Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[O:15][CH3:16])[CH:5]=[CH:4][N:3]=1.[NH2:17][C:18]1[CH:19]=[C:20]([CH2:24][S:25]([NH2:28])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=1.O(C(C)(C)C)[Na].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>CN(C=O)C>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:17][C:18]3[CH:19]=[C:20]([CH2:24][S:25]([NH2:28])(=[O:26])=[O:27])[CH:21]=[CH:22][CH:23]=3)[CH:7]=2)=[C:9]([O:15][CH3:16])[CH:10]=1
Reactant: Nc1cccc(CS(N)(=O)=O)c1
Reactant: COc1cc(F)ccc1-c1ccnc(Cl)c1
Agent: CC(C)(C)O[Na]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN(C)C=O
Product: COc1cc(F)ccc1-c1ccnc(Nc2cccc(CS(N)(=O)=O)c2)c1
Temperature: 110 °C

Procedure:
Intermediate A2 (119 mg, 0.5 mmol), (3-aminophenyl)methanesulfonamide (112 mg, 0.6 mmol), NaOC(CH3)3 (67 mg, 0.7 mmol), PdCl2(CH3CN)2 (6.5 mg, 0.025 mmol, 5 mol %), and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) [Xantphos] (23 mg, 0.04 mmol, 8 mol %) were dissolved in dry DMF (4 mL) and purged for 10 minutes with nitrogen. After heating at 110° C. for 18 hours the reaction mixture was filtered and the residue washed with toluene. The filtrate was concentrated under reduced pressure and purified by automated column chromatography (ISCO, gradient MeOH/DCM). The collected fractions which contained the title compound were further purified by preparative HPLC to yield 24 mg (12%) of G1 as an off-white solid. 1H NMR (300 MHz, d6-DMSO, 298K) δ 3.84 (s, 3H), 4.22 (s, 2H), 6.81-6.94 (m, 5H), 6.98 (s, 1H), 7.07 (dd, J=11.7 Hz, J=4.2 Hz, 1H), 7.26 (t, J=6.6 Hz, 1H), 7.39 (dd, J=6.9 Hz, J=6.0 Hz, 1H), 7.56-7.61 (m, 1H), 7.79 (d, J=7.5 Hz, 1H), 8.16 (d, J=6.0 Hz, 1H), 9.12 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=O)[N:10](C)[C:11]([S:20][CH3:21])=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:13]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:12]=[C:11]([S:20][CH3:21])[N:10]=1
Reactant: CSc1nc(-c2ccncc2)c(-c2ccc(F)cc2)c(=O)n1C
Reactant: O=P(Cl)(Cl)Cl
Product: CSc1nc(Cl)c(-c2ccc(F)cc2)c(-c2ccncc2)n1

Procedure:
5-(4-fluorophenyl)-3-methyl-2-methylthio-6-(4-pyridyl)-3H-pyrimidin-4-one (0.327 g, 1 mmol) and 5 ml of POCl3 in a 15-ml r.b.flask with a stir bar was stirred at 120° C. for 16 h. The remaining POCL3 was evaporated in vacuo. The dark brown residue was mixed with ice-water. The resulting acidic dark brown solution was neutralized to pH 7-8 with sat'd NaHCO3 and extracted by EtOAc (2×10 ml). The combined organic layers were washed with brine (10 ml) and dried over Na2SO4. 4-chloro-5-(4-fluorophenyl)-2-methylthio-6-(4-pyridyl)pyrimidine was isolated by flash chromatography with 50% EtOAc in hexane; MS: m/z (M+H)+ 332; C16H11ClFN3S requir.331.8.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[CH3:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][NH:12]1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][N:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]2[CH3:10])[N:7]=1
Reactant: CC1CCCCN1
Reactant: O=Cc1cccc(Br)n1
Solvent: ClCCl
Product: CC1CCCCN1Cc1cccc(Br)n1

Procedure:
6] To 6-bromo-2-pyridinecarboxaldehyde (400 mg, 2.15 mmol) was added 2-methylpiperidine (0.4 mL, 3.22 mmol) in dry CH2Cl2 (10 mL) to give 2-bromo-6-[(2-methylpiperidinyl)methyl]pyridine as a pale yellow solid. MS m/z: 269.1(M+H). Calc'd for C12H17BrN2: 269.18.
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]2[C:15]([N:16]=1)=[CH:14][C:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13][C:7]=1[CH:6]=2)[CH3:2].[Cl:17][CH2:18][CH2:19][CH2:20][S:21][C:22]1[N:23]([CH3:38])[C:24]([C:27]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:28]=2[CH:29]=[CH:30][C:31]([CH3:37])=[N:32]3)=[N:25][N:26]=1>>[ClH:17].[CH2:1]([CH:3]1[N:16]=[C:15]2[C:5](=[CH:6][C:7]3[CH2:13][CH2:12][N:11]([CH2:18][CH2:19][CH2:20][S:21][C:22]4[N:23]([CH3:38])[C:24]([C:27]5[CH:36]=[CH:35][CH:34]=[C:33]6[C:28]=5[CH:29]=[CH:30][C:31]([CH3:37])=[N:32]6)=[N:25][N:26]=4)[CH2:10][CH2:9][C:8]=3[CH2:14]2)[S:4]1)[CH3:2]
Reactant: Cc1ccc2c(-c3nnc(SCCCCl)n3C)cccc2n1
Reactant: CCc1nc2cc3c(cc2s1)CCNCC3
Product: CCC1N=C2CC3=C(C=C2S1)CCN(CCCSc1nnc(-c2cccc4nc(C)ccc24)n1C)CC3
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 from: 2-ethyl-6,7,8,9-tetrahydro-5H-[1,3]thiazolo[4,5-h][3]benzazepine (0.43 mmol) and 5-{5-[(3-chloropropyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylquinoline (0.52 mmol) and was obtained as a colourless slightly hygroscopic solid (60 mg).
Reaction SMILES: I[CH2:2][CH3:3].[F:4][C:5]1[C:10]2[NH:11][C:12](=[O:14])[O:13][C:9]=2[CH:8]=[C:7]([N+:15]([O-:17])=[O:16])[CH:6]=1.N12CCCN=C1CCCCC2>CN(C=O)C>[CH2:2]([N:11]1[C:10]2[C:5]([F:4])=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[CH:8][C:9]=2[O:13][C:12]1=[O:14])[CH3:3]
Reactant: O=c1[nH]c2c(F)cc([N+](=O)[O-])cc2o1
Reactant: CCI
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCn1c(=O)oc2cc([N+](=O)[O-])cc(F)c21

Procedure:
Prepared from iodoethane (0.61 ml, 7.57 mmol), 4-fluoro-6-nitro-1,3-benzoxazol-2(3H)-one (EXAMPLE 86, Step 5, 1.2 g, 6.06 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.13 ml, 7.57 mmol) in DMF (10 ml) according to the method of EXAMPLE 86, Step 6 (1.10 g, 80%); mp 121–2° C.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[C:8]([NH:11][CH2:12][CH2:13][NH2:14])(=[O:10])[CH3:9].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][N:2]([CH3:7])[S:3]([NH:14][CH2:13][CH2:12][NH:11][C:8](=[O:10])[CH3:9])(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CC(=O)NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCNS(=O)(=O)N(C)C
Reaction time: 0.5 h

Procedure:
A solution of 14.3 g (0.1 mole) of dimethylsulfamoyl chloride in 50 ml of methylene chloride was added dropwise to a rapidly stirred solution of 10.2 g (0.1 mole) of acetylethylene diamine and 10.1 g (0.1 mole) of triethylamine in 150 ml of methylene chloride at 25° C. After the addition was completed, the solution was stirred for 30 min and then washed in a separatory funnel with two 100 ml portions of water. The organic phase was separated, and dried over MgSO4, and then concentrated under reduced pressure to afford N-[2[(dimethylamino)sulfonylamino]ethyl]acetamide as an oil. The N-acetyl group was then removed by treatment of the oil with 100 ml of 15% HCl at 80° C. for 6 h. The solution was concentrated under reduced pressure to provide 12.6 g (73%) of product as an oil. The NMR spectrum was consistent with the assigned structure.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[N:19]=1.O>CS(C)=O>[C:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[N:19]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: COc1cccc(Cl)n1
Reactant: CC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cccc(N2CCC(NC(C)=O)CC2)n1
Temperature: 130 °C
Reaction time: 50 h
Yield: 43 %

Procedure:
A mixture of 0.088 mole of 4-acetamidopiperidine, 15 g of potassium carbonate, 0.088 mole of 2-chloro-6-methoxypyridine in 100 ml of dimethylsulfoxide is heated with stirring to 130° C. for 50 hours, then it is cooled, the mixture is poured into water and the suspension thus obtained is extracted with diethyl ether. The aqueous phase is extracted with methylene chloride, the organic phase is washed with water, it is dried on anhydrous sodium sulfate and evaporated to dryness. 4-acetamido-1-(6-methoxy-2-pyridyl)piperidine is thus obtained which, after crystallisation in 95% ethanol, melts at 125° to 127° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44]>>[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[N:17]2[CH2:18][CH2:19][CH:20]([CH2:23][N:24]([CH3:26])[CH3:25])[CH2:21][CH2:22]2)[CH:31]=[C:30]([F:43])[C:29]=1[OH:44]
Reactant: CN(C)CC1CCN(c2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CN(C)CC1CCN(c2c(C(=O)C3CC3)cnc3ccc(-c4cc(F)c(O)c(Cl)c4)cc23)CC1
Yield: 64.3 %

Procedure:
Following general procedure D, (6-bromo-4-{4-[(dimethylamino)methyl]piperidin-1-yl}quinolin-3-yl)(cyclopropyl)methanone (30 mg, 0.072 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (41 mg, 0.150 mmol) to afford the desired product (22.3 mg, 64%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 8.76 (s, 1H), 8.25 (d, J=1.6 Hz, 1H), 8.10-7.95 (m, 2H), 7.55-7.46 (m, 1H), 7.42 (dd, J=11.7, 2.3 Hz, 1H); 3.53 (d, J=12.7 Hz, 2H), 3.22 (t, J=11.6 Hz, 2H), 2.61 (d, J=6.6 Hz, 2H), 2.59-2.51 (m, 1H), 2.48 (s, 6H), 1.96 (d, J=10.0 Hz, 3H), 1.69-1.56 (m, 2H), 1.35-1.28 (m, 2H), 1.28-1.16 (m, 2H); ESI MS m/z 482 [C27H29ClFN3O2+H]+; HPLC 98.0% (AUC), tR=10.47 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]2[C:6]([CH:7]=[C:8]([C:17]([OH:19])=O)[C:9](=[O:16])[O:10]2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.CCCP(=O)=O.C(OCC)(=O)C.[NH2:41][C:42]1[CH:47]=[CH:46][C:45]([S:48]([NH2:51])(=[O:50])=[O:49])=[CH:44][C:43]=1[CH3:52]>C(Cl)Cl>[NH2:51][S:48]([C:45]1[CH:46]=[CH:47][C:42]([NH:41][C:17]([C:8]2[C:9](=[O:16])[O:10][C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:12]=3[CH2:13][CH2:14][CH3:15])=[O:19])=[C:43]([CH3:52])[CH:44]=1)(=[O:49])=[O:50]
Reactant: CCCc1c(OC)ccc2cc(C(=O)O)c(=O)oc12
Reactant: Cc1cc(S(N)(=O)=O)ccc1N
Agent: CCCP(=O)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCc1c(OC)ccc2cc(C(=O)Nc3ccc(S(N)(=O)=O)cc3C)c(=O)oc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of Intermediate 1 (0.10 g, 0.381 mmol) in CH2Cl2 (5.0 mL) was added diisopropyl ethyl amine (0.1 mL, 0.572 mmol) and a 50% solution of propylphosphonic anhydride in ethyl acetate (0.340 mL, 0.572 mmol). The mixture was stirred for 30 minutes at room temperature. 4-Amino-3-methylbenzenesulfonamide [CAS # 53297-70-4] (0.071 g, 0.381 mmol) was added to the reaction mixture at room temperature and stirred overnight. The reaction mixture was then poured onto ice water (25 mL) and CH2Cl2 (25 mL) added. The organic layer was separated and washed with brine (25 mL), dried with Na2SO4, filtered and concentrated to dryness. The residue was triturated with CH2Cl2/Hexanes and then the solid was purified with a MPLC to give the title compound as a white solid.
Reaction SMILES: CNC.[CH3:4][N:5]([CH:7]=[O:8])[CH3:6].C1(OC(=O)[NH:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[N+:29]([O-:31])=[O:30])C=CC=CC=1>O>[F:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][CH2:19][CH2:18][NH:17][C:7](=[O:8])[N:5]([CH3:6])[CH3:4])=[C:23]([N+:29]([O-:31])=[O:30])[CH:24]=1
Reactant: O=C(NCCCOc1ccc(F)cc1[N+](=O)[O-])Oc1ccccc1
Reactant: CN(C)C=O
Agent: CNC
Solvent: O
Product: CN(C)C(=O)NCCCOc1ccc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
A 50% dimethylamine aqueous solution (2.5 ml) was added to a DMF solution (25 ml) of phenyl[3-(4-fluoro-2-nitrophenoxy)propyl]carbamate (5.89 g, 17.6 mmol), and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution twice, and concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (dichloromethane: ethyl acetate=19:1→4:1→2:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 4.10 g of oily pale yellow 3-[3-(4-fluoro-2-nitrophenoxy)propyl]-1,1-dimethyl urea (yield: 82%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:4]=1[CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.F[B-](F)(F)F.C[N+](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:4]=1[CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:22])=[CH:18][N:17]=1
Reactant: O=C(O)c1ccc(OCc2c(-c3ccccn3)noc2CO)nc1
Reactant: NC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCOCC1)c1ccc(OCc2c(-c3ccccn3)noc2CO)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
To a solution of 6-(5-hydroxymethyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (70 mg, 0.21 mmol) in DMF (5 mL) was added 4-aminotetrahydropyrane (30 mg, 0.30 mmol), N,N,N′,N′-tetramethyl-O-(benzotriazole-1-yl)-uronium tetrafluoroborate (96 mg, 0.30 mmol) and N,N-diisopropyl ethylamine (0.15 mL, 0.84 mmol). The reaction mixture was stirred overnight at room temperature. After evaporation of the solvent the residue was partitioned (ethyl acetate/aqueous saturated sodium bicarbonate solution) and the organic phase was dried (Na2SO4) and concentrated. Chromatography (silica, dichloromethane:methanol=100:0 to 97:3) afforded the title compound (42 mg, 48%) as a white solid. MS: m/e=411.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16](O)=[O:17])[N:9]=1.C(Cl)(=O)C([Cl:25])=O>CN(C)C=O.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([Cl:25])=[O:17])[N:9]=1
Reactant: O=C(O)c1cccc(-c2noc(-c3ccccc3F)n2)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc(-c2noc(-c3ccccc3F)n2)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
Compound 25 of the present invention may be prepared according to Scheme A as follows. A slurry of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]benzoic acid (Compound A1, 15.0 g; 52.8 mmol) and 100 μL of dimethylformamide catalyst in 250 mL of anhydrous dichloromethane is allowed to cool to 0° C. Oxalyl chloride (9.2 mL, 105.5 mmol, 2.0 eq.) is added to this slurry over 3 minutes. The reaction mixture is then allowed to warm to room temperature, and is stirred for 16 h. The resultant yellow solution is concentrated in vacuo, azeotroped several times with anhydrous dichloromethane (2×50 mL) and dried under high vacuum for 2 hrs to give 15.5 g of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]benzoyl chloride (Compound A2) as a white solid (97%): 1H NMR (CDCl3) δ 7.23-7.38 (m, 2H), 7.58-7.71 (m, 2H), 8.22-8.29 (m, 2H), 8.50 (d, J=7.8 Hz, 1H), 8.91 (t, J=1.6 Hz, 1H).
Reaction SMILES: ClC1C=CC=CC=1C(Cl)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:22][C:23]([CH3:30])([C:27](O)=[O:28])[C:24]([OH:26])=[O:25].CCN(C(C)C)C(C)C.C1C=NC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C.[NH2:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][N:62]=1>C(Cl)Cl.CN1C(=O)CCC1.C(Cl)Cl.CN1C(=O)CCC1>[CH3:22][C:23]([CH3:30])([C:27]([NH:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][N:62]=1)=[O:28])[C:24]([OH:26])=[O:25]
Reactant: CC(C)(C(=O)O)C(=O)O
Reactant: NCc1ccccn1
Agent: CC(C)N=C=NC(C)C
Agent: Clc1ccccc1C(Cl)(c1ccccc1)c1ccccc1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C(=O)O)C(=O)NCc1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Chlorotrityl chloride resin (2.3 g, 3.0 mmol) was swelled in DCM for 20 mins and filtered. Dimethylmalonic acid (2 eq; 6.0 mmol; 793 mg) was dissolved i DCM:NMP 1:1 (10 mL) and added to the resin followed by DIPEA (6 eq; 18.0 mmol; 3.14 mL) and DCM (10 mL). The resin was shaken overnight at RT. The resin was filtered and washed with DCM:MeOH:DIPEA (17:2:1), DCM, NMP og DCM (2×25 mL of each). The resin was swelled in NMP for 20 mins and filtered. HOAt (3 eq; 9.0 mmol; 1.23 g), DIC (3 eq; 9.0 mmol; 1.40 mL) and NMP (25 mL) was added and the resin was shaken for 90 min at RT. The resin was filtrered and 2-(Aminomethyl)pyridine (2 eq; 6 mmol; 659 mg), DIPEA (4 eq; 6.0 mmol; 2.09 mL), and NMP (10 mL) was added. The resin was shaken for overnigth. The resin was filtered and washed with NMP (5×20 mL) and DCM (10×20 mL). TFA/TIS/water (95:2.5:2.5; 30 mL) was added to the resin and it was shaked for 1 hr, filtered and concentrated in vacuo to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][N:3]=1.[C:12](=[O:14])=[O:13].[CH2:15](OCC)[CH3:16]>C(OC(OC(OCC)=O)=O)C>[CH2:15]([O:13][C:12]([N:3]1[C:2]([NH2:1])=[C:10]2[C:5]([CH:6]=[C:7]([Cl:11])[CH:8]=[CH:9]2)=[N:4]1)=[O:14])[CH3:16]
Reactant: CCOCC
Reactant: O=C=O
Reactant: Nc1n[nH]c2cc(Cl)ccc12
Agent: CCOC(=O)OC(=O)OCC
Product: CCOC(=O)n1nc2cc(Cl)ccc2c1N

Procedure:
0.3 mol of 3-amino-6-chloroindazole in 250 ml of pyrocarbonic acid diethyl ester are heated, while stirring, to 50° C for about 5 hours, until the evolution of CO2 has ceased. After cooling, 250 ml of diethyl ether are added and 90% of theory of 3-amino-6-chloroindazole-2-carboxylic acid ethyl ester are isolated, by filtration, in the form of yellow crystals. Melting point: 163°-165° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][S:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27](=[O:45])[CH:28]([C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1)[CH3:29])[CH3:25]>>[CH2:24]([O:26][C:27](=[O:45])[CH:28]([C:30]1[CH:35]=[CH:34][C:33]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH2:14][S:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][CH:3]=2)=[CH:32][CH:31]=1)[CH3:29])[CH3:25]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CSCCc1ccccc1
Reactant: CCOC(=O)C(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)C(C)c1ccc(-c2ccc(-c3onc(C)c3CSCCc3ccccc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 108, Step 2, using 5-(4-bromo-phenyl)-3-methyl-4-phenethylsulfanylmethyl-isoxazole and 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic acid ethyl ester.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[N:9]=[N:10][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:12][CH:13]=1.[I:20]I>CCCCCC.O1CCCC1>[I:20][C:13]1[CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:10]=[N:9][C:8]=1[O:7][CH3:6]
Reactant: II
Reactant: COc1ccc(-c2ccncc2)nn1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1nnc(-c2ccncc2)cc1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
45 ml 1.6M solution of n-butyllithium in hexane are added at −30° C. to a 10.2 g 2,2,6,6-tertamethylpiperidine in 100 ml THF and the mixture stirred at 0° C. for 30 min. After cooling to −75° C. 11.2 g 3-methoxy-6-pyridin-4-yl-pyridazine dissolved 300 ml THF are added and the solution stirred at −75° C. for 35 min. The cold (−75° C.) reaction mixture is subsequently added at a cold (−75° C.) solution of 18.3 g iodine in 400 ml THF (tetrahydrofuran) and stirred at −75° C. for 1.5 h. The reaction is quenched by adding 80 ml methanol/THF (1:1) at −75° C. and 300 ml saturated aqueous NaHCO3 at room temperature and extracted with dichloromethane. The organic layer is ished with 5% aqueous Na2S2O3 and saturated sodium chloride solution, dried (MgSO4) and the solvens removed. The crude product is purified by chromatography on silica gel to yield 14.4 g of 4-iodo-3-methoxy-6-pyridin-4-yl-pyridazine.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH2:2][CH3:3].Cl[CH2:20][C:21]1[O:25][N:24]=[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=1>>[C:26]1([C:23]2[CH:22]=[C:21]([CH2:20][N:5]3[C:6]4[C:11](=[C:10]([C:13]([F:15])([F:16])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=4)[CH:12]=[C:4]3[CH2:1][CH2:2][CH3:3])[O:25][N:24]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: ClCc1cc(-c2ccccc2)no1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1cc(-c2ccccc2)no1

Procedure:
Synthesized in a manner similar to Example 23 using 2-propyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 5-(chloromethyl)-3-phenylisoxazole: MS (ES) m/z 410 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[CH:12]=[CH:13][C:14]([F:20])=[C:15]([CH:19]=2)[C:16](O)=[O:17])[CH:6]=[N:7][CH:8]=1)#[N:2].O.O[N:23]1C2C=CC=CC=2N=N1.N>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[CH:12]=[CH:13][C:14]([F:20])=[C:15]([CH:19]=2)[C:16]([NH2:23])=[O:17])[CH:6]=[N:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cncc(C#Cc2ccc(F)c(C(=O)O)c2)c1
Reactant: On1nnc2ccccc21
Agent: N
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1cncc(C#Cc2ccc(F)c(C(N)=O)c2)c1
Reaction time: 0.08 h
Yield: 42.2 %

Procedure:
Add N-(3-dimethylaminopropyl)-N-ethylcarbodiamide hydrochloride (128 mg, 0.66 mmol) to a solution of 5-(5-cyanopyridin-3-ylethynyl)-2-fluorobenzoic acid (prepared as described in EXAMPLE 120), (158 mg, 0.59 mmol) and 1-hydroxybenzotriazole hydrate (87 mg, 0.64 mmol) in N,N-dimethylformamide (5 mL) and stir for 5 min to form a gel. Add additional N,N-dimethylformamide (4 mL) to enable stirring of the reaction mixture and stir for 0.5 h. Bubble anhydrous ammonia gas through the reaction mixture for 1-2 min. and then stir for an additional 15 min. Dilute the reaction mixture with ethyl acetate and a saturated aqueous solution of sodium bicarbonate and separate the layers. Extract the aqueous phase once with ethyl acetate. Wash the combined organic phases once with an aqueous saturated solution of sodium chloride, dry (sodium sulfate), filter and concentrate. Purify the residue by silica gel chromatography, eluting with 20:80 ethyl acetate:dichloromethane, to give the title compound as a white solid (66 mg, 42%).
Reaction SMILES: C([C:6]1[C:7]([S:17]([NH:20][C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])(=[O:19])=[O:18])=[N:8][N:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[N:11][C:10]=12)(OCC)=O.Cl.O>CC(O)=O>[CH3:16][C:12]1[CH:13]=[C:14]([CH3:15])[N:9]2[N:8]=[C:7]([S:17]([NH:20][C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:18])=[O:19])[CH:6]=[C:10]2[N:11]=1
Reactant: CCOC(=O)c1c(S(=O)(=O)Nc2c(F)cccc2F)nn2c(C)cc(C)nc12
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(C)n2nc(S(=O)(=O)Nc3c(F)cccc3F)cc2n1
Temperature: 110 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
A slurry of 4.8 g (10.8 mmole) of 3-carboethoxy-5,7-dimethyl-N-(2,6-difluorophenyl) pyrazolo-[1,5-a]pyrimidine-2-sulfonamide in 30 ml glacial HOAc was stirred at room temperature with 1 ml concentrated HCl and 3 ml water for 2 hours. The mixture was then heated at 110° C. for 16 hours. A further 1 ml concentrated HCl and 5 ml water were added and the mixture stirred for 16 hours, then cooled to room temperature. The mixture was thrown onto ice and the resultant solid collected by filtration, washed with water and dried to give 2.34 g (64 percent) of the product as a brown powder, m.p. 201°-208° C. An analytical sample was recrystallized from CH3CN/EtOAc/-CH3OH, m.p. 209°-211° C. (dec). 1H NMR (DMSO-d-6): 10.3 (s, 1H, NH), 7.37 (m, 1H, benzene), 7.10 (m including s, 3H, aromatic and H-3 or H-6), 6.82 (s, 1H, H-3 or H-6), 2.63 (s, 3H, CH3), 2.53 (s, 3H, CH3) IR (KBr): 3400, 3050, 2800, 1625, 1600, 1540, 1480, 1430, 1325, 1290, 1240, 1170, 1140, 1000.