Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[O:15])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)N1CCOCC1
Yield: 63 %

Procedure:
(2R)-Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (2.15 g, 10 mmol) reacted with morpholine (1.3 mL, 15 mmol) in CH2Cl2 (30 mL) in the presence EDC (2.7 g, 15 mmol), HOBT (1.9 g, 15 mmol) and Et3N (2.1 mL, 15 mmol) at r.t. for 14 h. The mixture was evaporated to dryness and purified by column chromatography. After washing the resulting solid with aqueous NaHCO3 followed by H2O to remove HOBT contamination, pure compound (2R)-2-(morpholine-4-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester 11a (1.79 g, 63%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:17]([CH2:18][C:19](O)=[O:20])[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:17]([CH2:18][C:19](=[O:20])[N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C1CCNCC1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)c(Cl)c2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2ccc(Cl)c(Cl)c2)nc2cccnc21)N1CCCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under nitrogen bubbling, a mixture of 2-(3,4-dichlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.5 g, 0.011 mole) and 1,1'-carbonyldiimidazole (1.95 g, 0.011 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 4 hrs. Piperidine (1.87 g, 0.022 mole) was added and the reaction was allowed to stir at room temperature overnight.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][OH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13](Cl)(=[O:35])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[C:13]([O:12][CH2:11][CH2:10][O:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:35])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: O=C(OCCO)c1ccccc1
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)Cl
Product: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)OCCOC(=O)c1ccccc1

Procedure:
2-Benzoyloxyethyl erucate was prepared by the procedure of Example 1 from 16 gms (0.1 mole) of ethylene glycol monobenzoate and 35.5 gms (0.1 mole) of erucoyl chloride. The structure of the final product was characterized on the basis of NMR and IR spectral analyses as described in Example 1.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:7]1([NH:13][C:14]2[C:19]([CH:20]=[N:21][OH:22])=[CH:18][N:17]=[C:16]3[N:23]([CH2:26][CH3:27])[N:24]=[CH:25][C:15]=23)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Cl[O-].[Na+]>O1CCCC1>[CH:7]1([NH:13][C:14]2[C:15]3[CH:25]=[N:24][N:23]([CH2:26][CH3:27])[C:16]=3[N:17]=[CH:18][C:19]=2[C:20]2[CH2:1][C:2]3([CH2:6][CH2:5][CH2:4][CH2:3]3)[O:22][N:21]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CCn1ncc2c(NC3CCCCC3)c(C=NO)cnc21
Reactant: C=C1CCCC1
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Product: CCn1ncc2c(NC3CCCCC3)c(C3=NOC4(CCCC4)C3)cnc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 40 %

Procedure:
Methylene cyclopentane (0.073 ml, 0.0006 mole) was added to 4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde oxime (0.1 gm, 0.0003 mole) (example 8) in tetrahydrofuran. The reaction mixture was stirred at room temperature for about 5 minutes. Sodium hypochlorite (5 ml) was added slowly to the reaction mixture over a period of about 5 minutes and the mixture was allowed to stir at room temperature for about 5 h. The organic solvent was evaporated and the residue was extracted in ethyl acetate. The organic layer was concentrated and the title compound obtained was purified by preparative thin layer chromatography.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:18](/B(O)O)=[CH:19]\[CH2:20][CH2:21][CH2:22][CH3:23].[ClH:27]>CCOCC>[ClH:27].[CH:18](/[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)=[CH:19]\[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CN(C)CCCNc1ccc2ncc(Br)n2n1
Reactant: CCCC/C=C/B(O)O
Agent: Cl
Solvent: CCOCC
Product: CCCC/C=C/c1cnc2ccc(NCCCN(C)C)nn12
Yield: 40 %

Procedure:
Prepared from the product of step A and (E)-1-hexeneboronic acid according to general procedure 2. The free-base was converted to the HCl salt with 2N HCl in Et2O to provide the title compound (31 mg, 40%) as a brown solid; 1H NMR (500 MHz, CD3OD) δ 7.63 (d, J=9.7 Hz, 1H), 7.55 (s, 1H), 6.74 (d, J=9.7 Hz, 1H), 6.69-6.66 (m, 2H), 3.52 (t, J=6.5 Hz, 2H), 3.29-3.26 (m, 2H), 2.90 (s, 6H), 2.32-2.38 (m, 2H), 2.18-2.16 (m, 2H), 1.54-1.48 (m, 2H), 1.46-1.39 (m, 2H), 0.96 (t, J=7.3 Hz, 3H); 13C NMR (125 MHz, CD3OD) δ 155.6, 137.0, 134.2, 129.1, 126.8, 125.0, 116.3, 114.7, 57.3, 43.6, 38.5, 34.4, 23.8, 25.1, 23.1, 14.3; HPLC tR=9.2 min (Luna), 97.9%; ES-MS: (M+H)=302 m/z.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[C:12]([O:15][C@@H:16]1[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:20]([O:26][C:27](=[O:29])[CH3:28])[CH2:19][S:18][C@@H:17]1Br)(=[O:14])[CH3:13]>[O-2].[Zn+2]>[C:12]([O:15][C@@H:16]1[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@H:20]([O:26][C:27](=[O:29])[CH3:28])[CH2:19][S:18][C@H:17]1[S:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:8][CH:7]=1)(=[O:14])[CH3:13]
Reactant: FC(F)(F)c1ccc(S)cc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Agent: [O-2]
Agent: [Zn+2]
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2ccc(C(F)(F)F)cc2)SC[C@H]1OC(C)=O
Yield: 48 %

Procedure:
If the procedure described in Preparation IV is followed starting from 5.6 g (32.10-3 mol) of 4trifluoromethylbenzenethiol, 12.3 g (35.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide and 2.55 g (32.10-3 mol) of zinc oxide (ZnO), 7.4 g (yield: 48%) of the expected product are obtained after precipitation in ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C@H:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[C:14]2[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=2)[C:5]([F:20])=[CH:4][C:3]=1[S:21]([N:24](CC1C=CC(OC)=CC=1OC)[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][N:26]=1)(=[O:23])=[O:22].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C@H:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[C:14]2[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=2)[C:5]([F:20])=[CH:4][C:3]=1[S:21]([NH:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][N:26]=1)(=[O:22])=[O:23]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCC[C@@H]3c3ccnn3C)cc2Cl)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1cc(Cl)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 39.5 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 2-chloro-N-(2,4-dimethoxybenzyl)-5-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (50.6 mg, 0.0840 mmol) prepared in Example 19b, triethylsilane (0.05 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (15.0 mg, 39%) as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:15]=[C:6]2[C:7]([CH:13]=[O:14])=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[N:5]2[N:4]=1.[CH2:18]([Mg]Br)[CH3:19]>>[OH:14][CH:13]([C:7]1[C:6]2[N:5]([N:4]=[C:3]([C:2]([F:1])([F:16])[F:17])[CH:15]=2)[C:10]([O:11][CH3:12])=[CH:9][CH:8]=1)[CH2:18][CH3:19]
Reactant: COc1ccc(C=O)c2cc(C(F)(F)F)nn12
Reactant: CC[Mg]Br
Product: CCC(O)c1ccc(OC)n2nc(C(F)(F)F)cc12

Procedure:
The compound of Example 115 was reacted with ethyl magnesium bromide as in Example 134 to afford the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[C:14]([OH:19])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>CC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[C:14]([O:19][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(Br)c(O)c2)cc1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)Oc2ccc(Br)c(OCCN3CCCCC3)c2)cc1
Yield: 106.6 %

Procedure:
4-Bromo-3-hydroxyphenyl 4-methylbenzenesulfonate (17.6 g), potassium carbonate (7.32 g), 1-(2 chloroethyl)piperidine hydrochloride (9.2 g) and acetone (300 ml) were stirred at reflux for 3 h, the reaction mixture filtered and evaporated to give the product as light brown foam (24.2 g).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].C(N(CC)CC)C.[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>C1COCC1.C1(C)C=CC=CC=1>[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:19])=[C:2]([C:1]#[N:5])[C:3]#[N:4])=[CH:16][CH:15]=1
Reactant: N#CCC#N
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#CC(C#N)=C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
To a solution of malononitrile (30 mmol) and triethylamine (36 mmol) in THF/toluene (40 mL, 1:1) at 0° C. was slowly added 4-fluorobenzoyl chloride (30 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, the crude residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1:30), yielding the pure title compound (5.2 g, 93%) as a yellowish oil. MS (m/z) 189.2 [M+H]+ (100%). δH (300 MHz, CDCl3, 25° C.) 10.61 (br s, 1H), 7.80 (dd, J 8.7, 5.4 Hz, 2H), 7.06 (t, J 8.7 Hz, 2H).
Reaction SMILES: C(N(CC)CC)C.[H-].[Ca+2].[H-].[C:11]([OH:16])(=[O:15])[C:12]([CH3:14])=[CH2:13].[C:17]1([C:23](Br)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCOCC>[C:11]([O:16][C:23]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)(=[O:15])[C:12]([CH3:14])=[CH2:13]
Reactant: C=C(C)C(=O)O
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Ca+2]
Agent: [H-]
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=C(C)C(=O)OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2.5 h

Procedure:
5.05 g (0.05 mol) of dry triethylamine distilled in the presence of calcium hydride was added to 20 ml of anhydrous ether distilled in the presence of lithium aluminum hydride, and the mixture was cooled with ice in a nitrogen atmosphere. 0.86 g (0.01 mol) of methacrylic acid was added thereto and the mixture was stirred. While cooling the mixture with ice, 3.23 g (0.01 mol) of triphenylmethyl bromide dissolved in 10 ml of anhydrous ether was added thereto, whereby the reaction rapidly proceeded and triethylamine hydrobromide was precipitated. The reaction was continued for 2.5 hr until the salt was completely precipitated, and the resulting crystal was recovered by filtration. When the solvent and excess triethylamine were distilled off, triphenylmethyl methacrylate was obtained as a crystal, which was then recrystallized from ether to give 3.07 g (yield: 92.9%) of a colorless prismatic crystal.
Reaction SMILES: O.O.[C:3]1([CH:11]=[C:9]([OH:10])[CH:8]=[C:6]([OH:7])[CH:5]=1)[OH:4].[CH2:12]([CH:19]([C:25]([CH3:27])=O)[C:20](OCC)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C(O)C>[CH2:12]([C:19]1[C:20](=[O:21])[O:4][C:3]2[CH:11]=[C:9]([OH:10])[CH:8]=[C:6]([OH:7])[C:5]=2[C:25]=1[CH3:27])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(Cc1ccccc1)C(C)=O
Reactant: Oc1cc(O)cc(O)c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1c(Cc2ccccc2)c(=O)oc2cc(O)cc(O)c12

Procedure:
A solution of phloroglucinol dihydrate (20 g) and ethyl 2-benzylaceto-acetate (27.5 ml) in ethanol (320 ml) was treated with dry HCl at 0° C. for five hours and the solution was kept at that temperature overnight. The yellow solution was concentrated and triturated with water, the solids filtered, washed with water and dried. The resulting hydrate was thrice evaporated to dryness from toluene, triturated with pethroleum ether (bp. 40-60° C.) and filtered. Yield 33.4 g (96%). Melting point 258-260° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:9][OH:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[CH2:17]([O:1][C:2]1[C:3]([CH2:9][OH:10])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ccc(O)c(CO)n1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(OCc2ccccc2)c(CO)n1
Temperature: 60 °C

Procedure:
100 g of 3-hydroxy-6-methyl-2-pyridine methanol and 150 g of potassium carbonate were suspended in 400 ml of N,N-dimethylformamide. Under heating under stirring 60° C. in an oil bath, 85 ml of benzyl bromide was added dropwise thereinto. Further, after heating under stirring for 30 minutes, insoluble matters were filtered off. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was recrystallized from ethanol/hexane, to give 145 g of the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:6][CH:7]=1.[Cl:15][S:16](O)(=[O:18])=[O:17]>>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:14])[C:10]([F:11])([F:13])[F:12])[CH:5]=[CH:6][C:7]=1[S:16]([Cl:15])(=[O:18])=[O:17]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(Nc1cccc(Br)c1)C(F)(F)F
Product: O=C(Nc1ccc(S(=O)(=O)Cl)c(Br)c1)C(F)(F)F
Reaction time: 8 h

Procedure:
The crude N-(3-bromophenyl)-2,2,2-trifluoroacetamide was cooled to 0° C., then chlorosulfonic acid was added dropwise at 0° C. over 10 min. The r×n mix was stirred at 0° C. to rt overnight. LC/MS monitored the r×n. The r×n mix poured into ice-H2O (100 g) to quench the r×n. The sticky gum was washed with H2O and dried in vacuum to give the crude 2-bromo-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonyl chloride.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][CH:17]=[C:16]([C:20]3[CH:29]=[CH:28][C:27]4[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=4[CH:21]=3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>>[CH3:30][C:26]1([CH3:31])[CH2:25][CH2:24][C:23]([CH3:32])([CH3:33])[C:22]2[CH:21]=[C:20]([C:16]3[N:15]=[C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:19]=[N:18][CH:17]=3)[CH:29]=[CH:28][C:27]1=2
Reactant: CC(C)(C)OC(=O)N1CCN(c2cncc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n2)CC1
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3cncc(N4CCNCC4)n3)ccc21

Procedure:
The above compound is prepared analogously to FS201 starting from 6′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2,3,5,6-tetrahydro-1,2′-bipyrazinyl-4-carboxylic acid tert-butyl ester. Product is the hydrochloride.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:13](=[C:14]([OH:16])[CH:15]=1)[C:12](=[CH2:17])[C:11]1([OH:19])[O:18][N:6]2[CH2:7][CH:8]2[CH:10]1[NH:9]2.C(O[C:24](=[O:26])[CH3:25])(=O)C>N1C=CC=CC=1>[C:2]([O:16][C:14]1[CH:15]=[C:3]([CH2:2][O:1][C:24](=[O:26])[CH3:25])[CH:4]=[C:5]2[C:13]=1[C:12](=[CH2:17])[C:11]1([OH:19])[O:18][N:6]2[CH2:7][CH:8]2[CH:10]1[N:9]2[C:14](=[O:16])[CH3:13])(=[O:1])[CH3:3]
Reactant: C=C1c2c(O)cc(CO)cc2N2CC3NC3C1(O)O2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: C=C1c2c(OC(C)=O)cc(COC(C)=O)cc2N2CC3C(N3C(C)=O)C1(O)O2
Reaction time: 8 h

Procedure:
4-Hydroxymethyl-8-methylene-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-triene-6,9-diol (10 mg) was dissolved in pyridine (1 ml). To this solution was added acetic anhydride (100 μl), and the mixture was allowed to stand at room temperature overnight. The reaction mixture was evaporated to dryness in vacuo and the residual oil was subjected to preparative thin layer chromatography, which was developed with a mixture of methanol and chloroform (5:95, v/v) to give 4-acetoxymethyl-11-acetyl-9-hydroxy-8-methylene-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6-yl acetate (6 mg).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][N:4]=[C:5]([NH2:22])[NH:6][C:7]1[CH:11]=[N:10][N:9]([C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=2)[C:15]([O:17]C)=O)[N:8]=1.[CH2:25]([CH2:27][NH2:28])[OH:26]>>[OH:26][CH2:25][CH2:27][NH:28][C:15](=[O:17])[C:14]1[CH:19]=[CH:20][CH:21]=[C:12]([N:9]2[N:8]=[C:7]([NH:6][C:5]([NH2:22])=[N:4][CH2:3][C:2]([F:1])([F:24])[F:23])[CH:11]=[N:10]2)[CH:13]=1
Reactant: COC(=O)c1cccc(-n2ncc(NC(N)=NCC(F)(F)F)n2)c1
Reactant: NCCO
Product: NC(=NCC(F)(F)F)Nc1cnn(-c2cccc(C(=O)NCCO)c2)n1

Procedure:
A mixture of methyl 3-[4-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,3-triazol-2-yl]benzoate (0.2 g.) and ethanolamine (5 ml.) was heated at 80° overnight. The mixture was evaporated and the thick oily residue was purified by chromatography on silica gel using EtOAc and isopropanol (6:1 v/v) as eluant. The product was recrystallised from isopropanol to give N-(2-hydroxyethyl)-3-[4-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,3-triazol-2-yl]benzamide, m.p. 171°-173°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18].CS(O)(=O)=O.O>O1CCOCC1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:14][C:13]2[CH:15]=[CH:16][C:10]([CH3:9])=[C:11]([N+:17]([O-:19])=[O:18])[CH:12]=2)=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Agent: CS(=O)(=O)O
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(Nc2ncc(Br)cn2)cc1[N+](=O)[O-]

Procedure:
5-Bromo-2-chloropyrimidine 4 (50 mmol), 4-methyl-3-nitroaniline (60 mmol) and methylsulphonic acid (15 mmol) are heated at reflux in 1,4-dioxane (100 mL) for 16 h. The mixture is poured into water, filtered and dried under vacuum to give 5-bromo-N-(4-methyl-3-nitrophenyl)pyrimidin-2-amine 27 as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 10.25 (s, 1H), 8.68 (s, 2H), 8.49 (d, J=2.0 Hz, 1H), 7.86 (dd, J=2.4, 8.4 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 2.46 (s, 3H). MS (m/z) (M+1)+: 309.0, 311.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH:10]2[CH2:12][CH2:11]2)[CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][NH2:23])=[N:19][CH:20]=1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:23][CH2:22][CH2:21][C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:25])([F:13])[F:24])=[CH:20][N:19]=2)=[CH:3][C:4]=1[O:9][CH:10]1[CH2:12][CH2:11]1
Reactant: Clc1ccc(Br)cc1OC1CC1
Reactant: NCCc1ccc(C(F)(F)F)cn1
Product: FC(F)(F)c1ccc(CCNc2ccc(Cl)c(OC3CC3)c2)nc1

Procedure:
In analogy to the procedure described for the synthesis example 71 (step 1), the title compound (4-chloro-3-cyclopropoxy-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 357.1 [M+H]+) was prepared from (4-bromo-1-chloro-2-cyclopropoxy-benzene instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
Reaction SMILES: [SH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.Br[CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1>>[S:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[CH2:13][S:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: BrCc1cccs1
Reactant: Sc1ncnc2ccccc12
Product: c1csc(CSc2ncnc3ccccc23)c1
Yield: 22.9 %

Procedure:
The title compound(1.82 g) was prepared from 4-mercaptoquinazoline(5.0 g) and 2-bromomethylthiophene(8.15 g).
Reaction SMILES: FC(F)(F)C(O)=O.[N-:8]=[N+:9]=[N-:10].[Na+].[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:13].Cl>N1C(C)=CC=CC=1C>[CH2:17]([O:16][C:14]([C:12]1[NH:13][N:10]=[N:9][N:8]=1)=[O:15])[CH3:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C#N
Agent: Cl
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nnn[nH]1
Temperature: 0 °C
Reaction time: 6 h
Yield: 52.6 %

Procedure:
Trifluoroacetic acid (24.47 g, 0.21M) was added dropwise over 0.5 hr under nitrogen to a stirred suspension of sodium azide (12.59 g, 0.19M) in 2,6-lutidine (100 ml) at 8° to 12°. After stirring for 7 minutes ethyl cyanoformate (20.4 g, 0.20M) was added in one portion. The mixture was heated and stirred at 75° for 6 hours and then, after cooling, stirred at 20° for 16 hr. After cooling to 10° the mixture was added to ice (250 g) and 11 molar hydrochloric acid (100 ml) keeping the temperature below 20°. The product was extracted into ethyl acetate (1×250, 1×200, 2×100 ml) and the combined extracts dried over magnesium sulphate. After evaporation of the solvent under reduced pressure the oily product (38.22 g) was taken up in ether (50 ml) and hexane (25 ml) added. Storage at 4° for 2-3 days produced crystalline ethyl-1H-tetrazole-5-carboxylate that was filtered off, washed with chilled ether, and air dried, 14.12 g (52.6% yield), m.p. 88°-93°.
Reaction SMILES: [CH3:1][N:2]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[NH2:3].[CH3:11][C:12]([CH3:14])=O.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.C([O-])(=O)C.[Na+]>C(OCC)C>[CH3:1][N:2]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[N:3]=[C:12]([CH3:14])[CH3:11]
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: CC(C)=O
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)=NN(C)C(=O)OC(C)(C)C

Procedure:
To a stirred solution of 1,1-dimethylethyl 1-methylhydrazine carboxylate (179 g) (intermediate 5) in diethyl ether (2 L), at room temperature, acetone (126 ml), glacial acid acetic (7.7 ml) and sodium acetate (1.27 g) were added. After stirring over night, the reaction mixture was quenched with water, the organic phase was dried with sodium sulphate and the solvent evaporated to give the title compound (182.38 g) as a colourless oil.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][N:6]=1)=[O:4].Br[C:21]1[N:26]=[N:25][C:24]([NH2:27])=[N:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:27][C:24]1[N:25]=[N:26][C:21]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([NH:2][CH3:1])=[O:4])=[N:6][CH:7]=2)=[CH:22][N:23]=1
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Nc1ncc(Br)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CNC(=O)c1ccc(-c2cnc(N)nn2)cn1
Temperature: 120 °C
Yield: 45.7 %

Procedure:
A mixture of N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (200 mg, 0.80 mmol) (VWR, Cat. #200068-640), 6-bromo-1,2,4-triazin-3-amine (130 mg, 0.76 mmol, Example 2, Step 1), tetrakis(triphenylphosphine)palladium(0) (40 mg, 0.04 mmol) and potassium carbonate (0.32 g, 2.3 mmol) in toluene (1.3 mL), ethanol (0.66 mL) and water (0.66 mL) was heated at 120° C. for 1.5 h. The mixture was filtered and washed with methanol. The filtrate was purified by RP-HPLC (pH=10) to afford the desired product (80 mg, 45.54%). LCMS (M+H)+: m/z=231.4; LCMS (M+H+H2O)+: m/z=249.3.