Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[C@H:6]([NH2:40])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:37][CH3:38])([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH:30]([OH:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:24]([CH3:36])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:39])=[CH:9][CH:8]=1>CO.O1CCCC1>[NH2:40][C@H:6]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:20][CH3:21])([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH:30]([OH:35])[C:31]([CH3:32])([CH3:33])[CH3:34])=[C:24]([CH3:36])[CH:23]=3)[CH2:37][CH3:38])=[CH:15][C:14]=2[CH3:39])=[CH:11][CH:12]=1)[C:5]([OH:41])=[O:4]
Reactant: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc([C@@H](N)C(=O)OC)cc2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc([C@@H](N)C(=O)O)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.4 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.113 mL, 0.113 mmol) was added to a solution of (R)-amino-(4′-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2′-methyl-biphenyl-4-yl)-acetic acid methyl ester (Example 168-(2); 20.0 mg, 0.038 mmol) in methanol-tetrahydrofuran (1:1, 2 mL), and the mixture was stirred at room temperature for three hours. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate:methanol:water=4:2:0.6) to give the target compound as a colorless oil (18.5 mg, 94%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].[N:36]1([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:40][CH2:39][CH2:38][CH2:37]1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:44]3[CH2:45][CH2:46][CH:41]([N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[CH2:42][CH2:43]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(N2CCC(N3CCCC3)CC2)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 79.5 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide (80 mg, 0.16 mmol) in DCM (5 mL) was added 4-(1-pyrrolidinyl)piperidine (74 mg, 0.48 mmol). The resultant solution was stirred at room temperature over might. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM [90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (75 mg, 79%). LC-MS m/z 590 (M+H)+; 1H-NMR (MeOD) δ 1.27 (d, 6H), 1.34 (m, 2H), 1.83 (m, 4H), 1.90 (m, 2H), 2.31 (s, 3H), 2.40 (m, 1H), 2.68 (m, 4H), 2.77 (m, 2H), 4.11 (s, 2H), 4.23 (m, 1H), 4.44 (m, 2H), 7.17 (t, 2H), 7.46 (d, 1H), 7.52 (m, 1H), 7.68 (s, 1H), 7.86 (d, 1H).
Reaction SMILES: [H-].[Na+].C(OC([C:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:11][S:10][C:9]=1[NH:20][C:21](=[O:28])[CH2:22][C:23]([O:25]CC)=O)=O)C.Cl>C1COCC1.CO.[OH-].[Na+]>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]2[C:8]3[C:23]([OH:25])=[CH:22][C:21](=[O:28])[NH:20][C:9]=3[S:10][CH:11]=2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)CC(=O)Nc1scc(-c2ccc(Cl)cc2)c1C(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=c1cc(O)c2c(-c3ccc(Cl)cc3)csc2[nH]1
Temperature: 0 °C

Procedure:
To a suspension of NaH (60% suspension in mineral oil, pre washed with hexanes, 0.430 g, 10.73 mmol) in THF (25 mL) was added a solution of 4-(4-chlorophenyl)-2-(2-ethoxycarbonyl acetylamino)-thiophene-3-carboxylic acid ethyl ester (1.9308 g, 4.88 mmol) in THF (25 mL) dropwise via syringe. The reaction mixture was then heated to reflux for 3 hrs, cooled to 0° C. and quenched by dropwise addition of MeOH (5 mL) and H2O (2 mL). The reaction mixture was concentrated to give a crude solid which was then dissolved in MeOH (30 mL) and 40% NaOH (30 mL). The resulting mixture was heated at for 5 hours, cooled to room temperature and acidified with concentrated HCl. The mixture was concentrated under reduced pressure and DMSO/MeOH (1:1) was used to dissolve the residue and filtered. The filtrate was purified on a RP-HPLC system to afford the title compound. MS (ESI) m/e 275.9 (M−H)+; 1H NMR (400 MHz, DMSO-d6): δ ppm 11.55 (br s, 1H), 10.92 (s, 1H), 7.47–7.39 (m, 4H), 7.06 (s, 1H), 5.74 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)=[CH:5][CH:4]=1.Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CC(C)=O>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][N:9]([CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH3:30]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(NCCCOc2ccc3ccccc3c2)cc1
Solvent: CC(C)=O
Product: CCOC(=O)CN(CCCOc1ccc2ccccc2c1)c1ccc(OC)cc1

Procedure:
A mixture of (4-methoxyphenyl)-(3-(naphthalen-2-yloxy)propyl)amine (0.5 gm, 0.002 mole) and ethyl bromoacetate (0.62 ml, 0.003 mole) was taken in dry acetone (40 ml). It was refluxed for 10 hrs and the progress of reaction checked by TLC. Reaction mixture was filtered and the filtrate was concentrated to get the oily compound {N-(4-methoxy phenyl)-(3-(naphthalen-2-yloxy)propyl)amino}acetic acid ethyl ester, oil (yield 0.75 ml, 96%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[Cl:11][C:12]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:16][N:15]=[C:14]2[N:24]([CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][C@@H:32]([F:35])[CH2:31]3)[N:25]=[C:26](I)[C:13]=12>>[Cl:11][C:12]1[C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:16][N:15]=[C:14]2[N:24]([CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][C@@H:32]([F:35])[CH2:31]3)[N:25]=[C:26]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:13]=12
Reactant: F[C@@H]1CCN(CCn2nc(I)c3c(Cl)c(-c4ccccc4)nnc32)C1
Reactant: OB(O)c1ccc(F)cc1
Product: Fc1ccc(-c2nn(CCN3CC[C@@H](F)C3)c3nnc(-c4ccccc4)c(Cl)c23)cc1

Procedure:
Compound IIy was synthesized according to Example 1, but using 4-fluorophenylboronic acid instead of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 4-chloro-1-[2-[(3R)-3-fluoropyrrolidin-1-yl]ethyl]-3-iodo-5-phenyl-pyrazolo[3,4-c]pyridazine instead of 4-chloro-3-iodo-1-(2-(4-methylpiperazin-1-yl)ethyl)-5-phenyl-1H-pyrazolo[3,4-c]pyridazine in Step 8.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[B:9]1[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>C1COCC1>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][CH:28]=[C:20]([C:19]([F:18])([F:29])[F:30])[CH:21]=2)=[CH:4][C:3]=1[B:9]1[O:10][C:11]([CH3:17])([CH3:16])[C:12]([CH3:15])([CH3:14])[O:13]1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1B1OC(C)(C)C(C)(C)O1
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To a solution of 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.0 equiv.) in THF (0.1 M) at 0° C. was added 3-trifluoromethylbenzoylchloride (1.0 equiv.) and the reaction was stirred at room temperature for 3 h. The solution was concentrated and dried under vacuo to give N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(trifluoromethyl)benzamide as a tan solid in 96% yield. LCMS (m/z) (M+H)=406.2, Rt=1.24 min.
Reaction SMILES: [CH3:1][S:2]([O:5][C@@H:6]1[C@@H:12]([NH:13][C:14](=[O:26])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22](=[O:24])[CH3:23])[C:16]=2[CH3:25])[CH2:11][O:10][C:9]([CH3:28])(C)[O:8][CH2:7]1)(=[O:4])=[O:3].B(F)(F)F.CCOCC.C(OC(=O)C)(=O)C.CN(C)CCO>ClCCl.O.C1(C)C=CC=CC=1>[C:9]([O:8][CH2:7][C@@H:6]([C@@H:12]1[CH2:11][O:26][C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22](=[O:24])[CH3:23])[C:16]=2[CH3:25])=[N:13]1)[O:5][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:10])[CH3:28]
Reactant: CC(=O)Oc1cccc(C(=O)N[C@H]2COC(C)(C)OC[C@@H]2OS(C)(=O)=O)c1C
Agent: CN(C)CCO
Agent: FB(F)F
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC[C@H](OS(C)(=O)=O)[C@@H]1COC(c2cccc(OC(C)=O)c2C)=N1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
(5R, 6S)-N-(5-Methanesulfonyloxy-2,2-dimethyl-1,3-dioxepan-6-yl)-3-acetoxy-2-methylbenzamide (compound [9], 786 g, 1.89 mol) was dissolved in dichloromethane (6.29 L), and boron trifluoride diethyl ether (698 ml, 5.68 mol) was added, which was followed by stirring at room temperature for 23 hours. The reaction mixture was cooled to 11° C. and acetic anhydride (268 ml, 2.84 mol) was added, which was followed by stirring at said temperature for 2 hours. The reaction mixture was concentrated to 2.0 kg under reduced pressure and toluene (3.8 L) was added to the obtained residue to give a suspension. N,N-Dimethylethanolamine (571 ml, 5.68 mol) was added to the suspension over 40 minutes at not more than 20° C. Toluene (1.5 L) and water (4.8 L) were added and the mixture was stirred for one hour at room temperature. The organic layer was separated, washed successively with a 10% aqueous citric acid solution (5.00 L) and a 2% aqueous potassium carbonate solution (5.00 L) and dried over magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure to give (2R)-1-acetoxy-2-((4S)-2-(3-acetoxy-2-methylphenyl)-4,5-dihydrooxazol-4-yl)-2-methanesulfonyloxyethane (compound [10'], 1.04 kg) as a dark red oil.
Reaction SMILES: [CH2:1]([N:8]1[C:16]([S:17][CH2:18][CH2:19][CH2:20]N(C)C)=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(Cl)(=O)=[O:31])=CC=1.CNC>N1C=CC=CC=1>[CH2:1]([N:8]1[C:16]([S:17][CH2:18][CH2:19][CH2:20][OH:31])=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCCSc1c2ccccc2nn1Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CNC
Solvent: c1ccncc1
Product: OCCCSc1c2ccccc2nn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The resulting oil (7.3 g--yield: 61%), which tends to decompose if distillation thereof is attempted, shows by elemental analysis and under NMR spectrum to consist of practically pure 2-benzyl-3-(3-hydroxypropylthio)-indazole. (b) To a solution of 3 g (0.01 mols) of the preceding product in 15 ml of pyridine there is added 1.9 g (0.01 mols) of p-toluenesulfonylchloride. The mixture is left for 3 hours under stirring at room temperature, is then poured into 100 ml of a water-ice mixture and the oil which separates is extracted with ethyl ether. The oil which is obtained by removing the solvent is dissolved in 20 ml of a toluene solution containing 10% (0.044 mols) of dimethylamine and the resulting solution is heated for 16 hours at 120° in a closed test tube. At the end of the heating cycle, the toluene solution is extracted with an equal volume of 2 N HCl and made basic with NaOH. The oil which separates is extracted with ether and to the ether solution there is added gaseous HCl. The hydrochloride which precipitates is removed by filtration and recrystallized from isopropanol-isopropyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([CH2:8][CH:9]([CH3:20])[C:10]([N:12]2[CH2:19][CH2:18][CH2:17][C@H:13]2[C:14]([OH:16])=[O:15])=[O:11])=[O:7])=[CH:4][CH:3]=1.CCCCCC>C(OCC)(=O)C>[Br:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([CH2:8][CH:9]([CH3:20])[C:10]([N:12]2[CH2:19][CH2:18][CH2:17][C@@H:13]2[C:14]([OH:16])=[O:15])=[O:11])=[O:7])=[CH:4][CH:3]=1
Reactant: CC(CC(=O)c1ccc(Br)cc1)C(=O)N1CCC[C@H]1C(=O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(CC(=O)c1ccc(Br)cc1)C(=O)N1CCC[C@@H]1C(=O)O

Procedure:
The preceding compound, (72 g.) is converted to N-hydroxysuccinimide ester, m.p. 99°-104° C., as for Example 7 and the activated ester (94.6 g.) is coupled as for Example 9 with 44.9 g. of L-proline to give 70.7 g. of 1-[3-(4-bromobenzoyl)-2-methylpropionyl]-L-proline as a gum (mixture of diastereomers). The gum is dissolved in hot ethyl acetate (200 ml.) and hexane (250 ml.) added. Chilling gives 19.3 g. of solid which is recrystallized from ethyl acetate to give 10.3 g. of (S)-1-[3-(4-bromobenzoyl)-2-methylpropionyl]-L-proline, m.p. 165°-167° C. (isomer A). From the mother liquors additional isomer A is obtained and purified by chromatography on silica gel. From the column (R)-1-[3-(4-bromobenzoyl)-2-methylpropionyl]-L-proline (isomer B) is obtained. To a mixture of 10.2 g. of isomer A in 125 ml. of acetic acid is added 4.43 g. of bromine in 20 ml. of acetic acid. Anhydrous hydrogen bromide is added and the mixture stirred 3 hours. The mixture is concentrated to 1/3 volume and poured into ice and water. The mixture is extracted with dichloromethane and the extract washed with water, brine and dried (MgSO4). The solvent is removed under vacuum to give 12.7 g. of a glass (mixture of diastereomers). A mixture of 10.5 g. of the preceding glass in 150 ml. of acetonitrile is added dropwise to a mixture of sodium thioacetate (prepared from 2.9 ml. of thiolacetic acid and 1.4 g. of NaH (60% oil dispersion) in 150 ml. of acetonitrile. The mixture is stirred at room temperature for 18 hours, 30 ml. of acetic acid is added and the solvent is removed under vacuum. The residue is partitioned between dichloromethane and water. The dichloromethane layer is separated, washed with water, saline and dried (MgSO4). The solvent is removed and the residue chromatographed on a silica gel column with ethyl acetate-hexane-acetic acid (5:5:0.2) as solvent. The early fractions containing mainly one component are combined and chromatographed on silica gel to give 5.1 g. of solid. Crystallization from ethyl acetate-hexane gives 3.5 g. of [S-(R*,S*)]-1-[3-acetylthio-3-(4-bromobenzoyl)-2-methylpropionyl]-L-proline as white crystals, m.p. 136°-138° C.; [α]D +211°+1(c, 0.971, ethanol). The latter fractions from the column chromatography containing one component by thin layer chromatography are combined to give 1.2 g. of [S-(R*,R*)]-1-[3-acetylthio-3-(4-bromobenzoyl)-2-methylpropionyl]-L-proline as a white gla-s; [α]D -69±1(c, 0.983 ethanol).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[NH2:7][C:8]1[C:9]([CH2:10][OH:11])=[CH:13][CH:14]=[CH:15][N:16]=1
Reactant: Nc1ncccc1C(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncccc1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
To 100 mL of tetrahydrofuran solution containing 5.7 g of lithium aluminum hydride, 20 mL of tetrahydrofuran solution containing 13.8 g of 2-aminonicotinic acid was added, and heated for 2 hours under reflux. After cooling the reaction mixture back to room temperature, sodium sulfate decahydrate was slowly added until there are no bubbles, and stirred for 2 hours at room temperature. The insolubles were filtered through celite, the filtrate was concentrated under reduced pressure, and 10.7 g of (2-aminopyridin-3-yl)methanol [147-1] was obtained as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][S:33]([C:36]2[S:37][C:38](Br)=[CH:39][CH:40]=2)(=[O:35])=[O:34])[CH:27]=1.C(O)(C(F)(F)F)=O>ClCCl>[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][S:33]([C:36]2[S:37][C:38]([C:2]#[C:1][C:3]3[CH:4]=[N:5][N:6]4[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]5[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=5)=[N:8][C:7]=34)=[CH:39][CH:40]=2)(=[O:34])=[O:35])[CH:27]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: O=S(=O)(Nc1cccnc1)c1ccc(Br)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1cccnc1)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (178 mg, 0.5 mmol) and commercially available 5-bromo-thiophene-2-sulfonic acid pyridin-3-ylamide [CAS-No. 439934-18-6] (160 mg, 0.5 mmol) according to general procedure II and subsequent cleavage of the protecting group with TFA in dichloromethane at 0° C. Obtained as a yellow solid (200 mg, 67%). MS (ISN) 592.1 [(M−H)−]; mp 248° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH3:10].C([Li])CCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C>C1COCC1.CCCCCC>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([B:16]([OH:21])[OH:17])=[C:3]([CH3:10])[CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(Br)c(C)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)c(C)c1
Temperature: -62.5 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
A solution of 4-bromo-3-methylanisole (7, 92 g, 0.457 mol) in anhydrous THF (400 ml) was treated dropwise with a solution of n-butyl lithium (2.5 M solution in hexane, 201 mL, 0.503 mol, 1.1 equiv) in hexane at −60-−65° C. under N2. The resulting reaction mixture was stired at −60-65° C. for an additional 30 min before being treated dropwise with B(OiPr)3 (94.56 g, 116 mL, 0.503 mol, 1.1 equiv) at −60-−65° C. The reaction mixture was stirred at −60-−65° C. for an additional 1 h. The reaction was then quenched with saturated NH4Cl aqueous solution (400 mL) at −60-−65° C., and the resulting mixture was gradually warmed to 0° C. for 1 h and subsequently to room temperature. The two layers were separated, and the aqueous layer was extracted with EtOAc/THF (1:1, 200 mL). The combined organic extracts were then washed with H2O (200 mL), and saturated NaCl aqueous solution (200 mL), dried over MgSO4, and concentrated in vacuo. The residual white solids were then suspended in heptane (400 mL), and the resulting suspension was stirred at room temperature for 30 min. The solids were collected by filtration and washed with heptane (2×100 mL), dried in vacuo at 40-45° C. for overnight. The crude product (8, 57.9 g, 75.86 g theoretical, 76.3%) was obtained as a white powder.
Reaction SMILES: [C:1]1(=[O:16])[N:5]([N:6]2[CH:10]=[CH:9][CH:8]=[CH:7]2)[C:4](=[O:11])[C:3]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]12.[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>ClCCCl>[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([C:7]1[N:6]([N:5]2[C:4](=[O:11])[C:3]3=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]3[C:1]2=[O:16])[CH:10]=[CH:9][CH:8]=1)=[O:21]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: O=C1c2ccccc2C(=O)N1n1cccc1
Solvent: ClCCCl
Product: O=C(c1ccccc1Cl)c1cccn1N1C(=O)c2ccccc2C1=O
Yield: 123.7 %

Procedure:
To a vigorously stirred mixture of 1-phthalimidopyrrole (45 g, 0.212 mol) and o-chlorobenzoyl chloride (37 g, 0.212 mole) in 500 ml of 1,2-dichloroethane was added freshly pulverized, fused zinc chloride (43.3 g, 0.318 mol) in one portion. The reaction mixture was heated at gentle reflux for 4.5 hours and then quenched with 700 ml of crushed ice and 500 ml of dichloromethane. The organic layer was separated and washed with water (2×500 ml), dried over anhydrous MgSO4, filtered, and evaporated to give 92 g of an oil. This oil was purified by column chromatography (silica gel/dichloromethane) to give 33.8 g (45%) of needles, m.p. 158°-160° C.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[Cl:13][C:14]1[S:15][C:16]([CH2:19]Cl)=[CH:17][N:18]=1>CN(C=O)C>[Cl:13][C:14]1[S:15][C:16]([CH2:19][N:5]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])=[CH:17][N:18]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCc1cnc(Cl)s1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1cnc(Cl)s1
Reaction time: 0.75 h
Yield: 80.4 %

Procedure:
To a mixture of potassium phthalimide (10.4 g) and dry DMF (100 ml) was dropwise added a solution of 2-chloro-5-(chloromethyl)thiazole (9.0 g) obtained in the same manner as in Example 2, in 10 ml of DMF in an oil bath at 20° C. over 15 min. After completion of the addition stirring was continued at 60° C. for 45 min. followed by separation of insoluble materials by filtration on celite. The filtrate was concentrated under reduced pressure. To the residue was added 100 ml of dichloromethane again followed by separation of insoluble materials by filtration and concentration of the filtrate. The residue was purified by column chromatography (eluted with dichloromethane-ethyl acetate 20:1) to give 12.0 g of N-(2-chloro-5-thiazolylmethyl)phthalimide, mp 108°-109° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.[NH2:19][CH2:20][C:21]1[C:26]([Cl:27])=[CH:25][C:24]([C:28]([F:31])([F:30])[F:29])=[CH:23][N:22]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:19][CH2:20][C:21]2[C:26]([Cl:27])=[CH:25][C:24]([C:28]([F:31])([F:30])[F:29])=[CH:23][N:22]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCc1ncc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(NCc2ncc(C(F)(F)F)cc2Cl)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-aminomethyl-3-chloro-5-(trifluoromethyl) pyridine hydrochloride and DBU in DME. ES-MS m/e (%): 397 (M{37Cl}+H+, 30), 395 (M{35Cl}+H+, 100).
Reaction SMILES: [C:1]([NH:8][CH:9]([C:16]([OH:18])=O)[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:19][CH:20]([CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH:21]([OH:27])[CH:22]([CH:24]1[CH2:26][CH2:25]1)[OH:23]>>[CH:29]1([CH2:28][C@H:20]([NH:19][C:16]([CH:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH2:10][C:11]2[N:12]=[CH:13][S:14][CH:15]=2)=[O:18])[C@@H:21]([OH:27])[C@H:22]([CH:24]2[CH2:25][CH2:26]2)[OH:23])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: NC(CC1CCCCC1)C(O)C(O)C1CC1
Reactant: CC(C)(C)OC(=O)NC(Cc1cscn1)C(=O)O
Product: CC(C)(C)OC(=O)NC(Cc1cscn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1

Procedure:
In a manner analogous to the procedure described in Example 16(c), by condensing (RS)-Boc-3-(4-thiazolyl)alanine, prepared according to the synthesis described in EPA 0274259, and 3-amino-4-cyclohexyl-1-cyclopropyl-1,2-butanediol there is obtained tert-butyl [(RS)-1-[[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]carbamoyl]-2-(4-thiazolyl)ethyl]carbamate (1:1 epimer mixture) as a colourless solid; MS: 482 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:3]=1[CH2:20][CH2:21][OH:22].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32].Cl>ClCCl.O>[CH3:30][S:31]([O:22][CH2:21][CH2:20][C:3]1[N:4]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:5]2[C:10]([C:2]=1[CH3:1])=[CH:9][CH:8]=[CH:7][CH:6]=2)(=[O:33])=[O:32]
Reactant: Cc1c(CCO)n(S(=O)(=O)c2ccccc2)c2ccccc12
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1c(CCOS(C)(=O)=O)n(S(=O)(=O)c2ccccc2)c2ccccc12
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
To a solution of 2-[3-methyl-1-[benzenesulfonyl)indol-2-yl]ethanol (7.1 g) and triethylamine (2.96 g) in dichloromethane (71 ml) was added dropwise methanesulfonyl chloride (2.84 g) in dichloromethane (57 ml) at -40° C. After being stirred at the same temperature for 30 minutes, the reaction mixture was diluted with chilled water, and neutralized with 1N-hydrochloric acid. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give 2-[2-(methanesulfonyloxy)ethyl]-3-methyl-1-(benzenesulfonyl)indole (8.8 g) as amorphous powder.