Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:37]=[C:24]4[C:25]([C:29]5[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=5)=[CH:26][CH:27]=[CH:28][N:23]4[N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[CH3:36][O:35][C:31]1[CH:30]=[C:29]([C:25]2[C:24]3[N:23]([N:22]=[C:21]([NH:20][C:17]4[CH:18]=[CH:19][C:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[CH:15][CH:16]=4)[N:37]=3)[CH:28]=[CH:27][CH:26]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: COc1cccc(-c2cccn3nc(Nc4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)nc23)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(-c2cccn3nc(Nc4ccc(C5CCNCC5)cc4)nc23)c1

Procedure:
[8-(3-Methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-yl]-(4-piperidin-4-yl-phenyl)-amine was prepared from 4-{4-[8-(3-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester (0.405 g, 0.812 mmol) and trifluoroacetic acid (2 mL) in a manner analogous to Example 312 to give product (0.150 g, 46%). MP=88-90° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.60 (s, 1H), 8.78 (d, 1H), 7.85 (m, 2H), 7.65 (m, 3H), 7.40 (m, 1H), 7.15 (m, 3H), 7.05 (m, 1H), 3.86 (s, 3H), 3.00 (m, 2H), 2.55 (m, 3H), 2.35 (br m, 1H), 1.65 (m, 2H), 1.45 (m, 2H). MS=400 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:4](=[NH:8])[S:5][C:6]=1[CH3:7].[C:16]12([C:26](O)=[O:27])[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2>>[CH3:1][C:2]1[N:3]([CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:4](=[N:8][C:26]([C:16]23[CH2:25][CH:20]4[CH2:19][CH:18]([CH2:24][CH:22]([CH2:21]4)[CH2:23]2)[CH2:17]3)=[O:27])[S:5][C:6]=1[CH3:7]
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: Cc1sc(=N)n(CC2CCOCC2)c1C
Product: Cc1sc(=NC(=O)C23CC4CC(CC(C4)C2)C3)n(CC2CCOCC2)c1C
Yield: 13.1 %

Procedure:
The product of Example 58A (0.11 g, 0.49 mmol) and adamantane-1-carboxylic acid (97 mg, 0.54 mmol) were processed as described in Example 3B. Purification by column chromatography (SiO2, 0-20% methanol/methylene chloride gradient) afforded 25 mg (13%) of the title compound. MS (DCI/NH3) m/z 389 (M+H)+. Anal. Calculated for C22H32N2O2S: C, 68.00; H, 8.30; N, 7.21. Found: C, 67.61; H, 8.67; N, 7.17.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:16]([F:19])([F:18])[F:17])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([OH:15])=O)[CH:7]=[CH:6]2)#[N:2].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([NH:28][NH2:29])=O>>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[O:15][C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[CH:7]2)=[N:29][N:28]=1
Reactant: NNC(=O)c1ccccn1
Reactant: N#Cc1ccc2c(ccn2CC(=O)O)c1C(F)(F)F
Product: N#Cc1ccc2c(ccn2Cc2nnc(-c3ccccn3)o2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 35C from [5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]acetic acid and 2-pyridinecarbohydrazide: MS (ES) m/z 370 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][NH:4][N:3]=1.[CH2:9](Br)[CH:10]=[CH2:11].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:11]([N:3]1[C:2]([NH2:1])=[C:6]([C:7]#[N:8])[CH:5]=[N:4]1)[CH:10]=[CH2:9]
Reactant: N#Cc1c[nH]nc1N
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCn1ncc(C#N)c1N
Temperature: 80 °C
Yield: 39.8 %

Procedure:
3-Amino-4-pyrazolecarbonitrile 1 (Acros, 1.08 g, 10.0 mmol), allylbromide (Acros, 1.45 g, 12 mmol) and anhydrous potassium carbonate (Fisher, 1.65 g, 12 mmol) were suspended in 10 mL anhydrous DMF and heated at 80° C. under argon overnight. The solution was concentrated. Water was added (100 mL) and the organics were extracted with dichloromethane (3×100 mL). The combined dichloromethane fractions were washed with water (50 mL) and brine (50 mL) and were dried (magnesium sulfate). Concentration of the organics afforded a solid which was subjected to flash chromatography on silica gel (gradient elution 2:1 to 3:2 hexane:ethyl acetate). 589 mg (40%) of a white solid was obtained which was seen by NMR to contain an inseparable mixture of 5 and 6 in a 2.1:1 ratio. This mixture was used without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[C:10]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]4[O:29][CH2:30][O:31][C:25]=4[CH:24]=3)[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: Clc1nc(NCCc2ccc3c(c2)OCO3)c2c3c(sc2n1)CCCC3
Product: c1cnn(-c2nc(NCCc3ccc4c(c3)OCO4)c3c4c(sc3n2)CCCC4)c1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5,6,7,8-tetrahydro-4-(3,4-methylenedioxyphenethylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5,6,7,8-tetrahydro-4-(3,4-methylenedioxyphenethylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([N:3]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=1[CH:25]=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2].[BH4-].[Na+].[Cl-].[NH4+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C(O)C>[CH2:1]([N:3]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][C:16]=1[CH2:25][OH:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2]
Reactant: CCOC(=O)CCCCCCN(CC)c1ccc(C(F)(F)F)cc1C=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CCCCCCN(CC)c1ccc(C(F)(F)F)cc1CO
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
Ethyl 7-[ethyl-(2-formyl-4-trifluoromethyl-phenyl)-amino]-heptanoate (1.29 g) is dissolved in a mixed solvent of toluene (5 ml) and ethanol (1 ml), and thereto is added sodium borohydride (156 mg) and the mixture is stirred for 2 hours and 30 minutes. To the reaction solution are added a saturated aqueous ammonium chloride solution and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→3:1) to give ethyl 7-[ethyl-(2-hydroxymethyl-4-trifluoromethyl-phenyl)-amino]-heptanoate (589 mg). MS (m/z): 376 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:11](=[O:25])[C@@H:10]([CH2:26][C:27]([NH:29][NH2:30])=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH:32](=N)OCC>C1(C)C=CC=CC=1>[O:28]1[CH:32]=[N:30][N:29]=[C:27]1[CH2:26][C@H:10]1[CH2:9][C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C@@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:12]([CH2:21][CH:22]2[CH2:23][CH2:24]2)[C:11]1=[O:25]
Reactant: NNC(=O)C[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Reactant: CCOC=N
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C1[C@@H](Cc2nnco2)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N1CC1CC1

Procedure:
To a solution of 20 mg (45 μmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetohydrazide (Example 51) in 0.2 mL of toluene was added ethyl formimidate hydrochloride (6.4 mg, 58 μmol). The reaction mixture was heated to reflux for 14 h and then the reaction was concentrated under reduced pressure. Separation by reversed phase HPLC (10 to 90% AcCN/H2O in 40 min) provided the title compound as a colorless film.
Reaction SMILES: C1C=C[NH+]=CC=1.Br[Br-]Br.[CH2:10]([N:17]1[C:29]2[CH2:28][CH2:27][CH2:26][C:25](=[O:30])[C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Cl:31])[CH:22]=2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Br-].[Li+].C(=O)([O-])[O-].[Li+].[Li+]>C1COCC1.CN(C=O)C>[CH2:10]([N:17]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:30])[C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Cl:31])[CH:22]=2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CCCc2c1c1cc(Cl)ccc1n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Oc1cccc2c1c1cc(Cl)ccc1n2Cc1ccccc1
Temperature: 75 °C
Reaction time: 5 h
Yield: 72.9 %

Procedure:
Pyridinium bromide perbromide (0.5495 g, 0.0017 mol) is added to a solution of 9-benzyl-6-chloro-1,2,3,9-tetrahydro-4H-carbazol-4-one (0.4406 g, 0.0014 mol) in THF (2.8 mL) and DMF (1.5 mL) and the mixture is heated to 75° C. After stirring for 5 h, THF is removed under reduced pressure and the residue is partitioned between dichloromethane and brine. The combined organic layers are washed with dilute sodium thiosulfate/brine and the aqueous layer is backwashed with dichloromethane. The combined organic layers are dried over magnesium sulfate and concentrated under reduced pressure to give a residue. A mixture of the resulting residue, lithium bromide (0.2799 g, 0.0032 mol), lithium carbonate (0.2286 g, 0.0031 mol) and DMF (6 mL) is heated at 120° C. for two hours. The DMF is removed under high vacuum and the residue is partitioned between dichloromethane and water. The combined organic layers are dried over sodium sulfate and concentrated to an oil. The oil is chromatographed on silica gel (100 mL) using dichloromethane (100%) to give 0.3139 g (72%) of the title compound. An aliquot (0.0391) is recrystallized from dichloromethane/methanol/hexane to give 0.0272 g of product; MS (ESI−) for C19H14ClNO m/z 306.0 (M−H)−; IR (drift) 1470, 1452, 1334, 1293, 1284, 1266, 1231, 1146, 1112, 885, 796, 777, 746, 717, 702 cm−1; 1H NMR (CDCl3) δ5.41, 5.49, 6.60, 6.97, 7.13, 7.28, 7.35, 8.33. Anal. Calcd for C19H14ClNO: C, 74.15; H, 4.59; N, 4.55; Cl, 11.52. Found: C, 73.07; H, 4.63; N, 4.59.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)[C:6](OCC)=[O:7])C.CC(C[AlH]CC(C)C)C.Cl.C(OCC)(=O)C>C1COCC1>[Br:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH:5]([CH2:4][OH:3])[CH2:6][OH:7])=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(Cc1ccc(Br)cc1)C(=O)OCC
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCC(CO)Cc1ccc(Br)cc1
Reaction time: 3 h
Yield: 96.6 %

Procedure:
2-(4-Bromo-benzyl)-malonic acid diethyl ester 21 (1.5 g, 3.8 mmol) was dissolved in 5 mL THF and the solution was added slowly to DIBALH (1M in toluene, 25 mL) via a syringe at 0° C. and stirred at the same temperature for 3 hr. HCl (2N, 50 mL) was then added to break the complex. After standard work up with ethyl acetate, crude product 22 (0.9 g, 99%) was obtained, which was used directly for the next step without further purification: 1H NMR δ 7.39 (d, 2H, J=8.2 Hz), 7.04 (d, 2H, J=8.2 Hz), 3.60 (m, 4H), 2.55 (d, 2H, J=7.4 Hz), 1.96 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[CH:4][C:5]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[N:19]=1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CO.C(OCC)(=O)C.COCCOC>[Cl:1][C:2]1[C:3]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([F:17])[N:19]=2)=[CH:4][C:5]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: CC1(C)OB(c2cccc(F)n2)OC1(C)C
Reactant: O[C@H]1CC[C@H](Nc2cc(I)c(Cl)cn2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: ClCCl
Product: O[C@H]1CC[C@H](Nc2cc(-c3cccc(F)n3)c(Cl)cn2)CC1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
A mixture of trans-4-(5-chloro-4-iodopyridin-2-yl-amino)cyclohexanol (575 mg, 1.631 mmol), 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (655 mg, 2.94 mmol), PdCl2(dppf).CH2Cl2 adduct (133 mg, 0.163 mmol), DME (15 ml), and t 2M sodium carbonate (4.48 ml, 8.97 mmol) reaction mixture was stirred at 95° C. for 2 hr, followed by LCMS. The reaction mixture was cooled to room temperature, mixed with 20 ml of ethyl acetate, 15 ml of methanol, filtered and concentrated to yield a crude product. The crude was purified by silica gel chromatography using a 40 g column, eluting from 35%-85% ethyl acetate with hexane. The desired fractions were combined and concentrated to constant mass, giving 440 mg of titled compound as free base. LCMS (m/z): 322.2 (MH+), retention time=0.53 min.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]1=O)=[O:18])([CH3:15])([CH3:14])[CH3:13]>CO>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH:21]=[C:22]([C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([OH:2])[CH:4]=3)[NH:8][CH:7]=2)[CH2:23][CH2:24]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: Oc1ccc2[nH]ccc2c1
Agent: [Na]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc(O)cc23)CC1

Procedure:
To a solution of sodium (4.8 g; 210 mmol) in dry methanol (130 ml), there are added, at room temperature, 5-hydroxyindole (4 g; 30.04 mmol) and N-(tert-butoxycarbonyl)piperidone (8.9 g; 45.1 mmol).
Reaction SMILES: C[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([CH3:20])=[C:15]([CH2:21][CH3:22])[N:14]=1>>[CH3:20][C:16]1[C:17]([N:3]2[CH2:4][CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:2]2)=[N:18][C:13]([Cl:12])=[N:14][C:15]=1[CH2:21][CH3:22]
Reactant: CC1NCCc2ccccc21
Reactant: CCc1nc(Cl)nc(Cl)c1C
Product: CCc1nc(Cl)nc(N2CCc3ccccc3C2)c1C
Yield: 56.7 %

Procedure:
In accordance with the same procedure as in Step 1 of Example 1, except that 1-methyl-1,2,3,4-tetrahydroisoquinoline (2.3 g, 15.6 mmol) and 2,4-dichloro-5-methyl-6-ethylpyrimidine (2.7 g, 14.1 mmol) prepared in Preparation 4 were used as starting materials, 2.3 g of the titled compound was prepared. (Yield: 54%)
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:12]([NH:14][CH2:15][CH2:16][NH:17]C(=O)OC(C)(C)C)=[O:13])=[N:9][O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.[ClH:32]>>[ClH:32].[NH2:17][CH2:16][CH2:15][NH:14][C:12]([C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:11][O:10][N:9]=1)=[O:13]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1nocc1-c1ccccc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: NCCNC(=O)c1nocc1-c1ccccc1
Yield: 94.1 %

Procedure:
5.0 % (15.1 mmol) of t-butyl [2-(4-phenyl-3-isoxazolecarboxamido)ethyl]carbamate were stirred at room temperature for 16 hours with trifluoroacetic acid analogously to Example 13. After concentration there was obtained a residue which was converted into the hydrochloride. Recrystallization of the crude product from methanol/ether yielded 3.B g (94.1%) of N-(2-aminoethyl)4-phenyl-3-isoxazolecarboxamide hydrochloride as white crystals, melting point 211°-212°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[OH:24].[F:25][C:26]([F:32])([F:31])[S:27](O)(=[O:29])=[O:28]>N1C=CC=CC=1>[O:24]([C:3]1[CH:4]=[CH:5][C:6]([C:8]2[N:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][N:13]=2)=[CH:7][C:2]=1[F:1])[S:27]([C:26]([F:32])([F:31])[F:25])(=[O:29])=[O:28]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: CCCCCCCCCCc1cnc(-c2ccc(O)c(F)c2)nc1
Solvent: c1ccncc1
Product: CCCCCCCCCCc1cnc(-c2ccc(OS(=O)(=O)C(F)(F)F)c(F)c2)nc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
1.00 g (3.03 mM) of 2-fluoro-4-(5-decylpyrimidine-2-yl)phenol, 3 ml of pyridine were mixed and stirred on a common salt-ice bath. To the mixture, 1.00 ml (5.94 mM) of anhydrous trifluoromethanesulfonic acid was added dropwise and stirred for 20 minutes, followed by further stirring for 70 minutes at room temperature. After the reaction, the reaction mixture was left standing overnight and then was poured into ice water, followed by extraction with isopropyl ether. The isopropyl ether layer was successively washed with a common salt aqueous solution, 12%-HCl and a common salt aqueous solution, followed by drying with anhydrous sodium sulfate. The sodium sulfate was removed by filtration and the filtrate was concentrated into a solid product, whereby 1.32 g of 2-fluoro-4-(5-decylpyrimidine-2-yl)phenyl triflate (Yield: 94.3%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11](/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:13][C:14]=1I)C1C=CC=CC=1.[CH2:22]([NH:29][C:30](=[O:48])[N:31]([CH3:47])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>[CH2:22]([NH:29][C:30](=[O:48])[N:31]([C:32]1[CH:37]=[C:36]([C:14]2[CH:13]=[CH:12][C:11](/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])=[CH:10][C:9]=2[OH:8])[CH:35]=[CH:34][CH:33]=1)[CH3:47])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: COC(=O)/C=C/c1ccc(I)c(OCc2ccccc2)c1
Reactant: CCCCCCCNC(=O)N(C)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C/C(=O)OC)cc2O)c1
Yield: 118.9 %

Procedure:
A solution of 4.6 g (11.67 mmol, 1 eq) of methyl (E)-3-(3-benzyloxy-4-iodophenyl)acrylate, 4.8 g (12.83 mmol, 1.1 eq) of 3-heptyl-1-methyl-1-[3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]urea (prepared as in Example 1e) in 18 ml of dimethylformamide+3 mL of 2M potassium phosphate solution, in the presence of 128 mg (5 mol %) of palladium acetate and 408 mg (10 mol %) of 2-(dicyclohexylphosphino)biphenyl is stirred at 80° C. for 5 hours. The reaction medium is hydrolyzed in water and then extracted with ethyl acetate. The organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate. The solvents are evaporated off and the oil obtained is chromatographed on silica (7/3 heptane/ethyl acetate). 5.89 g of methyl (E)-3-[3′-(3-heptyl-1-methylureido)-2-hydroxybiphenyl-4-yl]acrylate are obtained in oil form. Yield=98%
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([O:15]CC)=O>C1(OC)C=CC=CC=1>[Cl:12][C:9]1[CH:8]=[CH:7][C:6]2[NH:5][N:4]=[C:3]3[C:13](=[O:15])[N:5]([C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=4)[N:4]=[C:2]3[C:11]=2[CH:10]=1
Reactant: CCOC(=O)c1nnc2ccc(Cl)cc2c1Cl
Solvent: COc1ccccc1
Product: O=c1c2n[nH]c3ccc(Cl)cc3c-2nn1-c1ccccc1
Yield: 67.6 %

Procedure:
In an inert atmosphere, 6 g of the product of Step A were mixed with 60 ml of anisole and the insoluble matter was removed by filtering. 2.4 ml of phenyl hydrazine were added to the filtrate and the mixture was placed in a water bath at 150° C. for 21/2 hours. The mixture was cooled, dried, washed with ethyl acetate and evaporated to dryness. The residue was washed with an aqueous solution of N hydrochloric acid and was dissolved in a solution of 25 ml of concentrated ammonia and 75 ml water. The solution was filtered and the aqueous phase was extracted with ether. Sodium phosphate was added and the product was purified by triturating in ethanol, then in water. The product was dried to obtain 2.22 g of 8-chloro-2,5-dihydro-2-phenyl-3H-pyrazolo[4,3-c]cinnolin-3-one melting at >280° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH:24]1([O:28][C:29]2[CH:30]=[N:31][CH:32]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:34]=2)[CH2:27][CH2:26][CH2:25]1>>[CH:27]1([CH2:24][O:28][C:29]2[CH:34]=[C:33]([C:2]3[CH:11]=[CH:10][C:9]4[N:8]=[CH:7][C:6]5[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]6[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=6)[C:5]=5[C:4]=4[CH:3]=3)[CH:32]=[N:31][CH:30]=2)[CH2:26][CH2:25]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC1(C)OB(c2cncc(OC3CCC3)c2)OC1(C)C
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cncc(OCC5CC5)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-cyclobutoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 60.1.1) to give the title compound as a white solid. (HPLC: tR 2.39 min (Method A); M+H=441 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99-8.98 (m, 1H), 8.32-8.27 (m, 2H), 8.15 (s, 1H), 8.13-8.09 (m, 1H), 8.02-7.97 (m, 1H), 7.59-7.57 (m, 1H), 7.37-7.35 (m, 1H), 4.02-3.92 (m, 2H), 3.90 (s, 3H), 3.58 (s, 3H), 1.96 (s, 3H), 1.32-1.23 (m, 1H), 0.65-0.59 (m, 2H), 0.41-0.36 (m, 2H))
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13](=[O:20])[CH2:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH2:21](O)[CH3:22]>S(=O)(=O)(O)O.CCOC(C)=O>[CH2:21]([O:20][C:13]1[C:14]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:11]([S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:3])=[O:2])[CH:12]=1)[CH3:22]
Reactant: CCO
Reactant: Cc1ccc(S(=O)(=O)N2CC(=O)c3cccnc32)cc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOc1cn(S(=O)(=O)c2ccc(C)cc2)c2ncccc12
Temperature: 25 °C
Yield: 49 %

Procedure:
1-Tosyl-1H-pyrrolo[2,3-b]pyridin-3(2H)-one (234 mg, 0.815 mmol) was dissolved in ethanol (8 mL). A few drops of concentrated sulfuric acid were added, and the mixture was heated at reflux for 5 hours. The mixture was then allowed to cool to room temperature. The mixture was then diluted with EtOAc, washed with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated. Flash 40 Biotage (40S cartridge, DCM) afforded 3-ethoxy-1-tosyl-1H-pyrrolo[2,3-b]pyridine (126 mg, 49%). 1H NMR (400 MHz, CDCl3) δ 8.42-8.45 m, 1H), 7.95-7.99 (m, 2H), 7.83-7.87 (m, 1H), 7.20-7.25 (m, 2H), 7.11-7.17 (m, 1H), 7.06 (s, 1H), 4.03-4.11 (m, 2H), 2.34 (s, 3H), 1.45-1.50 (m, 3H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH2:6][CH:5]2[CH2:14][NH:15][S:16]([CH2:19][CH3:20])(=[O:18])=[O:17].[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1B(O)O>C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:12][C:7]1([CH3:13])[CH2:6][CH:5]([CH2:14][NH:15][S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:22]3[S:21][CH:25]=[CH:24][CH:23]=3)[CH:3]=2)[O:8]1
Reactant: OB(O)c1cccs1
Reactant: CCS(=O)(=O)NCC1CC(C)(C)Oc2ccc(I)cc21
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCS(=O)(=O)NCC1CC(C)(C)Oc2ccc(-c3cccs3)cc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
410 mg (1 mmol) of ethanesulfonic acid (6-iodo-2,2-dimethylchroman-4-yl)methylamide were dissolved in 5 ml of toluene and 130 mg (1 mmol) of thiopheneboronic acid, 40 mg of palladium tetrakis(triphenylphosphine) in 5 ml of ethanol and 1.1 ml of 2-molar cesium carbonate solution were added. The mixture was stirred overnight at 80° C. After removing the solvent, the residue was taken up in methylene chloride and washed with water. After drying and removing the solvent, the residue obtained was purified by column chromatography (eluent heptane/ethyl acetate 1:1), and 260 mg (71 %) of ethanesulfonic acid (2,2-dimethyl-6-thiophen-2-yl-chroman-4-yl)methylamide were obtained as an oil.