Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:19]=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])=[CH:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+].[O:26]1[C:30]2([CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]2)[O:29][CH2:28][CH2:27]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][CH2:11][NH:10][C:8](=[O:9])[C:7]1[CH:6]=[CH:5][C:4]([CH2:3][NH:2][CH:33]2[CH2:34][CH2:35][C:30]3([O:29][CH2:28][CH2:27][O:26]3)[CH2:31][CH2:32]2)=[CH:19][CH:18]=1)[CH3:17]
Reactant: CCOC(=O)CCNC(=O)c1ccc(CN)cc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCCl
Product: CCOC(=O)CCNC(=O)c1ccc(CNC2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.2 g Ethyl 3-(4-aminomethylbenzoylamino)propanoate hydrochloride (4.18 mmol) was mixed with 20 mL 1,2-dichloroethane and 6 mL saturated K2CO3 by vigorous stirring. The phases were separated and the aqueous phase was extracted with another 20 mL 1,2-dichloroethane. 240 μL HOAc was added to the combined 1,2-dichloroethane phase followed by 0.691 g 1,4-dioxaspiro[4.5]decan-8-one (4.42 mmol). 1.272 g NaBH(OAc)3 (6 mmol) was added and the reaction was stirred for 16 hours at 25° C. The reaction volume was reduced on a rotary evaporator to about 20 mL and then poured into a mixture of 60 mL H2O and 10 mL sat. K2CO3. The phases were separated and the aqueous phase was extracted twice with 40 mL 1,2-dichloroethane. The combined 1,2-dichloroethane fractions were dried over MgSO4 and evaporated to afford the title compound. The crude product was used in the next step without further purification.
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.Cl[C:36]1[N:44]=[C:43]2[C:39]([N:40]=[C:41]([CH2:46][N:47]3[CH2:52][CH2:51][CH:50]([C:53]([OH:56])([CH3:55])[CH3:54])[CH2:49][CH2:48]3)[N:42]2[CH3:45])=[C:38]([N:57]2[CH2:62][CH2:61][O:60][CH2:59][CH2:58]2)[N:37]=1.[F:63][C:64]1[C:65]([N+:71]([O-:73])=[O:72])=[C:66]([NH2:70])[CH:67]=[CH:68][CH:69]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[F:63][C:64]1[C:65]([N+:71]([O-:73])=[O:72])=[C:66]([NH:70][C:36]2[N:44]=[C:43]3[C:39]([N:40]=[C:41]([CH2:46][N:47]4[CH2:52][CH2:51][CH:50]([C:53]([OH:56])([CH3:54])[CH3:55])[CH2:49][CH2:48]4)[N:42]3[CH3:45])=[C:38]([N:57]3[CH2:58][CH2:59][O:60][CH2:61][CH2:62]3)[N:37]=2)[CH:67]=[CH:68][CH:69]=1
Reactant: Nc1cccc(F)c1[N+](=O)[O-]
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Nc3cccc(F)c3[N+](=O)[O-])nc21
Yield: 73.4 %

Procedure:
A microwave vial equipped with a magnetic follower was charged with Pd2(dba)3 (5.7 mg, 0.006 mmol), Xphos (11.9 mg, 0.025 mmol), 2-[1-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl)-piperidin-4-yl]-propan-2-ol (102 mg, 0.25 mmol), 3-fluoro-2-nitro-phenylamine (47 mg, 0.30 mmol), cesium carbonate (114 mg, 0.35 mmol) and DMF (1 mL). The vial was capped, the reaction mixture was degassed for 5 min and irradiated at 150° C. for 30 min. The reaction mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with MeOH and the desired product was eluted with 2M NH3 in MeOH. The solvents were removed and the residue was subjected to flash chromatography (Si—PCC, 0-5% MeOH in EtOAc) to give 2-{1-[2-(3-fluoro-2-nitrophenylamino)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]piperidin-4-yl}propan-2-ol as a red oil (97 mg, 73%). LCMS (Method H): RT 0.27 min and 3.18 min; [M+H]+ 529
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10](C(O)=O)[C:5]=2[O:4][CH2:3][CH2:2]1.[ClH:14].[NH2:15]O>>[ClH:14].[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([NH2:15])[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C(O)c1cccc2c1OCCO2
Agent: Cl
Product: Nc1cccc2c1OCCO2
Temperature: 120 °C

Procedure:
1,4-Benzodioxan-5-carboxylic acid (120 g) was added in portions at 40° C. to a stirred mixture of hydroxylamine hydrochloride (52 g) and polyphosphoric acid (380 g), then the mixture was heated to an internal temperature of 120° C. The source of heat was removed, and the mixture was stirred vigorously until frothing subsided, then it was stirred at 165° C. for 90 minutes, cooled to 80° C., added to an excess of ice-water, and basified by the addition of 5M aqueous sodium hydroxide solution. The product was extracted into ethyl acetate (6×500 ml), the extracts were dried (MgSO4), and the solvent removed in vacuo. The residue was dissolved in ethyl acetate (800 ml), and the cloudy solution was filtered then saturated with hydrogen chloride. The resulting solid was collected by filtration, washed with ethyl acetate, and dried in vacuo at ambient temperature to give 1,4-benzodioxan-5-amine monohydrochloride as a buff solid (65.9 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[CH3:20][O:21][CH2:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[CH2:27][NH:28][CH3:29]>>[C:8]1([C:5]2[N:6]=[CH:7][C:2]([N:28]([CH2:27][C:26]3[CH:30]=[CH:31][CH:32]=[C:24]([O:23][CH2:22][O:21][CH3:20])[CH:25]=3)[CH3:29])=[N:3][C:4]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CNCc1cccc(OCOC)c1
Reactant: Clc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Product: COCOc1cccc(CN(C)c2cnc(-c3ccccc3)c(-c3ccccc3)n2)c1

Procedure:
In the same manner as in the step 1 of Example 9, except that 2-chloro-5,6-diphenylpyrazine was used in place of 2-chloro-5,6-di-p-tolylpyrazine and 3-(methoxymethoxy)-N-methylbenzylamine was used in place of 4-(methylamino)-1-butanol, the desired compound was prepared as a colorless crystal having a melting point of 109 to 111° C.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([C:8]2[CH:32]=[CH:31][CH:30]=[CH:29][C:9]=2[C:10]([N:12]([CH2:16][CH2:17][NH:18]S(C2C=CC(C)=CC=2)(=O)=O)[CH:13]([CH3:15])[CH3:14])=O)=[O:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)O>>[Cl:1][C:2]1[CH:34]=[CH:33][C:5]([C:6](=[O:7])[C:8]2[CH:32]=[CH:31][CH:30]=[CH:29][C:9]=2[C:10]2[N:12]([CH:13]([CH3:15])[CH3:14])[CH2:16][CH2:17][N:18]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)NCCN(C(=O)c2ccccc2C(=O)c2ccc(Cl)cc2)C(C)C)cc1
Agent: O=S(=O)(O)O
Product: CC(C)N1CCN=C1c1ccccc1C(=O)c1ccc(Cl)cc1
Reaction time: 17 h

Procedure:
Eighteen grams of 2-(p-chlorobenzoyl)-N-[2(p-toluenesulfonamido)ethyl]N-isopropylbenzamide and 65 ml. of 90% (v/v) sulfuric acid were mixed together and heated in a steam bath for thirty minutes. The solution was left standing at room temperature for 17 hours. The mixture was quenched with 800 ml. of ice water and extracted with ethyl acetate. The aqueous portion was cooled and made basic with 50% sodium hydroxide solution. The mixture was extracted with ethyl acetate. The organic portion was extracted with water then dried over magnesium sulfate. The solvent was removed in vacuo. The residue was recrystallized from ethyl acetate-hexane to obtain 4'-chloro-2-(1-isopropyl-2-imidazolin-2-yl)benzophenone, m.p. 114°-117°C. Anal. Calc'd for C19H19N2ClO: C, 69.82; H, 5.86; N, 8.57; Cl, 10,85. Found: C, 69.62; H, 6.05; N, 8.35; Cl, 10.87.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[F:18][CH:19]([F:30])[O:20][C:21]1[CH:22]=[CH:23][C:24]([C:27](O)=[O:28])=[N:25][CH:26]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:24]3[CH:23]=[CH:22][C:21]([O:20][CH:19]([F:30])[F:18])=[CH:26][N:25]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Reactant: O=C(O)c1ccc(OC(F)F)cn1
Product: C[C@]1(c2cc(NC(=O)c3ccc(OC(F)F)cn3)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 5-difluoromethoxy-pyridine-2-carboxylic acid (CAS 1174323-34-2) following procedure I yielded the title compound as a white foam. MS (ISP): m/z=413.3 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[O:7])[N:4]([CH3:8])[C:3]1=[NH:9].[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[N:18]=[C:19]=[O:20]>O1CCCC1>[CH3:1][N:2]1[CH2:6][C:5](=[O:7])[N:4]([CH3:8])[C:3]1=[N:9][C:19]([NH:18][C:12]1[C:11]([CH3:10])=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:17])=[O:20]
Reactant: Cc1cccc(C)c1N=C=O
Reactant: CN1CC(=O)N(C)C1=N
Solvent: C1CCOC1
Product: Cc1cccc(C)c1NC(=O)N=C1N(C)CC(=O)N1C

Procedure:
A mixture of 6.35 g (0.050 mole) of 1,3-dimethyl-2-iminoimidazolidin-4-one and 7.25 g (0.050 mole) of 2,6-dimethylphenylisocyanate in 75 ml. of dry tetrahydrofuran is stirred at room temperature for two hours followed by refluxing it for thirty minutes. The reaction mixture is evaporated in vacuo to give a solid, which is crystallized from tetrahydrofuran-ether. Two more recrystallizations from the same solvent mixture gives pure product, 1-(1,3-dimethyl-4-oxo-2-imidazolidinylidene)-3-(2,6-dimethylphenyl) urea; m.p. 115.5°-118.5° C.
Reaction SMILES: [CH:1](=O)[C:2]1C=CC=CC=1.CO[C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1.FC(F)(F)C(O)=O>CCO>[CH:15]1[C:14]2[C:13](=[CH:12][CH:11]=[CH:18][CH:17]=2)[CH:2]=[CH:1][N:16]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=Cc1ccccc1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2cnccc2c1
Temperature: 25 °C

Procedure:
To a stirred solution of benzaldehyde AB (2.0 g, 11.13 mmol) in EtOH (25 mL) were added 4-methoxybenzylamine (PMBNH2; 1.91 g, 13.92 mmol) and a catalytic amount of trifluoroacetic acid (TFA; 5 mol %) at RT, and the mixture was gradually heated to reflux temperature under inert atmosphere. After completion of reaction (8 h, monitored by TLC), the reaction mixture was cooled to RT and concentrated under reduced pressure. The obtained solid residue was subjected to crystallization (50% CH2Cl2/pentane) to afford colorless crystalline isoquinoline derivative AC (2.0 g, 6.69 mmol, 60%). 1H NMR (500 MHz, CDCl3): δ 8.75 (s, 1H), 7.72 (s, 1H), 7.45 (d, J=8.5 Hz, 1H), 7.38 (d, J=8.5 Hz, 1H), 7.32 (d, J=9.0 Hz, 2H), 6.89 (d, J=9.0 Hz, 2H), 6.46 (s, 1H), 5.02 (br s, 1H), 4.43 (s, 2H), 3.80 (s, 3H). MS (ESI): m/z 299 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[N:6][C:7]([N:10]3[CH2:15][CH2:14][CH:13]([C:16]4([CH3:38])[CH2:20][C:19]5[CH:21]=[C:22]([C:25]6[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH:26]=6)[CH:23]=[CH:24][C:18]=5[O:17]4)[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.FC1C2OC(C3(O)CCN(C4N=CC(CCC)=CN=4)CC3)CC=2C=C(C2CCNCC=2)C=1>>[CH:1]1([C:4]2[CH:5]=[N:6][C:7]([N:10]3[CH2:15][CH2:14][CH:13]([C:16]4([CH3:38])[CH2:20][C:19]5[CH:21]=[C:22]([C:25]6[CH2:30][CH2:29][NH:28][CH2:27][CH:26]=6)[CH:23]=[CH:24][C:18]=5[O:17]4)[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)CC(C)(C2CCN(c4ncc(C5CC5)cn4)CC2)O3)CC1
Agent: CCCc1cnc(N2CCC(O)(C3Cc4cc(C5=CCNCC5)cc(F)c4O3)CC2)nc1
Solvent: O=C(O)C(F)(F)F
Product: CC1(C2CCN(c3ncc(C4CC4)cn3)CC2)Cc2cc(C3=CCNCC3)ccc2O1

Procedure:
Compound 11G was prepared from Compound 11F and TFA in a similar manner to the procedure described for Compound 1J in Example 1. LC/MS (m/z)=417 (M+H)+.
Reaction SMILES: FC1C=C(C2N=C(SC)N=C(N3CCOC[C@@H]3C)C=2)C=NC=1.Cl[C:24]1[CH:29]=[C:28]([Cl:30])[N:27]=[C:26]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][C@@H:32]2[CH3:37])[N:25]=1.[CH:38]1([NH:41][C:42](=[O:59])[NH:43][C:44]2[CH:49]=[CH:48][C:47](B3OC(C)(C)C(C)(C)O3)=[CH:46][CH:45]=2)[CH2:40][CH2:39]1>>[Cl:30][C:28]1[N:27]=[C:26]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][C@@H:32]2[CH3:37])[N:25]=[C:24]([C:47]2[CH:48]=[CH:49][C:44]([NH:43][C:42]([NH:41][CH:38]3[CH2:39][CH2:40]3)=[O:59])=[CH:45][CH:46]=2)[CH:29]=1
Reactant: C[C@H]1COCCN1c1nc(Cl)cc(Cl)n1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Agent: CSc1nc(-c2cncc(F)c2)cc(N2CCOC[C@@H]2C)n1
Product: C[C@H]1COCCN1c1nc(Cl)cc(-c2ccc(NC(=O)NC3CC3)cc2)n1
Yield: 31 %

Procedure:
Method as described for intermediate 5 using (S)-4-(4,6-dichloropyrimidin-2-yl)-3-methylmorpholine (intermediate 1B) and 4-(3-cyclopropylureido)phenyl boronic acid pinacol ester to afford an orange solid (400 mg, 31%).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([S:20][CH3:21])[N:17]=[C:18](Cl)[C:9]=2[C:8]1=[O:22].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1OB(O)O>>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([S:20][CH3:21])[N:17]=[C:18]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[O:33][CH3:32])[C:9]=2[C:8]1=[O:22]
Reactant: CSc1nc(Cl)c2c(n1)NCCCN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C2=O
Reactant: COc1ccccc1OB(O)O
Product: COc1ccccc1-c1nc(SC)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Yield: 88.6 %

Procedure:
In a similar manner to Reference Example 10, 6-[3,5-bis(trifluoromethyl)benzyl]-4-chloro-5,6,7,8,9,10-hexahydro-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 7; 2.43 g) was reacted with 2-methoxyphenylboric acid (912 mg) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methoxyphenyl)-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine (2.47 g, 89%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[F:11][C:12]1[CH:26]=[CH:25][C:15]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:14]([OH:27])[CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[C:20]([O:19][C:18]([NH:17][CH2:16][C:15]1[CH:25]=[CH:26][C:12]([F:11])=[CH:13][C:14]=1[O:27][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[O:24])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCc1ccc(F)cc1O
Reactant: CCOC(=O)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CCCCOc1cc(F)ccc1CNC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
Ethyl 5-bromopentanoate (14.9 mmol) was added dropwise over 15 minutes to a mixture of tert-butyl 4-fluoro-2-hydroxybenzylcarbamate (Example 15; 12.4 mmol) and potassium carbonate (16.1 mmol) in DMA (37 ml). The reaction was heated at 60° C. for 4 hours, followed by the addition of another amount of ethyl 5-bromopentanoate (4.5 mmol) and potassium carbonate (4.8 mmol) and heating at 60° C. for 2 hours. The solvent was evaporated. The residue was taken up in AcOEt and filtered. The filtrate was washed with AcOEt (×3) and concentrated in vacuo. The residue was purified by column chromategraphy over SiO2 (Hexanes/AcOEt, 8/1, v/v) to afford the target compound (4.1 gr, 96% purity).
Reaction SMILES: O1C=CC(NC[C@@H:8]2[O:12][C:11](=[O:13])N(C3C=CC(N4CC[C@H](NC(=O)C)C4)=C(F)C=3)C2)=N1.Cl.[NH2:31][C@H:32]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][C:40]([N:43]3[CH2:47][C@H:46]([CH2:48][N:49]([C:58]4[CH:62]=[CH:61][O:60][N:59]=4)C(OCC(Cl)(Cl)Cl)=O)[O:45][C:44]3=[O:63])=[CH:39][C:38]=2[F:64])[CH2:33]1.ClC(OC)=O>>[CH3:8][O:12][C:11]([NH:31][C@H:32]1[CH2:36][CH2:35][N:34]([C:37]2[CH:42]=[CH:41][C:40]([N:43]3[CH2:47][C@H:46]([CH2:48][NH:49][C:58]4[CH:62]=[CH:61][O:60][N:59]=4)[O:45][C:44]3=[O:63])=[CH:39][C:38]=2[F:64])[CH2:33]1)=[O:13]
Reactant: CC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](CNc4ccon4)OC3=O)cc2F)C1
Reactant: N[C@H]1CCN(c2ccc(N3C[C@H](CN(C(=O)OCC(Cl)(Cl)Cl)c4ccon4)OC3=O)cc2F)C1
Agent: COC(=O)Cl
Agent: Cl
Product: COC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](CNc4ccon4)OC3=O)cc2F)C1

Procedure:
Using essentially the method for the intermediate of Example 12, starting from 3-(4-(3(S)-aminopyrrolidin-1-yl)-3-fluorophenyl)-5(R)-(N-(2,2,2-trichloroethyloxycarbonyl)isoxazol-3-ylaminomethyl)oxazolidin-2-one hydrochloride salt (360 mg, 0.63 mM) and methyl chloroformate gave the desired product (280 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:23]([F:26])([F:25])[F:24])=[N:4][N:5]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Br:27]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C1C=CC=CC=1>[Br:27][CH2:1][C:2]1[C:3]([C:23]([F:26])([F:24])[F:25])=[N:4][N:5]([C:13]2[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(C(F)(F)F)nn(-c2ccc(S(N)(=O)=O)cc2)c1-c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(CBr)c2-c2ccccc2)cc1

Procedure:
To a solution of 4-[4-methyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide prepared in Example 201 (500 mg, 1.3 mmol) in carbon tetrachloride (9 mL) and benzene (4 mL) was added N-bromosuccinimide (285 mg, 1.6 mmol). The mixture was irradiated with a sunlamp for 3.5 hours. The reaction mixture was partitioned between dichloromethane and water and the organic solution was dried and concentrated to give the desired product, 412 mg (69%).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:7][C:6](=[O:8])[CH2:5][C:4]([CH3:10])([CH3:9])[P:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][C:20]([CH:26]([CH3:28])[CH3:27])=[CH:19][C:18]=1[CH:29]([CH3:31])[CH3:30].[CH2:33](O)[CH2:34][CH2:35][OH:36].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:32][C:2]1([CH3:1])[P:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[C:22]([CH:23]([CH3:24])[CH3:25])=[CH:21][C:20]([CH:26]([CH3:28])[CH3:27])=[CH:19][C:18]=2[CH:29]([CH3:31])[CH3:30])[C:4]([CH3:9])([CH3:10])[CH2:5][C:6]2([O:36][CH2:35][CH2:34][CH2:33][O:8]2)[CH2:7]1
Reactant: OCCCO
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P2C(C)(C)CC(=O)CC2(C)C)c(C(C)C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1cc(C(C)C)c(-c2ccccc2P2C(C)(C)CC3(CC2(C)C)OCCCO3)c(C(C)C)c1
Temperature: 125 °C
Yield: 66.3 %

Procedure:
A flask was charged with 0.40 g of 2,2,6,6-tetramethyl-1-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphinan-4-one (0.89 mmol, 1.0 equiv), 10 mL of argon-sparged toluene, 0.65 mL of 1,3-propanediol (8.9 mmol, 10 equiv) and 0.015 g of p-toluenesulfonic acid monohydrate (0.09 mmol, 0.1 equiv). The atmosphere was purged with argon and the reaction flask was equipped with a Dean-Stark trap and warmed in an oil bath at 125 ° C. for 20 h under argon atmosphere. The distilled toluene was collected in the Dean-Stark trap. The reaction mixture was cooled to room temperature, quenched with saturated aqueous sodium bicarbonate and partitioned between toluene and water. The aqueous solution was back extracted once with toluene, the combined organic solution was washed once with water, dried over potassium carbonate and concentrated in vacuo. The unpurified material was purified by flash chromatography over silica gel with gradient elution using acetone/heptane mixtures. After concentration. 0.3 g (66% yield) of 8,8,10,10-tetramethyl-9-(2′,4′,6′-triisopropylbiphenyl-2-yl)-1,5-dioxa-9-phosphaspiro[5.5]undecane was isolated as a solid. 1H NMR (C6D6, 500 MHz) δ ppm 1.02 (d, 6H, J=10 Hz), 1.12 (d, 6H, J=7 Hz), 1.24 (d, 6H, J=7 Hz), 1.31-1.28 (pent, 2H, J=5.5 Hz), 1.42 (d, 6H, J=20 Hz), 1.45 (d, 6H, J=7 Hz), 2.13 (d, 2H, J=14.5 Hz), 2.25 (dd, 2H, J=14.5, 6 Hz), 2.80 (sept, 2H, J=7 Hz), 2.86 (sept, 1H, J=7 Hz), 3.48 (t, 2H, J=5.5 Hz), 3.72 (t, 2H, J=5.5 Hz), 7.01 (td, 1H, J=7.5, 1.5 Hz), 7.08 (br t, 1H, J=7.5 Hz), 7.24 (s, 2H), 7.26-7.24 (m, 1H), 7.89 (br d, 1H, J=8 Hz); 31P NMR (C6D6, 200 MHz) δ ppm-2.7 (br singlet).
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH:6]1[CH:11]=[C:10](Cl)[CH:9]=[C:8]([C:13]([O:15]O)=[O:14])[CH:7]=1.[C:17]([O:20][CH2:21]CC1CCCCC1=O)(=[O:19])[CH3:18]>ClCCl>[C:17]([O:20][CH2:21][CH2:9][CH:10]1[O:15][C:13](=[O:14])[CH2:8][CH2:7][CH2:6][CH2:11]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OCCC1CCCCC1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OCCC1CCCCC(=O)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under an argon atmosphere, sodium bicarbonate (1.78 g, 21.20 mmol) and 80-90% w/w MCPBA (4.95 g, 28.26 mmol) were added to a solution of (±)-2-(2'-acetoxyethyl)cyclohexanone (2.60 g, 14.13 mmol) (0.50 mmol) in dichloromethane (70 ml) at room temperature. The mixture was stirred at room temperature for 3 h, and diluted with dichloromethane (80 ml) and washed sequentially with a saturated sodium sulphite solution (3×100 ml), distilled water (100 ml) and brine (100 ml). The organic phase was dried over magnesium sulphate. After filtration, the solvent was evaporated under reduced pressure to give the crude product which was purified by flash column chromatography using hexane-ethyl acetate (2:3) as eluent to give (±)-7-(2'-acetoxyethyl)-2-oxepanone, as a colourless oil (2.76 g, 98% yield). Rf 0.40 (hexane-ethyl acetate, 7:3).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[C:14]([CH3:19])[CH:13]=1.Br[CH2:21][CH2:22][CH2:23][C:24]#[N:25].O>CN(C=O)C.CC(OC)(C)C>[CH3:19][C:14]1[CH:13]=[C:12]([O:11][CH3:10])[CH:18]=[CH:17][C:15]=1[NH:16][CH2:21][CH2:22][CH2:23][C:24]#[N:25]
Reactant: N#CCCCBr
Reactant: COc1ccc(N)c(C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: COc1ccc(NCCCC#N)c(C)c1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A solution of DIPEA (39 mL, 1 eq) and 4-methoxy-2-methylaniline (30 g, 0.22 mol) in anh. DMF (90 mL), under N2, was heated at 100° C. 4-Bromobutanenitrile (21 mL, 1 eq) was added dropwise. The internal temperature was raised to 110° C. and the reaction mixture was stirred for 2 hr. The mixture was cooled down to r.t. and diluted with MTBE (240 mL). Water (270 mL) was added and the phases were separated. The organic layer was further washed with water (150 mL) and evaporated to 150 mL. Fresh MTBE (150 mL) was added and the mixture again evaporated to 150 mL. The mixture was treated with cHex (540 mL) over 20 min and the resulting suspension left at room temperature for 1.5 hr. The suspension was filtered and the cake washed with a mixture MTBE (30 mL)/cHex (90 mL). The title compound was collected as a violet solid (23.8 g, 53%).
Reaction SMILES: [C:1]([C:3]1C=CC(C(C2C(=O)CCCC=2OCC)NC(NC2C=CC=C(C(F)(F)F)C=2)=O)=C(F)C=1)#N.[Br:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]([C:57]2[C:62](=[O:63])[CH2:61][CH2:60][CH2:59][C:58]=2[OH:64])[NH:43][C:44]([NH:46][C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([C:53]([F:56])([F:55])[F:54])[CH:48]=2)=[O:45])=[C:38]([O:65][CH3:66])[CH:37]=1>>[Br:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]([C:57]2[C:58](=[O:64])[CH2:59][CH2:60][CH2:61][C:62]=2[O:63][CH2:1][CH3:3])[NH:43][C:44]([NH:46][C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([C:53]([F:55])([F:54])[F:56])[CH:48]=2)=[O:45])=[C:38]([O:65][CH3:66])[CH:37]=1
Reactant: COc1cc(Br)ccc1C(NC(=O)Nc1cccc(C(F)(F)F)c1)C1=C(O)CCCC1=O
Reactant: CCOC1=C(C(NC(=O)Nc2cccc(C(F)(F)F)c2)c2ccc(C#N)cc2F)C(=O)CCC1
Product: CCOC1=C(C(NC(=O)Nc2cccc(C(F)(F)F)c2)c2ccc(Br)cc2OC)C(=O)CCC1

Procedure:
The title compound is prepared in analogy to 1-((4-cyano-2-fluorophenyl)(2-ethoxy-6-oxocyclohex-1-enyl)methyl)-3-(3-(trifluoromethyl)phenyl)urea (intermediate 41) using ici 1-((4-bromo-2-methoxyphenyl)(2-hydroxy-6-oxocyclohex-1-enyl)methyl)-3-(3-(trifluoromethyl)phenyl)urea (intermediate 48, 900 mg, 1.75 mmol) as starting material. Yield: 910 mg; ESI mass spectrum [(79Br)-M+H]+=541, [(81Br)-M+H]+=543; Retention time HPLC: 0.92 min (Z011_S03).