Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([N:9]1[CH2:14][CH:13]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=[O:8].[CH2:21]([NH:24][CH:25]1[CH2:33][CH2:32][C:28]2[N:29]=[CH:30][S:31][C:27]=2[CH2:26]1)[CH2:22][CH3:23]>>[CH2:21]([N:24]([CH:25]1[CH2:33][CH2:32][C:28]2[N:29]=[CH:30][S:31][C:27]=2[CH2:26]1)[CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([N:9]1[CH2:14][CH:13]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=[O:8])[CH2:22][CH3:23]
Reactant: CCCNC1CCc2ncsc2C1
Reactant: O=CCCCNC(=O)N1CC=C(c2ccccc2)CC1
Product: CCCN(CCCCNC(=O)N1CC=C(c2ccccc2)CC1)C1CCc2ncsc2C1
Yield: 45 %

Procedure:
Compound 62 is prepared from 62C and 1C as described for 1. The salt of maleic acid is crystallized from acetonitrile/diethylether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH2:7][NH:8][C:9]1[N:14]=[C:13]([C:15]2[CH:24]=[C:23]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:31][CH3:32])[CH:21]=3)[CH:16]=2)[CH:12]=[CH:11][N:10]=1.[Br:38][C:39]1[C:47]2[C:42](=[N:43][CH:44]=[N:45][C:46]=2Cl)[NH:41][N:40]=1>>[Br:38][C:39]1[C:47]2[C:42](=[N:43][CH:44]=[N:45][C:46]=2[N:28]2[CH2:27][CH2:26][N:25]([C:23]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:31][CH3:32])[CH:21]=4)[CH:16]=[C:15]([C:13]4[CH:12]=[CH:11][N:10]=[C:9]([NH:8][CH2:7][CH2:6][C:5]5[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:14]=4)[CH:24]=3)[CH2:30][CH2:29]2)[NH:41][N:40]=1
Reactant: COc1ccc2cc(-c3ccnc(NCCc4ccc(OC)c(OC)c4)n3)cc(N3CCNCC3)c2c1
Reactant: Clc1ncnc2[nH]nc(Br)c12
Product: COc1ccc2cc(-c3ccnc(NCCc4ccc(OC)c(OC)c4)n3)cc(N3CCN(c4ncnc5[nH]nc(Br)c45)CC3)c2c1

Procedure:
4-{4-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-6-methoxy-2-naphthyl}-N-[2-(3,4-dimethoxyphenyl)ethyl]pyrimidin-2-amine was synthesized according to General Procedure E except N-(3,4-dimethoxyphenethyl)-4-(6-methoxy-4-(piperazin-1-yl)naphthalen-2-yl)pyrimidin-2-amine and 3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine were used. 4-{4-[4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl]-6-methoxy-2-naphthyl}-N-[2-(3,4-dimethoxyphenyl)ethyl]pyrimidin-2-amine 179 was isolated as a yellow solid. M.p.=130-133° C. 400 MHz 1H NMR (DMSO-d6) δ: 13.07 (br s, 1H), 8.39 (m, 3H), 7.98 (m, 2H), 7.73 (s, 1H), 7.27 (s, 1H), 6.91 (s, 1H), 6.85 (s, 2H), 6.44 (m, 1H), 4.02 (s, 3H), 3.80-3.76 (m, 8H), 3.41-3.39 (m, 4H), 2.95 (m, 2H), 2.84 (m, 2H); Experimental Elemental Analysis (1.73 equivalents of water and 0.38 equivalent of diethyl ether)=56.44% C, 4.74% H, 16.68% N; Calculated Elemental Analysis 56.44% C, 5.50% H, 16.68% N; LCMS (m/z): 697 [M+H].
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18]C(=O)OC(C)(C)C)=[CH:12][CH:11]=2)[N:9]=1)(=[O:3])[CH3:2].[ClH:26]>C(OCC)(=O)C>[ClH:26].[NH2:18][CH2:17][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]2[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][CH:7]=2)=[CH:15][CH:14]=1
Reactant: CC(=O)Nc1nc(-c2ccc(CCNC(=O)OC(C)(C)C)cc2)cs1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc(-c2ccc(CCN)cc2)cs1
Yield: 106 %

Procedure:
tert-Butyl (2-{4-[2-(acetylamino)-1,3-thiazol-4-yl]phenyl}ethyl)carbamate (250 mg) was dissolved in ethyl acetate (4 mL) and 4 N hydrogen chloride in ethyl acetate (2 mL). The solvent was evaporated in vacuo. The solid was washed with ethyl acetate and ethyl ether to give N-{4-[4-(2-aminoethyl)phenyl]-1,3-thiazol-2-yl}acetamide hydrochloride (220 mg, 106%).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[CH2:15][C:14]([CH3:19])([CH3:18])[CH2:13][C:12]2=[O:20])=[CH:7][CH:6]=1)=[O:3].[CH:21]1([CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:23][CH2:22]1>>[CH3:18][C:14]1([CH3:19])[CH2:15][C:16](=[O:17])[N:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:28]3[CH2:29][CH2:30][N:25]([CH2:24][CH:21]4[CH2:23][CH2:22]4)[CH2:26][CH2:27]3)=[O:3])=[CH:6][CH:7]=2)[C:12](=[O:20])[CH2:13]1
Reactant: C1CN(CC2CC2)CCN1
Reactant: CC1(C)CC(=O)N(c2ccc(OC(=O)Cl)cc2)C(=O)C1
Product: CC1(C)CC(=O)N(c2ccc(OC(=O)N3CCN(CC4CC4)CC3)cc2)C(=O)C1

Procedure:
The title compound was prepared from 4-(4,4-dimethyl-2,6-dioxo-piperidin-1-yl)-phenyl chloroformate and 1-cyclopropylmethyl-piperazine, preparative HPLC (Method C) (45%, off-white crystals). HPLC-MS m/z=400.3 (M+1), Rt: 1.83 min.
Reaction SMILES: COC[O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][S:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH3:42])[C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22]COC)=[CH:18][CH:17]=3)([CH3:15])[CH2:11][S:12]2)=[CH:7][CH:6]=1.Cl.O>C(O)(C)C.O1CCCC1>[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][S:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH3:42])[C:10]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)([CH3:15])[CH2:11][S:12]2)=[CH:7][CH:6]=1
Reactant: COCCOCCSCCCCCCCCCC1c2ccc(OCOC)cc2SCC1(C)c1ccc(OCOC)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: COCCOCCSCCCCCCCCCC1c2ccc(O)cc2SCC1(C)c1ccc(O)cc1
Reaction time: 48 h
Yield: 74 %

Procedure:
To a solution of 7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methyl-4-{9-[2-(2-methoxyethoxy)ethylthio]nonyl}thiochroman (68 mg, 0.109 mmol) in isopropanol (5.5 ml) and tetrahydrofuran (0.9 ml) was added 5N-HCl (1.47 ml) at room temperature, which was stirred for 2 days. Water was added thereto, and the resulting solution was extracted with ethyl acetate. Then, the organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica gel (n-hexane:ethyl acetate=1:1) to give the title compound (43 mg, yield 74%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=4)[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.[CH3:42][S:43]([NH2:46])(=[O:45])=[O:44]>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[CH:28][CH:27]=[C:23]([C:24](=[O:25])[NH:46][S:43]([CH3:42])(=[O:45])=[O:44])[CH:22]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)O)c3)cc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NS(C)(=O)=O)c3)cc12
Yield: 71.5 %

Procedure:
In a 1 dram vial with stir bar were combined 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (35 mg, 0.090 mmol), DMAP (33 mg, 0.27 mmol), EDC hydrochloride (26 mg, 0.14 mmol), and methanesulfonamide (25 mg, 0.26 mmol). DMF (0.5 mL) was added, the vial was capped, and the reaction was stirred at r.t. overnight. The reaction was filtered, purified by prep HPLC, and concentrated to give 30 mg (72% yield) of the title compound as a white powder. 1H NMR (500 MHz, DMSO-d6) δ ppm 12.36 (br. s., 1H) 8.53 (d, J=4.58 Hz, 1H) 8.27 (s, 1H) 7.97-8.05 (m, 2H) 7.84-7.96 (m, 3H) 7.77-7.82 (m, 1H) 7.71-7.76 (m, 1H) 7.56 (t, J=7.78 Hz, 1H) 7.40 (t, J=8.85 Hz, 2H) 3.17 (s, 3H) 2.86 (d, J=4.58 Hz, 3H). LC/MS was performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A=10% CH3CN/90% H2O/0.1% TFA, solvent B=90% CH3CN/10% H2O/0.1% TFA, start % B=0, final % B=100, gradient time=2 min, stop time=3 min, flow rate=4 ml/min, column: Sunfire C18 5 μm 4.6×50 mm; HPLC Rt=1.56 min, (ES+) m/z (MH+)=467. Analytical HPLC were performed using a Shimadzu-VP instrument with UV detection at 220 nm and 254 nm. Analytical HPLC method: solvent A=5% CH3OH/95% H2O/10 mM NH4HCO3, solvent B=95% CH3OH/5% H2O/10 mM NH4HCO3, start % B=10, final % B=100, gradient time=15 min, stop time=18 min, flow rate=1 ml/min. Column: Phenomenex Gemini C18, 4.6 mm, 3 μm, Rt=11.93 min, purity=100%; column: Waters Xbridge Phenyl 4.6×150 mm, 3.5 μm, Rt=13.97 min, purity=99%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)(=[O:33])=[O:32].C(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>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]>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([S:31]([NH:34][CH:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)(=[O:33])=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(NC1CCCCC1)c1ccccc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)NC3CCCCC3)cc2F)cn1
Temperature: 80 °C
Yield: 62.1 %

Procedure:
To a 5 mL microwave vial were added a stirbar, 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine (54 mg, 0.17 mmol), 2-bromo-N-cyclohexylbenzenesulfonamide (58 mg, 0.18 mmol), Pd(dppf)Cl2.CH2Cl2 (10 mg, 0.013 mmol), and K2CO3 (80 mg, 0.58 mmol). The vial was capped and flushed with nitrogen before adding 1 mL N2 sparged DMSO and heating at 80° Celsius for 20 hours. The vial was cooled to rt and the reaction mixture subjected to FCC purification to give the title compound (45 mg, 62%). MS (ESI): mass calcd. for C22H23FN4O2S, 426.15; m/z found, 427.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.43-8.35 (m, 1H), 8.05-8.03 (d, J=1.4, 1H), 8.03-7.99 (dd, J=7.9, 1.4, 1H), 7.92-7.84 (m, 1H), 7.70-7.64 (m, 1H), 7.64-7.58 (m, 1H), 7.44-7.37 (m, 2H), 7.32-7.24 (m, 2H), 6.72 (s, 2H), 2.85-2.72 (m, 1H), 1.69-1.52 (m, 5H), 1.48-1.39 (m, 1H), 1.19-0.93 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[OH:39])[C:5]([N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=O.Cl[CH2:41][C:42]([N:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[O:39][CH2:41][CH2:42][N:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1)[CH2:5][N:7]([CH:33]([CH3:35])[CH3:34])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=2[CH2:17]1
Reactant: O=C(CCl)N1CCCCC1
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)c(F)c2)C(C)C)c1
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCN3CCCCC3)c(F)c2)C(C)C)c1
Yield: 37 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(3-fluoro-4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 2-chloro-1-piperidin-1-ylethanone (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.2 mg) was obtained.
Reaction SMILES: C([O:5][C:6](=[O:15])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)(C)(C)C.[ClH:16]>C1COCC1>[ClH:16].[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][C:6]([OH:15])=[O:5]
Reactant: CC(C)(C)OC(=O)COc1ccccn1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)COc1ccccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl(pyridin-2-yloxy)acetate (0.18 g) in THF (1.5 mL) was added 6 mol/L hydrochloric acid (1.5 mL) at 0° C., and the mixture was warmed to room temperature, and stirred for 2 hr. The solvent was evaporated under reduced pressure, and the resultant solid was recrystallized from ethyl acetate and diisopropyl ether to give the title compound (0.11 g).
Reaction SMILES: [OH-].[K+].O.[F:4][CH2:5][C:6]([CH2:16][F:17])([C:8](=[O:15])[CH2:9][N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)[CH3:7].[CH:18]1([CH2:24]Br)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>CS(C)=O>[F:17][CH2:16][C:6]([CH2:5][F:4])([C:8](=[O:15])[CH:9]([N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)[CH2:24][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH3:7]
Reactant: CC(CF)(CF)C(=O)Cn1cncn1
Reactant: BrCC1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(CF)(CF)C(=O)C(CC1CCCCC1)n1cncn1
Yield: 54.9 %

Procedure:
A solution of 101.4 g (1.81 mol) of potassium hydroxide into 7.2 ml of water was added to a solution of 369.4 g (1.81 mol) of 2,2-bisfluoromethyl-4-(1,2,4-triazol-1-yl)-butan-3-one in 2 liters of dimethylsulphoxide at room temperature, with stirring. 320.5 g (1.81 mol) of cyclohexylmethyl bromide were added dropwise to this mixture, with stirring, the temperature of the reaction mixture being kept between 20° and 40° C. by cooling. The reaction mixture was stirred at 60° C. for a further 15 hours and then poured into 2 liters of water. The resulting mixture was extracted twice with 1 liter of methylene chloride each time, the combined organic phases were washed four times with 2 liters of water each time and dried over sodium sulphate and the solvent was stripped off. The resulting oily product was taken up in acetone, and 326 g of naphthalene-1,5-disulphonic acid were added to the solution. The precipitate which thereby formed was filtered off with suction and suspended in 2 liters of methylene chloride. This suspension was shaken twice with 2 liters of saturated aqueous sodium bicarbonate solution each time. The organic phase was then washed with 2 liters of water and, after drying over sodium sulphate, was concentrated under reduced pressure. 297.5 g (63% of theory) of 2,2-bis-fluoromethyl-5-cyclohexyl-4-(1,2,4-triazol-1-yl)-pentan-3-one were obtained in this manner in the form of an oil. nD20 =1.4837.
Reaction SMILES: [OH-].[K+].[O:3]1[CH2:8][CH2:7][O:6]CC1.[CH2:9]([N:16]1[CH2:23][CH2:22]C2(CO2)[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>O>[CH2:9]([N:16]1[CH2:23][CH2:22][C:8]([CH2:7][OH:6])([OH:3])[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(CN2CCC3(CC2)CO3)cc1
Reactant: C1COCCO1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: OCC1(O)CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
85% potassium hydroxide (40.6 g) was dissolved in water (615 mL) and mixed with dioxane (103 mL). A dioxane solution (103 mL) of the compound (25.0 g) obtained in Step 1 was added dropwise to the mixture at 90° C. over 60 minutes under nitrogen atmosphere and stirred at the same temperature for 20 minutes. With cooling the reaction solution with ice-water, the pH of the solution was adjusted to 9 with concentrated hydrochloric acid, the mixture was saturated with salt, and extracted with ethyl acetate. The organic layer was combined and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was crystallized from hexane:ether and collected by filtration to obtain the titled compound (24.6 g) as crystals.
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:11]Br>C(O)(=O)C>[Br:11][C:8]1[CH:9]=[N:10][C:2]([OH:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cccnc1O
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(O)c1cc(Br)cnc1O
Temperature: 75 °C
Yield: 77.9 %

Procedure:
To a suspension of 5.0 g (35.9 mmol) of 2-hydroxy-nicotinic acid in 30 ml acetic acid was added dropwise 7.5 g (46.7 mmol) bromine. The mixture was maintained at 70-80° C. overnight. The mixture was cooled and the acetic acid was removed under reduced pressure. Water (100 ml) was added and the product was filtered and washed with water (3×100 ml). The solid was dried in a vacuum oven at 65° C. for 48 hours to provide 6.1 g (78% yield) of the title compound. MS: m/z (APCI, AP+) 219.0 [M.]+. CHN Analysis: Calcd: C, 33.06; H, 1.85; N, 6.42. Found: C, 32.91; H, 1.78; N, 6.23.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[N:10][CH:11]=1)=[O:5].[CH3:26][Mg]Br>C1COCC1>[OH:5][CH:4]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[N:10][CH:11]=1)[CH3:26]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Solvent: C1CCOC1
Product: CC(O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
tert-Butyl 4-(5-(methoxy(methyl)carbamoyl)pyridin-2-yl)piperazine-1-carboxylate (1.45 g, 4.1 mmol) was taken into THF (20 mL) and the solution cooled to 0° C. under a nitrogen atmosphere. Methyl magnesium bromide (3.0M in ethyl ether, 3.5 mL) was added in portions and the mixture was allowed to stir 10 minutes followed by addition of another 1.5 mL aliquot then the mixture was warmed to room temperature. The solution was then partitioned with ethyl ether and water and the organic phase washed with brine then dried over anhydrous sodium sulfate, filtered and concentrated. The residue was taken into methanol (25 mL) followed by portion-wise addition of sodium borohydride solid (250 mg) over 10 minutes. The mixture was allowed to stir at room temperature another 10 minutes then concentrated. The residue was partitioned with ethyl ether and water and the aqueous phase extracted ethyl ethyl ether (2×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give tert-butyl 4-(5-(1-hydroxyethyl)pyridin-2-yl)piperazine-1-carboxylate (1.48 g) which was carried forward without further purification.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:32][C:18]4[CH:19]=[N:20][N:21](COCC[Si](C)(C)C)[C:22](=[O:23])[C:17]=4[C:16]=3[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.C1(OC2C=C(C3NC4C=NN(COCC[Si](C)(C)C)C(=O)C=4C=3CCC)C=CC=2OC(F)F)CC1>>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:32][C:18]4[CH:19]=[N:20][NH:21][C:22](=[O:23])[C:17]=4[C:16]=3[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:13])[F:14])[CH2:2][CH2:3]1
Reactant: CCCCCc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)[nH]c2cnn(COCC[Si](C)(C)C)c(=O)c12
Agent: CCCc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)[nH]c2cnn(COCC[Si](C)(C)C)c(=O)c12
Product: CCCCCc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)[nH]c2cn[nH]c(=O)c12
Yield: 40.9 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 6-(c) except for using 0.32 g (0.60 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-pentyl-5-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 68-(c) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-propyl-5-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo-[2,3-d]pyridazin-4-one, whereby 99 mg of the title compound was obtained as a white solid. (Yield: 41%)
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:19][CH2:20][CH3:21])[N:6]2[CH2:13]/[C:14](=[N:17]/[H])/[NH:15][OH:16].[CH3:22][C:23]1[C:27]([C:28](O)=O)=[C:26]([C:31]([F:34])([F:33])[F:32])[O:25][N:24]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:19][CH2:20][CH3:21])[N:6]2[CH2:13][C:14]1[N:17]=[C:28]([C:27]2[C:23]([CH3:22])=[N:24][O:25][C:26]=2[C:31]([F:34])([F:32])[F:33])[O:16][N:15]=1
Reactant: Cc1noc(C(F)(F)F)c1C(=O)O
Reactant: [H]/N=C(/Cn1c(CCC)cc2c(Cl)c(C#N)ccc21)NO
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2c(C)noc2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Synthesized as described in Example 32A and Example 33 using (1Z)-2-(4-chloro-5-cyano-2-propyl-1H-indol-1-yl)-N-hydroxyethanimidamide (0.030 g, 0.1 mmol) in anhydrous THF (5 mL) with propanephosphonic acid cyclic anhydride (T3P) (0.034 g, 0.12 mmol), 3-methyl-5-(trifluoromethyl)-4-isoxazolecarboxylic acid (0.0195 g, 0.1 mmol) and DIEA (0.016 mg, 0.12 mmol) and stirred at rt for 1 h and then heated at 120° C. for 2 h in the microwave: 1H NMR (400 MHz, CDCl3-d) δ 7.89 (s, 1 H), 7.52 (d, J=8.4 Hz, 1 H), 7.46 (d, J=8.4 Hz, 1 H), 5.47 (s, 2 H), 2.97 (t, 2 H), 2.55 (s, 3 H), 1.79-1.70 (m, 2 H), 1.05 (t, 3 H); MS (ES) m/z 450 (M+1).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:26][CH2:27][C:28]([NH:31][S:32]([C:35]1[S:39][C:38]([NH2:40])=[N:37][CH:36]=1)(=[O:34])=[O:33])([CH3:30])[CH3:29]>>[OH:26][CH2:27][C:28]([NH:31][S:32]([C:35]1[S:39][C:38]([NH:40][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:14])=[N:37][CH:36]=1)(=[O:34])=[O:33])([CH3:30])[CH3:29]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1cnc(N)s1
Product: CC(C)(CO)NS(=O)(=O)c1cnc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 2-amino-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.13) according to general procedure II. Yellow solid. MS (ISP) 589.2 [(M−H)−]; mp 280° C.
Reaction SMILES: [C:1]1([C:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].S(Cl)(Cl)=O.[C:21]([N:26]1[CH2:31][CH2:30][CH:29](O)[CH2:28][CH2:27]1)([O:23][CH2:24][CH3:25])=[O:22]>C(O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH:1]1([CH:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:8][CH:29]2[CH2:30][CH2:31][N:26]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:27][CH2:28]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)N1CCC(O)CC1
Reactant: O=C(c1ccccc1)C1CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(OC(c2ccccc2)C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 123 %

Procedure:
Cyclohexyl phenyl ketone (5.0 g, 27 mmol) was dissolved in ethanol (50 mL) and cooled by ice. Sodium borohydride (510 mg, 13.5 mmol) was added thereto at 0° C. The completion of the addition, the mixture was heated to a room temperature, and the disappearance of the raw material was confirmed by TLC. The reaction solution was concentrated and then diluted with water, and the diluted solution was neutralized with a 1-N hydrochloric acid aqueous solution. Ethyl acetate was added thereto, the mixture was subjected to extraction. Then the extract was dried over sodium sulfate. The solvent was distilled off, and the residue was used for the next step without purification. The resulting viscous oil was dissolved in dichloromethane (10 mL), and thionyl chloride (10 mL, 140 mmol) was added dropwise thereto at a room temperature. After the dropping was completed, the completion of the reaction was confirmed by TLC. After the completion of the reaction, toluene was added to the reaction mixture, and unreacted thionyl chloride was distilled off. The resulting light-yellow oil and 1-carboethoxy-4-hydroxypiperidine (2.1 g, 12 mmol) were mixed, and the mixture was stirred at an oil bath temperature of 130° C. overnight. After the completion of the reaction was confirmed by TLC, the reaction mixture was allowed to cool down. Ethyl acetate was added to the resulting residue, and then the resulting mixture was washed with water. The organic layer was dried over sodium sulfate, and then the solvent was distilled off. Thus a brown oil was obtained. The resulting oil was purified by silica gel column chromatography (hexane/ethyl acetate (volume ratio)=10:1) to give the title compound (5.1 g, 510).