Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[F:10].[I:11]I>CCO.[O-]S([O-])(=O)=O.[Ag+].[Ag+]>[NH2:1][C:2]1[C:9]([I:11])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[F:10]
Reactant: II
Reactant: N#Cc1ccc(N)c(F)c1
Agent: [Ag+]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: N#Cc1cc(F)c(N)c(I)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 4-amino-3-fluorobenzonitrile (147 mmol), I2 (147 mmol) and Ag2SO4 (147 mmol) in EtOH (700 mL) was stirred at room temperature for 1.5 h. The mixture was filtered and concentrated. The residue was dissolved in EtOAc and washed (sat. Na2S2O3×3). The organic layer was dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (SiO2, 95:5 to 70:30 cyclohexane/EtOAc) to yield the desired product.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([CH3:12])[C:9]([CH3:11])=[CH:10][C:5]=2[O:4][N:3]=1.I[CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.[Li+].CC([N-]C(C)C)C>C1COCC1>[CH3:12][C:8]1[C:9]([CH3:11])=[CH:10][C:5]2[O:4][N:3]=[C:2]([CH2:1][CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17][CH2:16]3)[C:6]=2[CH:7]=1
Reactant: Cc1cc2onc(C)c2cc1C
Reactant: CC(C)(C)OC(=O)N1CCC(CI)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc2onc(CCC3CCN(C(=O)OC(C)(C)C)CC3)c2cc1C
Yield: 77.8 %

Procedure:
The procedure described in Example 1d was followed using 3,5,6-trimethyl-1,2-benzisoxazole (0.600 g, 3.73 mmol), 4-iodomethyl-1-piperidinecarboxylic acid, 1-(1,1-dimethylethyl) ester (1.30 g, 4.10 mmol), and 1M LDA (4.10 mL, 4.10 mmol) in dry THF (10 mL). After purification, the title compound (1.04 g, 78%) was obtained as a clear oil.
Reaction SMILES: [H-].[Na+].O1CCCC1.[CH2:8]([C@H:11]1[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]1)[CH2:9][CH3:10].[CH2:18]([C@H:23]1[CH2:28][CH2:27][C@H:26](/[CH:29]=[CH:30]/[CH2:31]Br)[CH2:25][CH2:24]1)[CH2:19][CH2:20][CH2:21][CH3:22]>O>[CH2:18]([C@H:23]1[CH2:24][CH2:25][C@H:26](/[CH:29]=[CH:30]/[CH2:31][O:17][C@H:14]2[CH2:15][CH2:16][C@H:11]([CH2:8][CH2:9][CH3:10])[CH2:12][CH2:13]2)[CH2:27][CH2:28]1)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCC[C@H]1CC[C@H](/C=C/CBr)CC1
Reactant: CCC[C@H]1CC[C@H](O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC[C@H]1CC[C@H](/C=C/CO[C@H]2CC[C@H](CCC)CC2)CC1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 0.1 g of sodium hydride and 25 ml of tetrahydrofuran was treated with 0.5 g of trans-4-propylcyclohexanol while gassing with nitrogen, stirred for a further 2 hours, then treated with 1.0 g of (E)-3-(trans-4-pentylcyclohexyl)allyl bromide and subsequently heated to 70° C. overnight. Thereafter, the reaction mixture was treated with 500 ml of water and extracted four times with 50 ml of hexane each time. The combined organic phases were washed twice with 500 ml of water each time, dried over magnesium sulphate, filtered and then concentrated. The residue was purified by chromatography on silica gel with toluene. The trans-4-propylcyclohexyl (E)-3-(trans-4-pentylcyclohexyl)allyl ether obtained was recrystallized from acetone at -25° C.. This gave 1.2 g of pure product with m.p. (C-I) 26° C..
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:10]=1[Cl:11])=[O:5])C.[OH-].[Li+].O>CO>[Cl:11][C:10]1[N:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnn(C2CCCCC2)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cnn(C2CCCCC2)c1Cl
Temperature: 82.5 °C
Yield: 95.6 %

Procedure:
5-Chloro-1-cyclohexyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.969 g, 7.67 mmol) was dissolved in methanol (11.5 mL). Lithium hydroxide (0.250 g; 10.44 mmol) and water (11.5 mL) were added. The mixture was heated at 80-85° C. for 1.5 hours, cooled to room temperature and concentrated in vacuo to remove the methanol. The residue was diluted with tetrahydrofuran and concentrated again to ensure complete removal of the methanol. This residue was then diluted with water and acidified with 6N HCl (1.80 mL) to pH 2-2.5. The solid which precipitated out of solution was collected by filtration, washed with water and dried under reduced pressure at 100° C. to give 5-chloro-1-cyclohexyl-1H-pyrazole-4-carboxylic acid (1.676 g, 96%) which was used without further purification. Mass spectrum: m/z: 229.0 (M+H)
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][C:10]=2[F:16])=[C:6]([CH3:17])[C:5](=[O:18])[N:4]2[CH2:19][CH2:20][O:21][C:3]=12.[CH2:22]([C:25]1([S:28](Cl)(=[O:30])=[O:29])[CH2:27][CH2:26]1)[CH:23]=[CH2:24]>N1C=CC=CC=1>[F:16][C:10]1[CH:11]=[C:12]([I:15])[CH:13]=[CH:14][C:9]=1[NH:8][C:7]1[C:2]([NH:1][S:28]([C:25]2([CH2:22][CH:23]=[CH2:24])[CH2:27][CH2:26]2)(=[O:30])=[O:29])=[C:3]2[O:21][CH2:20][CH2:19][N:4]2[C:5](=[O:18])[C:6]=1[CH3:17]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCO2
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Solvent: c1ccncc1
Product: C=CCC1(S(=O)(=O)Nc2c(Nc3ccc(I)cc3F)c(C)c(=O)n3c2OCC3)CC1
Yield: 34.8 %

Procedure:
Using the same reaction conditions and workup as described for the preparation of Example 7A, 8-amino-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-2,3-dihydro-oxazolo[3,2-a]pyridin-5-one (I-7f: 0.46 g, 0.001 mol) in dry pyridine (3 mL) was reacted with 1-allyl-cyclopropane sulfonyl chloride (0.25 g, 0.0014 mol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in DCM) afforded 0.19 g of the product (30% yield).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:9]([O:11][C:12](=[O:29])[NH:13][C:14]2[C:15]([CH3:28])=[N:16][O:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][C:20]=2[O:26][CH3:27])[CH3:10])[CH:6]=[CH:7][CH:8]=1.CC1(C)C(C)(C)OB([C:40]2[CH:45]=[CH:44][C:43]([C:46]3([C:49]([NH:51][S:52]([CH3:55])(=[O:54])=[O:53])=[O:50])[CH2:48][CH2:47]3)=[CH:42][CH:41]=2)O1>>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:9]([O:11][C:12](=[O:29])[NH:13][C:14]2[C:15]([CH3:28])=[N:16][O:17][C:18]=2[C:19]2[CH:24]=[CH:23][C:22]([C:40]3[CH:41]=[CH:42][C:43]([C:46]4([C:49]([NH:51][S:52]([CH3:55])(=[O:54])=[O:53])=[O:50])[CH2:48][CH2:47]4)=[CH:44][CH:45]=3)=[CH:21][C:20]=2[O:26][CH3:27])[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: CC1(C)OB(c2ccc(C3(C(=O)NS(C)(=O)=O)CC3)cc2)OC1(C)C
Reactant: COc1cc(Br)ccc1-c1onc(C)c1NC(=O)O[C@H](C)c1cccc(C(F)(F)F)c1
Product: COc1cc(-c2ccc(C3(C(=O)NS(C)(=O)=O)CC3)cc2)ccc1-c1onc(C)c1NC(=O)O[C@H](C)c1cccc(C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6 using [5-(4-bromo-2-methoxy-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(3-trifluoromethyl-phenyl)-ethyl ester and N-{1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarbonyl}-methanesulfonamide.
Reaction SMILES: [Cl:1][C:2]([Cl:23])([Cl:22])[C:3]1[N:8]=[C:7]([C:9]([Cl:12])([Cl:11])[Cl:10])[N:6]=[C:5]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[N:4]=1.S(Cl)([Cl:26])=O>>[Cl:11][C:9]([Cl:12])([Cl:10])[C:7]1[N:8]=[C:3]([C:2]([Cl:1])([Cl:22])[Cl:23])[N:4]=[C:5]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([Cl:26])=[O:18])=[CH:20][CH:21]=2)[N:6]=1
Reactant: O=C(O)c1ccc(-c2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(-c2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)cc1
Reaction time: 6 h

Procedure:
4-(4,6-Bis(trichloromethyl)-s-triazin-2-yl)-benzoic acid (87 pw) is added to thionyl chloride (350 pw). Upon heating to reflux in the absence of moisture and with vigorous stirring, a distinct evolution of SO2 can be observed. After 6 hours, a clear solution is present. Excess thionyl chloride is distilled, towards the end by applying a vacuum. The residue containing in virtually quantitative yield pure 4-(4,6-bis(trichloromethyl)-s-triazin-2-yl)benzoyl chloride is recrystallized from hexane, m.p. 100 to 101° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][C@@H:38]4[C@@H:36]([CH:37]4[C:40](O)=[O:41])[CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:43][CH2:44][CH3:45])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:46]1[CH2:50][CH2:49][CH:48]([OH:51])[CH2:47]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][C@@H:36]4[C@@H:38]([CH:37]4[C:40]([N:46]4[CH2:50][CH2:49][CH:48]([OH:51])[CH2:47]4)=[O:41])[CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:43][CH2:44][CH3:45])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: OC1CCNC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1C[C@@H]2C(C(=O)O)[C@@H]2C1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1C[C@@H]2C(C(=O)N3CCC(O)C3)[C@@H]2C1

Procedure:
In a manner analogous to the method described in examples 99, (1S,5R)-3-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-3-aza-bicyclo[3.1.0]hexane-6-carboxylic acid (prepared from the ethyl ester, example 135) was coupled with pyrrolidin-3-ol (Aldrich) to give the title compound as a mixture of diastereomers. HR-MS (ES, m/z) calculated for C39H46Cl2N5O4 [(M+H)+] 718.2922, observed 718.2921.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:12][CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH2:16][N:17]([CH:24]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]1=[O:31])[C:18]2=[O:23].C(N(CC)CC)C>C1COCC1>[CH2:1]([NH:8][C:9]([NH:12][CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH2:16][N:17]([CH:24]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]1=[O:31])[C:18]2=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=NCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CCC(N2Cc3c(CNC(=O)NCc4ccccc4)cccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
Benzyl isocyanate (0.4 g, 2.7 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and triethylamine (0.3 g, 2.9 mmol) in THF (30 mL). The mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was stirred with 1N HCl (30 mL). The mixture was filtered, and the solid was slurried with hot methanol (15 mL) to give 1-benzyl-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-urea (0.8 g, 88%) as a white solid: mp 304-306° C., 1H NMR (DMSO-d6) δ 1.97-2.02 (m, 1H), 2.30-2.34 (m, 1H), 2.50-2.65 (m, 1H), 2.85-2.98 (m, 1H), 4.21-4.52 (m, 6H), 5.09-5.16 (dd, J=4.5 and 13.0 Hz, 1H, CH), 6.51-6.53 (m, 2H), 7.23-7.61 (m, 8H), 11.01 (s, 1H), 13C NMR (DMSO-d6) δ 22.56, 31.18, 40.01, 42.96, 46.14, 51.52, 121.38, 126.52, 126.95, 128.17, 130.23, 131.60, 136.11, 139.80, 140.78, 157.95, 168.09, 170.95, 172.82; Anal. calcd. for C22H22N4O4: C, 65.01; H, 5.46; N, 13.78. Found: C, 64.90; H, 5.53; N, 13.46.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][N:9]([C:12]3[N:34]=[CH:33][CH:32]=[CH:31][C:13]=3[C:14]([NH:16][CH:17]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH:18]([OH:22])[C:19]([OH:21])=O)=[O:15])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:36][O:37][NH2:38]>>[F:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][CH:17]([NH:16][C:14](=[O:15])[C:13]2[CH:31]=[CH:32][CH:33]=[N:34][C:12]=2[N:9]2[CH:10]=[CH:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8]2)[CH:18]([OH:22])[C:19]([NH:38][O:37][CH3:36])=[O:21])=[CH:29][CH:28]=1
Reactant: CON
Reactant: O=C(NC(Cc1ccc(F)cc1)C(O)C(=O)O)c1cccnc1-n1ccc(-c2ccccc2)n1
Agent: Cl
Product: CONC(=O)C(O)C(Cc1ccc(F)cc1)NC(=O)c1cccnc1-n1ccc(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.3 by reacting 3-(2-(3-phenyl-1H-pyrazol-1-yl)nicotinamido)-2-hydroxy-4-(4-fluorophenyl)-butanoic acid with O-methylhydroxylamine hydrochloride. ESI-MS [M+H]+: 490.1
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[C:17]([CH2:21][OH:22])[CH:18]=[CH:19][CH:20]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1.Cl[CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>CC#N>[CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][O:22][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: ClCCN1CCOCC1
Reactant: Cc1nc(C)c(-c2ccnc(Nc3cccc(CO)c3)n2)s1
Solvent: CC#N
Product: Cc1nc(C)c(-c2ccnc(Nc3cccc(COCCN4CCOCC4)c3)n2)s1

Procedure:
By alkylation of {3-[4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino]-phenyl}-methanol with 4-(2-chloro-ethyl)-morpholine. Yellow solid. Anal. RP-HPLC: tR=8.5 min (10-70% MeCN, purity>95%). 1H-NMR (DMSO-D6) δ: 2.56 (s, 3H, CH3), 2.57 (s, 3H, CH3), 2.63 (m, 2H, CH2), 3.58 (m, 4H, J=4.5 Hz, CH2x2), 4.14 (t, 2H, J=7.5 Hz, CH2), 4.58 (d, 2H, J=5.0 Hz, CH2), 5.28 (t, 1H, J=5.5 Hz, NH), 7.06 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 7.26 (m, 2H, Ph-H), 7.36 (s, 1H, Ph-H), 7.42 (m, 1H, Ph-H), 8.43 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 9.12 (sbr, 1H, Ph-H). MS (ESI+) m/z 426.46 [M+H]+ (C22H27N5O2S requires 425.55).
Reaction SMILES: [N:1]1[C:11]2[NH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[S:16])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.[CH3:22][O+](C)C>ClCCl>[CH3:22][S:16][C:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[NH:10][C:11]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[N:6]=1
Reactant: C[O+](C)C
Reactant: S=C1Nc2cccnc2Nc2ccccc21
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CSC1=Nc2cccnc2Nc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5H-benzo[e]pyrido[3,2-b][1,4]diazepine-6(11H)-thione (0.106 g, 0.465 mmol) in dichloromethane (5 ml) was added trimethyloxonium tetrafluoroborate (0.076 g, 0.512 mmol). The reaction mixture was stirred at room temperature for 15 minutes and then warmed to 40° C. for 2 hours. The reaction was quenched by adding water (10 ml). The organic layer was separated, dried with sodium sulfate and concentrated to afford the desired product, 6-(methylthio)-11H-benzo[e]pyrido[3,2-b][1,4]diazepine as a dark yellow solid which turned to oil on standing (0.092 g, 82%). The crude product was used in the next step without any further purification. 400 MHz 1H NMR (CDCl3) δ: 7.9-7.85 (m, 1H), 7.60-7.54 (m, 1H), 7.44-7.38 (m, 1H), 7.3-7.22 (m, 1H), 6.98-6.90 (m, 2H), 6.78-6.72 (m, 1H), 6.29 (br s, 1H), 2.53 (s, 3H); LCMS [M+H]: 242.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:34])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:20]([CH:22]4[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]4)[OH:21])=[C:14]([C:16]([O:18]C)=O)[N:15]=[C:7]3[C:6]=2[CH:33]=1.C[O-].[Na+].C([NH2:40])=O>>[Br:1][C:2]1[C:3]([F:34])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:20]([OH:21])[CH:22]4[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])[CH2:23]4)=[C:14]([C:16](=[O:18])[NH2:40])[N:15]=[C:7]3[C:6]=2[CH:33]=1
Reactant: COC(=O)c1nc2n(c1C(O)C1CN(C(=O)OC(C)(C)C)C1)C1CC(C1)c1cc(F)c(Br)cc1-2
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CC(C(O)c2c(C(N)=O)nc3n2C2CC(C2)c2cc(F)c(Br)cc2-3)C1
Yield: 82 %

Procedure:
tert-butyl 3-((10-bromo-2-carbamoyl-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepin-3-yl)(hydroxy)methyl)azetidine-1-carboxylate was prepared similarly to as described in General Procedure L. Methyl 10-bromo-3-((1-(tert-butoxycarbonyl)azetidin-3-yl)(hydroxy)methyl)-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was reacted with sodium methoxide and formamide to afford 160 mg (82% yield) of the title compound.
Reaction SMILES: COC([N:5]1[CH2:12][C@@H:11]2[C@@H:7]([N:8]([CH2:13][CH2:14][C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([N:24]5[CH:28]=[N:27][N:26]=[CH:25]5)[CH:22]=4)[NH:17][CH:16]=3)[CH2:9][CH2:10]2)[CH2:6]1)=O.O.NN.[OH-].[K+]>C(O)CO>[N:26]1[N:27]=[CH:28][N:24]([C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH:16]=[C:15]3[CH2:14][CH2:13][N:8]2[CH2:9][CH2:10][C@@H:11]3[CH2:12][NH:5][CH2:6][C@H:7]23)[CH:25]=1
Reactant: COC(=O)N1C[C@H]2CCN(CCc3c[nH]c4ccc(-n5cnnc5)cc34)[C@H]2C1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: c1cc2[nH]cc(CCN3CC[C@@H]4CNC[C@@H]43)c2cc1-n1cnnc1
Temperature: 100 °C
Yield: 62 %

Procedure:
A mixture of cis-1-[2-(5-[1,2,4]triazol-4-yl-1H-indol-3-yl)-ethyl)-hexahydro-pyrrolo[3,4-b]pyrrole-5-carboxylic acid methyl ester (enantiomer B) (1.9 g, 5.0 mmol), hydrazine hydrate (1.2 ml, 25 mmol) and powdered potassium hydroxide (3.4 g, 61 mmol) in dry ethylene glycol (25 ml) was stirred and heated at 100° C. under nitrogen for 16 hours. Upon cooling the mixture was partitioned between dichloromethane and water. The aqueous was further extracted with dichloromethane ) and n-butanol (×2). The combined extracts were evaporated and the residue was purified by chromatography on neutral alumina (grade III) (dry loaded), eluting with CH2Cl2 /MeOH/NH3 (95:5:0.5) to give the title amine (1.0 g, 62%) as a pale yellow foam; δ (250 MHz, d6 -DMSO) 1.33-1.48 (1H, m), 1.90-2.04 (1H, m), 2.14-2.26 (1H, m), 2.40 (1H, dd, J=11.8, 4.9 Hz), 2.56-2.96 (11H, m), 3.07 (1H, t, J=7.4 Hz), 7.30 (1H, dd, J=8.6, 2.1 Hz, Ar--H), 7.34 (1H, d, J=2.2 Hz, Ar--H), 7.48 (1H, d, J=8.6 Hz, Ar--H), 7.79 (1H, d, J=2.0 Hz, Ar--H), 9.03 (2H, s, Triazole-H), 11.11 (1H, br s, NH).
Reaction SMILES: [CH3:1][OH:2].C(N(CC)CC)C.[P:10](Cl)([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([O: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])=[O:11].Cl.C(N(CC)CC)C.ClCl>C1(C)C=CC=CC=1>[P:10]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([O: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])([O:2][CH3:1])=[O:11]
Reactant: CCCCCCCCCCCCOP(=O)(Cl)OCCCCCCCCCCCC
Reactant: CO
Agent: Cl
Agent: ClCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCOP(=O)(OC)OCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 5 g. (0.15 mole) of methanol and 12.12 g. (0.12 mole) of triethylamine in 200 ml. of toluene was stirred at ambient temperature (22° C.) and a total of 45.25 g. (0.1 mole) of dilauryl chlorophosphate (prepared as described in Preparation 1) was added dropwise over a period of 13 minutes. After the addition was complete, the reaction mixture was stirred for a further 1.5 hour at ambient temperature before being filtered to remove triethylamine hydrochloride (7.85 g.). The filtrate was heated to 95° C. for a few minutes before being cooled to 5° C. and filtered. The solid so isolated was a further 2.82 g. of triethylamine hydrochloride. The filtrate was evaporated to dryness and the residue was triturated with 150 ml. of ether. The insoluble material (triethylamine hydrochloride; 0.33 g.; total triethylamine hydrochloride=11 g.=80 percent theoretical) was removed by filtration and the filtrate was evaporated to dryness to yield 44 g. of methyl dilaurylphosphate which was found to contain 0.09 percent of hydrolyzable chlorine corresponding to the presence of 1.15 percent of starting material (dilauryl chlorophosphate).
Reaction SMILES: [OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.CCN(CC)CC.[NH2:37][CH2:38][CH2:39][OH:40].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(Cl)Cl>[OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:37][CH2:38][CH2:39][OH:40])=[O:27])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: O=C(O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Reactant: NCCO
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCO)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.3 %

Procedure:
To a solution of 4-(((1R,2R)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (100 mg, 0.26 mmol), Et3N (157 mg, 1.56 mmol) and 2-amino ethanol (40 mg, 0.65 mmol) in DCM (5 mL), was added T3P (0.33 mL, 50 wt % solution in ethyl acetate, 0.52 mmol) and then stirred at room temperature for 12 h. The reaction mixture was quenched with water (25 mL) and extracted with DCM (3×25 mL). The organic layer was washed with brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by CombiFlash using 20% ethyl acetate in chloroform as an eluent to yield 80 mg (72%) of the title compound as an off white solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[CH2:11][C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH:13]=1)C>C1COCC1>[O:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:12]([CH2:11][CH2:10][OH:9])=[CH:13]1
Reactant: CCOC(=O)Cc1coc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCc1coc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of LiAlH4 (200 mg, excess) in THF at 0° C., ethyl(-1-benzofuran-3-yl)acetate (1.02 g, 5 mmol) in THF (20 mL) was added slowly. After the addition, the reaction mixture was stirred at room temperature for 1 hr and quenched with saturated NH4Cl solution. The product was extracted with chloroform and washed well with water. It was dried over anhydrous MgSO4, filtered and concentrated. The product 2-(1-benzofuran-3-yl)ethanol obtained as a white oil was pure enough to be taken to next step without further purification. Yield: 800 mg (98%); (M+H): 163.
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][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[C:55]([CH2:57][C:58](O)=[O:59])#[N:56]>>[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].[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][CH:47]1[CH2:52][CH2:51][N:50]([C:58](=[O:59])[CH2:57][C:55]#[N:56])[CH2:49][CH2:48]1
Reactant: N#CCC(=O)O
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: N#CCC(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 41 %

Procedure:
The desired compound was prepared according to the procedure of Example A27 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-piperidin-4-ylacetamide tris(trifluoroacetate) and cyanoacetic acid as starting materials in 41% yield. LCMS for C27H28ClN8O2 (M+H)+: m/z=531.2.