Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:9]2[NH:10][C:11]3[C:16]([C:8]=2[C:7]([C:22]2[C:23]([CH3:39])=[C:24]([NH:28]C(=O)OCC4C=CC=CC=4)[CH:25]=[CH:26][CH:27]=2)=[C:6]([CH3:40])[N:5]=1)=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][O:20][CH3:21])[CH:12]=3)(=[O:3])[NH2:2]>[Pd].O1CCCC1.CO>[NH2:28][C:24]1[C:23]([CH3:39])=[C:22]([C:7]2[C:8]3[C:16]4[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:4]([C:1]([NH2:2])=[O:3])=[N:5][C:6]=2[CH3:40])[CH:27]=[CH:26][CH:25]=1
Reactant: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)nc(C)c(-c3cccc(NC(=O)OCc4ccccc4)c3C)c12
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)nc(C)c(-c3cccc(N)c3C)c12
Reaction time: 1.5 h
Yield: 94 %

Procedure:
A solution of benzyl 3-(1-carbamoyl-7-(2-methoxyethoxy)-3-methyl-9H-pyrido[3,4-b]indol-4-yl)-2-methylphenylcarbamate (0.4846 g, 0.900 mmol) and 10% palladium on carbon (0.192 g, 0.180 mmol) in tetrahydrofuran (Ratio: 1.000, Volume: 23.99 ml) and methanol (Ratio: 1.5, Volume: 36.0 ml) was hydrogenated. After 1.5 h, the reaction was flushed with nitrogen, filtered through a wad of CELITE®, and rinsed. The filtrate was concentrated in vacuo, dissolved in EtOAc (100 mL), dried over MgSO4, filtered and concentrated in vacuo to give 4-(3-amino-2-methylphenyl)-7-(2-methoxyethoxy)-3-methyl-9H-pyrido[3,4-b]indole-1-carboxamide (0.3800 g, 0.846 mmol, 94% yield) as a solid, LC/MS (M+H)=405.18.
Reaction SMILES: COC1C=CC(C2SC3C=CC(OC)=CC=3C=2)=C(N)C=1.Cl.[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:26](O)=O.FC1C=[C:44](C=CC=1OCCN1CCCCC1)[CH2:45][NH:46][C:47]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:48]=1[C:55]1[S:59][C:58]2[CH:60]=[CH:61][C:62]([O:64][CH3:65])=[CH:63][C:57]=2[CH:56]=1>>[CH2:45]([N:46]([CH2:26][C:25]1[CH:29]=[CH:30][C:31]([O:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:23]([F:22])[CH:24]=1)[C:47]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:48]=1[C:55]1[S:59][C:58]2[CH:60]=[CH:61][C:62]([O:64][CH3:65])=[CH:63][C:57]=2[CH:56]=1)[CH3:44]
Reactant: COc1ccc(-c2cc3cc(OC)ccc3s2)c(NCc2ccc(OCCN3CCCCC3)c(F)c2)c1
Reactant: O=C(O)c1ccc(OCCN2CCCCC2)c(F)c1
Agent: COc1ccc(-c2cc3cc(OC)ccc3s2)c(N)c1
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(OC)ccc1-c1cc2cc(OC)ccc2s1

Procedure:
Synthesized from 5-methoxy-2-(5-methoxybenzo[b]thiophen-2-yl)phenylamine and 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 114, [3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][5-methoxy-2-(5-methoxybenzo[b]thiophen-2-yl)phenyl]amine (236 mg) was used according to an analogous synthetic method to Example 36 to provide ethyl[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][5-methoxy-2-(5-methoxybenzo[b]thiophen-2-yl)phenyl]amine (202 mg). The total amount of this compound was used according to an analogous synthetic method to Example 111 to provide the title compound (136 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([CH2:18][C:19]([O:21]CC)=[O:20])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:4][CH:3]=1.[OH-].[Na+].O>CO.C(#N)C>[NH3:9].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([CH2:18][C:19]([OH:21])=[O:20])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC1CCCc2nc(C3CCCC3)n(Cc3ccc(Cl)cc3)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC#N
Product: N
Product: O=C(O)CC1CCCc2nc(C3CCCC3)n(Cc3ccc(Cl)cc3)c21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Intermediate 51 (170 mg) was dissolved in 2 ml methanol followed by 4 M equivalent of sodium hydroxide and the mixture stirred at room temperature for 24 hr. The reaction mixture was reduced in vacuo and dissolved in a minimum amount of 1:1 acetonitrile:water. This mixture was passed through an SCX ion exchange column (5 g). The column was washed with 1:1 acetonitrile:water, followed by acetonitrile. The product was eluted with 2M ammonia in methanol and reduced in vacuo. LC/MS MH+ 372, Rt 2.12 mins (5 min run, TFA modifier).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[N:16][N:15]=[CH:14]2.[CH3:27][CH2:28][N:29](C(C)C)C(C)C.C(N)C>S(Cl)(Cl)=O.C1COCC1.C(OCC)(=O)C>[CH2:28]([NH:29][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[N:16][N:15]=[CH:14]3)[CH:4]=1)[CH3:27]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(C(=O)O)cc1-c1ccc2c(N3CCOCC3)nncc2c1
Agent: CCN
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc(C)c(-c2ccc3c(N4CCOCC4)nncc3c2)c1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
4-Methyl-3-(1-morpholinophthalazin-6-yl)benzoic acid (100 mg, 286 μmol) was dissolved in thionyl chloride (5.7 mL) and heated to 65° C. for 1 h before being concentrated in vacuo. The concentrate was dissolved in THF (5.7 mL), and DIPEA (150 μL, 859 μmol) and ethylamine—2 M in THF (0.71 mL) were added at 0° C. The reaction mixture was warmed to RT and stirred for 3 h, then diluted with 50 mL of ethyl acetate, added to a separation funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed 3× with 50 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated in vacuo to give a crude residue, which was purified by chromatography to afford the title compound. MS (ES+): 377(M+H)+.
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[O:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1.CI>O1CCCC1>[CH3:1][C:16]1([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:18][O:13][CH2:14][CH2:15]1
Reactant: [Li]CCCC
Reactant: COC(=O)C1CCOCC1
Solvent: CI
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCOCC1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
At −78° C., 22.1 ml of n-butyllithium (35.4 mmol, 1.6M in hexane) were slowly added dropwise to a solution of 4.91 ml (35.0 mmol) of diisopropylamine in 45 ml of tetrahydrofuran, and the mixture was stirred at −78° C. for another 10 min and at 0° C. for another 25 min. Subsequently, at −78° C., a solution of 5.00 g (34.7 mmol) of methyl tetrahydro-2H-pyran-4-carboxylate in 45 ml of tetrahydrofuran was added, and the mixture was stirred at −78° C. for another 15 min and at 0° C. for another 30 min. At −78° C., 2.16 ml (34.7 mmol) of methyl iodide were added dropwise, and the reaction mixture was slowly warmed to −25° C. and then to room temperature overnight. The reaction was terminated by addition of 80 ml of 0.1N hydrochloric acid, and the phases were separated. The aqueous phase was extracted twice with ethyl acetate, the combined organic phases were dried over magnesium sulphate and filtered and the solvent was removed under reduced pressure. The resulting suspension was triturated with 20 ml of methyl tert-butyl ether, the precipitate was filtered off with suction and the mother liquor was concentrated under reduced pressure, giving the title compound. Yield: 5.88 g (purity 95%, quant.)
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:25])=[CH:15]/[C:16]3[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.[O:27]([CH3:39])[C@H:28]1[O:36][C@H:35]([CH2:37][OH:38])[C@@H:33]([OH:34])[C@H:31]([OH:32])[C@H:29]1[OH:30]>CCOCC.N1C=CC=CC=1>[CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:25])=[CH:15]/[C:16]3[CH:24]=[CH:23][C:19]([C:20]([O:30][C@@H:29]4[C@@H:31]([OH:32])[C@H:33]([OH:34])[C@@H:35]([CH2:37][O:38][C:20](=[O:21])[C:19]5[CH:23]=[CH:24][C:16](/[CH:15]=[C:14](/[C:6]6[CH:5]=[CH:4][C:3]7[C:2]([CH3:26])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=7[CH:7]=6)\[CH3:25])=[CH:17][CH:18]=5)[O:36][C@@H:28]4[O:27][CH3:39])=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.[CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:25])=[CH:15]/[C:16]3[CH:24]=[CH:23][C:19]([C:20]([O:32][C@H:31]4[C@H:33]([OH:34])[C@@H:35]([CH2:37][O:38][C:20](=[O:21])[C:19]5[CH:23]=[CH:24][C:16](/[CH:15]=[C:14](/[C:6]6[CH:5]=[CH:4][C:3]7[C:2]([CH3:26])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=7[CH:7]=6)\[CH3:25])=[CH:17][CH:18]=5)[O:36][C@H:28]([O:27][CH3:39])[C@@H:29]4[OH:30])=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: C/C(=C\c1ccc(C(=O)Cl)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Solvent: c1ccncc1
Solvent: CCOCC
Product: CO[C@H]1O[C@H](COC(=O)c2ccc(/C=C(\C)c3ccc4c(c3)C(C)(C)CCC4(C)C)cc2)[C@@H](O)[C@H](O)[C@H]1OC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Product: CO[C@H]1O[C@H](COC(=O)c2ccc(/C=C(\C)c3ccc4c(c3)C(C)(C)CCC4(C)C)cc2)[C@@H](O)[C@H](OC(=O)c2ccc(/C=C(\C)c3ccc4c(c3)C(C)(C)CCC4(C)C)cc2)[C@H]1O
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of 100 mmol of p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-propenyl]-benzoyl chloride in 450 ml of ether was added while stirring at 0° C. over a period of 1 hour to a solution of 19.5 g of methyl α-D-glucopyranoside in 500 ml of pyridine. The mixture was stirred at 0° C. for a further 4 hours and at room temperature for 16 hours and then evaporated to dryness. The residue was dissolved in ethyl acetate and the extract was washed with 3 N hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and water. After drying over sodium sulphate, the organic phase was evaporated and the residue was chromatographed on silica gel (hexane/ethyl acetate) to give methyl 2,6-bis-O-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-propenyl]-benzoyl]-α-D-glucopyranoside, melting point 203°-204° C. (from ethyl acetate), [α]D25 =+27.4° (c=1 in chloroform), and methyl 3,6-bis-O-[p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-propenyl]-benzoyl]-α-D-glucopyranoside, melting point 128°-129° C. (with decomposition, from methanol), [α]D25 =+135° (c=1 in chloroform).
Reaction SMILES: [Si:1]([O:8][CH:9]1[C:13]2=[CH:14][C:15]3[CH:16]=[C:17]([C:21](=[N:25]C(C)(C)C)[CH2:22][CH2:23][CH3:24])[CH:18]=[CH:19][C:20]=3[N:12]2[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:30]([C:39](OC)=[O:40])([C:35](OC)=[O:36])[C:31]([O:33][CH3:34])=[O:32]>O(C1C=CC=CC=1)C1C=CC=CC=1>[Si:1]([O:8][CH:9]1[C:13]2=[CH:14][C:15]3[CH:16]=[C:17]([C:21]4[NH:25][C:35](=[O:36])[C:30]([C:31]([O:33][CH3:34])=[O:32])=[C:39]([OH:40])[C:22]=4[CH2:23][CH3:24])[CH:18]=[CH:19][C:20]=3[N:12]2[CH2:11][CH2:10]1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: CCCC(=NC(C)(C)C)c1ccc2c(c1)cc1n2CCC1O[Si](C)(C)C(C)(C)C
Reactant: COC(=O)C(C(=O)OC)C(=O)OC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCc1c(-c2ccc3c(c2)cc2n3CCC2O[Si](C)(C)C(C)(C)C)[nH]c(=O)c(C(=O)OC)c1O
Temperature: 25 °C
Yield: 27.6 %

Procedure:
A solution of N-(1-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-7-yl)butylidene)-2-methylpropan-2-amine (3.8 g, 9.0 mmol) and trimethyl methanetricarboxylate (2.6 g. 13.5 mmol) in Ph2O (10 mL) was heated at 220° C. for 30 min. The reaction mixture was then cooled to room temperature and triturated with Et2O to afford the title compound as an off-white solid (1.2 g, 30%).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][S:3][CH2:4][CH2:5][OH:6].[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(O)COCCO>[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:4][CH3:5].[CH2:24]([O:7][CH2:1][CH2:2][S:3][CH2:4][CH2:5][OH:6])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH3:9]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: OCCSCCO
Solvent: OCCOCCO
Product: CCCCCCCCCCCCCCCCCCBr
Product: CCCCCCCCCCCCCCCCOCCSCCO

Procedure:
Following the procedure described in preparation 1, but using thiodiethylene glycol and 1-bromohexadecane, instead of diethylene glycol and 1-bromooctadecane, respectively, the title compound was obtained in a similar yield.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[F:15][C:16]([F:46])([F:45])[C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25][N:24]2[C:33](OC2C=CC([N+]([O-])=O)=CC=2)=[O:34])=[CH:19][CH:18]=1.O>C1COCC1>[CH3:9][N:8]([CH3:10])[C:6]([C:5]1[CH:11]=[CH:12][C:2]([NH:1][C:33]([N:24]2[CH2:25][CH2:26][C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:23]2[C:20]2[CH:21]=[CH:22][C:17]([C:16]([F:45])([F:15])[F:46])=[CH:18][CH:19]=2)=[O:34])=[CH:3][CH:4]=1)=[O:7]
Reactant: CN(C)C(=O)c1ccc(N)cc1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc(NC(=O)N2CCc3ccccc3[C@H]2c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-N,N-dimethylbenzamide (74 mg, 452 μmol) in THF (0.5 mL) was added sodium hydride, 60% dispersion in mineral oil (19 μL, 452 μmol). The resulting mixture was then subjected to a microwave irradiation at 150° C. for 5 min. Then, (R)-4-nitrophenyl 1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (100 mg, 226 μmol, example 88) was added and the mixture was stirred at RT for overnight. Then, H2O (0.5 mL) was added slowly and the mixture was extracted with EtOAc (2×1 mL). The combined organic extracts were dried over MgSO4 and concentrated. The residue was dissolved in DMSO (1.0 mL) and the solution mixture was then purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the desired compound, which was dissolved in MeOH (1.0 mL). Then, the solution was washed through PL-HCO3 MP-Resin (200 mg per 6 mL tube) and the resin was washed with MeOH (2×0.3 mL). The combined washings were concentrated and dried under vacuum to give the title compound as light brown solid. MS (ESI, positive ion) m/z: 468 (M+H).
Reaction SMILES: Cl[C:2]([C:6]1[C:7]([Cl:12])=[N:8][CH:9]=[CH:10][CH:11]=1)=[CH:3][C:4]#[N:5].Cl.[CH2:14]([CH:16]1[CH2:18][CH:17]1[NH2:19])[CH3:15].C(N(CC)CC)C>C(#N)C>[Cl:12][C:7]1[C:6]([C:2]([NH:19][CH:17]2[CH2:18][CH:16]2[CH2:14][CH3:15])=[CH:3][C:4]#[N:5])=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: N#CC=C(Cl)c1cccnc1Cl
Reactant: CCC1CC1N
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCC1CC1NC(=CC#N)c1cccnc1Cl
Yield: 57.3 %

Procedure:
To a solution of 3-chloro-3-(2-chloropyridin-3-yl)acrylonitrile (1.4 g, 7.03 mmol, 1 eq.) in 15 ml of acetonitrile was added 2-ethylcyclopropanamine hydrochloride (1.02 g, 8.44 mmol, 1.2 eq.) followed by triethylamine (TEA) (1.06 g, 10.55 mmol, 1.5 eq.). The reaction was microwaved (130° C., 2000 s, fixed hold, high absorption) and the solvent evaporated. The residual oil was triturated in ethyl acetate and the white solid removed by filtration. After concentration under vacuum, the residual oil was subjected to column chromatography to give 3-(2-chloropyridin-3-yl)-3-[(2-ethylcyclopropyl)amino]acrylonitrile (0.998 g, 51% yield).
Reaction SMILES: F[C:2]1[C:3]([O:12][C:13]2[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([NH2:8])[CH:7]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[OH:30]>>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][C:3]=1[O:12][C:13]1[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)c1ccc(Oc2cc([N+](=O)[O-])c(N)cc2F)cn1
Reactant: Oc1ccccc1Cl
Product: CS(=O)(=O)c1ccc(Oc2cc(N)c(N)cc2Oc2ccccc2Cl)cn1

Procedure:
The entitled compound was obtained in the same method as in Example 196 (step 4) to (step 5) or in accordance with the method or by combining it with an ordinary method but using 5-fluoro-4-(6-methanesulfonyl-pyridin-3-yloxy)-2-nitro-phenylamine obtained in Example 196 (step 3) and 2-chlorophenol.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([NH:11][C:12]2[C:13](=[O:29])[N:14]([C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:21]([O:23][CH3:24])=[O:22])[CH:15]=[CH:16][N:17]=2)[CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][Cl:39]>C(#N)C>[Cl:39][CH2:38][CH2:37][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([NH:11][C:12]2[C:13](=[O:29])[N:14]([C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:21]([O:23][CH3:24])=[O:22])[CH:15]=[CH:16][N:17]=2)[CH2:9][CH2:10]1
Reactant: COC(=O)c1ccc(C)c(-n2ccnc(NC3(c4ccccc4O)CC3)c2=O)c1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(C)c(-n2ccnc(NC3(c4ccccc4OCCCl)CC3)c2=O)c1
Temperature: 83 °C
Reaction time: 10 h

Procedure:
A solution of methyl 3-(3-(1-(2-hydroxyphenyl)cyclopropylamino)-2-oxopyrazin-1(2H)-yl)-4-methylbenzoate (Example 167c) 0.45 g) dissolved in acetonitrile (8 mL) was treated with potassium carbonate (1.589 g) and 1-bromo-2-chloroethane (0.953 mL) under nitrogen. The resulting suspension was stirred at 83° C. for 10 h.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[O:7]1[CH:9]([CH2:10][O:11][C:12]2[S:13][C:14]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH:23]([CH3:26])[CH2:24][CH3:25])=[O:18])=[CH:15][N:16]=2)[CH2:8]1.O1C(COC2SC(C(N)=O)=CN=2)C1>C(O)C>[O:4]1[CH2:5][CH2:6][N:1]([N:16]2[CH:15]=[C:14]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH:23]([CH3:26])[CH2:24][CH3:25])=[O:18])[S:13][CH:12]2[O:11][CH2:10][CH:9]([OH:7])[CH3:8])[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: CCC(C)CCCNC(=O)c1cnc(OCC2CO2)s1
Agent: NC(=O)c1cnc(OCC2CO2)s1
Solvent: CCO
Product: CCC(C)CCCNC(=O)C1=CN(N2CCOCC2)C(OCC(C)O)S1

Procedure:
This example illustrates further methods according to the invention of preparing the compounds of formula I to the invention. In this example 1 g. of morpholine is added to a solution containing 0.3 g. of 1,2-epoxy-3-(5-4'-methylhexylaminocarbonylthiazol -2-oxy)-propane in 20 ml. of anhydrous absolute ethanol at 20° C. The resulting mixture is monitored by thin-layer chromatographic analysis and allowed to stand until conversion of the 1,2-epoxy-3-(5-aminocarbonylthiazol -2-oxy)-propane is essentially complete. The mixture is then evaporated to dryness yielding a crude residue of 1-(N-morpholino-3-(5-4'-methylhexylaminocarbonylthiazol-2-oxy)-2-propanol which is then further purified by thin-layer chromatography on silica gel.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Na+].Cl[CH2:13][C:14]([OH:16])=[O:15].Cl>CS(C)=O.O>[CH2:1]([O:9][CH2:13][C:14]([OH:16])=[O:15])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OCCc1ccccc1
Reactant: O=C(O)CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)COCCc1ccccc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 75.3 %

Procedure:
To a stirred mixture of phenethyl alcohol (1.0 g, 8.18 mmol) in DMSO (16 mL) under nitrogen flow, NaH (0.39 g, 16.37 mmol) was added in one portion and the mixture was stirred at 60° C. for 10 min. Following the addition of chloroacetic acid (0.77 g, 8.18 mmol), the reaction mixture was heated at 80° C. for 3 h. The cooled mixture was then poured into H2O and the aqueous phase acidified to pH 1.0 with a 2.0 N HCl solution. The aqueous phase was then extracted with EtOAc (3×20 mL), and the combined organic phase washed with brine and dried over Na2SO4 to afford the title compound (1.11 g, 75%), which was used in the following step without further purification. 1H NMR (DMSO-d6): δ 2.83 (t, J=7.0 Hz, 2H), 3.67 (t, J=7.0 Hz, 2H), 4.00 (s, 2H), 7.15-7.32 (m, 5H), 12.64 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH:6]1[CH2:10][CH2:9][CH2:8][NH:7]1.C(=O)([O-])[O-].[K+].[K+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>O>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([N:1]2[CH2:5][CH2:4][CH2:3][CH:2]2[CH:6]2[CH2:10][CH2:9][CH2:8][N:7]2[C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C1CNC(C2CCCN2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCCC2C2CCCN2c2ccc([N+](=O)[O-])cc2)cc1
Yield: 37.5 %

Procedure:
2.6 g (˜15 mmol) of [2,2′]bipyrrolidinyl (1) obtained above were refluxed in the presence of 5 g (35.7 mmol) of potassium carbonate and 5 g (35.7 mmol) of para-fluoronitrobenzene in 25 ml of water overnight. The agglomerate formed was filtered off and then rinsed with acetone and isopropanol to give 2.15 g of a mixture of two isomers (55/45) (44%). After purification by chromatography on silica gel, a majority isomer was isolated (1.2 g), the analyses for which were:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([CH3:11])[C:3]=1[OH:12].NC1C=C(C)C(O)=C(C)C=1.C1COC2C=CC(NC3C(F)=CN=C(NC4C=CC=C(O)C=4)N=3)=CC=2O1.[Cl:49][C:50]1[N:55]=[C:54](Cl)[C:53]([F:57])=[CH:52][N:51]=1>>[Cl:49][C:50]1[N:55]=[C:54]([NH:8][C:6]2[CH:7]=[C:2]([CH3:1])[C:3]([OH:12])=[C:4]([CH3:11])[CH:5]=2)[C:53]([F:57])=[CH:52][N:51]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1O
Agent: Cc1cc(N)cc(C)c1O
Agent: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Product: Cc1cc(Nc2nc(Cl)ncc2F)cc(C)c1O

Procedure:
Using general hydrogenation conditions, 2,6-dimethyl-4-nitrophenol was reduced to 4-amino-2,6-dimethylphenol. In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 4-amino-2,6-dimethylphenol (823 mg, 6 mmol) and 2,4-dichloro-5-fluoropyrimidine (500 mg, 3 mmol) gave 2-chloro-N4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-4-pyrimidineamine. Compound 2-chloro-N4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-4-pyrimidineamine (500 mg, 1.87 mmol) and 3-(methoxycarbonylmethyleneoxy)aniline (500 mg, 2.76 mmol) reacted to give N4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine (500 mg, 65%). 1H NMR (CD3OD): δ 2.16 (s, 6H), 3.76 (s, 3H), 4.51 (s, 2H), 6.79 (ddd, J=0.9, 2.4 and 8.1 Hz, 1H), 7.01-7.06 (m, 2H), 7.15 (s, 2H), 7.26 (t, J=8.1 Hz, 1H), 7.93 (d, J=5.7 Hz, 1H); 19F NMR (282 MHz, CD3OD): δ −163.31; LCMS: ret. time: 20.44 min.; purity: 84.25%; MS (m/e): 413.03 (MH+).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[CH:6]([C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:12]=[C:11]([CH:18]([CH3:20])[CH3:19])[CH:10]=1)([CH3:8])[CH3:7].[C:21](O)(=[O:23])[CH3:22]>S(=O)(=O)(O)O>[C:21]([O:3][CH:2]([C:12]1[C:13]([CH:15]([CH3:17])[CH3:16])=[CH:14][C:9]([CH:6]([CH3:8])[CH3:7])=[CH:10][C:11]=1[CH:18]([CH3:20])[CH3:19])[C:1]([OH:5])=[O:4])(=[O:23])[CH3:22]
Reactant: O=CC(=O)O
Reactant: CC(=O)O
Reactant: CC(C)c1cc(C(C)C)cc(C(C)C)c1
Agent: O=S(=O)(O)O
Product: CC(=O)OC(C(=O)O)c1c(C(C)C)cc(C(C)C)cc1C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Glyoxylic acid (1.99 g, 27 mmol) and 1,3,5-triisopropylbenzene (5.0 g, 24.5mmol) were mixed in 30 mL glacial acetic acid and 2 mL concentrated sulfuric acid. The resulting solution was heated to reflux for 5 hours andthen stirred at room temperature for 16 hours. The reaction mixture was poured into 100 g ice and the resulting mixture was extracted with diethylether. The organic layer was dried over MgSO4, filtered, and concentrated to give an oily solid which was recrystallized from hexanes to give 3.29 g of acetyloxy[2,4,6-tris(1-methylethyl)phenyl]acetic acid, mp 166°-169° C.