7][C@H:6]1[OH:14].[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.[Cl-].[Na+].O>[F:23][C:2]([F:1])([CH2:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:3][CH2:4][C@@H:5]1[C@@H:12]2[C@@H:8]([O:9][C:10](=[O:13])[CH2:11]2)[CH2:7][C@H:6]1[O:14][CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][O:24]1
Reactant: C1=COCCC1
Reactant: O=C1C[C@@H]2[C@@H](CCC(F)(F)COc3ccccc3)[C@H](O)C[C@@H]2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C1C[C@@H]2[C@@H](CCC(F)(F)COc3ccccc3)[C@H](OC3CCCCO3)C[C@@H]2O1
Temperature: 25 °C

Procedure:
(3aR,4R,5R,6aS)-4-(3,3-Difluoro-4-phenoxybutyl)-5-hydroxyhexahydro-2H-cyclopenta[b]furan-2-one, prepared in Step D, is dissolved in DCM (0.1 M) under a nitrogen atmosphere. Dihydropyran (1.1 molar equivalents) is added, followed by a catalytic amount of p-toluenesulfonic acid. The reaction is stirred at room temperature under a nitrogen atmosphere and the reaction progress is monitored by TLC. Upon completion, brine is added to the reaction mixture and the layers are separated. The organic phase is dried over sodium sulfate, filtered, and the solvent is evaporated. The crude product is purified by flash chromatography on regular silica gel eluted with ethyl acetate-hexanes to afford the title intermediate.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([CH3:32])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]3)=[CH:13][CH:12]=2)=[O:9])=[N:6][CH:7]=1.[F:33][C:34]1[CH:35]=[C:36]([OH:40])[CH:37]=[CH:38][CH:39]=1.CC(CCCC(CCCC(CCCC(CCC(O)=O)C)C)C)C>Cl[Cu]>[F:33][C:34]1[CH:35]=[C:36]([O:40][C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]([CH3:32])[C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]4)=[CH:13][CH:12]=3)=[O:9])=[N:6][CH:7]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Br)cn3)cc2)CCN1C(=O)OC(C)(C)C
Reactant: Oc1cccc(F)c1
Agent: Cl[Cu]
Agent: CC(C)CCCC(C)CCCC(C)CCCC(C)CCC(=O)O
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Oc4cccc(F)c4)cn3)cc2)CCN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared from 1,1-dimethylethyl (2S)-4-({4-[[(5-bromo-2-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D72) and 3-fluorophenol using a method similar to that described for D73 in Description 73 although 1 eq. CuCl and 0.25 eq. THMD were used. MS (ES): MH+ 535.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([N:30]=CN(C)C)[CH:25]=3)=[O:23])=[N:17][CH:18]=[C:19]([CH3:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:35]([F:38])([F:37])[F:36].C([O-])(O)=O.[Na+]>OS(O)(=O)=O.C(O)(C(F)(F)F)=O.O>[NH2:30][C:26]1[CH:25]=[C:24]([C:22]([C:16]2[C:15]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:35]([F:37])([F:38])[F:36])[CH:4]=3)(=[O:10])=[O:9])=[CH:20][C:19]([CH3:21])=[CH:18][N:17]=2)=[O:23])[CH:29]=[CH:28][N:27]=1
Reactant: COCN(c1cc(C)cnc1C(=O)c1ccnc(N=CN(C)C)c1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cnc(C(=O)c2ccnc(N)c2)c(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Temperature: 25 °C
Yield: 63.2 %

Procedure:
A mixture of 4-chloro-N-{2-[2-(dimethylamino-methyleneamino)-pyridine-4-carbonyl]-5-methyl-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzene sulfonamide (23 mg, mmol) in 5% H2SO4 in TFA (4 mL) and water (1 mL) was stirred at 50° C. for 2 days. The reaction mixture was cooled to room temperature, diluted with water (5 mL) and treated with saturated aqueous NaHCO3 solution slowly till pH 7-8. The mixture was extracted with EtOAc (2×25 mL), dried (anhydrous Na2SO4) and concentrated. The obtained residue was column purified (SiO2, 10% MeOH—CH2Cl2) to afford N-[2-(2-amino-pyridine-4-carbonyl)-5-methyl-pyridin-3-yl]-4-chloro-3-trifluoro methyl-benzenesulfonamide (12 mg) in 63% yield. 1H NMR (400 MHz, CDCl3) δ 10.75 (s, 1H), 8.24 (s, 1H), 8.18 (m, 1H), 8.07 (dd, 1H), 7.95 (d, 1H), 7.75 (d, 1H), 7.63 (d, 1H), 7.15 (s, 1H), 6.95 (d, 1H), 2.25 (s, 3H); ESMS m/z (relative intensity): 471.0 (M+H)+ (100).
Reaction SMILES: C([O:8][C:9]([C@:11]12[CH2:18][CH2:17][C@@:14]([CH:19]=[CH:20][C:21]([O:23][CH3:24])=[O:22])([CH2:15][CH2:16]1)[CH2:13][CH2:12]2)=[O:10])C1C=CC=CC=1>C(O)C.O.[Pd]>[CH3:24][O:23][C:21]([CH2:20][CH2:19][C:14]12[CH2:15][CH2:16][C:11]([C:9]([OH:10])=[O:8])([CH2:18][CH2:17]1)[CH2:12][CH2:13]2)=[O:22]
Reactant: COC(=O)C=C[C@]12CC[C@@](C(=O)OCc3ccccc3)(CC1)CC2
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: COC(=O)CCC12CCC(C(=O)O)(CC1)CC2

Procedure:
4-(2-Methoxycarbonyl-vinyl)-bicyclo[2.2.2]octane-1-carboxylic acid benzyl ester (XX, Example 95, 35 g, 106.6 mmol) is dissolved in ethyl alcohol/water (9/1, 300 ml) and is placed in a Porter pressure bottle. Palladium on carbon (10%, 5 g) is added and the mixture is hydrogenated (65 psi) for 48 hr. The reaction mixture is filtered through a pad of celite and the combined filtrates were concentrated to give the title compound, NMR (400 MHz, CDCl3) δ 3.58, 2.18, 1.74, 1.44 and 1.38.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7](Cl)=[O:8])(=[O:3])[CH3:2].[NH2:14][C@H:15]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]([NH:14][C@H:15]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(=O)SCC(CC(C)C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)C(CSC(C)=O)CC(C)C

Procedure:
2-Acetylthiomethyl-4-methylpentanoyl chloride and (L)-phenylalanine, ethyl ester are reacted in methylene chloride in the presence of diisopropylethylamine at a temperature below 0° according to the procedure of Example 26 to yield (±)-N-[2-(acetylthiomethyl)-4-methyl-1-oxopentyl]-L-phenylalanine, ethyl ester as an off-white foam.
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([CH2:9]O)[OH:8])[OH:6])[OH:4].O.[NH2:12][NH2:13]>CO>[CH:9](=[N:12][NH2:13])[C@H:7]([C@@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8]
Reactant: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: NN
Solvent: O
Solvent: CO
Product: NN=C[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
A solution of 4.0 g of D-arabinose in 10 ml of methanol and 10 ml of hydrazine hydrate was stirred overnight, then evaporated to dryness in vacuo. The residue was triturated with 25 ml of methanol and the solid was collected, giving 3.5 g of D-arabinose hydrazone.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:16]([O-])([OH:18])=[O:17].O>C(O)(=O)C>[N+:16]([C:11]1[CH:10]=[C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:14]=[CH:13][C:12]=1[OH:15])([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(OCc2ccccc2)cc1
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1O
Yield: 70.5 %

Procedure:
To 20 g (0.1 mole) of 4-phenylmethoxy-phenol in 200 ml acetic acid were added, dropwise at room temperature, 7.26 ml of nitric acid (d=1.4, 0.105 mole). 2 Hours after completion of the addition the reaction medium was poured onto cold water and extracted twice with 250 ml of methylene chloride. The organic phase was washed twice with 200 ml of water and dried over sodium sulfate. Then the solvent was evaporated and the residue flash chromatographed using ethyl acetate/heptane 30/70 as eluting solvent to give 17.3 g (Yield=70.6%) of 2-nitro-4-phenylmethoxy-phenol.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[C:10]([NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=[CH:7][N:6]2[C:18]=1[CH3:19].[CH3:20][OH:21]>>[CH3:20][O:21][CH2:2][C:3]1[N:4]=[C:5]2[C:10]([NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=[CH:7][N:6]2[C:18]=1[CH3:19]
Reactant: Cc1c(CCl)nc2c(NC(=O)C(C)(C)C)cccn12
Reactant: CO
Product: COCc1nc2c(NC(=O)C(C)(C)C)cccn2c1C
Yield: 99 %

Procedure:
A solution of 12.8 g 2-chloromethyl-3-methyl-8-pivaloylaminoimidazo[1,2-a]pyridine in 600 ml of dry methanol is refluxed for 5 h. The reaction mixture is concentrated in vacuo to half the volume. After addition of 200 ml of saturated sodium bicarbonate solution, the mixture is extracted with diethyl ether. The organic phase is washed with water and dried over anhydrous sodium sulfate. Removal of the. solvent in vacuo yields 12.5 g (99%) of the title compound (m.p. 104° C.).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([CH3:13])[SH:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[SH:14][CH2:15][CH2:16][OH:17]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([S:12][S:14][CH2:15][CH2:16][OH:17])[CH3:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(S)Cc1ccc2c(c1)OCO2
Reactant: OCCS
Product: CC(Cc1ccc2c(c1)OCO2)SSCCO
Yield: 64 %

Procedure:
5.0 g of the title compound was prepared from 8.4 g of 2-(1,3-benzodioxol-5-yl)-1-methylethanethiol and 2.24 g of 2-mercaptoethanol as a colorless oil according to the same procedure as that described in Example 1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[Li]CCCC.CCCCCC.[CH2:20]([N:22]([CH2:41][CH3:42])[CH2:23][CH2:24][N:25]1[C:35]2[C:30](=[C:31]([C:37]([F:40])([F:39])[F:38])[CH:32]=[C:33]([I:36])[CH:34]=2)[C:28](=[O:29])[C:26]1=[O:27])[CH3:21]>C1COCC1>[CH2:41]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][N:25]1[C:35]2[C:30](=[C:31]([C:37]([F:38])([F:40])[F:39])[CH:32]=[C:33]([I:36])[CH:34]=2)[C:28]([OH:29])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[F:8])[C:26]1=[O:27])[CH3:42]
Reactant: Fc1ccccc1Br
Reactant: CCN(CC)CCN1C(=O)C(=O)c2c1cc(I)cc2C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCN(CC)CCN1C(=O)C(O)(c2ccccc2F)c2c1cc(I)cc2C(F)(F)F
Reaction time: 0.17 h
Yield: 8.9 %

Procedure:
To a solution of 1-bromo-2-fluorobenzene (0.09 mL, 0.823 mmol) in THF (4 mL) was added dropwise 1.53 N BuLi in hexane (0.54 mL, 0.826 mmol) over 10 min at −78° C. and the mixture was stirred for 10 min. The resulting solution was then transferred into the cooled solution of 1-(2-diethylaminoethyl)-4-trifluoromethyl-6-iodoisatin (330 mg, 0.75 mmol) in THF (2 mL) at −78° C. via a cannula. The mixture was stirred for 30 min at the same temperature and the reaction was quenched with aqueous NaHCO3. The mixture was extracted with ethyl acetate and the extracts were dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography with 50:1 to 30:1 chloroform/methanol to give the title compound (35.9 mg, 9%).
Reaction SMILES: C(O[C:4]([C:6]1[NH:10][C:9]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)[O:13][C:8]=2[CH:7]=1)=[O:5])C.C(OC(=O)C(CC)CCN1C(=S)N2C3C=C(C4C=CC([N+]([O-])=O)=CC=4)OC=3C=C2C1=O)C.[CH2:55]([O:57][C:58](=[O:67])[CH2:59][C:60]([CH3:66])([CH3:65])[CH2:61][N:62]=[C:63]=[S:64])[CH3:56].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[CH2:55]([O:57][C:58](=[O:67])[CH2:59][C:60]([CH3:66])([CH3:65])[CH2:61][N:62]1[C:63](=[S:64])[N:10]2[C:9]3[CH:11]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=4)[O:13][C:8]=3[CH:7]=[C:6]2[C:4]1=[O:5])[CH3:56]
Reactant: CCOC(=O)CC(C)(C)CN=C=S
Reactant: CCOC(=O)c1cc2oc(-c3ccc([N+](=O)[O-])cc3)cc2[nH]1
Agent: CCOC(=O)C(CC)CCN1C(=O)c2cc3oc(-c4ccc([N+](=O)[O-])cc4)cc3n2C1=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CC(C)(C)CN1C(=O)c2cc3oc(-c4ccc([N+](=O)[O-])cc4)cc3n2C1=S
Temperature: 140 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
2-(4-nitro-phenyl)-4H-furo[3,2-b]pyrrole-5-carboxylic acid ethyl ester (212 mg, 0.71 mmol, 1 molequivalent), prepared as described hereinabove (see, preparation of Compound 1), was placed in a round bottom flask and 4-isothiocyanato-3,3-dimethyl-butyric acid ethyl ester (1.4 grams, 7.1 mmol, 10 molequivalents) was added thereto, followed by addition of grinded anhydrous potassium carbonate (K2CO3; 147 mg, 1.1 mmol, 1.5 molequivalents). The mixture was heated while stirring at 140° C. for 16 hours. The reaction mixture was thereafter dissolved in chloroform and 5% citric acid solution, the organic phase was extracted, and the aqueous layer was washed with chloroform several times. The combined organic layers were dried over Na2SO4, the solvent was removed under reduced pressure, and the crude product was triturated in ethanol to give Compound 7 (322 mg, 40% yield) as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7]C)=O.[C:13]1([NH:19][NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C[O-].[Na+].CO>O>[C:13]1([N:19]([C:5](=[O:7])[C:4]2[CH:9]=[CH:10][C:11]([Cl:12])=[C:2]([Cl:1])[CH:3]=2)[NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(Cl)c(Cl)c1
Reactant: NNc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NN(C(=O)c1ccc(Cl)c(Cl)c1)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture consisting of 71.8 g. (0.35 mole) methyl 3,4-dichlorobenzoate, 37.9 g. (0.35 mole) phenylhydrazine, 21.6 g. (0.40 mole) sodium methoxide, and 175 ml. methanol was heated at the reflux temperature for 22 hrs. After cooling the reaction mixture to about 25°C., it was poured into 500 ml. water. The aqueous mixture was filtered and the solids that collected on the filter were dissolved in 500 ml. ethanol. Refrigeration caused crystals to form which were recovered by filtration. There was thus obtained 3,4-dichlorobenzoic acid phenylhydrazide melting at 169° to 172°C. An analytical sample melting at 171.5° to 173° C. was obtained by recrystallization from ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=O)[CH:5]=[N:6][CH:7]=1.[NH2:10][C:11]1[N:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=1>C(O)=O.O.[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:17]/[C:15]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:10])[N:16]=2)[CH:5]=[N:6][CH:7]=1
Reactant: O=Cc1cncc(Br)c1
Reactant: Cc1ccnc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: O
Product: Nc1nccc(/C=C/c2cncc(Br)c2)n1
Temperature: 25 °C
Yield: 71.4 %

Procedure:
A solution of 5-bromo-pyridine-3-carbaldehyde (436 mg, 2.34 mmol) and 2-amino-4-methylpyrimidine (246 mg, 2.35 mmol) in formic acid (96%, 3 mL) was heated for 18 h. After cooling to rt, it was then diluted with water and basified to pH ˜13 with 1 N NaOH. The mixture was then extracted with methylene chloride. The combined extracts was washed with water (1×), dried over MgSO4 and concentrated. The residue was chromatographed on silica gel eluting with CH2Cl2:MeOH:NH4OH (100:5:0.5) to give the title compound (463 mg, 71%). MS (DCI/NH3) m/z 277, 279 (M+1)+.
Reaction SMILES: BrC1C=C(C=CC=O)C=C(OC)C=1OC.COC1C=C(C=C(OC)C=1OC)C=O.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:42]=[CH:43][CH:44]=[O:45])[CH:35]=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39].[CH3:46][O:47][C:48]1[CH:49]=[C:50]([OH:54])[CH:51]=[CH:52][CH:53]=1.N1CCOCC1>CO>[CH3:41][O:40][C:36]1[CH:35]=[C:34]([CH:42]=[CH:43][CH:44]=[O:45])[CH:33]=[C:32]([O:31][CH3:30])[C:37]=1[O:38][CH3:39].[CH3:46][O:47][C:48]1[CH:49]=[C:50]2[C:51]([CH:42]([C:34]3[CH:33]=[C:32]([O:31][CH3:30])[C:37]([O:38][CH3:39])=[C:36]([O:40][CH3:41])[CH:35]=3)[CH2:43][CH:44]([OH:45])[O:54]2)=[CH:52][CH:53]=1
Reactant: COc1cccc(O)c1
Agent: COc1cc(C=CC=O)cc(Br)c1OC
Agent: COc1cc(C=CC=O)cc(OC)c1OC
Agent: COc1cc(C=O)cc(OC)c1OC
Solvent: C1COCCN1
Solvent: CO
Product: COc1ccc2c(c1)OC(O)CC2c1cc(OC)c(OC)c(OC)c1

Procedure:
3-(3,4,5-Trimethoxyphenyl)-propenal was prepared following the procedure for 3-(3-bromo-4,5-dimethoxyphenyl)-propenal as described in Example 15a using 3,4,5-trimethoxy benzaldehyde. 7-Methoxy-2-hydroxy-4-(3,4,5-trimethoxy-phenyl)-chroman was synthesized by the same procedure as Example 18 from 3-(3,4,5-trimethoxyphenyl)-propenal (71 mg; 0.32 mmol) and 3-methoxy phenol (43 mg; 0.35 mmol) using morpholine (30 μl) as a base in methanol (2.5 ml) (14 mg; 13%). 1H NMR (acetone-d6): 6.64 (dd, J=1.1, 8.5 Hz) and 6.59 (dd, J=1.0, 8.4 Hz) (1H), 6.54 (one doublet and one singlet overlapped, J=2.7 Hz; 2H), 6.38 (dd, J=2.6, 8.5 Hz; 1H), 6.34 (d overlapping with other small signals, J=2.3 Hz; 1H), 6.13 (d, J=6.8 Hz) and 6.08 (dd, J=1.0, 4.5 Hz) (1H), 5.62-5.65 and 5.47-5.51 (m each, 1H), 4.13-4.21 (overlapping dd, J=6.6, 10.2 Hz; 1H), 3.78, 3.77, 3.73, 3.72 (s each, 12H), 2.31 (ddd, J=2.1, 5.7, 13.1 Hz) and 2.08-2.13 (m) (2H).
Reaction SMILES: ClC1C=CC=C(Cl)C=1C(NC1C(C2NC3C=CC(CN4CCOCC4)=CC=3N=2)=NNC=1)=O.[F:33][C:34]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[C:47]([F:53])[C:35]=1[C:36]([NH:38][C:39]1[C:40]([C:44](O)=O)=[N:41][NH:42][CH:43]=1)=[O:37].[NH2:54][C:55]1[CH:56]=[C:57]([C:62]([N:64]2[CH2:69][CH2:68][O:67][CH2:66][CH2:65]2)=[O:63])[CH:58]=[CH:59][C:60]=1[NH2:61]>>[F:33][C:34]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[C:47]([F:53])[C:35]=1[C:36]([NH:38][C:39]1[C:40]([C:44]2[NH:61][C:60]3[CH:59]=[CH:58][C:57]([C:62]([N:64]4[CH2:65][CH2:66][O:67][CH2:68][CH2:69]4)=[O:63])=[CH:56][C:55]=3[N:54]=2)=[N:41][NH:42][CH:43]=1)=[O:37]
Reactant: COc1cc(F)c(C(=O)Nc2c[nH]nc2C(=O)O)c(F)c1
Reactant: Nc1ccc(C(=O)N2CCOCC2)cc1N
Agent: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)c1c(Cl)cccc1Cl
Product: COc1cc(F)c(C(=O)Nc2c[nH]nc2-c2nc3cc(C(=O)N4CCOCC4)ccc3[nH]2)c(F)c1

Procedure:
The compound was prepared in a manner analogous to 2,6-dichloro-N-[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (Example 94E), however using 4-(2,6-difluoro-4-methoxy-benzoylamino)-1H-pyrazole-3-carboxylic acid (Example 96A) and (3,4-diamino-phenyl)-morpholin-4-yl-methanone (Example 94B) to give 2,6-difluoro-4-methoxy-N-{3-[5-(morpholine-4-carbonyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}-benzamide (24 mg) as a beige solid. (LC/MS: Rt 2.94, [M+H]+ 483.20).
Reaction SMILES: C(C1C=CC2C(C)(C)CCC(C)(C)C=2C=1)=O.O[CH:18]([P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])[C:19]1[CH:28]=[CH:27][C:26]2[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]([CH3:32])([CH3:31])[C:21]=2[CH:20]=1.S(Cl)([Cl:43])=O>>[Cl:43][CH:18]([P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])[C:19]1[CH:28]=[CH:27][C:26]2[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]([CH3:32])([CH3:31])[C:21]=2[CH:20]=1
Reactant: O=S(Cl)Cl
Reactant: CCOP(=O)(OCC)C(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: CC1(C)CCC(C)(C)c2cc(C=O)ccc21
Product: CCOP(=O)(OCC)C(Cl)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 88 %

Procedure:
(216 g (1 mole) of 2-formyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene were converted to 251 g (71%) of diethyl 1-hydroxy-1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-yl)-methylphosphonate of melting point 93°-95° C., and 188.4 g (88%) of the title compound were obtained from 203 g (0.57 mole) of the last-mentioned compound and 287 ml of thionyl chloride. Since the material decomposes during distillation, the working up procedure was modified as follows. The crude product obtained after removal of the thionyl chloride was dissolved in toluene, and the solution stirred with 5 g of potassium carbonate for 20 minutes. The solid was filtered off, the solvent was remoVed and the solidified mass was comminuted in a mortar. The material thus obtained (m.p. 65°-66° C.) was about 85% pure according to the H-NMR spectrum.