Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])[S:5][CH:6]=1.Br[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]#[N:34])[CH:28]=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]([C:33]#[N:34])[CH:28]=3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)Nc2nc(C)cs2)n1
Reactant: N#Cc1cc(Br)ccn1
Product: Cc1cc(-c2ccnc(C#N)c2)cc(C(=O)Nc2nc(C)cs2)n1

Procedure:
The title compound, was prepared from 6-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide in accordance with the general method of example 131, step 2 using 4-Bromo-2-cyanopyridine instead of 3-Trifluoromethyl-5-bromopyridine to yield the final compound as a off-white solid, MS (ISP): m/e=336.3 (M+H)+.
Reaction SMILES: [C:1]1([C:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:8][CH2:9][C@H:10]([OH:21])[CH2:11][S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:36]I>O1CCCC1>[C:28]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:8][CH2:9][C@H:10]([O:21][CH3:36])[CH2:11][S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CI
Reactant: COc1ccccc1SC[C@@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1SC[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
34.8 g (0.076 mol) of 1-(3-triphenylmethyloxy-2-(S)-hydroxypropylthio)-2-methoxybenzene (XII-1), in solution in 50 ml of distilled tetrahydrofuran, are introduced dropwise into a round-bottomed flask, kept under an inert atmosphere, comprising a suspension of 3.5 g of sodium hydride (0.087 mol) in 30 ml of distilled tetrahydrofuran. The mixture is stirred at ambient temperature for 3 hours and then 5.1 ml (0.082 mol) of methyl iodide are added. After stirring at ambient temperature for 2 hours, the mixture is concentrated under reduced pressure and then the residue is taken up in dichloromethane. The solution obtained is cooled and then diluted with ice-cold water. The phases are separated and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with water and with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by flash chromatography on silica gel (eluent: dichloromethane/cyclohexane=70:30) to give 35.8 g (0.076 mol) of the title compound (XIII-1) in the form of an oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][S:7][CH2:6][C@@H:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[N:4]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3]1=[O:22].Br[CH:24]([CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].C(OCC)(=O)C>C1CCCCC1>[CH2:28]([O:27][C:25]([CH:24]([NH:1][C@H:2]1[CH2:8][S:7][CH2:6][C@@H:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[N:4]([CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:3]1=[O:22])[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CSC[C@H]1c1cccs1
Reactant: O=C(OCc1ccccc1)C(Br)CCc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CC(C)(C)OC(=O)CN1C(=O)[C@@H](NC(CCc2ccccc2)C(=O)OCc2ccccc2)CSC[C@H]1c1cccs1

Procedure:
282 mg of t-butyl α-[6(R)-amino-5-oxo-3(S)-(2-thienyl)perhydro-1,4-thiazepin-4-yl]acetate [prepared as described in Example 16(g)] were N-alkylated with 684 mg of benzyl 2-bromo-4-phenylbutyrate in the same manner as in Example 1(h). The reaction product was subjected to silica gel column chromatography using a 1:4 by volume mixture of ethyl acetate and cyclohexane, to separate it into two isomers, A and B (ascribed to the asymmetric carbon atom to which the phenethyl group is attached).
Reaction SMILES: [H-].[Na+].Br.[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:18]3[C:14]([S:15][CH2:16][CH2:17]3)=[N:13][C:12]=2[C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[CH:7][CH:6]=1.FC(F)(F)S(O[CH2:32][C:33]([F:36])([F:35])[F:34])(=O)=O>O1CCCC1>[F:34][C:33]([F:36])([F:35])[CH2:32][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:18]3[C:14]([S:15][CH2:16][CH2:17]3)=[N:13][C:12]=2[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:32][C:33]([F:34])([F:35])[F:36])=[CH:21][CH:20]=2)=[CH:9][CH:10]=1
Reactant: Oc1ccc(-c2nc3n(c2-c2ccc(O)cc2)CCS3)cc1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)COc1ccc(-c2nc3n(c2-c2ccc(OCC(F)(F)F)cc2)CCS3)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 6.14 g. of sodium hydride [50% dispersion in oil, (0.128 mole)] in 150 ml. of tetrahydrofuran (distilled from lithium aluminum hydride) at 0° C. under nitrogen was added 10.0 g. (0.0256 mole) of 5,6-bis(p-hydroxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole hydrobromide. After 30 minutes, 17.82 g. (0.0768 mole) of 2,2,2-trifluoroethyl trifluoromethanesulfonate was added dropwise, maintaining the temperature below 0° C. After stirring overnight at room temperature, the suspension was added portionwise to 500 ml. of ice water under nitrogen and extracted three times with methylene chloride. The organic layer was washed with water, dried over potassium carbonate and concentrated in vacuo. The residue was recrystallized from methylene chloride-hexane to give 5,6-bis[p-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydroimidazo[2,1-b]thiazole, m.p. 163°-164° C.
Reaction SMILES: [CH2:1]([C:4]1[C:12]([Cl:13])=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][C:6]=2[C:5]=1[OH:14])[CH:2]=[CH2:3].[H-].[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:1]([C:4]1[C:5]([O:14][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6]2[C:10](=[CH:11][C:12]=1[Cl:13])[CH2:9][CH2:8][CH2:7]2)[CH:2]=[CH2:3]
Reactant: C=CCc1c(Cl)cc2c(c1O)CCC2
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: C=CCc1c(Cl)cc2c(c1OCc1ccccc1)CCC2
Yield: 89.2 %

Procedure:
Treatment of 5-allyl-6-chloroindan-4-ol (4.5 g, 0.0216 mol) with sodium hydride (60 wt. %, 1.32 g, 0.033 mol) followed by benzyl bromide (6.0 g, 0.035 mol) generally according to the procedure described for Intermediate 38 gave 5.76 g (89%) of 5-allyl-4-(benzyloxy)-6-chloroindane as a colorless oil. 1H NMR (CDCl3) 8H 7.40 (m, 5H); 7.05 (s, 1H); 6.00 (m, 1H); 5.00(m, 2H); 4.90 (s, 2H); 3.53 (dd, 2H); 2.90 (m, 4H); 2.05 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:21])[C:7](=[O:20])[C:8]([CH3:19])([CH3:18])[CH2:9][N:10]2[CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1OC.O.Cl>C(O)C>[CH:13]1([N:10]2[CH2:9][C:8]([CH3:19])([CH3:18])[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[C:11]2=[N:12][C:2]([NH:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=2)=[N:3][CH:4]=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CCO
Solvent: O
Product: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc21
Yield: 96.2 %

Procedure:
To a solution of 10-chloro-2-cyclopentyl-4,4,6-trimethyl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 126; 308 mg, 1 mmol) and 4-amino-3-methoxybenzoic acid (Aldrich; 155 mg, 1.13 mmol) in ethanol (5 mL) was added water (15 mL) and concentrated hydrochloric acid (0.17 mL, 2 mmol). The mixture was heated under reflux for 36 hours. The reaction was cooled and a precipitate formed. This was filtered, dried and triturated under cold acetonitrile refiltered and dried in vacuo. To give the title compound as a brown solid (394 mg, 96%)
Reaction SMILES: [C:1]([O:11][C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([Br:27])[CH:21]=2)=[C:14]([Cl:28])[C:13]=1[CH2:29][CH3:30])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:31][CH:32]([CH3:36])[C:33](Cl)=[O:34]>>[C:1]([O:11][C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:33](=[O:34])[CH:32]([Cl:31])[CH3:36])=[C:22]([Br:27])[CH:21]=2)=[C:14]([Cl:28])[C:13]=1[CH2:29][CH3:30])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCc1c(OC(=O)C=Cc2ccccc2)cc(Cl)c(Oc2ccc(N)c(Br)c2)c1Cl
Reactant: CC(Cl)C(=O)Cl
Product: CCc1c(OC(=O)C=Cc2ccccc2)cc(Cl)c(Oc2ccc(NC(=O)C(C)Cl)c(Br)c2)c1Cl
Yield: 54.6 %

Procedure:
Ethyl(3,5-dichloro-4-[4-amino-3-bromophenoxy]phenyl) cinnamate (70 mg) was coupled with 2-chloropropionyl chloride (30 mg), using the method described in Example 1(h). After purification on column (silica gel, ethyl acetate/petrolium ether, 1:9), 45 mg (83%) of ethyl(3,5-dichloro-4-[3-bromo-4-(2-chloropropionamido)phenoxy]phenyl) cinnamate was obtained. A part of the ethyl ester (50 mg) was hydrolysed using the method described in Example 1(i), to give 40 mg (84%) of 3,5-dichloro-4-(3-bromo-4-[2-chloropropionamido]-phenoxy)phenylcinnamic acid.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][CH:5]([O:8][CH3:9])[CH2:6][NH2:7].[C:10](Cl)(=[O:14])[C:11]([CH3:13])=[CH2:12]>O>[CH3:3][O:4][CH:5]([O:8][CH3:9])[CH2:6][NH:7][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12]
Reactant: C=C(C)C(=O)Cl
Reactant: COC(CN)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=C(C)C(=O)NCC(OC)OC
Temperature: -10 °C
Yield: 82.4 %

Procedure:
220 g (5.5 mol) of sodium hydroxide are dissolved in 300 g of water and 700 g of ice in a 3-litre reactor having a stirrer and a cooling system. The sodium hydroxide solution is cooled to 10° C. and 526 g (5.0 mol) of aminoacetaldehyde dimethylacetal and 50 mg of 4-hydroxy-2,2,6,-tetramethylpiperidin-1-oxide (radical inhibitor) are added. 548.6 g (5.5 mol) of methacrylic acid chloride are slowly added at 10° C. to the solution over a period of 3.5 hours. When the addition is complete, the pH value drops slowly to 7.2 and amine can no longer be detected by GC. The reaction mixture is extracted with 500 ml of petroleum ether, and in order to remove impurities, the aqueous phase is saturated with sodium chloride and extracted three times with 500 ml of tert-butyl methyl ether. The organic phase is dried with magnesium sulfate, filtered and concentrated using a rotary evaporator. The resulting 882.2 g of yellowish oil are slowly stirred into 2000 ml of petroleum ether at -10° C. by means of an Ultraturax. The product crystallises, and is isolated by filtration and dried. 713.8 g of methacrylamidoacetaldehyde dimethylacetal (86% of theory), melting point 30°-32° C., are obtained; the product is 99.7% according to GC.
Reaction SMILES: [N:1]1[C:6]2[CH2:7][CH2:8][CH2:9][C:5]=2[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:34])/[CH:18]=[CH:19]/[CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:23][CH2:22]3)=[CH:13][CH:12]=2)=[N:3][CH:2]=1>[Pt]=O.C(O)C>[N:1]1[C:6]2[CH2:7][CH2:8][CH2:9][C:5]=2[C:4]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17](=[O:34])[CH2:18][CH2:19][CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:23][CH2:22]3)=[CH:15][CH:16]=2)=[N:3][CH:2]=1
Reactant: O=C(/C=C/CC1CCN(Cc2ccccc2)CC1)c1ccc(Nc2ncnc3c2CCC3)cc1
Agent: O=[Pt]
Solvent: CCO
Product: O=C(CCCC1CCN(Cc2ccccc2)CC1)c1ccc(Nc2ncnc3c2CCC3)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 78.8 %

Procedure:
30 ml of ethanol and 0.1 g of platinum oxide were added to 0.24 g of (E)-N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-[4-(1-benzylpiperidin-4-yl)-2-butenoyl]aniline, and the mixture was stirred at room temperature under a hydrogen stream for 45 minutes. After removing the solid by filtration, the solvent was removed by distillation and the obtained residue was applied to silica gel column chromatography to obtain 0.19 g of the title compound as white powder.
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[F:40][C:41]1[CH:49]=[CH:48][C:44]([C:45](Cl)=[O:46])=[CH:43][CH:42]=1>>[F:40][C:41]1[CH:49]=[CH:48][C:44]([C:45]([O:1][CH:2]2[CH2:20][CH:19]3[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]4[C:16]([C:22]([NH:24][S:25]([CH:28]5[CH2:30][CH2:29]5)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]3=[O:21])[CH2:15]4)[CH2:3]2)=[O:46])=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)c3ccc(F)cc3)CN2C1=O
Yield: 9 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.176 mmol) and 4-fluorobenzoyl chloride (42 mg, 0.35 mmol). The final trituration (diethyl ether/hexane) and filtration gave 11 mg (9.1%) of 18-(4-fluorobenzoyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 95.0% pure (HPLC), MS m/z 689 (M−H)−, HRMS: calcd. 691.2813 and found 691.2827 (M+H)+, mp 154-156° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.N#N.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13]>C1COCC1.CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccnc(Cl)n1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
To a mixture of Pd(PPh3)2Cl2 (0.9 g) and PPh3 (0.7 g) in THF (200 mL) and Et3N (300 mL) was added 2,4-dichloropyrimidine (40 g, 0.27 mol) under a stream of N2. After bubbling N2 into the solution for 15 min, CuI (0.5 g) was added, followed by (trimethylsilyl)acetylene (29 g, 0.29 mol). The mixture was heated at reflux for 4.5 h. The mixture was cooled to rt and filtered, washing with EtOAc. The filtrated was concentrated and the residue was diluted with hexanes (500 mL) and loaded directly onto a short pad of SiO2. The product was eluted with 10% EtOAc/hexanes to provide a light orange solid (49.3 g), which was used without further purification. TLC: Rf=0.42. mp 51-54° C. IR: 3125 (w), 2961 (w), 1557 (s), 1523 (s). 1H NMR: 8.58 (d, J=5.0 Hz, 1H), 7.30 (d, J=5.0 Hz, 1H), 0.28 (s, 9H). 13C NMR: 162.23, 160.16, 153.41, 122.52, 104.23, 100.75, 0.01. Anal. Calcd for C9H11ClN2Si: C, 51.29; H, 5.26; N, 13.29. Found: C, 51.45; H, 5.16; N, 13.33.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1.[CH:20]1[N:24]=[CH:23][N:22]2[CH2:25][CH2:26][C:27](=[O:28])[C:21]=12.[Cl-].[NH4+]>CCCCCC.C1COCC1>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([C:27]3([OH:28])[C:21]4[N:22]([CH:23]=[N:24][CH:20]=4)[CH2:25][CH2:26]3)[CH:8]=2)=[CH:14][CH:15]=1
Reactant: O=C1CCn2cncc21
Reactant: Fc1ccc(-c2cccc(Br)c2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC1(c2cccc(-c3ccc(F)cc3)c2)CCn2cncc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 45.1 %

Procedure:
A solution (1.6 M; 1.98 ml) of n-butyl lithium in hexane was gently added dropwise to a solution of 3-bromo-4′-fluoro-1,1′-biphenyl (753 mg) in THF (10 ml) at −78° C., and the mixture was stirred at −78° C. for 30 min. A solution of 5,6-dihydro-7Hpyrrolo[1,2-c]imidazol-7-one (244 mg) in THF (10 ml) solution was gently added dropwise and the mixture was stirred at −78° C. for 1 h. A saturated aqueous ammonium chloride solution was added to the reaction mixture and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent, ethyl acetate→ethyl acetate:methanol=5:1) and recrystallized from acetone-hexane to give the title compound (265 mg) as colorless needle crystals.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][C:11]#[C:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[O:1]([CH2:8][CH2:9][CH2:10][C:11]#[C:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][OH:18])=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(C#CCCCOc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1ccc(C#CCCCOc2ccccc2)cc1
Reaction time: 0.92 h
Yield: 101.2 %

Procedure:
A solution of 2.02 g of 4-(5-phenoxy-1-pentyn-1-yl)benzaldehyde in 5 ml of absolute ethanol was stirred with 0° C. bath cooling and 640 mg of sodium borohydride was added in portions. After stirring for 55 minutes the reaction mixture was quenched by the addition of water and then evaporated in vacuo. The residue was mixed cautiously with 2% sulfuric acid and extracted twice with ethyl acetate. The combined extracts were washed with saturated sodium chloride and then a sodium hydrogen carbonate solution. They were dried over magnesiumsulfate and evaporated in vacuo to yield 2.06 g of the 4-(Phenoxy-1-pentyn-1-yl)-benzyl alcohol which was sufficiently pure to use without purification.
Reaction SMILES: [CH:1]([N:4]1[CH2:14][CH:13]2[CH2:15][CH2:16][CH:6]([C:7]3[C:12]2=[CH:11][C:10]([NH2:17])=[CH:9][CH:8]=3)[CH2:5]1)([CH3:3])[CH3:2].Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([NH:35][CH3:36])(=[O:34])=[O:33])[C:22]([Cl:37])=[CH:21][N:20]=1>>[Cl:37][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([NH:35][CH3:36])(=[O:34])=[O:33])=[N:24][C:19]([NH:17][C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[CH:6]2[CH2:16][CH2:15][CH:13]3[CH2:14][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5]2)=[N:20][CH:21]=1
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CC(C)N1CC2CCC(C1)c1cc(N)ccc12
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CN(C(C)C)C2)ncc1Cl

Procedure:
2-[5-Chloro-2-(10-isopropyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzenesulfonamide was prepared from 10-isopropyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide in an analogous manner to Example 273. Product isolated as a clear thin film (21 mg, 33%). LCMS (m/e) 527 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 9.13 (s, 1H), 8.48 (d, 1H, J=8.3 Hz), 7.99 (s, 1H), 7.94 (dd, 1H, J=1.5 and 8.0 Hz), 7.58-7.51 (m, 1H), 7.26-7.19 (m, 3H), 7.08 (s, 1H), 6.98 (dd, 1H, J=3.4 and 5.3 Hz), 5.21 (bs, 1H), 3.00-2.90 (m, 1H), 2.89-2.77 (m, 4H), 2.62 (d, 3H, J=2.7 Hz), 2.31 (d, 2H, J=1.0 Hz), 2.16 (d, 2H, J=8.1 Hz), 1.55 (d, 2H, J=8.2 Hz), 0.94 (d, 6H, J=6.6 Hz).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH:3]1[CH3:26].[F:27][C:28]([Mg]Br)([F:30])[F:29]>O1CCCC1>[F:27][C:28]([F:30])([F:29])[C:2]1([OH:1])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH:3]1[CH3:26]
Reactant: FC(F)(F)[Mg]Br
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)C(C)C3)c(F)c2)C(=O)O1
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(C(F)(F)F)C(C)C3)c(F)c2)C(=O)O1
Yield: 78 %

Procedure:
By reacting (S)-N-{3-[4-(4-oxo-3-methyl-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (2.40 mmol) and trifluoromethyl magnesium bromide (2.6 mmol) in tetrahydrofuran (20 ml) followed by silica gel chromatographic separation of diastereomer the compound was obtained in 78% yield. M.P. 144-146° C. and MS (M+1)=434 (MH+, 100%) for M.F.=C19H23F4N3O4.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[CH3:23][N:24]([CH3:46])[CH2:25][CH2:26][N:27]1[CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:33]=2)[C:28]1=[O:45]>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:32]3[CH:33]=[C:34]4[C:29](=[CH:30][CH:31]=3)[C:28](=[O:45])[N:27]([CH2:26][CH2:25][N:24]([CH3:46])[CH3:23])[CH2:35]4)[C:16]2=[CH:15][N:14]=1
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Reactant: CN(C)CCN1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5c(c4)CN(CCN(C)C)C5=O)n[nH]c3n2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 2-[2-(dimethylamino)ethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=495.1.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH:13]([NH:17][CH:18]([CH2:20][CH3:21])[CH3:19])([CH2:15][CH3:16])[CH3:14]>C1C=CC=CC=1.C(N(CC)CC)C>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([N:17]([CH:18]([CH2:20][CH3:21])[CH3:19])[CH:13]([CH2:15][CH3:16])[CH3:14])=[O:5]
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1Cl
Reactant: CCC(C)NC(C)CC
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCC(C)N(C(=O)c1cc(Cl)cc(Cl)c1Cl)C(C)CC
Temperature: 25 °C

Procedure:
Into a 250 ml flask, provided with a reflux condenser, were introduced 10 g of 2,3,5-trichlorobenzoyl chloride in 20 ml of anhydrous C6H6, a solution of 5.3 g of di-sec.butylamine in 7 ml of anhydrous C6H6 and 5 g of triethylamine. This mass was then heated to reflux temperature for about 1 hour. Thereupon it was left to cool down to room temperature and the solvent was removed under reduced pressure in a rotating evaporator. The mass was then washed with acidulated H2O, with H2O and was then extracted with ethyl ether. The etheric extract was then dried on anhydrous Na2SO4, filtered and the solvent removed under reduced pressure. 12.6 g of yellowing crystals of 2,3,5-trichloro-N,N-di-sec.butyl-benzamide were obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:24]2[CH2:28][CH2:27][CH2:26][S:25]2(=[O:30])=[O:29])[CH:3]=1.[O:31]=[C:32]1[NH:36][C@H:35]([CH2:37][O:38][C:39](=[O:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:34][O:33]1>>[C:39]([O:38][CH2:37][C@@H:35]1[CH2:34][O:33][C:32](=[O:31])[N:36]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:24]2[CH2:28][CH2:27][CH2:26][S:25]2(=[O:30])=[O:29])[CH:3]=1)(=[O:46])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4COC(=O)c4ccccc4)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Yield: 95.9 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 91 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (1.72 g) described in Preparation Example 181 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (852 mg), the title compound (2.12 g) was obtained.