Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N:11]2[N:20]=[CH:19][C:18]3[C:13](=[C:14]([F:25])[CH:15]=[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:17]=3)[C:12]2=[O:26])[C:3]=1[CH:4]=[O:5].[CH3:27][N:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([NH:43][C:44]2[CH:49]=[CH:48][C:47]([N:50]3[CH2:55][CH2:54][N:53]([CH:56]4[CH2:59][O:58][CH2:57]4)[CH2:52][C@@H:51]3[CH3:60])=[CH:46][N:45]=2)[C:29]1=[O:61].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C1COCC1>[C:21]([C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([F:25])[CH:15]=1)[C:12](=[O:26])[N:11]([C:6]1[CH:7]=[C:8]([F:10])[CH:9]=[C:2]([C:32]3[CH:31]=[C:30]([NH:43][C:44]4[CH:49]=[CH:48][C:47]([N:50]5[CH2:55][CH2:54][N:53]([CH:56]6[CH2:57][O:58][CH2:59]6)[CH2:52][C@@H:51]5[CH3:60])=[CH:46][N:45]=4)[C:29](=[O:61])[N:28]([CH3:27])[CH:33]=3)[C:3]=1[CH:4]=[O:5])[N:20]=[CH:19]2)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cc(F)cc(Br)c3C=O)ncc2c1
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(B3OC(C)(C)C(C)(C)O3)cn(C)c2=O)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3C=O)cn(C)c2=O)nc1
Temperature: 100 °C
Yield: 49.1 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 2-bromo-6-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-fluorobenzaldehyde 102b (100 mg, 0.24 mmol), (S)-1-methyl-3-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 105f (115 mg, 0.24 mmol), PdCl2(dppf) (22 mg, 0.03 mmol), K3PO4 (102 mg, 0.48 mmol), sodium acetate (39 mg, 0.48 mmol), THF (15 mL), and water (5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 2 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 40:1 dichloromethane/methanol to afford 104a as a yellow solid (82 mg, 49%). MS: [M+H]+ 696.3
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:33])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][C:16]3[C:17](=[O:28])[C:18]([O:26][CH3:27])=[C:19]([O:24][CH3:25])[C:20](=[O:23])[C:21]=3[CH3:22])[C:10]=2[O:29]C(=O)C)[CH:2]=1.C(=O)([O-])O.[Na+]>CO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:33])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][C:16]3[C:17](=[O:28])[C:18]([O:26][CH3:27])=[C:19]([O:24][CH3:25])[C:20](=[O:23])[C:21]=3[CH3:22])[C:10]=2[OH:29])[CH:2]=1
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)Nc3cccnc3)c2OC(C)=O)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)Nc3cccnc3)c2O)=C(C)C1=O
Yield: 64.4 %

Procedure:
N-(Pyridin-3-yl)-3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide (0.060 g, 0.133 mmol) was dissolved in methanol (2 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (1.5 ml), the solution was stirred at room temperature for 2 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (ethyl acetate:hexane=4:1) and then recrystallized from methanol to obtain the titled compound (0.035 g, 0.0857 mmol, 64%).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13](Cl)(=[O:15])=[O:14].[NH2:18][C:19]1[C:20]([O:27][CH3:28])=[N:21][C:22]([O:25][CH3:26])=[N:23][CH:24]=1>N1C=CC=CC=1>[CH3:1][N:2]([CH3:17])[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[S:13]([NH:18][C:19]1[C:20]([O:27][CH3:28])=[N:21][C:22]([O:25][CH3:26])=[N:23][CH:24]=1)(=[O:15])=[O:14]
Reactant: COc1ncc(N)c(OC)n1
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Solvent: c1ccncc1
Product: COc1ncc(NS(=O)(=O)c2cccc3c(N(C)C)cccc23)c(OC)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
5-Dimethylamino-1-naphthalenesulphonyl chloride (0.296 g) and 5-amino-2,4-dimethoxypyrimidine (0.155 g) were mixed together as solids. Pyridine (10 mls) was added and the solution was stirred at 0° C. for 30 minutes. The mixture was then heated at 80° C. for 5 hours. Volatile material was removed by evaporation and the residue was purified by elution with dichloromethane through a silica gel Mega Bond Elut column to give 5-dimethylamino-N-(2,4-dimethoxy-5-pyrimidinyl)-1-naphthalenesulphonamide (0.28 g), m.p. 201° C.; 1H NMR (d6 -DMSO): 2.85 (s, 6H), 3.1 (s, 3H), 3.8 (s, 3H), 7.3 (d, 1H), 7.55 (q, 2H); 7.95 (d, 1H), 8.05 (s, 1H), 8.30 (d, 1H), 8.48 (d, 1H), 9.85 (s, 1H); mass spectrum (+ve CI): 389 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:14]([CH2:22][CH2:23][N:24]=3)[C:15]([NH2:21])=[N:16][C:17]=2[C:18]=1[O:19][CH3:20])[C:2]1[CH:7]=CC=CC=1.ClCCC[S:29]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)(=[O:31])=[O:30]>>[CH3:20][O:19][C:18]1[C:17]2[N:16]=[C:15]([NH2:21])[N:14]3[CH2:22][CH2:23][N:24]=[C:13]3[C:12]=2[CH:11]=[CH:10][C:9]=1[O:8][CH2:1][CH2:2][CH2:7][S:29]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)(=[O:31])=[O:30]
Reactant: O=S(=O)(CCCCl)N1CCOCC1
Reactant: COc1c(OCc2ccccc2)ccc2c1N=C(N)N1CCN=C21
Product: COc1c(OCCCS(=O)(=O)N2CCOCC2)ccc2c1N=C(N)N1CCN=C21

Procedure:
The procedure used for the preparation of Example 1 was used to prepare the title compound from 5-amino-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-ol bistrifluoroacetate salt (Intermediate A) and 4-[(3-chloropropyl)sulfonyl]morpholine (Intermediate E). High vacuum drying gave the title compound (100%): 1H NMR (DMSO-d6+2 drops TFA-d) δ: 2.17-2.22 (2H, m), 3.14-3.17 (4H, m), 3.22-3.27 (2H, m), 3.61-64 (4H, m), 3.83 (3H, s), 4.16-4.20 (2H, m), 4.28-4.35 (4H, m), 7.30 (1H, d), 7.89 (1H, d).
Reaction SMILES: C([O:3][C:4](=[O:49])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([F:34])[CH:29]=3)[CH:25]=[C:24]([C:35]3[CH:40]=[CH:39][N:38]=[C:37]([F:41])[CH:36]=3)[CH:23]=2)[C:10]=1[CH2:42][CH2:43][C:44]([O:46]CC)=[O:45])C>[OH-].[Na+]>[F:41][C:37]1[CH:36]=[C:35]([C:24]2[CH:23]=[C:22]([CH:27]=[C:26]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([F:34])[CH:29]=3)[CH:25]=2)[O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]2[C:10]([CH2:42][CH2:43][C:44]([OH:46])=[O:45])=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:49])=[O:3])[CH:40]=[CH:39][N:38]=1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccnc(F)c3)cc(-c3ccnc(F)c3)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(-c3ccnc(F)c3)cc(-c3ccnc(F)c3)c2)c1CCC(=O)O
Yield: 55.6 %

Procedure:
A similar procedure as described in Example 1, step 3 was used, starting from 4-[3-{6-[3,5-bis-(2-fluoro-pyridin-4-yl)-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (220 mg, 0.32 mmol) and 1.0 N aqueous NaOH (10 mL) to afford 4-[3-{6-[3,5-bis-(2-fluoro-pyridin-4-yl)-phenoxy]-hexyl}-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (110 mg, 56%) as an amorphous white solid: ES(+)-HRMS m/e calculated for C35H36F2N2O6 (M+H)+ 619.2614, found 619.2615.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([OH:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][C:19]([O:21]C)=[O:20].[OH-].[K+]>O.C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]2[CH:6]=[C:18]([C:19]([OH:21])=[O:20])[O:10][C:4]=2[CH:3]=1
Reactant: COC(=O)CCl
Reactant: O=Cc1ccc(Br)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2ccc(Br)cc2o1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
8.0 g (39.8 mmol) of 4-bromo-2-hydroxybenzaldehyde and 1.47 g (3.98 mmol) of tetra-N-butylammonium iodide are, together with 22 g (159.19 mmol) of anhydrous potassium carbonate, initially charged. 9.07 g (83.57 mmol) of methyl chloroacetate are added. The reaction mixture is heated at 130° C. for 4 h and then cooled to 0° C. using an ice bath. 100 ml of THF and 13.4 g (238.8 mmol) of potassium hydroxide in 50 ml of water are added and the mixture is then stirred at RT overnight. The solvent is removed under reduced pressure. The residue is diluted with water and acidified with conc. hydrochloric acid. The product is filtered off and dried under high vacuum. For fine purification, the product is purified on silica gel 60 (mobile phase: toluene→toluene/acetic acid 50:1→toluene/ethyl acetate/acetic acid 35:5:1). The solvent is removed under reduced pressure. 3.8 g (40% of theory) of the title compound are isolated.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.[I-].[K+].[CH2:22]([O:24][C:25](=[O:36])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=[O:35])[CH3:34])[CH:27]=1)[CH3:23].[H-].[Na+]>C(C(C)=O)C.CS(C)=O.O>[CH2:22]([O:24][C:25](=[O:36])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]([C:33](=[O:35])[CH3:34])[CH2:2][CH2:3][CH2:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][CH2:8][C:7]3[CH:16]=[CH:17][CH:18]=[CH:19][C:6]2=3)[CH:27]=1)[CH3:23]
Reactant: CCOC(=O)c1cccc(NC(C)=O)c1
Reactant: ClCCCN1c2ccccc2CCc2ccccc21
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCC(C)=O
Product: CCOC(=O)c1cccc(N(CCCN2c3ccccc3CCc3ccccc32)C(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-(3-chloropropyl)-10,11-dihydro-5H-dibenz[b,f]azepine (1.5 g, 0.0055 mol, prepared similarly as described in example 2) and potassium iodide (5.4 g, 0.0327 mol) in methyl ethyl ketone (100 ml) was heated at reflux temperature for 1 h and then stirred at room temperature overnight. The mixture was filtered and the solvent evaporated in vacuo. The crude halogenide was dissolved in dry dimethyl sulfoxide (15 ml) and kept. A solution of 3-acetylaminobenzoic acid ethyl ester (1.5 g, 7.4 mmol) in dry dimethyl sulfoxide (15 ml) was heated to 50° C. and sodium hydride (0.32 g, 8.1 mmol, 60% oil dispersion) was added in portions. The resulting mixture was heated at 120° C. for 2.5 h, and the mixture was allowed to cool to 80° C. before the above solution containing the halogenide was added. The resulting mixture was heated at 115-120° C. overnight and then allowed to cool to room temperature. Water (100 ml) was added and the resulting mixture was extracted with dichloromethane (3×200 ml). The organic extracts were discarded and pH of the aqueous phase was adjusted to 7. The aqueous phase was extracted with ethyl acetate (100 ml) and dichloromethane (2×100 ml), and the combined organic extracts were dried (MgSO4). The volatiles were removed in vacuo to give a residue which was purified by flash chromatography on silica gel (200 g) using ethyl acetate as eluent, affording 1.0 g of 3-(N-acetyl-N-(3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)-1-propyl)-amino)benzoic acid ethyl ester as an oil.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([C@@H:9]1[C@@H:14]([OH:15])[C@H:13]([OH:16])[C@@H:12]([CH2:17][OH:18])[O:11][C@@:10]1([NH2:53])[N:19]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:20](=[O:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[C:54]([O:58][C:59]([NH:61][CH2:62][C:63](O)=[O:64])=[O:60])([CH3:57])([CH3:56])[CH3:55]>O1CCCC1>[C:54]([O:58][C:59]([NH:61][CH2:62][C:63]([NH:1][C@H:2]([C:7]([C@@H:9]1[C@@H:14]([OH:15])[C@H:13]([OH:16])[C@@H:12]([CH2:17][OH:18])[O:11][C@@:10]1([NH2:53])[N:19]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:20](=[O:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6])=[O:64])=[O:60])([CH3:57])([CH3:56])[CH3:55]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@@H](N)CC(C)C
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](CC(C)C)NC(=O)CNC(=O)OC(C)(C)C
Yield: 79 %

Procedure:
from N-(2-L-leucyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-oleamide and N-tert-butyloxycarbonyl-glycine. Yield 79%. [α]D =-1.4° (c=0.87, tetrahydrofuran).
Reaction SMILES: BrP(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2:22][C:23]1[C:24]([C:40]([OH:42])=O)=[N:25][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35](=[O:39])[N:36]([CH3:38])[CH3:37])=[CH:31][CH:30]=2)=[CH:27][N:28]=1.[O:43]1[CH:47]=[CH:46][CH:45]=[C:44]1[C:48]([NH:50][NH2:51])=O.CCN(C(C)C)C(C)C>C(#N)C>[NH2:22][C:23]1[N:28]=[CH:27][C:26]([C:29]2[CH:30]=[CH:31][C:32]([C:35]([N:36]([CH3:37])[CH3:38])=[O:39])=[CH:33][CH:34]=2)=[N:25][C:24]=1[C:40]1[O:42][C:48]([C:44]2[O:43][CH:47]=[CH:46][CH:45]=2)=[N:50][N:51]=1
Reactant: NNC(=O)c1ccco1
Reactant: CN(C)C(=O)c1ccc(-c2cnc(N)c(C(=O)O)n2)cc1
Agent: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccco4)o3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.3 %

Procedure:
Dibromo(triphenyl)phosphorane was added to a solution of 3-amino-6-[4-(dimethylcarbamoyl)phenyl]pyrazine-2-carboxylic acid (100 mg, 0.35 mmol) and furan 2-carbohydrazide (44.1 mg, 0.35 mmol) in acetonitrile (3.0 mL) at room temperature. Bright yellow solution observed. The resulting solution was stirred at room temperature for 30 min. After this time, DIPEA (304 μL, 1.75 mmol) was added dropwise and the reaction mixture stirred at room temperature for 30 min. The reaction mixture was filtered to leave a yellow solid. The solid was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. Product fractions were freeze dried to give the product as a yellow solid (67.6 mg, 51% yield); 1H NMR (400.0 MHz, DMSO) d 2.97 (m, 6H), 6.87 (m, 1H), 7.54-7.56 (m, 3H), 7.57 (br s, 2H), 8.15 (m, 3H) and 8.98 (1H, s) ppm; MS (ES+) 377.17
Reaction SMILES: [OH:1][C:2]1[C:3]([I:19])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[N:6]=[CH:5]2.[C:20]([CH:24]1[CH2:29][CH2:28][CH:27](OS(C)(=O)=O)[CH2:26][CH2:25]1)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+].C(O)(C)(C)C.CC(=O)CC>C(Cl)Cl>[C:20]([C@H:24]1[CH2:29][CH2:28][C@H:27]([O:1][C:2]2[C:3]([I:19])=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([C@:12]2([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]2)[N:6]=[CH:5]3)[CH2:26][CH2:25]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: C[C@@]1(c2ncc3c(I)c(O)ccc3n2)COC(=O)N1
Reactant: CC(C)(C)C1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)(C)O
Solvent: ClCCl
Solvent: CCC(C)=O
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc([C@]4(C)COC(=O)N4)ncc3c2I)CC1
Temperature: 80 °C

Procedure:
(R)-4-(6-Hydroxy-5-iodo-quinazolin-2-yl)-4-methyl-oxazolidin-2-one (350.0 mg, 0.0009431 mol), methanesulfonic acid 4-tert-butyl-cyclohexyl ester (884.0 mg, 0.003772 mol) and cesium carbonate (921.8 mg, 0.002829 mol) were dissolved in a mixture of tert-butyl alcohol (19.9 mL, 0.208 mol) and 2-butanone (6.6 mL, 0.074 mol). The reaction mixture was heated at 80° C. for 1 hour (MW), an additional methanesulfonic acid 4-tert-butyl-cyclohexyl ester (500 mg) was added, and the mixture was heated at 80° C. for an additional for 1 hour. LC/MS indicated that reaction was completed. Removal of solvents gave a solid mixture, which was treated with DCM and filtered. The filtrate was then washed with water, brine and dried over Na2SO4. The crude mixture was then purified via chromatography (SiO2, 24 gm, 0-100% ethyl acetate/hexanes) to give 451 mg desired product (94%). 1H NMR (CHLOROFORM-d) δ: 9.55 (s, 1H), 7.94 (d, J=9.3 Hz, 1H), 7.61 (d, J=9.3 Hz, 1H), 6.07 (s, 1H), 5.16 (d, J=8.8 Hz, 1H), 4.50 (d, J=8.8 Hz, 1H), 4.24-4.42 (m, 1H), 2.24 (d, J=12.0 Hz, 2H), 1.92 (d, J=9.5 Hz, 2H), 1.76 (s, 3H), 1.63 (d, J=11.3 Hz, 1H), 1.22-1.39 (m, 2H), 1.15 (br. s., 2H), 0.81-0.98 (m, 9H). MS (M+1): 510.10.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([OH:12])=[O:11])[CH2:3]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[F:36][C:37]1[CH:38]=[C:39]([CH:43]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[CH:46]=2)O)[CH:40]=[CH:41][CH:42]=1>CN(C=O)C.O>[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([C:10]([O:12][CH:43]([C:39]1[CH:40]=[CH:41][CH:42]=[C:37]([F:36])[CH:38]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[CH:46]=1)=[O:11])[CH2:3]2
Reactant: OC(c1cccc(F)c1)c1cccc(F)c1
Reactant: O=C(O)C1CN2CCC1CC2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OC(c1cccc(F)c1)c1cccc(F)c1)C1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
Quinuclidine-3-carboxylic acid hydrochloride (817 mg, 4.26 mmol), EDC (1.23 g, 6.39 mmol), and HOBT (979 mg, 6.39 mmol) were dissolved in dry DMF (40 ml). DIPEA (2.61 ml, 14.9 mmol) and bis(3-fluorophenyl)methanol (1.03 mg, 4.69 mmol) were added, and the mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted several times with Et2O. The organic phases were collected and washed with brine, dried (Na2SO4), filtered, and evaporated. The residue was purified by flash chromatography (DCM/MeOH=9/1) to obtain bis(3-fluorophenyl)methyl quinuclidine-3-carboxylate (874 mg, racemic mixture).
Reaction SMILES: NC1C(N[C@@H]2CC[C@H](C(NC(C)C)=O)CC2)=CC(OCCN2CCCCC2)=NC=1.[OH:30][C:31]([CH:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:45]=[C:44]([NH:46][C@@H:47]3[CH2:52][CH2:51][C@H:50]([C:53]([NH:55][CH:56]([CH3:58])[CH3:57])=[O:54])[CH2:49][CH2:48]3)[C:43]([N+:59]([O-])=O)=[CH:42][N:41]=2)[CH2:36][CH2:35]1)([CH3:33])[CH3:32]>>[NH2:59][C:43]1[C:44]([NH:46][C@@H:47]2[CH2:52][CH2:51][C@H:50]([C:53]([NH:55][CH:56]([CH3:58])[CH3:57])=[O:54])[CH2:49][CH2:48]2)=[CH:45][C:40]([N:37]2[CH2:36][CH2:35][CH:34]([C:31]([OH:30])([CH3:33])[CH3:32])[CH2:39][CH2:38]2)=[N:41][CH:42]=1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(N3CCC(C(C)(C)O)CC3)ncc2[N+](=O)[O-])CC1
Agent: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(OCCN3CCCCC3)ncc2N)CC1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(N3CCC(C(C)(C)O)CC3)ncc2N)CC1

Procedure:
The title compound was synthesized using a method analogous to the preparation of cis-4-(5-amino-2-(2-(piperidin-1-yl)ethoxy)pyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide starting from cis-4-(2-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide (yellow solid). MS m/z=418.2 [M+H], calc 417.59 for C23H39N5O2.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.O.O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].S(=O)(=O)(O)O>O>[Cl:1][CH2:2][C:3](=[O:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1
Reactant: OC(CCl)COc1ccc(Cl)cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(CCl)COc1ccc(Cl)cc1
Reaction time: 48 h

Procedure:
To a stirred suspension of 44.2 parts of 1-chloro3-(p-chlorophenoxy)-2-propanol in 75 parts of water are added 32.3 parts of sodium dichromate dihydrate. Then there is added dropwise, during a 5 hour-period, a solution of 45 parts of sulfuric acid in 25 parts of water at a temperature <30° C. Upon completion, stirring is continued for 48 hours. The reaction mixture is poured onto water and the product is extracted twice with diisopropyl ether. The combined extracts are washed three times with water, dried, filtered and evaporated. The residue solidifies on scratching in ether. The solid product is crystallized from diisopropyl ether, yielding 25.2 parts of 1-chloro-3-(p-chlorophenoxy)-2-propanone.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH2:17]([O:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]1[CH2:34][CH2:35][CH2:36][C:37](=O)[C:29]1=[CH:28]2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[NH4+].[Cl-]>CN(C=O)C>[CH2:17]([O:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]1[CH2:34][CH2:35][CH2:36][C:37](=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:29]1=[CH:28]2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1CCCn2c1cc1cc(OCc3ccccc3)ccc12
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)C=C1CCCn2c1cc1cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86 %

Procedure:
To a solution of ethyl 2-(diethoxyphosphoryl)acetate (3.11 mL, 15.65 mmol) in DMF (10 mL) was added sodium hydride (60% dispersion in mineral oil) (626 mg, 15.65 mmol) at 0° C. The reaction was slowly warmed to room temperature and stirred for 10 min. 2-(Benzyloxy)-7,8-dihydropyrido[1,2-a]indol-9(6H)-one (570 mg, 1.956 mmol) in DMF was added. The reaction was heated at 65° C. for 2 h, cooled down, poured into saturated NH4Cl aqueous solution, and extracted with ethyl acetate. The combined organics were washed with water, dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography to give the title compound (608 mg). LCMS m/z=362.5 [M+H]+.
Reaction SMILES: O[CH2:2][C:3]([NH:6][C:7]([C:9]1[C:10]2[C:23]3[C:22]([C:24]([NH:26][C:27]([CH3:31])([CH2:29][OH:30])[CH3:28])=O)=[CH:21][CH:20]=[CH:19][C:18]=3[O:17][CH2:16][O:15][C:12]3([O:32][CH2:33][O:34][C:11]=23)[CH2:13][CH:14]=1)=[O:8])([CH3:5])[CH3:4]>S(Cl)(Cl)=O>[CH2:33]1[O:34][C:11]2[C:10]([C:23]3[C:18]4[O:17][CH2:16][O:15][C:19]=4[CH:20]=[CH:21][C:22]=3[C:24]3[O:30][CH2:29][C:27]([CH3:28])([CH3:31])[N:26]=3)=[C:9]([C:7]3[O:8][CH2:2][C:3]([CH3:4])([CH3:5])[N:6]=3)[CH:14]=[CH:13][C:12]=2[O:32]1
Reactant: CC(C)(CO)NC(=O)C1=CCC23OCOC2=C1c1c(cccc1C(=O)NC(C)(C)CO)OCO3
Solvent: O=S(Cl)Cl
Product: CC1(C)COC(c2ccc3c(c2-c2c(C4=NC(C)(C)CO4)ccc4c2OCO4)OCO3)=N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
N,N'-Bis(3-hydroxy-2-methylpropan-2-yl)-5,6-methylenedioxy-5,6'-methylenedioxy-2,2'-biphenyldicarboxamide (3 g) is added to thionyl chloride (20 ml), and the mixture is stirred at room temperature for 2 hours. The reaction mixture is distilled under reduced pressure to remove thionyl chloride, and the residue is dissolved in ethyl acetate. The solution is washed, dried and distilled to remove the solvent, and the residue is crystallized from diisopropyl ether to give 5,6-methylenedioxy-5',6'-methylenedioxy-2,2'-bis(4,4-dimethyl-4,5-dihydro-2-oxazolyl)biphenyl (2 g) as colorless crystal. M.p. 152°-154° C.
Reaction SMILES: CO[C:3](=[NH:34])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([S:20](=[O:33])(=[O:32])[NH:21][CH2:22][C:23]3[C:28]([F:29])=[CH:27][CH:26]=[C:25]([F:30])[C:24]=3[F:31])=[CH:16][CH:15]=2)=[O:12])[CH:5]=1.[NH3:35].CO>>[F:31][C:24]1[C:25]([F:30])=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[CH2:22][NH:21][S:20]([C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:11](=[O:12])[NH:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([NH2:35])=[NH:34])=[CH:15][CH:16]=1)(=[O:32])=[O:33]
Reactant: COC(=N)c1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3c(F)ccc(F)c3F)cc2)c1
Reactant: N
Solvent: CO
Product: N=C(N)c1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3c(F)ccc(F)c3F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-{3-[4-(2,3,6-Trifluorobenzylsulfamoyl)-phenyl]-ureido}-benzimidic acid methyl ester (250 mg, 0.5 mmol) was dissolved in NH3/MeOH (15 ml, 7 M). The solution was stirred overnight at rt. Further 10 ml of NH3/MeOH (7 M) were added and the mixture stirred for 3 h at 65° C. The solvents were evaporated and the solid residue purified by flash chromatography on silica gel with a gradient of AcOEt and MeOH. The fractions with the desired product were collected, evaporated and the product crystallized from MeOH/Et2O. Yield 50%.