Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:10]1([CH2:9][CH2:8][O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCCCCCOCCc1ccccc1
Reactant: NCc1ccccc1
Product: c1ccc(CCOCCCCCNCc2ccccc2)cc1

Procedure:
N-[5-(2-Phenylethoxy)pentyl]benzenemethanamine (8.6 g) was prepared in a similar manner from [2-[(5-bromopentyl)oxy]ethyl]benzene (10 g) and benzylamine (30 ml). The undistilled product was used without further purification in Example 1(c).
Reaction SMILES: [C:1]([C:3]1[CH:41]=[CH:40][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([C:10]([C:13]3[C:21]([O:22][CH3:23])=[CH:20][C:19]([CH3:24])=[C:18]4[C:14]=3[CH:15]=[CH:16][N:17]4C(OC(C)(C)C)=O)(O)[CH3:11])=[N:9][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2N=C(C(C3C(OC)=CC(C)=C4C=3C=CN4C(OC(C)(C)C)=O)(O)C)N(COCC[Si](C)(C)C)C=2C=1)#N>>[CH3:23][O:22][C:21]1[C:13]([C:10]([C:8]2[NH:7][C:6]3[CH:40]=[CH:41][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[N:9]=2)=[CH2:11])=[C:14]2[C:18](=[C:19]([CH3:24])[CH:20]=1)[NH:17][CH:16]=[CH:15]2
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(C)(O)c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Agent: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(C)(O)c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Product: C=C(c1nc2cc(C#N)ccc2[nH]1)c1c(OC)cc(C)c2[nH]ccc12

Procedure:
The title compound was synthesized from a mixture of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxy ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 26-A) in a similar manner as shown in Example 114. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.07 (s) 7.65-7.84 (m) 7.44-7.56 (m) 7.15-7.36 (m, 1H) 6.82 (d, J=2.91 Hz, 1H) 6.58 (dd, J=14.84, 1.71 Hz, 1H) 6.14 (dd, J=2.97, 1.96 Hz, 1H) 5.56-5.75 (m, 1H) 3.57 (d, J=0.88 Hz, 3H) 2.53 (br. s., 3H). HRMS calcd. for C20H16N4O (M+H)+ 329.1402. found 329.1395.
Reaction SMILES: [CH3:1][C@@H:2]1[C@:19]([O:27]C(C)=O)(C(COC(C)=O)=O)[C@:18]2([CH3:31])[C@H:4]([C@H:5]3[C@:15](F)([C@@H:16](O)[CH2:17]2)[C@:14]2([CH3:34])[C:8](=[CH:9][C:10]([CH:12]=[CH:13]2)=[O:11])[C@@H:7]([F:35])[CH2:6]3)[CH2:3]1.F[C@@H]1C2[C@](C)(C=CC(=O)C=2)[C@@H]2[C@H]([C@H]3[C@@](C[C@@H]2O)(C)C(=O)CC3)C1.F[C@@H]1C2[C@](C)(C=CC(=O)C=2)C2[C@H]([C@H]3[C@@](CC=2)(C)C(=O)CC3)C1>>[F:35][C@@H:7]1[C:8]2[C@:14]([CH3:34])([CH:13]=[CH:12][C:10](=[O:11])[CH:9]=2)[C:15]2[C@H:5]([C@H:4]3[C@@:18]([CH2:17][CH:16]=2)([CH3:31])[C:19](=[O:27])[C:2](=[CH2:1])[CH2:3]3)[CH2:6]1
Reactant: CC(=O)OCC(=O)[C@@]1(OC(C)=O)[C@@H](C)C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Agent: C[C@]12C=CC(=O)C=C1[C@@H](F)C[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Agent: C[C@]12C=CC(=O)C=C1[C@@H](F)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)C(=O)CC[C@@H]12
Product: C=C1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)C1=O

Procedure:
Likewise diflorasone diacetate (6α,9α-difluoro-11β,17α,21-trihydroxy-16β-methylpregna-1,4-diene-3,20-dione 17,21-diacetate, U.S. Pat. No. 3,980,778) can be produced using the process of the present invention. First, 6α-fluoro-11β-hydroxyandrosta-1,4-diene-3,17-dione (U.S. Pat. No. 2,867,630) is dehydrated to 6α-fluoroandrost-1,4,9(11)-triene-3,17-dione by means well known to those skilled in the art, see Steroid Reactions, C. Djerassi, Holden-Day, San Francisco, 1963 p. 238 & 239. The 16-methylene group is then added by the process of U.S. Pat. No. 4,416,821 to produce 6α-fluoro-16-methyleneandrosta-1,4,9(11)-triene-3,17-dione which is converted by the process of the present invention to 6α-fluoro-17α-hydroxy-16-methylenepregna-1,4,9(11)-triene-3,20-dione. The 21-hydroxy function of the corticoids is next introduced as described above followed by transformation of the 16-methylene group to a 16β-methyl group also described above to give 6α-fluoro-17α,21-dihydroxy-16β -methylpregna-1,4,9(11)-triene-3,20-dione 21-acetate which is acylated according to the procedure described in U.S. Pat. No. 4,154,748 (Examples 6 and 7) to produce 6α-fluoro-17α,21-dihydroxy-16β-methylpregna-1,4,9(11)-triene-3,20-dione 17,21-diacetate (U.S. Pat. No. 3,980,778, Example 6). 6α-Fluoro-17α,21-dihydroxy-16β-methylpregna-1,4,9(11)-triene-3,20-dione-17,21-diacetate is then converted to difluorasone diacetate by the process of U.S. Pat. No. 3,980,778 (Examples 7 and 8).
Reaction SMILES: [C:1]1([C:7](=[CH2:11])[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:14])=O.C(C1C=CC=C(O)C=1O)(C)(C)C>CN(C=O)C>[C:1]1([C:7](=[CH2:11])[C:8]([Cl:14])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: C=C(C(=O)O)c1ccccc1
Agent: CC(C)(C)c1cccc(O)c1O
Solvent: CN(C)C=O
Product: C=C(C(=O)Cl)c1ccccc1

Procedure:
and is prepared by treating a DMF solution of 2-phenyl-acrylic acid with thionyl chloride in the presence of tert-butylcatechol to afford 2-phenyl-acryloyl chloride. The latter is subsequently treated with a 30% aqueous solution of ammonia according to the following literature: K. Nishiyama, Y. Inouye Agric. Biol. Chem. 1982, 46, 1027-1034.
Reaction SMILES: CC(C)=O.[CH2:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:5]([O:20][C:17]1[CH:18]=[CH:19][C:14]([Br:13])=[CH:15][CH:16]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Oc1ccc(Br)cc1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Brc1ccc(OCc2ccccc2)cc1
Yield: 73 %

Procedure:
To 200 ml of acetone were added 63.5 g of benzyl chloride, 95.15 g of 4-bromophenol, and 69.1 g of potassium carbonate, and the mixture was allowed to react at reflux for 8 hours. After completion of the reaction, the reaction mixture was added into 200 ml of water and extracted with 200 ml of chloroform. The extract was washed with 200 ml of water to obtain a crude product. The crude product was distilled by a Claisen flask to obtain 108.1 g of a distillate, which was further purified by silica gel column chromatography using benzene as an eluent to give 96 g (theoretical yield: 73%) of the entitled compound having a melting point of 47° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:12])[C:9]([NH2:11])=[O:10].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.[CH3:31][Si:32]([C:35]#[CH:36])([CH3:34])[CH3:33]>CN(C=O)C.[Cu]I.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>[CH3:31][Si:32]([C:35]#[C:36][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:12])[C:9]([NH2:11])=[O:10])([CH3:34])[CH3:33]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C(N)=O)c1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: CN(C)C=O
Product: CC(C(N)=O)c1ccccc1C#C[Si](C)(C)C
Temperature: 60 °C
Reaction time: 5 h

Procedure:
A mixture of 2-(2-iodophenyl)propanamide I13 (16.5 g, 0.060 mol), CuI (0.229 g, 1.20 mmol), tri-tert-butylphosphonium tetrafluoroborate (0.348 g, 1.20 mmol), PdCl2(PPh3)2 (0.421 g, 0.600 mmol) and trimethylsilylacetylene (10.3 mL, 0.072 mol) in DMF (60 mL) was bubbled with N2 for 10 minutes. Et3N (50 mL) was then added and the mixture was stirred under nitrogen at 60° C. for 5 hours. The reaction mixture was cooled and the volatiles were removed in vacuo. The dark brown residue was adsorbed onto silica and purified by column chromatography (Biotage Isolera, 120 g SiO2 cartridge, 0-30% EtOAc in petroleum benzine 40-60° C.) to give the title compound I15 as an orange oil (11.5 g, 78%). LCMS-D: rt 3.49 min; m/z 246 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N.[CH3:8][C:9]1[C:21]([CH3:22])=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([C:23](O)=[O:24])[C:18]=3[NH:19]2)=[CH:11][CH:10]=1>>[CH3:8][C:9]1[C:21]([CH3:22])=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([C:23]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:24])[C:18]=3[NH:19]2)=[CH:11][CH:10]=1
Reactant: Cc1ccc2c([nH]c3c(C(=O)O)cccc32)c1C
Reactant: C1COCCN1
Agent: N
Product: Cc1ccc2c([nH]c3c(C(=O)N4CCOCC4)cccc32)c1C
Yield: 75 %

Procedure:
Under the conditions of Example 31, but with the difference that excess morpholine is added to the reaction mixture in place of the ammonia, 7,8-dimethylcarbazole-1-carboxylic acid is converted into the carboxylic acid morpholide. After recrystallization from dioxane -- water, 7,8-dimethylcarbazole-1-carboxylic acid morpholide is obtained in a 75% yield, m.p. 183° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:6]([C:8]1[CH:9]=[CH:10][C:11]([N:14]([CH3:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:12][CH:13]=1)=O.C(OP([CH2:35][C:36]([N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)=[O:37])(OCC)=O)C.[H-].[Na+]>>[CH3:21][N:14]([C:11]1[CH:10]=[CH:9][C:8]([C:6]([C:5]2[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:35][C:36]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[O:37])=[CH:13][N:12]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOP(=O)(CC(=O)N1CCOCC1)OCC
Reactant: COc1ccc(C(=O)c2ccc(N(C)c3ccccc3)nc2)cc1OC
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(C(=CC(=O)N2CCOCC2)c2ccc(N(C)c3ccccc3)nc2)cc1OC
Yield: 32.1 %

Procedure:
In the same manner as in Example 1, using 5-(3,4-dimethoxybenzoyl)-2-(N-methylanilino)pyridine (500 mg), diethylphosphonoacetic acid morpholide (800 mg) and 60% sodium hydride (150 mg), E-isomer (250 mg) and Z-isomer (212 mg) of 4-[3-(2-(N-methylanilino)-5-pyridyl)-3-(3,4-dimethoxyphenyl)acryloyl]morpholine (Compound No.62) were obtained.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H][H].C#C>C(O)C.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH3:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]/[CH:4]=[CH:3]\[CH2:2][CH2:1][OH:13]
Reactant: CCCCCCCCC#CCCO
Reactant: [H][H]
Agent: [Pd]
Agent: C#C
Agent: CC(=O)[O-]
Solvent: CCO
Product: CCCCCCCC/C=C\CCO
Yield: 95.2 %

Procedure:
A mixture of 24 g of 3-dodecyn-1-ol in 400 ml of ethanol and 1 g of Lindlar catalyst was hydrogenated under 1 atmosphere of hydrogen. The progress of the reaction was followed by gas chromatography until the acetylene was consumed. The catalyst was removed by filtration through celite and the ethanol evaporated. The resulting residue was distilled to give 23.09 g of 3Z-dodecen-1-ol, bp 83-86/0.3 mm.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:28]1[CH:33]=[C:32]([O:34]C)[C:31]([F:36])=[C:30]([F:37])[CH:29]=1.B(Br)(Br)Br>ClCCl.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:28]1[CH:33]=[C:32]([OH:34])[C:31]([F:36])=[C:30]([F:37])[CH:29]=1
Reactant: COc1cc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc(F)c1F
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(O)c(F)c(F)c3)n(-c3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
(S)-2-(1-((6-Amino-5-(3,4-difluoro-5-methoxyphenyl)pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (87 mg, 0.17 mmol) was dissolved in 3 mL dichloromethane. A solution of boron tribromide (1M, 520 μl, 0.52 mmol) was added dropwise and the reaction was stirred at room temperature overnight. Further tribromide (1M in dichloromethane, 260 μl, 0.26 mmol) was added dropwise and stirred for 2 h more. The mixture was diluted with ethyl acetate and washed with a solution of 4% sodium bicarbonate, water, brine and dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified by reverse phase using SP1® Purification System to give 25 mg (44% yield) of the title compound as a solid. Purity 99%.
Reaction SMILES: C([O:3][P:4]([CH2:9][O:10][C@H:11]([CH2:24][OH:25])[CH2:12][O:13][N:14]1[CH:22]=[N:21][C:20]2[C:15]1=[N:16][CH:17]=[N:18][C:19]=2[NH2:23])([O:6]CC)=[O:5])C.C[Si](Br)(C)C>CN(C=O)C>[OH:25][CH2:24][C@@H:11]([O:10][CH2:9][P:4]([OH:5])([OH:6])=[O:3])[CH2:12][O:13][N:14]1[CH:22]=[N:21][C:20]2[C:15]1=[N:16][CH:17]=[N:18][C:19]=2[NH2:23]
Reactant: CCOP(=O)(CO[C@H](CO)COn1cnc2c(N)ncnc21)OCC
Agent: C[Si](C)(C)Br
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2OC[C@@H](CO)OCP(=O)(O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-9-[2-(diethoxyphosphorylmethoxy)-3-hydroxypropoxy)adenine (0.16 g, 0.43 mmol) in dry DMF (3 ml) was added trimethylsilyl bromide (0.56 ml, 4.3 mmol) and the solution stirred at ambient temperature for 4 hours. The solvent was removed under reduced presence and the residue co-evaporated with acetone/water 1:1 (x3). The solid residue was crystallised from acetone/water (0.1 g, 77%), m.p. 200°-205°. UV: λmax (EtOH), 260 (11,800) nm. IR: νmax (KBr) 3449, 3400, 3199, 3105, 2951, 2897, 1711, 1680, 1612, 1569, 1467, 1420, 1355, 1330, 1305, 1244, 1216, 1128, 1080, 924, 866 cm-1. 1H NMR: δH [(CD3)2SO]3.54 (2H, m, CH2OH), 3.70-3.85 (3H, m, OCH2P, CH), 4.36 (1H, dd, J=11 Hz, J=7 Hz, NOCHB), 4.55 (1H, dd, J=11 Hz, J=3 Hz, NOCHA), 7.51 (2H, br.s, D2O exchangeable NH2), 8.17 (1H, s, H-2 or H-8), 8.50 (1H, s, H-2 or H-8), 3.5-7.0 (3H, broad, PO(OH)2, OH). Found: C, 32.07; H, 4.73; N, 20.46%. C9H14N5O5P 1 H2O requires: C, 32.05; H, 4.78; N, 20.76%. m/z: (FAB, thioglycerol matrix) 320 (MH+). [α]D25 (0.1M NaOH)-11.5° (c=0.2).
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH2:6]([O+](CC)CC)[CH3:7].[CH2:13]([O:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([NH2:21])=[O:20])[CH2:14][CH3:15]>C(Cl)Cl>[F:1][B-:2]([F:5])([F:4])[F:3].[CH2:13]([O:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](=[NH:21])[O:20][CH2:6][CH3:7])[CH2:14][CH3:15]
Reactant: CCCOc1ccccc1C(N)=O
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCCOc1ccccc1C(=N)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.5 %

Procedure:
A solution of triethyloxonium fluoroborate (33.0 g., 0.175 mole) in methylene chloride (75 ml.) was added during 10 minutes to a stirred solution of 2-n-propoxybenzamide (31.3 g., 0.175 mole) in methylene chloride (150 ml.). The solution was stirred for an additional 18 hours at room temperature. The solution was concentrated to about one-fifth volume and was diluted with diethyl ether to precipitate the ethyl 2-n-propoxybenzimidate fluoroborate (44.0 g., 85% yield), m.p. 108°-112°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([NH2:15])[CH2:10]2)[C:5]([F:16])=[CH:4][N:3]=1.[C:17]([O:21][C:22]([N:24]=[C:25]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])N1C=CC=N1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[C:34]([O:33][C:32]([NH:31][C:25](=[N:24][C:22](=[O:23])[O:21][C:17]([CH3:20])([CH3:19])[CH3:18])[NH:15][C@@H:11]1[CH2:12][CH2:13][CH2:14][C@H:9]([NH:8][C:6]2[C:5]([F:16])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:10]1)=[O:38])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Reactant: N[C@@H]1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N[C@@H]1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (1S,3R)—N1-(2-chloro-5-fluoro-pyrimidin-4-yl)cyclohexane-1,3-diamine, 70a, (0.122 g, 0.500 mmol) in CH2Cl2 (10 mL) was added tert-butyl N—(N-tert-butoxycarbonyl-C-pyrazol-1-yl-carbonimidoyl)carbamate (0.155 g, 0.500 mmol). The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated in vacuo and used without further purification: 1H NMR (300 MHz, CDCl3) δ 11.51 (s, 3H), 8.29 (d, J=8.3 Hz, 3H), 7.88 (d, J=2.8 Hz, 3H), 5.01 (d, J=7.4 Hz, 3H), 4.28-4.18 (m, 4H), 2.48 (d, J=11.7 Hz, 3H), 2.12 (d, J=9.4 Hz, 3H), 1.87 (dd, J=10.3, 3.5 Hz, 3H), 1.52 (s, 24H), 1.50 (s, 25H), 1.24-1.10 (m, 8H); LCMS RT=3.97 (M+H) 487.12.
Reaction SMILES: CC([O-])(C)C.[K+].CS(O[CH:12]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([F:31])[CH:25]=1)[CH2:13][CH:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH3:15])(=O)=O.[O:32]1[CH2:37][CH2:36][CH:35]([NH:38][C:39]2[N:44]=[C:43]([C:45]3[CH:50]=[CH:49][NH:48][C:47](=[O:51])[CH:46]=3)[CH:42]=[CH:41][N:40]=2)[CH2:34][CH2:33]1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[Si:17]([O:16][CH:14]([CH3:15])[CH2:13][CH:12]([N:48]1[CH:49]=[CH:50][C:45]([C:43]2[CH:42]=[CH:41][N:40]=[C:39]([NH:38][CH:35]3[CH2:34][CH2:33][O:32][CH2:37][CH2:36]3)[N:44]=2)=[CH:46][C:47]1=[O:51])[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([F:31])[CH:25]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(CC(OS(C)(=O)=O)c1ccc(Cl)c(F)c1)O[Si](C)(C)C(C)(C)C
Reactant: O=c1cc(-c2ccnc(NC3CCOCC3)n2)cc[nH]1
Agent: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1CCOC1
Product: CC(CC(c1ccc(Cl)c(F)c1)n1ccc(-c2ccnc(NC3CCOCC3)n2)cc1=O)O[Si](C)(C)C(C)(C)C
Temperature: 95 °C
Reaction time: 2 h
Yield: 22.7 %

Procedure:
Potassium 2-methylpropan-2-olate (135 mg, 1.20 mmol), tetrabutylammonium iodide (67 mg, 0.18 mmol), and a solution of 3-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)butyl methanesulfonate (0.75 mmol) in anhydrous THF (15 mL) were added to a suspension of 4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (163 mg, 0.600 mmol) in anhydrous THF (5.0 mL). The resulting mixture was stirred at 95° C. under microwave irradiation for 2 hours. The reaction was quenched with water (20 mL). The mixture was further diluted with DCM. After removal of the insoluble by filtration, the filtrate was extracted with DCM. The combined organic phases were dried over Na2SO4 and concentrated. The residue was purified by Combiflash (0.5% NH3HCO3/CH3CN) to afford 1-(3-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)butyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (80 mg, 26% yield). LCMS (ESI) m/z: 587.2 [M+H]+.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:28][C:29](=O)[CH2:30][C:31]1[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=1>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:29](=[O:28])[CH2:30][C:31]1[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Reactant: COC(=O)Cc1cnn(C)c1
Product: COc1ccc(N2CCN(C(=O)Cc3cnn(C)c3)[C@@H](Cc3ccccc3)C2)cc1OC1CCC1
Yield: 4 %

Procedure:
Prepared using the same procedure described in Example 275 from (S)-3-benzyl-1-(3-cyclobutyloxy-4-methoxy-phenyl)-piperazine and (1-methyl-1H-pyrazol-4-yl)-acetic acid methyl ester [prepared by treatment of (1H-pyrazol-4-yl)-acetic acid methyl ester with NaH followed by MeI; used as obtained after aqueous workup] with heating for 15 days to afford the title compound as a tan solid (12 mg, 4%). LC/MS (Method B) 3.55 min, [M+1]+ 475.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([O:16][C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([Si](C(C)(C)C)(C)C)[CH:21]=[C:20]3[CH:33]([CH3:35])[CH3:34])=[C:11]([CH3:36])[CH:10]=1)(C)(C)C.[OH-].[Na+]>C(O)C>[CH:33]([C:20]1[C:19]2[C:23](=[CH:24][CH:25]=[C:17]([O:16][C:12]3[C:11]([CH3:36])=[CH:10][C:9]([O:8][CH2:7][C:6]([OH:37])=[O:5])=[CH:14][C:13]=3[CH3:15])[CH:18]=2)[NH:22][CH:21]=1)([CH3:35])[CH3:34]
Reactant: Cc1cc(OCC(=O)OC(C)(C)C)cc(C)c1Oc1ccc2c(c1)c(C(C)C)cn2[Si](C)(C)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(OCC(=O)O)cc(C)c1Oc1ccc2[nH]cc(C(C)C)c2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 114.4 %

Procedure:
0.24 g (0.46 mmol) of tert-butyl-[4-({1-[tert-butyl-(dimethyl)silyl]-3-isopropyl-1H-indol-5-yl}oxy)-3,5-dimethylphenoxy]acetate (Example XIII) is introduced dissolved in 5 ml of ethanol and 2.5 ml (2.50 mmol) of 1N sodium hydroxide solution are added. The batch is stirred at room temperature for 2.5 h. The solvent is evaporated in a rotary evaporator, the batch is diluted with 50 ml of water and the mixture is acidified with 1N hydrochloric acid solution. The aqueous phase is extracted twice with ethyl acetate, the combined organic phases are dried and the solvent is removed in vacuo. 0.186 g (87.3%) of {4-[(3-isopropyl-1H-indol-5-yl)oxy]-3,5-dimethyl-phenoxy}acetic acid is obtained
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[S:21][C:22](S(C)(=O)=O)=[N:23][N:24]=4)[CH:18]=3)[N:13]([S:29]([C:32]3[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[CH:12]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[C:39]([O:43][C:44]([NH:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1)=[O:45])([CH3:42])([CH3:41])[CH3:40]>O1CCOCC1>[CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[S:21][C:22]([N:49]5[CH2:50][CH2:51][C@@H:47]([NH:46][C:44](=[O:45])[O:43][C:39]([CH3:41])([CH3:40])[CH3:42])[CH2:48]5)=[N:23][N:24]=4)[CH:18]=3)[N:13]([S:29]([C:32]3[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=3)(=[O:30])=[O:31])[CH:12]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(OC(C)C)n3)c3cc(-c4nnc(S(C)(=O)=O)s4)ccc32)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(OC(C)C)n3)c3cc(-c4nnc(N5CC[C@@H](NC(=O)OC(C)(C)C)C5)s4)ccc32)cc1
Yield: 74.6 %

Procedure:
A yellow solution of 2-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-5-(methylsulfonyl)-1,3,4-thiadiazole (107.4 mg, 0.189 mmol) and (3R)-(+)-3-(tert-butoxycarbonylamino)pyrrolidine (TCI America, Portland, Oreg.; 141 mg, 0.755 mmol) in dioxane (1.0 mL) was heated in an open microwave vial at 90° C. for 2 days. Chromatographic purification of the resulting dry residue (silica gel, 0-100% EtOAc/Hex) furnished (R)-tert-butyl 1-(5-(3-(6-isopropoxypyridin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-thiadiazol-2-yl)pyrrolidin-3-ylcarbamate (95 mg, 0.141 mmol, 75%) as an off-white solid: MS (ESI, pos. ion) m/z: 675.1 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 8.78 (d, J=1.0 Hz, 1H), 8.02-8.08 (m, 2H), 7.94-7.99 (m, 1H), 7.82 (d, J=8.4 Hz, 2H), 7.61 (t, J=7.8 Hz, 1H), 7.28 (d, J=7.4 Hz, 1H), 7.24 (d, J=8.4 Hz, 2H), 6.63 (d, J=8.2 Hz, 1H), 5.57 (spt, J=6.2 Hz, 1H), 4.66-4.84 (m, 1H), 4.41 (br. s., 1H), 3.83 (dd, J=10.6, 6.1 Hz, 1H), 3.67-3.73 (m, 1H), 3.59-3.67 (m, 1H), 3.48-3.55 (m, 1H), 3.45 (dd, J=10.6, 4.1 Hz, 1H), 2.34 (s, 3H), 1.46 (s, 9H), 1.45 (br. s., 3H), 1.44 (br. s., 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(CC2C=CC=CC=2)C=CC=CC=1.[OH2:21]>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]=[O:21]
Reactant: c1ccc(Cc2ccccc2)cc1
Reactant: O
Solvent: Nc1ccccc1
Product: C=O

Procedure:
A further improved and thus preferred embodiment of the process according to the invention is achieved in that a partial quantity (D") of the organic phase (D) leaving extraction stage (3) is separated and extracted countercurrently in an upstream, preferably multistage, extraction stage (2) with at least a partial quantity, preferably with the entire stream of (C) and the partial stream (D") is calculated in such a manner that the polyamine contained in (D") is as far as possible transferred into the aqueous phase leaving the extraction unit (2), the said aqueous phase, optionally after the addition of water from stream (Y) and/or auxiliary amine and/or further aqueous phase from stream (C) is introduced into extraction stage (3) and the organic phase (R) arising in (2), which is substantially composed of hydrophobic solvent and optionally auxiliary amine, is also introduced into extraction stage (3) and, as a constituent of the organic phase (B), is used as a solvent for the starting polyamine (A). The auxiliary amine used is preferably aniline and the polyamine mixture of the diphenylmethane series used is preferably a polyamine mixture of the kind obtained during acid-catalyzed aniline/formaldehyde condensation.