Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C@H:5]1[CH2:9][N:8]([CH2:10][C:11](=[O:22])[NH:12][C:13]2[S:14][C:15]3[CH2:16][CH2:17][CH2:18][NH:19][C:20]=3[N:21]=2)[CH2:7][C@@H:6]1[NH:23][C:24]([C:26]1[S:27][C:28]([Cl:31])=[CH:29][CH:30]=1)=[O:25].I[CH:33]([CH3:35])[CH3:34]>C1COCC1>[CH:33]([CH:18]1[CH2:17][CH2:16][C:15]2[S:14][C:13]([NH:12][C:11]([CH2:10][N:8]3[CH2:9][C@H:5]([O:4][CH3:3])[C@@H:6]([NH:23][C:24]([C:26]4[S:27][C:28]([Cl:31])=[CH:29][CH:30]=4)=[O:25])[CH2:7]3)=[O:22])=[N:21][C:20]=2[NH:19]1)([CH3:35])[CH3:34]
Reactant: CO[C@H]1CN(CC(=O)Nc2nc3c(s2)CCCN3)C[C@@H]1NC(=O)c1ccc(Cl)s1
Reactant: CC(C)I
Agent: Cl
Solvent: C1CCOC1
Product: CO[C@H]1CN(CC(=O)Nc2nc3c(s2)CCC(C(C)C)N3)C[C@@H]1NC(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
94.3 A suspension of 60 mg 5-chloro-thiophene-2-carboxylic acid {(3S,4S)-4-methoxy-1-[(4,5,6,7-tetrahydro-thiazolo[5,4]pyridin-2-ylcarbamoyl)-methyl]-pyrrolidin-3-yl}-amide dihydrochloride in 3 ml THF was treated with 0.03 ml TEA and 0.01 ml 2-iodopropane. After stirring at r.t. overnight, the reaction mixture was again treated with 0.03 ml TEA and 0.03 ml 2-iodopropane and heated to 70° C. overnight. Then, it was concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2->CH2Cl2/MeOH 9:1) to give 51 mg 5-chloro-thiophene-2-carboxylic acid {(3S,4S)-1-[(5-isopropyl-4,5,6,7-tetrahydro-thiazolo[5,4]pyridin-2-ylcarbamoyl)-methyl]-4-methoxy-pyrrolidin-3-yl}-amide as yellow solid. MS 498.4 ([M+H]+)
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].[CH3:27][C:28]1[CH:29]=[C:30]([N:34]=[C:35]=[O:36])[CH:31]=[CH:32][CH:33]=1>>[CH3:27][C:28]1[CH:29]=[C:30]([NH:34][C:35](=[O:36])[NH:1][CH2:2][C:3]([N:5]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:4])[CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)CN(C(=O)CN)c1ccccc1Oc1ccccc1
Reactant: Cc1cccc(N=C=O)c1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2ccccc2Oc2ccccc2)c1
Yield: 26.3 %

Procedure:
Using a procedure similar to that described in Example 1, but starting with tert-butyl 2-[2-amino-N-(2-phenoxyphenyl)acetamido]acetate (4.7 g) and 3-methylphenyl isocyanate (1.9 g), and after recrystallisation in ethyl acetate, tert-butyl 2-{2-[3-(3-methylphenyl)ureido]-N-(2-phenoxyphenyl)acetamido}acetate (1.7 g), m.p. 204° C., is obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][S:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23](O)=[O:24])[CH2:10]2)=[CH:5][C:4]=1[F:26])[CH3:2].O[N:28]=[C:29]([O:31][CH2:32][CH3:33])[NH2:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:32]([O:31][C:29]1[N:30]=[C:23]([CH:11]2[CH2:10][CH:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[C:4]([F:26])[CH:5]=3)[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][S:20][CH2:19][CH2:18]3)=[O:16])[CH2:12]2)[O:24][N:28]=1)[CH3:33]
Reactant: CCOC(N)=NO
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCSCC3)C2)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1noc(C2CC(c3ccc(CC)c(F)c3)CN(C(=O)N3CCSCC3)C2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
309 mg (0.81 mmol) of the compound from Example 36A and 169 mg (1.62 mmol) of ethyl N′-hydroxyimidocarbamate [G. Zinner, G. Nebel, Arch. Pharm. 1970, 303, 385-390] were initially charged in 3.1 ml of DMF and reacted with 463 mg (1.22 mmol) of HATU and 0.42 ml (315 mg, 2.44 mmol) of N,N-diisopropylethylamine. The mixture was stirred at RT for 15 minutes; the reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed repeatedly with water, dried over sodium sulphate and concentrated under reduced pressure. The residue was taken up in 3.0 ml of DMF and converted at 180° C. for two minutes in the microwave (Emrys Optimizer). The reaction mixture was purified by means of preparative HPLC. Yield: 108 mg (30% of theory)
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[BH4-].[Na+].O>CO>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][OH:10])=[CH:11][CH:12]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)Cc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To a solution of 4-isobutylbenzaldehyde (2.4 g) in methanol (10 mL) was added sodium borohydride (0.85 g) at room temperature, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (2.3 g).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH2:8][CH2:9][OH:10].[C:11]([O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25]I)=[CH:18][CH:17]=1)([CH3:14])([CH3:13])[CH3:12].O>CN(C=O)C>[C:11]([O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][N:3]2[CH:7]=[CH:6][N:5]=[C:4]2[CH2:8][CH2:9][OH:10])=[CH:20][CH:21]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: OCCc1ncc[nH]1
Reactant: CC(C)(C)Oc1ccc(CCCCI)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)Oc1ccc(CCCCn2ccnc2CCO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
65% sodium hydride (1.78 g) was added to a solution of 2-(1H-imidazol-2-yl)ethanol (5.62 g) in DMF (80 ml) at 0° C., and the mixture was stirred at room temperature for 30 min. A solution of 1-tert-butoxy-4-(4-iodobutyl)benzene (13.3 g) in DMF (20 ml) was added to the mixture at 0° C., and the mixture was stirred at the same temperature for 5 hr. The reaction mixture was combined with water and extracted with ethyl acetate. The extract was washed successively with water (twice), and saturated brine, dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Chromatorex; eluent hexane:ethyl acetate=2:5) to give the titled compound (9.53 g) as a colorless amorphous form.
Reaction SMILES: CO[C:3]1[C:4]2[CH2:12][N:11]([C:13]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:14]=3[C:15]#[N:16])[CH2:10][CH2:9][C:5]=2[N:6]=[CH:7][N:8]=1.CN(C)C1C=CC=CC=1.CN(C)C=O.P(Cl)(Cl)([Cl:38])=O.[OH-].[Na+]>C(#N)C>[Cl:38][C:3]1[C:4]2[CH2:12][N:11]([C:13]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:14]=3[C:15]#[N:16])[CH2:10][CH2:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ncnc2c1CN(c1ccc(C)cc1C#N)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CN(C)c1ccccc1
Product: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Temperature: 110 °C
Reaction time: 0.67 h

Procedure:
A mixture of 2-(4-methoxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (4.15 g, 14.1 mmol), N,N-dimethylaniline (0.181 mL, 1.4 mmol), N,N-dimethylformamide (0.21 mL, 2.7 mmol) and acetonitrile (35 mL) was heated to dissolve at 105° C. Phosphoryl chloride (5.3 mL, 56 mmol) was added dropwise over 3 mins, and the reaction was heated to reflux at 110° C. After 40 mins, additional phosphoryl chloride (5.3 mL, 0.056 mol) was added dropwise over 3 mins. After another 20 hours, 1H NMR showed that the reaction was ca 70% complete and the reaction mixture was allowed to cool and poured over ice (200 g) and 45% aq. NaOH (75 mL) was added. The mixture was extracted with CH2Cl2 (3×200 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by silica gel column (0-100% EtOAc/hexane) to yield a brown oil which became a solid in the freezer.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10]N=C(CC)CC)([O-:3])=[O:2]>Cl.CO>[CH2:9]([C:4]1[O:10][C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]=1[CH3:6])[CH3:8]
Reactant: CCC(CC)=NOc1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: CO
Product: CCc1oc2c([N+](=O)[O-])cccc2c1C
Yield: 91.6 %

Procedure:
A mixture of pentan-3-one O-(2-nitrophenyl)oxime (10.50 g) in 10% hydrogen chloride-methanol (105 ml) was refluxed for 4 hours. After concentration in vacuo, the residue was extracted with ethyl acetate and water. The obtained organic layer was washed with saturated aqueous sodium bicarbonate, brine and dried over, sodium sulfate. After evaporation in vacuo, the residue was purified by column chromatography on silica gel (eluate; ethyl acetate:n-hexane=1:6) to give a solid. The resulting solid was triturated with a mixture of ethanol and water (2:1) and the precipitate was collected to give 2-ethyl-3-methyl-7-nitrobenzo[b]furan (4.44 g).
Reaction SMILES: C([O:4][C:5]1[CH:19]=[CH:18][C:8]([CH2:9][O:10][CH2:11][CH2:12][N:13]2[N:17]=[CH:16][CH:15]=[N:14]2)=[CH:7][CH:6]=1)C=C.CN1C(=O)CC(=O)N(C)C1=O>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:14]1[N:13]([CH2:12][CH2:11][O:10][CH2:9][C:8]2[CH:18]=[CH:19][C:5]([OH:4])=[CH:6][CH:7]=2)[N:17]=[CH:16][CH:15]=1
Reactant: C=CCOc1ccc(COCCn2nccn2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: ClCCl
Product: Oc1ccc(COCCn2nccn2)cc1
Temperature: 40 °C
Reaction time: 4.5 h
Yield: 86 %

Procedure:
A solution of 950 mg (3.66 mmol) 2-[2-(4-allyloxy-benzyloxy)-ethyl]-2H-[1,2,3]-triazole in 20 ml dichloromethane was added to a solution of 1.71 g (11.0 mmol) 1,3-dimethylbarbituric acid and 104 mg (0.09 mmol) Pd(PPh3)4 in 40 ml dichloromethane and stirred for 4.5 h at 40° C. The mixture was extracted with 3×40 ml sat. NaHCO3-solution and 15 ml water and the combined aqueous phases were reextracted with 2×40 ml dichloromethane. The organic extracts were combined and dried over MgSO4. Solvents were distilled off and the residue purified by chromatography on silica gel (ethyl acetate/n-heptane 2:1) to yield 690 mg (86%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[N:12]1.[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[N:12]1)[NH2:8]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(-n2ccc(-c3ccccn3)n2)c(F)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(-n2ccc(-c3ccccn3)n2)c(F)c1
Yield: 83.8 %

Procedure:
The above-described product 18a (7.87 g, 27.7 mmol) was dissolved in ethanol (50 mL), together with Pd/C (0.787 g). The mixture was reacted overnight at room temperature with a flow of hydrogen. After completion of the reaction, the solvent was evaporated. After recrystallization with ethyl acetate/petroleum ether, the product 19a (5.9 g) was obtained as a yellow solid, with a yield of 83.4%.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([O:12][CH:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[C:10]=2[N:11]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([NH:34][S:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)(=[O:37])=[O:36])[CH:31]=[N:32][CH:33]=2)O1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH3:19][N:16]1[CH2:17][CH2:18][CH:13]([O:12][C:9]2[C:10]3[N:11]=[C:2]([C:28]4[CH:29]=[C:30]([NH:34][S:35]([C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)(=[O:36])=[O:37])[CH:31]=[N:32][CH:33]=4)[CH:3]=[CH:4][C:5]=3[N:6]=[CH:7][N:8]=2)[CH2:14][CH2:15]1
Reactant: CN1CCC(Oc2ncnc3ccc(Cl)nc23)CC1
Reactant: CC1(C)OB(c2cncc(NS(=O)(=O)c3ccccc3)c2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CN1CCC(Oc2ncnc3ccc(-c4cncc(NS(=O)(=O)c5ccccc5)c4)nc23)CC1
Temperature: 25 °C
Yield: 14.3 %

Procedure:
A mixture of 6-chloro-4-(1-methylpiperidin-4-yloxy)pyrido[3,2-d]pyrimidine (Intermediate 6) (0.074 g, 0.265 mmol), N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzene sulfonamide (Intermediate 2) (0.143 g, 0.398 mmol), PdCl2(dppf)-CH2Cl2Adduct (43.4 mg, 53.0 μmol) and 1N aq. sodium bicarbonate (0.531 ml, 0.531 mmol) in dioxane (1.06 ml) was refluxed for 3 hours. After cooling to room temperature, the reaction mixture was filtered through a Celite pad and washed with CH2Cl2. The filtrate was concentrated in vacuo. The residue was purified by prep TLC (EtOAc only) to give N-(5-(4-(1-methylpiperidin-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfonamide (0.018 g, 14%) as a yellow solid. 1H-NMR (DMSO-d6, Varian 400 MHz) δ 1.88-1.99 (2H, m), 2.12-2.21 (2H, m), 2.26 (3H, s), 2.28-2.36 (2H, m), 2.77-2.85 (2H, m), 5.43 (1H, s), 6.54 (1H, brs), 7.47-7.60 (4H, m), 7.83-7.89 (2H, m), 8.31-8.39 (2H, m), 8.49 (1H, d, J=8.8 Hz), 8.84 (1H, s), 8.91 (1H, s). m/z=477.2 [M+1]+.
Reaction SMILES: [CH3:1][NH2:2].C([O:5][C:6](=O)[CH2:7][N:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[C:17]([C:19]#[C:20][C:21]3[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=3)[N:16]=[C:15]2[CH3:28])=[CH:10][C:9]1=[O:29])C>C(O)C>[CH3:1][NH:2][C:6](=[O:5])[CH2:7][N:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[C:17]([C:19]#[C:20][C:21]3[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=3)[N:16]=[C:15]2[CH3:28])=[CH:10][C:9]1=[O:29]
Reactant: CN
Reactant: CCOC(=O)Cn1ccc(-n2cc(C#Cc3cccc(C)c3)nc2C)cc1=O
Solvent: CCO
Product: CNC(=O)Cn1ccc(-n2cc(C#Cc3cccc(C)c3)nc2C)cc1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 2 ml of a 8M solution of methylamine in ethanol were added 67 mg (0.18 mmol) of [4-(2-methyl-4-m-tolylethynyl-imidazol-1-yl)-2-oxo-2H-pyridin-1-yl]-acetic acid ethyl ester (Example 13). The reaction vessel was closed and the yellow solution was stirred for 16 h at room temperature. The solution was then evaporated to dryness yielding 63 mg of the title compound as a light brown solid, MS: m/e=361.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:4]=1[OH:10].[C:11]1(=O)[CH2:15][CH2:14][CH2:13][CH2:12]1.C([O-])([O-])OC.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]2[O:10][C:11]3([O:6][C:5]=2[CH:7]=[CH:8][CH:9]=1)[CH2:15][CH2:14][CH2:13][CH2:12]3
Reactant: COc1cccc(O)c1O
Reactant: O=C1CCCC1
Agent: COC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: c1ccccc1
Product: COc1cccc2c1OC1(CCCC1)O2

Procedure:
A mixture of 3-methoxycatechol (22.6 g), cyclopentanone (27.1 g), methyl orthoformate (34.2 g), p-toluenesulfonic acid.monohydrate (0.2 g), and benzene (300 ml) was heated under reflux for 24 hours. After being allowed to stand for cooling, a dilute solution of sodium hydroxide was added to the mixture followed by extraction with ether. The organic layer was washed with a saturated saline and dried over anhydrous potassium carbonate. The solvent was distilled off under reduced pressure to give Compound IIax-a (30 g, 90%) as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[C:11]1([CH3:19])[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Mg]Cl.C(O)(=O)C>C1COCC1.O.O.C([O-])(=O)C.[Mn+3].C([O-])(=O)C.C([O-])(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH3:19])[C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: Cc1ccccc1[Mg]Cl
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: [Mn+3]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1-c1cc(Cl)ncc1C(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 50.9 %

Procedure:
13.0 g (82.5 mMol) 6-Chloro-nicotinic acid in 65 ml THF were cooled to 0° C. and 206.3 ml (206.3 mMol) o-tolylmagnesium chloride solution (1M in THF) were added over 45 minutes. The solution obtained was further stirred 3 hours at 0° C. and overnight at room temperature. It was cooled to −60° C. and 103.8 ml (1.8 Mol) acetic acid were added, followed by 35 ml THF and 44.24 g (165 mMol) manganese(III) acetate dihydrate. After 30 minutes at −60° C. and one hour at room temperature, the reaction mixture was filtered and THF removed under reduced pressure. The residue was partitioned between water and dichloromethane and extracted. The crude product was filtered on silica gel (eluent: ethyl acetate/toluene/formic acid 20:75:5) then partitioned between 200 ml aqueous half-saturated sodium carbonate solution and 100 ml dichloromethane. The organic phase was washed with 50 ml aqueous half-saturated sodium carbonate solution. The combined aqueous phases were acidified with 25 ml aqueous HCl 25% and extracted with dichloromethane. The organic extracts were dried (Na2SO4) and concentrated under reduced pressure to yield 10.4 g (51%) of 6-chloro-4-o-tolyl-nicotinic acid as a yellow foam.
Reaction SMILES: [CH3:1]/[C:2](=[CH:6]\[CH:7]=[CH:8]\[C:9](\[CH3:26])=[CH:10]\[CH2:11][C:12]1[C:17]([Cl:18])=[CH:16][C:15]([O:19][C:20]([F:23])([F:22])[F:21])=[C:14]([CH3:24])[C:13]=1[Cl:25])/[CH:3]=[CH:4]/[OH:5]>[O-2].[O-2].[Mn+4].C(Cl)Cl>[CH3:1]/[C:2](/[CH:6]=[CH:7]/[CH:8]=[C:9](\[CH3:26])/[CH:10]=[CH:11]/[C:12]1[C:17]([Cl:18])=[CH:16][C:15]([O:19][C:20]([F:22])([F:21])[F:23])=[C:14]([CH3:24])[C:13]=1[Cl:25])=[CH:3]\[CH:4]=[O:5]
Reactant: CC(/C=C/O)=C\C=C\C(C)=C\Cc1c(Cl)cc(OC(F)(F)F)c(C)c1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(/C=C/C=C(C)/C=C/c1c(Cl)cc(OC(F)(F)F)c(C)c1Cl)=C\C=O

Procedure:
(2E,4E,6E,8E)-3,7-dimethyl-9-[2,6-dichloro-3methyl-4-(trifluoromethoxy)phenyl]-nonatetraen-1-ol (0.6mmol) could be dissolved in 20 ml. of methylene chloride and added to a suspension of 1.1 g. of activated manganese dioxide in 40 ml. of methylene chloride with stirring. Ater the reaction is complete, the resulting mixture is filtered and the filtrate evaporated to give (2E,4E,6E,8E)-3,7-dimethyl-9-[2,6-dichloro-3-methyl-4-(trifluoromethoxy)phenyl]-nonatetraen-1-al, which is further purified by crystallization or chromatography using conventional procedures.
Reaction SMILES: [Br:1]Br.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4]1>C(O)(=O)C>[Br:1][C:9]1[CH:10]=[C:11]2[C:6]([C:5]([C:12]([OH:14])=[O:13])=[CH:4][NH:3]2)=[CH:7][CH:8]=1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(O)c1c[nH]c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
Bromine (49.58 g, 3100 mmol) is added slowly to a white suspension of Indole-3-carboxylic acid (50 g, 310 mmol) in 500 mL of acetic acid at room temperature, and the mixture is stirred at room temperature overnight. The solid formed is filtered and dried under vacuum for 3 hours to afford 45 g of the title compound as a grey solid (60%). MS (m/e): 240 (M+1)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:17]([O:19][C:20]([C:22]1[O:23][C:24]([CH2:27]Cl)=[CH:25][CH:26]=1)=[O:21])[CH3:18]>CN(C)C=O>[CH2:17]([O:19][C:20]([C:22]1[O:23][C:24]([CH2:27][O:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)=[CH:25][CH:26]=1)=[O:21])[CH3:18]
Reactant: CCOC(=O)c1ccc(CCl)o1
Reactant: Cc1ccc(-c2ccc(O)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(COc2ccc(-c3ccc(C)cc3)cc2)o1
Temperature: -5 °C
Reaction time: 0.33 h
Yield: 83.9 %

Procedure:
4′-Methyl-biphenyl-4-ol (Intermediate 5; 2.0 g, 10.9 mmol) was added to a suspension of sodium hydride (60% dispersion; 384 mg, 9.6 mmol) in N,N-dimethylformamide (30 mL) and the mixture was stirred at −5° C. for 20 min. A solution of 5-(chloro-methyl)-furan-2-carboxylic acid ethyl ester (1.6 g, 8.5 mmol) in N,N-dimethylformamide (60 mL) was added and the reaction mixture was stirred overnight at room temperature. The solvents were evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were washed with water and brine, dried (sodium sulfate), filtered, evaporated, and chromatographed, eluting with 0-50% methylene chloride/hexanes to give 5-(4′-methyl-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid ethyl ester (2.4 g, 84%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH2:14][CH3:15])[N:8]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33]([C:34]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=1)[C:7]2=[O:53])([O-])=O>O1CCOCC1.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH2:14][CH3:15])[N:8]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[N:33]([C:34]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:32]=[N:31][N:30]=3)=[CH:21][CH:22]=1)[C:7]2=[O:53]
Reactant: CCc1nc2ccc([N+](=O)[O-])cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ni]
Solvent: C1COCCO1
Product: CCc1nc2ccc(N)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
6-Nitro-2-ethyl-3-[(2'-(N-triphenylmethyl-tetrazol-5-yl)-biphen-4-yl)-methyl]-quinazolin-4(3H)-one (0.11 g) was hydrogenated in dioxane (2.0 ml) sloution under 1 atm H2 for 1 hr in the presence of Raney nickel catalyst.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[N:17]=[CH:16][C:15]([C:18](O)=[O:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.[NH2:48][CH2:49][CH2:50][NH:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55]>CN(C)C1C=CN=CC=1.ClCCl.CCCCCC>[C:54]([O:53][C:52](=[O:58])[NH:51][CH2:50][CH2:49][NH:48][C:18]([C:15]1[CH:16]=[N:17][C:12]([CH:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:10])=[O:9])[C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])=[CH:13][CH:14]=1)=[O:19])([CH3:57])([CH3:55])[CH3:56]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 42.8 %

Procedure:
To a dichloromethane (5 ml) solution of the [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylic acid (100 mg, 0.236 mmol) obtained in Example 50 were added triethylamine (40 μl, 0.283 mmol), 4-dimethylaminopyridine (14 mg, 0.118 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (54 mg, 0.283 mmol) and t-butyl N-(2-aminoethyl)carbamate (45 μl, 0.283 mmol). The resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with dichloromethane. The diluted mixture was washed sequentially with water, a saturated aqueous solution of sodium bicarbonate and brine. The resulting organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=1:1 eluate was concentrated under reduced pressure to give the title compound (57 mg, 0.101 mmol, 43%) as a white powder.