Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19][NH2:20].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19][NH:20][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CN(C)CCCN
Reactant: CCCCCCCCCCCC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)NCCCN(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 500 ml RB flask containing a solution of lauroyl chloride (19.38 g., 89 mM) in dry chloroform (200 ml) was cooled to 0° C. on an ice bath. A solution of N,N-dimethyl-1, 3-propanediamine (10.40 g., 51 mM) and triethylamine (9.40 g., 93 mM) in dry chloroform (25 ml) was added dropwise to the cold solution through an addition funnel, then allowed to warm to room temperature and stirred for 2 hours. The chloroform was removed under reduced pressure and the residue redissolved in an ethanol/water mixture (1:1) and neutralized with sodium bicarbonate, followed by extraction with chloroform (4×50 ml). The combined extracts were dried (MgSO4), concentrated, and the residue distilled under reduced pressure (bp 171° C., 10μ) to give 23.92 g. (68%) of the subject compound as an amber solid.
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1>C(O)(C(F)(F)F)=O.[Pt]=O>[N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH:6]([C:11]([O:13][CH3:14])=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc2ncccc12
Agent: O=[Pt]
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CCCc2ncccc21
Reaction time: 8 h

Procedure:
Methyl quinoline-5-carboxylate (3.67 g, 19.61 mmol) was dissolved in TFA (60 ml) and added platinum oxide (0.49 g, 2.16 mmol) then hydrogenated at room temperature overnight. Filtered off the catalyst and evaporated to dryness. The residue was chromatographed through a 120 g ISCO Redi-sep column and eluted with 5% of (10% NH4OH in MeOH) in DCM to yield methyl 5,6,7,8-tetrahydroquinoline-5-carboxylate 1H-NMR (600 MHz, CDCl3): δ ppm 8.42 (d, J=3.7 Hz, 1H), 7.485 (d, J=7.7 Hz, 1H), 7.06-7.08 (m, 1H), 3.82 (t, J=5.6 Hz, 1H), 3.72 (d, J=3.2 Hz, 3H), 3.02-2.93 (m, 1H), 2.88-2.93 (m, 1H), 2.16-2.20 (m, 1H), 1.97-2.05 (m, 2H), 1.85-1.90 (m, 1H); LC-MS: M+1=192.
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C@H:20]3[NH:24][C:23](=[O:25])[C@H:22]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:21]3)=[CH:14][CH:13]=2)=[N:10][CH:11]=1)(=[NH:5])[NH2:4].Cl.Cl[C:33]([O:35][CH3:36])=[O:34]>C(Cl)Cl.O>[CH3:36][O:35][C:33]([NH:5][C:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C@H:20]3[NH:24][C:23](=[O:25])[C@H:22]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:21]3)=[CH:14][CH:13]=2)=[N:10][CH:11]=1)=[NH:4])=[O:34]
Reactant: COC(=O)C[C@@H]1C[C@@H](COc2ccc(-c3ccc(C(=N)N)cn3)cc2)NC1=O
Reactant: COC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C[C@@H]1C[C@@H](COc2ccc(-c3ccc(C(=N)NC(=O)OC)cn3)cc2)NC1=O
Temperature: 25 °C

Procedure:
3 ml of 0.2M sodium hydroxide solution are added dropwise to 100 mg of (3S,5S)-5-[[4-(5-amidino-2-pyridyl)phenyl]oxymethyl]-3-[(methoxycarbonyl)methyl]-2-pyrrolidinone×1.6 HCl×1.5 H2O and 19.4 μl of methyl chloroformate in 10 ml of methylene chloride with vigorous stirring at ambient temperature. Then the mixture is stirred for a further 21/2 hours at ambient temperature. It is diluted with methylene chloride, the organic phase is separated off, dried and evaporated down.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH3:38])[C:5]([C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]2([C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]=1)=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.CO>ClCCl.C(OCC)(=O)C>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2([C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]2[CH2:2][CH2:3][N:4]([CH3:38])[C:5](=[O:6])[C:7]=12)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN(CCO)C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CN1CCn2c(CC3(c4cccc5ccccc45)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Temperature: 0 °C
Yield: 101.3 %

Procedure:
To a solution of 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-methyl-amide (351) (85 mg, 0.17 mmol) in dichloromethane (20 mL) was added triphenyl phosphine (174 mg, 0.67 mmol) and the reaction mixture was cooled to 0° C., followed by the addition of diisopropyl azodicarboxylate (0.2 mL, 0.1 mmol). The reaction mixture was stirred for 15 min at the same temperature (silica TLC, 5% methanol in ethyl acetate; Rf=0.3). The dichloromethane was removed in vacuum and the crude mass was purified by silica gel (normal, 100-200 mesh) column chromatography using a gradient eluent mixture of 50% ethyl acetate in hexane to 100% ethyl acetate to get 9-benzyloxy-2-methyl-6-(1-naphthalen-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (352) (85 mg, semi pure) as a white sticky solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][C@H:47]1[CH2:52][CH2:51][CH2:50][NH:49][CH2:48]1.[C:55](Cl)(=[O:62])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:55]([N:49]1[CH2:50][CH2:51][CH2:52][C@H:47]([CH2:46][C:45]([NH:44][C:36]2[CH:37]=[CH:38][C:39]3[NH:40][C:41]4[N:42]=[C:26]([NH:27][C:28]5[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=5)[CH2:33][CH2:34][C:35]=2[CH:43]=3)[N:25]=[CH:24][C:23]=4[Cl:22])=[O:53])[CH2:48]1)(=[O:62])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(C[C@H]1CCCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@H]1CCCN(C(=O)c2ccccc2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 51 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3R)-piperidin-3-yl]acetamide tris(trifluoroacetate) and benzoyl chloride as the starting materials in 51% yield. LCMS for C31H31ClN7O2 (M+H)+: m/z=568.0.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([OH:5])[CH2:2]1.[H-].[Na+].[Br:8][C:9]1[C:10](Cl)=[N:11][C:12]([Cl:16])=[N:13][C:14]=1[CH3:15]>C1COCC1>[Br:8][C:9]1[C:14]([CH3:15])=[N:13][C:12]([Cl:16])=[N:11][C:10]=1[O:5][CH:3]1[CH2:4][O:1][CH2:2]1
Reactant: OC1COC1
Reactant: Cc1nc(Cl)nc(Cl)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(Cl)nc(OC2COC2)c1Br
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 61.4 %

Procedure:
To a solution of oxetan-3-ol (0.368 g, 4.96 mmol) in anhydrous THF (16 mL) at 0° C. was added NaH (60% in mineral oil, 213 mg, 5.32 mmol). The mixture was stirred at 0° C. for 20 min, then 5-bromo-2,4-dichloro-6-methylpyrimidine (0.800 g, 3.30 mmol) was added to the mixture at 0° C. and stirred for 5 min. After this time the reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The residue was purified using ISCO chromatography (24 g silica gel, 1-25% EtOAc in hexanes in 40 min) to give the title compound (0.566 g, 61%) as a white oil. 1H NMR (CDCl3, 500 MHz) δ 5.71-5.66 (m, 1H), 5.030-4.99 (m, 2H), 4.79-4.76 (m, 2H), 2.59 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])[N:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[N:60]1([CH:65]2[CH2:70][CH2:69][N:68]([S:71]([NH2:74])(=[O:73])=[O:72])[CH2:67][CH2:66]2)[CH2:64][CH2:63][CH2:62][CH2:61]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:19][C:13]1[C:14]([F:18])=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][S:10][C:4]1[N:3]=[C:2]([NH:74][S:71]([N:68]2[CH2:67][CH2:66][CH:65]([N:60]3[CH2:61][CH2:62][CH2:63][CH2:64]3)[CH2:70][CH2:69]2)(=[O:72])=[O:73])[CH:7]=[C:6]([O:8][CH3:9])[N:5]=1
Reactant: NS(=O)(=O)N1CCC(N2CCCC2)CC1
Reactant: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1cc(NS(=O)(=O)N2CCC(N3CCCC3)CC2)nc(SCc2cccc(F)c2F)n1

Procedure:
The title compound was prepared according to the procedure outlined in example 129 using 4-Chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-methoxypyrimidine (the product of example 35 step i) (0.3 g), tris(dibenzylideneacetone)-dipalladium (0) (20 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (15 mg), cesium carbonate (0.70 g) and 4-pyrrolidin-1-ylpiperidine-1-sulfonamide (the product from step i), (0.4 g). The resulting crude material was purified using silica gel chromatography eluting with 5% methanol in DCM and trituration with Et2O to give the title compound as a white solid.
Reaction SMILES: C(OC([NH:11][C@@H:12]1[C@@H:17]2[CH2:18][C@@H:14]([CH:15]=[CH:16]2)[C@@H:13]1[C:19]([O:21][CH3:22])=[O:20])=O)C1C=CC=CC=1.[ClH:23].O1CCOCC1>C(OCC)(=O)C.[Pd].C(OCC)C>[ClH:23].[NH2:11][C@@H:12]1[C@@H:17]2[CH2:18][C@@H:14]([CH2:15][CH2:16]2)[C@@H:13]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)[C@@H]1[C@H](NC(=O)OCc2ccccc2)[C@H]2C=C[C@@H]1C2
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(=O)[C@H]1[C@@H]2CC[C@@H](C2)[C@H]1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl (1S,2S,3R,4R)-3-{[(benzyloxy)carbonyl]amino}bicyclo[2.2.1]hept-5-ene-2-carboxylate (1 g, 3.32 mmol) was dissolved in ethyl acetate (15 mL). 5% Palladium on carbon (120 mg) was added. The flask was degassed and backfilled with hydrogen gas via balloon. The mixture was stirred at 25° C. for 16 h. The mixture was passed through a plug of Celite and the filtrate was concentrated in vacuo to afford a thick clear oil. The oil was dissolved in diethyl ether (10 mL) and added dropwise, with vigorous stirring, to a mixture of 4.0 M hydrochloric acid solution in 1,4-dioxane (1.8 mL, 7.2 mmol) in diethyl ether (18 mL). The desired product began to precipitate as a white solid. Additional diethyl ether (10 mL) was added and the mixture was stirred for 10 min. The precipitate was collected by vacuum filtration and washed with additional diethyl ether (2×8 mL). The solid was further dried in vacuo for 1 h to afford the desired product, methyl (1R,2S,3R,4S)-3-aminobicyclo[2.2.1]heptane-2-carboxylate hydrochloride (0.554 g, 2 7 mmol, 81%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.18-1.27 (3H, m), 1.37-1.61 (2H, m), 1.90 (1H, d, J=11.0 Hz), 2.35 (1H, d, J=3.8 Hz), 2.44 (1H, d, J=3.1 Hz), 2.75 (1H, d, J=8.7 Hz), 3.29-3.34 (1H, m), 3.61 (3H, s), 8.03 (3H, bs). LC-MS (ESI) calcd for C9H15NO2 (free amine) 169.11, found 170.3 [M+H+] (100%), 339.3 [2M+H+] (50%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:25]([C:29]1[CH:38]=[C:37]2[C:32]([C:33](=[O:55])[N:34]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41](B4OC(C)(C)C(C)(C)O4)[C:40]=3[CH3:54])[CH:35]=[N:36]2)=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:25]([C:29]1[CH:38]=[C:37]2[C:32]([C:33](=[O:55])[N:34]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([C:2]4[CH:3]=[C:4]([NH:10][C:11]5[CH:16]=[CH:15][C:14]([C:17]([N:19]6[CH2:24][CH2:23][O:22][CH2:21][CH2:20]6)=[O:18])=[CH:13][N:12]=5)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=4)[C:40]=3[CH3:54])[CH:35]=[N:36]2)=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: Cn1nc(Cl)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1cnc2cc(C(C)(C)C)ccc2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)c(=O)n(C)n2)cccc1-n1cnc2cc(C(C)(C)C)ccc2c1=O
Yield: 27.5 %

Procedure:
A solution of 6-Chloro-2-methyl-4-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-2H-pyridazin-3-one (56 mg, 0.16 mmol), 7-tert-Butyl-3-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3H-quinazolin-4-one (68 mg, 0.16 mmol), tetrakis(triphenylphosphine)palladium(0) (19 mg, 0.016 mmol), and sodium carbonate (52 mg, 0.49 mmol) in 2 mL 1,2-dimethoxyethane and 1 mL water was heated on the microwave synthesizer at 170° C. for 12.5 minutes. The resulting mixture was partitioned between ethylacetate and water. The ethylacetate layer was washed with brine, dried over anhydrous MgSO4, concentrated in vacuo, and purified by preparative TLC (10% MeOH/CH2Cl2) to yield 7-tert-Butyl-3-(2-methyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-3H-quinazolin-4-one (26.4 mg, 0.044 mmol). MS (ESI) 606 (M+H)+.
Reaction SMILES: [F:1][C:2]1([C:6]2[NH:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]=2)[CH2:5][O:4][CH2:3]1.Cl[C:16]1[N:24]=[C:23]2[C:19]([N:20]=[C:21]([CH2:26][N:27]3[CH2:32][CH2:31][CH:30]([C:33]([OH:36])([CH3:35])[CH3:34])[CH2:29][CH2:28]3)[N:22]2[CH3:25])=[C:18]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[N:17]=1>>[F:1][C:2]1([C:6]2[N:7]([C:16]3[N:24]=[C:23]4[C:19]([N:20]=[C:21]([CH2:26][N:27]5[CH2:32][CH2:31][CH:30]([C:33]([OH:36])([CH3:35])[CH3:34])[CH2:29][CH2:28]5)[N:22]4[CH3:25])=[C:18]([N:37]4[CH2:38][CH2:39][O:40][CH2:41][CH2:42]4)[N:17]=3)[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=2)[CH2:3][O:4][CH2:5]1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: FC1(c2nc3ccccc3[nH]2)COC1
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(C4(F)COC4)nc4ccccc43)nc21

Procedure:
Following General Procedure I for Buchwald coupling, 2-(3-fluorooxetan-3-yl)-1H-benzimidazole and 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol were reacted to give 262. LCMS m/z: 565.3 (MH+)
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:11]=[C:12]([CH2:14][CH2:15]Cl)[S:13][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:18][C:19]1[CH:33]=[CH:32][C:22]2[C:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[N:24][O:25][C:21]=2[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.C1(C)C=CC=CC=1>[C:1]([N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[CH:11]=[C:12]([CH2:14][CH2:15][N:29]3[CH2:28][CH2:27][CH:26]([C:23]4[C:22]5[CH:32]=[CH:33][C:19]([F:18])=[CH:20][C:21]=5[O:25][N:24]=4)[CH2:31][CH2:30]3)[S:13][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)N1CCCc2cc(CCCl)sc2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(=O)N1CCCc2cc(CCN3CCC(c4noc5cc(F)ccc45)CC3)sc2C1
Temperature: 90 °C
Reaction time: 5 h
Yield: 54.7 %

Procedure:
A mixture of 1.6 g of 7-acetyl-2-chloroethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine, 1.8 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)-piperidine hydrochloride, 2.6 g of potassium carbonate and 1 g of potassium iodide in 15 ml of dimethylformamide and 15 ml of toluene was stirred at 90° C. for 5 hours and concentrated in vacuo. To the residue were added ethyl acetate and water, and separated. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatograhy on a silica gel to give 1.5 g of 7-acetyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine as an oil. The oil was treated with hydrochloric acid in isopropyl alcohol and recrystallized from ethanol-isopropyl ether to give 7-acetyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepine hydrochloride 3/2hydrate, m.p. 210° C. (decomposition).
Reaction SMILES: N=C=N.[CH2:4]([CH:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:12]([OH:14])=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH2:22][CH:23]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH:24]([OH:41])[CH:25]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:37]([O:36][C:34]([NH:33][CH:25]([CH:24]([OH:41])[CH:23]([NH:22][C:12](=[O:14])[CH:11]([CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: O=C(O)C(Cc1ccccc1)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)C(N)Cc1ccccc1
Agent: N=C=N
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NC(=O)C(Cc1ccccc1)Cc1ccccc1

Procedure:
According to the carbodiimide coupling procedure of Example 55, dibenzylacetic acid was coupled to the resultant compound of Example 11 to give the desired compound.
Reaction SMILES: [CH3:1]N(C=O)C.[F:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([OH:16])[CH:8]=1.C(=O)([O-])O.[K+].IC>O>[F:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([O:13][CH3:1])=[O:12])=[C:9]([OH:16])[CH:8]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc(F)cc1O
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CI
Product: COC(=O)c1ccc(F)cc1O
Reaction time: 0.17 h

Procedure:
1.1 50 ml of DMF are added under argon to 6.0 g of 4-fluoro-2-hydroxybenzoic acid and 4.52 g of potassium hydrogencarbonate, and the mixture is stirred for 10 minutes. 3.05 ml of iodomethane are added dropwise, and the mixture is stirred at 40° for 3 hours. The mixture is poured into 150 ml of water and subjected to conventional work-up, giving 6.48 g of methyl 4-fluoro-2-hydroxybenzoate (“1a”).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH:42]=[CH2:43])[C:38]2=[N:44][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:50][CH2:49][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]2[CH:25]=[C:26]([F:47])[C:27]([F:46])=[CH:28][C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=C(CC)C2=NC3=CN2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(F)=CC=2C2C=C3C=CC=2)CC1)C(OC)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH2:42][CH3:43])[C:38]2=[N:44][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]2[CH:25]=[C:26]([F:47])[C:27]([F:46])=[CH:28][C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:49][CH2:50]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=Cc1c(C)c([C@H](OC(C)(C)C)C(=O)OC)c2n3cc(nc13)-c1cccc(c1)-c1cc(F)c(F)cc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Agent: CCc1c(C)c([C@H](OC(C)(C)C)C(=O)OC)c2n3cc(nc13)-c1cccc(c1)-c1cc(F)ccc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Product: CCc1c(C)c([C@H](OC(C)(C)C)C(=O)OC)c2n3cc(nc13)-c1cccc(c1)-c1cc(F)c(F)cc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Yield: 91 %

Procedure:
Prepared in 91% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-5-ethenyl-17,18-difluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for methyl(2S)-2-(tert-butoxy)-2-[(22S)-5-ethyl-17-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate. LCMS (ESI, M+1): 704.4.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N+:14]([O-])=O)=[CH:4][CH:3]=1.[CH3:19][C:20]([Mg]Br)=[CH:21][CH3:22].[Cl-].[NH4+]>O1CCCC1>[F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[C:20]([CH3:19])=[C:21]([CH3:22])[NH:14][C:9]=23)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnccc1OCc1ccc(F)cc1
Reactant: CC=C(C)[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1[nH]c2c(OCc3ccc(F)cc3)ccnc2c1C
Temperature: -20 °C
Reaction time: 5 h
Yield: 46.9 %

Procedure:
4-(4-Fluorobenzyloxy)-3-nitropyridine (4.8 g, 19.34 mmol) prepared in Preparation 2 was dissolved in anhydrous tetrahydrofuran (200 ml) under a nitrogen atmosphere. 1-Methyl-1-propenyl magnesium bromide (0.5M in tetrahydrofuran solution, 116 ml, 58.02 mmol) was added at −78° C. to the solution, which was then stirred for 5 hours at −20° C. 20% Ammonium chloride solution (20 ml) was added to the reaction mixture, which was then extracted with ethyl acetate (200 ml) twice. The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/methylene chloride/methanol=10/10/1, (v/v/v)) to give the titled compound as a pale yellow solid (2.45 g, 28.3%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH2:18][CH3:19])([C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[C:6]=2[CH:20]=1.[C:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[C:27]([F:29])[CH:28]=1)#[N:22]>>[CH2:18]([C:7]1([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[C:6]2[CH:20]=[C:2]([C:25]3[CH:24]=[C:23]([CH:28]=[C:27]([F:29])[CH:26]=3)[C:21]#[N:22])[CH:3]=[CH:4][C:5]=2[NH:11][C:10](=[O:12])[CH2:9][O:8]1)[CH3:19]
Reactant: CCC1(c2ccsc2)OCC(=O)Nc2ccc(Br)cc21
Reactant: N#Cc1cc(F)cc(B(O)O)c1
Product: CCC1(c2ccsc2)OCC(=O)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21

Procedure:
Prepared from 7-bromo-5-ethyl-5-thien-3-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 3-cyano-5-fluorobenzeneboronic acid using the coupling procedure described in example 1. 1H-NMR (DMSO-d6) δ 10.07 (s, 1H), 8.07 (t, J=1.5 Hz, 1H), 7.94 (dt, J=10.3, 2.0 Hz, 1H), 7.80 (m, 1H), 7.73 (dd, J=8.3, 2.0 Hz, 1H), 7.63 (d, J=2.4 Hz, 1H), 7.57 (dd, J=4.9, 2.9 Hz, 1H), 7.27 (m, 2H), 7.17 (dd, J=4.9, 1.5 Hz, 1H), 4.02 (d, J=15.6 Hz, 1H), 3.96 (d, J=15.6 Hz, 1H), 2.54 (m, 1H), 2.49 (m, 1H), 0.74 (t, J=7.3 Hz, 3H); MS (ES) m/z 393 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[F:10].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+].[OH-].[K+]>ClC(Cl)C.ClCCl.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:4][C:3]=1[F:10]
Reactant: O=Cc1ccc(Br)c(F)c1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CC(Cl)Cl
Product: Fc1cc(CN2CCOCC2)ccc1Br
Yield: 70.3 %

Procedure:
4-Bromo-3-fluorobenzaldehyde (4.69 g, 23.10 mmol) was dissolved in degassed dichloroethane (40 mL) and stirred under nitrogen. Morpholine (2.015 mL, 23.10 mmol) was added followed by sodium triacetoxyborohydride (6.37 g, 30.03 mmol) portionwise. The reaction was stirred over night. Saturated NaHCO3 (aq) was added. The phases were separated and the organic phase was washed with 2M HCl (aq). A solid precipitated in the separation funnel. The solid was isolated by filtration. The water phase and the solid were combined and dichloromethane was added. The pH was adjusted to ca 10 by adding solid KOH. The water phase was extracted with dichloromethane (2×) and the organic phase was dried and concentrated to give 4-(4-bromo-3-fluorobenzyl)morpholine (4.45 g, 70%) as a solid.