Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][C:7]1[CH:61]=[CH:60][C:10]([CH2:11][C:12]2[CH:13]=[C:14]([C@@:19]3(OC)[C@H:24]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@@H:23]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C@H:22]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C@@H:21]([CH2:49][O:50][CH2:51][C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[O:20]3)[CH:15]=[CH:16][C:17]=2[Cl:18])=[CH:9][CH:8]=1)[CH:2]=[CH2:3].C([SiH](CC)CC)C.B(F)(F)F.O>C(Cl)Cl>[CH2:1]([O:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][C:12]2[CH:13]=[C:14]([C@H:19]3[C@H:24]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@@H:23]([O:33][CH2:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C@H:22]([O:41][CH2:42][C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[C@@H:21]([CH2:49][O:50][CH2:51][C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[O:20]3)[CH:15]=[CH:16][C:17]=2[Cl:18])=[CH:60][CH:61]=1)[CH:2]=[CH2:3]
Reactant: C=CCOCCc1ccc(Cc2cc([C@]3(OC)O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: O
Solvent: ClCCl
Product: C=CCOCCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Reaction time: 3 h
Yield: 60 %

Procedure:
(2S,3R,4S,5R,6R)-2-(3-(4-(2-(allyloxy)ethyl)benzyl)-4-chlorophenyl)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-2-methoxytetrahydro-2H-pyran (intermediate BJ) (55 mg, 0.065 mmol) was taken up in 1 mL anhydrous DCM kept under argon, and triethylsilane (31.4 μL, 0.197 mmol) was added. The mixture was brought to −20° C. and borontrifluoride diethyletherate (20.1 μL, 0.164 mmol) was added. The mixture was allowed to warm and stirred at −5° C. to 0° C. for 3 h. Water (0.5 mL) was added to quench the reaction and the organic layer was separated. The aqueous layer was extracted with DCM (1 mL), and the combined organic solution was washed with brine (1 mL), dried (Na2SO4), filtered and evaporated. Preparative TLC using 10:1 hexane:EtOAc gave intermediate BK (39.5 mg, yield 60%). 1H NMR (300 MHz, CDCl3): δ 7.30-7.03 (m, 27H), 5.90 (m, 1H), 5.22 (m, 2H), 4.88-4.70 (m, 3H), 4.65-4.38 (m, 5H), 4.16-4.08 (m, 3H), 4.05-3.88 (m, 4H), 3.82-3.72 (m, 5H), 3.60-3.52 (m, 3H); LC-ESI-MS (m/z): 808 (M+H).
Reaction SMILES: [I:1]I.[CH2:3]([C:5]1[NH:6][C:7]([CH2:12][CH3:13])=[CH:8][C:9](=[O:11])[CH:10]=1)[CH3:4].[OH-].[Na+]>O>[CH2:3]([C:5]1[NH:6][C:7]([CH2:12][CH3:13])=[CH:8][C:9](=[O:11])[C:10]=1[I:1])[CH3:4]
Reactant: CCc1cc(=O)cc(CC)[nH]1
Reactant: II
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1cc(=O)c(I)c(CC)[nH]1
Reaction time: 1 h
Yield: 36.9 %

Procedure:
Iodine (720 mg) was added to a solution of compound F (430 mg) and sodium hydroxide (120 mg) in water (15 ml) and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration and purified by flash chromatography, eluting with methanol/dichloromethane (1:19 v/v), to give 2,6-diethyl-3-iodo-4(1H)pyridone (G) (290 mg), m.p. 225°-227° C.; NMR (d6 -DMSO): 1.15(t, 6H), 2.5(q, 2H), 2.8(q, 2H), 5.9(s, 1H), 11.4(br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][C:37]1[CH:38]=[N:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=1)[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([N:16]3[CH2:19][C:18]4([CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)[CH2:17]3)=[CH:15][C:10]=2[N:9]=[CH:8]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH2:36][C:37]1[CH:38]=[N:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=1)[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([N:16]3[CH2:19][C:18]4([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH2:17]3)=[CH:15][C:10]=2[N:9]=[CH:8]1
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(N5CC6(CCN(C(=O)OC(C)(C)C)CC6)C5)ccc43)cc2OC)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(COc2ccc(Cn3cnc4cc(N5CC6(CCNCC6)C5)ccc43)cc2OC)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
To a stirred solution of tert-butyl 2-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (0.53 g, 0.88 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (5.0 mL. 64.90 mmol). The reaction mixture was allowed to stir at room temperature. After 1 h, the mixture was concentrated, and the residue partitioned between 3 M ammonium hydroxide solution and dichloromethane. The phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and concentrated. Chromatographic purification (Combi-Flash, 40 g SiO2 gold column, 1-15% methanol/dichloromethane elute) afforded 0.28 g (64%) of the product as a solid: 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J=2.1 Hz, 1H), 7.80 (s, 1H), 7.65 (dd, J=8.5, 2.4 Hz, 1H), 7.10 (d, J=8.6 Hz, 1H), 6.88-6.79 (m, 2H), 6.78-6.65 (m, 3H), 6.47 (dd, J=8.6, 2.1 Hz, 1H), 5.18 (s, 2H), 5.00 (s, 2H), 3.92 (s, 3H), 3.75 (s, 3H), 3.61 (s, 4H), 2.86-2.78 (m, 4H), 2.54 (b, 1H), 1.82-1.74 (m, 4H) ppm; (M+1)=500.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][NH2:14]>>[NH:13]([C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[NH2:14]
Reactant: Cc1cc(Cl)nc2ccccc12
Reactant: NN
Product: Cc1cc(NN)nc2ccccc12

Procedure:
A solution of 2-chloro-4-methylquinoline (1.00 g, 5.63 mmol) in NH2NH2 was reacted as outlined in Scheme 1 above to give the title compound which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([NH2:7])[CH:3]=1.[NH:8](C(OC(C)(C)C)=O)[CH2:9][CH2:10][C:11](O)=[O:12]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[NH2:8][CH2:9][CH2:10][C:11]([NH:7][C:4]1[CH:3]=[C:2]([CH3:1])[O:6][N:5]=1)=[O:12]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: Cc1cc(N)no1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1cc(NC(=O)CCN)no1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of DMAP (9.77 g, 0.08 mol), TEA (55.23 ml, 0.396 mol) and DCI (49.01 ml, 0.317 mol) in DCM (250 ml) is treated with 5-methyl-isoxazole-3-ylamine (28.8 g, 0.290 mol) and Boc-Beta-Ala-OH (50 g, 0.264 mol). The reaction mixture is stirred at room temperature for 18 hours and then diluted with DCM (1750 ml). The mixture is washed with 10% citric acid (2×500 ml), saturated sodium hydrogen carbonate solution (2×500 ml) and brine (600 ml). The organic portion is dried (MgSO4), concentrated in vacuo and the crude residue is stirred with iso-hexanes (750 ml) for 1 hour. The resulting solid is dissolved in dioxane (400 ml) and treated with 4M HCl in dioxane (350 ml). After 1 hour the precipitate is filtered and washed with dioxane (100 ml) to afford the title compound as the hydrochloride salt [MH+169.84].
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:11]1([C:14]2[N:19]=[CH:18][C:17]([CH:20]([CH2:23][C:24]3([C:27]([F:30])([F:29])[F:28])[CH2:26][CH2:25]3)[CH2:21][NH2:22])=[CH:16][CH:15]=2)[CH2:13][CH2:12]1>>[CH:11]1([C:14]2[N:19]=[CH:18][C:17]([CH:20]([CH2:23][C:24]3([C:27]([F:30])([F:28])[F:29])[CH2:26][CH2:25]3)[CH2:21][NH:22][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])=[CH:16][CH:15]=2)[CH2:12][CH2:13]1
Reactant: NCC(CC1(C(F)(F)F)CC1)c1ccc(C2CC2)nc1
Reactant: O=C(O)c1ccccc1F
Product: O=C(NCC(CC1(C(F)(F)F)CC1)c1ccc(C2CC2)nc1)c1ccccc1F

Procedure:
From 2-fluorobenzoic acid and 2-(6-cyclopropyl-pyridin-3-yl)-3-(1-trifluoromethyl-cyclopropyl)-propylamine. LCMS (MH+): m/z=407.1, tR (minutes, Method G)=2.01
Reaction SMILES: [C:1]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])C)=[CH:10][CH:9]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3].C([O-])(=O)C=C>>[C:1]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH:15]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[CH:12][CH:13]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCc1ccc(OC(C)OCCCC)cc1
Agent: C=CC(=O)[O-]
Product: C=C(C)C(=O)OCc1ccc(OC2CCCCO2)cc1

Procedure:
4-(1-butoxyethoxy)benzyl methacrylate (or acrylate), and
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:4][C:3]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23].C([Li])CCC.C[O:30]B(OC)OC.[OH-].[Na+].OO>CCOCC.O>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[O:15][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[OH:30])[N:8]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:7]=[CH:6]2
Reactant: COB(OC)OC
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(Br)cc21
Agent: OO
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(O)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
(15d; prepared according to Example 110, Steps A-E: 6-Bromo-5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazole (1.36 g, 3.6 mmol) was dissolved in dry ether (17.5 mL) and cooled to −78° C. n-Butyl lithium (1.7 mL of 2.5 M in hexane) was added dropwise over 10 minutes and the mixture was stirred for 30 minutes. Trimethylborate (6 mL, 53.5 mmol) was added drop-wise over 10 minutes and the reaction mixture was allowed to warm to room temperature and stir for 18 hours. The mixture was cooled to −10° C. and 2N NaOH (3.6 mL) and water (3 mL) were added followed by H2O2 (3.6 mL) and 2N NaOH (3.6 mL). The reaction mixture was stirred at room temperature for 2 hours when white precipitate formed. Water (3 mL), 4N NaOH (4 mL), and H2O2 (1 mL) was added and the mixture stirred for another 20 minutes. The mixture was then diluted with ether and the layers separated. The aqueous layer was washed with ether, acidified and then extracted with ether (2×). The combined ether extracts were washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to afford 0.465 g product (41% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH2:13][CH3:14])[C:3]([OH:12])([C:6]1[CH:7]=[N:8][CH:9]=[N:10][CH:11]=1)[C:4]#[CH:5].I[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>C(#N)C>[OH:12][C:3]([C:6]1[CH:11]=[N:10][CH:9]=[N:8][CH:7]=1)([C:2]([CH3:15])([CH3:1])[CH2:13][CH3:14])[C:4]#[C:5][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: Ic1cccnc1
Reactant: C#CC(O)(c1cncnc1)C(C)(C)CC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCC(C)(C)C(O)(C#Cc1cccnc1)c1cncnc1
Temperature: 65 °C
Reaction time: 0.67 h
Yield: 128 %

Procedure:
A stirred mixture of 4,4-dimethyl-3-hydroxy-3-pyrimidin-5-ylhex-1-yne (412 mg, 2 mmol), 3-iodopyridine (412 mg, 2 mmol), triethylamine (300 μl, 2.2 mmol), copper-I-iodide (20 mg), and bis(triphenylphosphine) palladium-II-chloride (20 mg) in dry acetonitrile (5 ml) under nitrogen was heated at 65° C. After 40 minutes, the reaction was cooled and quenched with dilute aqueous hydrochloric acid. The mixture was neutralised with ammonia, extracted with ethyl acetate (3×20 ml), and the organic extracts were combined. Washing with ammonia, water, and brine, drying over magnesium sulphate and concentration under reduced pressure gave yellow crystals (720 mg). Recrystallisation from ethyl acetate gave the desired product of melting point 170.5°-171.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[F:27][C:28]1[CH:35]=[C:34]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:13])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:31][CH2:30][C:29]1[CH:32]=[CH:33][C:34]([O:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[CH:35][C:28]=1[F:27]
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: NCc1ccc(Oc2ccccc2)cc1F
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc(Oc4ccccc4)cc3F)c2CC1)C(F)(F)F

Procedure:
Using a method similar to the General Procedure 5-3, couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.1 g, 2.5 mmol) with 2-fluoro-4-phenoxy-benzylamine (550 mg, 2.5 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) and then SCX chromatography to obtain 7-chloro-6-(2-fluoro-4-phenoxy-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine. MS (ES+) m/z: 493 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[C:8]2[N:9]([C:13]([C@H:25]3[CH2:30][CH2:29][C@H:28]([CH2:31][NH2:32])[CH2:27][CH2:26]3)=[N:14][C:15]=2[C:16]2[NH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]=[CH:11][N:12]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:6][C:7]1[C:8]2[N:9]([C:13]([CH:25]3[CH2:26][CH2:27][CH:28]([CH2:31][NH:32][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:29][CH2:30]3)=[N:14][C:15]=2[C:16]2[NH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]=[CH:11][N:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: NC[C@H]1CC[C@H](c2nc(-c3cc4ccccc4[nH]3)c3c(N)nccn32)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NCC1CCC(c2nc(-c3cc4ccccc4[nH]3)c3c(N)nccn23)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methanesulfonyl chloride (4.40 μL, 0.057 mmol was added to a mixture of 1-{trans-4-[8-amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazin-3-yl]cyclohexyl}methanamine (20.5 mg, 0.057 mol) and PS-DIEA (3.90 mmol/g loading; 60 mg, 0.2 mmol) in DCM (1.14 mL). The reaction mixture was stirred for 30 min at r.t. for 18 h. The crude reaction mixture was then concentrated and residue purified by mass directed preparative HPLC to afford 4 mg of desired product MS (ES+): m/z 439.10 (100) [MH+]. 1H NMR (CD3OD, 400 MHz): δ 8.24 (br s, 2H), 7.61 (m, 2H), 7.46 (dd, J=8.4, 0.8 Hz, 1H), 7.19 (ddd, J=7.2, 1.2, 1.2 Hz, 1H), 7.08 (ddd, J=7.2, 1.2, 1.2 Hz, 1H), 6.75 (d, J=0.8 Hz, 1H), 3.14 (m, 1H), 2.07 (m, 4H), 1.85 (m, 2H), 1.64 (m, 1H), 1.26 (m, 2H).
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:23][CH2:24][N:25]([CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)CC2C=CC=CC=2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1>[Pd].C(O)C>[ClH:1].[F:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH2:23][CH2:24][NH:25][CH2:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([NH:17][S:18]([CH3:21])(=[O:19])=[O:20])=[CH:15][CH:16]=2)=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)N(CCN(CCc2ccccc2)Cc2ccccc2)c2ccc(F)cc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc(C(=O)N(CCNCCc2ccccc2)c2ccc(F)cc2)cc1

Procedure:
Hydrogenate N-(4-fluorophenyl)-4-[(methylsulfonyl)amino]-N-[2-[(2-phenylethyl)(phenylmethyl)amino]ethyl]benzamide hydrochloride over palladium on carbon in ethanol at 30-40 psi. Follow the progress of the reaction by thinlayer chromatography on silica gel. At the completion of the reaction remove the catalyst by filtration and evaporate the solvent in vacuo to obtain the title compound.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:14]([O:18][C:19]([NH:21][C@@H:22]([C@@H:47]([O:58][Si:59]([C:62]([CH3:65])([CH3:64])[CH3:63])([CH3:61])[CH3:60])[C:48]1[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=1)[CH2:23][N:24]([C:32]1[S:33][C:34]([C:37]2[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[C:39](F)[CH:38]=2)=[N:35][N:36]=1)[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:20])([CH3:17])([CH3:16])[CH3:15]>O1CCOCC1>[C:27]([O:26][C:25]([N:24]([CH2:23][C@@H:22]([NH:21][C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[C@@H:47]([O:58][Si:59]([C:62]([CH3:63])([CH3:64])[CH3:65])([CH3:61])[CH3:60])[C:48]1[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=1)[C:32]1[S:33][C:34]([C:37]2[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[C:39]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])[CH:38]=2)=[N:35][N:36]=1)=[O:31])([CH3:28])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N[C@H](CN(C(=O)OC(C)(C)C)c1nnc(-c2ccc([N+](=O)[O-])c(F)c2)s1)[C@@H](O[Si](C)(C)C(C)(C)C)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1cc(-c2nnc(N(C[C@@H](NC(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)c3ccc(C(F)(F)F)cc3)C(=O)OC(C)(C)C)s2)ccc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 99.4 %

Procedure:
To a solution of sodium hydride (60% dispersion in mineral oil, 0.15 g, 3.74 mmol) in dioxane (2 mL) was added a solution of diethyl malonate (0.57 mL, 3.74 mmol) in dioxane (3 mL). The mixture was stirred for 15 minutes and then a solution of tert-butyl ((2R,3S)-2-((tert-butoxycarbonyl)amino)-3-((tert-butyl(dimethyl)silyl)oxy)-3-(4-(trifluoromethyl)phenyl)propyl)(5-(3-fluoro-4-nitrophenyl)-1,3,4-thiadiazol-2-yl)carbamate (0.58 g, 0.75 mmol) in dioxane (3 mL) was added. The reaction mixture was stirred 16 hours, concentrated in vacuo, and the reaction was quenched with saturated NH4Cl. The mixture was extracted with EtOAc three times. The organic phase was dried over Na2SO4, concentrated in vacuo and purified by chromatography on silica gel (0-15% EtOAc-hexane) to provide the product as a yellow solid (0.68 g, 99%). LCMS (API-ES) m/z: 856 (M+H+-56).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH2:9]([O:11][C:12]([C:14]1[C:18]2[CH:19]=[CH:20][C:21]([OH:23])=[CH:22][C:17]=2[O:16][N:15]=1)=[O:13])[CH3:10].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN1C(=O)CCC1.C(Cl)Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:9]([O:11][C:12]([C:14]1[C:18]2[CH:19]=[CH:20][C:21]([O:23][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)=[CH:22][C:17]=2[O:16][N:15]=1)=[O:13])[CH3:10]
Reactant: CCOC(=O)c1noc2cc(O)ccc12
Reactant: Clc1ccnc(Cl)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1noc2cc(Oc3ccnc(Cl)n3)ccc12
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A suspension of 2.7 g (18.1 mMol) 2,4-dichloropyrimidine, 4.12 g (19.9 mMol) 6-hydroxy-benzo[d]isoxazole-3-carboxylic acid ethyl ester [preparation see: J. Am. Chem. Soc. 97 (1974), 7305] and 8.45 g (39.8 mMol) K3PO4 in 90 ml NMP is stirred for 22 h at rt. Then the mixture is diluted with 0.5 l CH2Cl2 and 0.9 l of a 5% citric acid solution. The organic phase is separated off, washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; CH2Cl2) gives the title compound: MS: [M+1]+=320; TLC(CH2Cl2/EtOAc 49:1): Rf=0.42.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][Cl:15]>>[Cl:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: ClCCCCCCBr
Product: ClCCCCCCSc1ccccc1

Procedure:
Prepared by Procedure R and Scheme Z using benzenethiol and 1-bromo-6-chlorohexane.
Reaction SMILES: Br[CH2:2][C:3]1[S:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[O:15][CH3:16])[N:4]=1.[F:17][C:18]1[C:26]([OH:27])=[CH:25][CH:24]=[C:23]([F:28])[C:19]=1[C:20]([NH2:22])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:4]=[C:3]([CH2:2][O:27][C:26]3[C:18]([F:17])=[C:19]([C:23]([F:28])=[CH:24][CH:25]=3)[C:20]([NH2:22])=[O:21])[S:7][N:6]=2)=[C:9]([O:15][CH3:16])[CH:10]=1
Reactant: NC(=O)c1c(F)ccc(O)c1F
Reactant: COc1cc(Cl)ccc1-c1nsc(CBr)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(Cl)ccc1-c1nsc(COc2ccc(F)c(C(N)=O)c2F)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 28.6 %

Procedure:
To a solution of 5-(bromomethyl)-3-(4-chloro-2-methoxyphenyl)-1,2,4-thiadiazole (0.06 g, 0.19 mmol) in DMF (4 ml) was added 2,6-difluoro-3-hydroxybenzamide (0.029 g, 0.17 mmol) and potassium carbonate (0.091 g, 0.66 mmol). The reaction mixture was stirred at room temperature for 90 min under nitrogen atmosphere. After the completion of the reaction (TLC monitoring), the reaction mixture was evaporated to dryness under vacuum, added 25 ml water and extracted with ethyl acetate (3×25 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was purified over silica gel (100-200 M, 100% EtOAc) to get the desired product (0.02 g, 26%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:33][CH2:34][CH3:35]>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH2:33][CH2:34][CH3:35])[C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1
Reactant: CCCI
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.9 %

Procedure:
To a stirred solution of 1.0 g (0.0033 mole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-20) and 10 mL of dimethylformamide was added 3.23 g (0.0099 mole) cesium carbonate followed by 0.8 mL (0.0099 mole) of 1-iodopropane. The mixture was stirred at room temperature for 18 hours, then water was added. After 15 minutes, the mixture was extracted with ethyl acetate. The organic layer was washed with water, 5% aqueous sodium metabisulfite solution and then brine. The aqueous layers were reextracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from hexanes-dichloromethane to give 1.0 g of 2-Chloro-9-cyclopentyl-7,7-difluoro-5-propyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-144) as white crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:15][C:14]([CH:16]=[O:17])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[K+].[K+].[CH3:66][O:67][C:68]1[CH:69]=[C:70]([CH:72]=[CH:73][C:74]=1[O:75][CH3:76])[NH2:71]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:66][O:67][C:68]1[CH:69]=[C:70]([NH:71][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]4[S:15][C:14]([CH:16]=[O:17])=[CH:13][CH:12]=4)=[CH:9][N:10]=3)[N:7]=2)[CH:72]=[CH:73][C:74]=1[O:75][CH3:76]
Reactant: O=Cc1ccc(-c2cnc3ccc(Cl)nn23)s1
Reactant: COc1ccc(N)cc1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1ccc(Nc2ccc3ncc(-c4ccc(C=O)s4)n3n2)cc1OC
Temperature: 100 °C
Yield: 34.7 %

Procedure:
To a solution of 5-(6-chloroimidazo[1,2-b]pyridazin-3-yl)thiophene-2-carbaldehyde (200 mg, 0.758 mmol, 1.0 equiv), xantphos (88 mg, 0.152 mmol, 0.2 equiv), palladium acetate (17 mg, 0.0758 mmol, 0.1 equiv), and potassium carbonate (2.10 g, 1.52 mmol, 20 equiv) in dioxane (6.0 mL) was added 3,4-dimethoxyaniline (116 mg, 0.758 mmol, 1.0 equiv) and heated to 100° C. for 2 h. Purification by column chromatography using 2% methanol in dichloromethane elution gave the 100 mg of the brown solid, 35%.