Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Cl:31][C:32]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:33]=1[CH2:34]Br>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:34][C:33]3[C:36]([F:40])=[CH:37][CH:38]=[CH:39][C:32]=3[Cl:31])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1cccc(Cl)c1CBr
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Product: Cc1nc2c(ccn2Cc2c(F)cccc2Cl)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 2-chloro-6-fluorobenzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.48-7.40 (m, 1 H), 7.33-7.27 (m, 2 H), 7.23-7.17 (m, 1 H), 7.10-7.03 (m, 1 H), 7.00-6.95 (m, 1 H), 6.91 (t, J=7.7 Hz, 1 H), 6.21-6.14 (m, 1 H), 5.72-5.55 (m, 3 H), 4.31-4.24 (m, 2 H), 2.92-2.77 (m, 2 H), 2.74 (s, 3 H), 2.06 (s, 2 H), 1.02-0.92 (s, 9 H); LC/MS (m/z) ES+=537.38 (M+1).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:2].[CH3:13][O:14][C:15]1[CH:22]=[CH:21]C(CN)=[CH:17][CH:16]=1.C(Cl)Cl>O1CCCC1>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:11]([CH2:12][NH:8][C:1]([N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)=[O:2])=[CH:17][CH:16]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(CNC(=O)n2ccnc2)cc1

Procedure:
23.6 g of carbonyldiimidazole are added in portions to a solution of 20 g of 4-methoxybenzylamine in 100 ml of anhydrous tetrahydrofuran, the temperature being kept below 10° C. When the addition is complete, the mixture is allowed to return to room temperature and stirring is maintained for three hours. After filtration, the tetrahydrofuran phase is evaporated under vacuum and the residue obtained is taken up with methylene chloride, washed with water and then dried. The oil obtained after evaporation of the methylene chloride is crystallized from ether. The crystals obtained are filtered off and then dried. 22.7 g of N-(4-methoxybenzyl)imidazolecarboxamide are thus recovered in the form of crystals melting at 117° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8]Br.[Mg].II.[C:13]([CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)(=[O:15])[CH3:14]>CCOCC.II>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:13]([CH:16]1[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:20][CH2:21]1)([OH:15])[CH3:14]
Reactant: BrCc1ccccc1Br
Reactant: CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(C(C)(O)Cc2ccccc2Br)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.5 %

Procedure:
A mixture of 1-bromo-2-(bromomethyl)benzene (4.40 g, 17.60 mmol), magnesium (0.984 g, 40.5 mmol), and I2 (2.2 mg, 8.80 μmol) in Et2O (87 mL) was heated to reflux under argon until the reaction initiated (indicated by decolorization of I2) and then stirred at room temperature for 2 hours. After this time, the reaction mixture was added to a solution of tert-butyl 4-acetylpiperidine-1-carboxylate (2 g, 8.80 mmol) in Et2O (1.2 mL) and then stirred for 19 hours. At the conclusion of this period, the reaction mixture was quenched with aqueous NH4Cl (saturated, 20 mL) and extracted with EtOAc (3×25 mL). The combined organic layers were washed with H2O (3×15 mL) and brine (15 mL). The resulted organic layer was separated, dried (Na2SO4), filtered, and concentrated to yield a residue. The residue was purified by column chromatography (silica gel, hexanes/EtOAc gradient 0 to 60% EtOAc) to afford Compound 11A as a white semi-solid (1.14 g, 31% yield).
Reaction SMILES: CN([C:4]([O:8][N:9]1N=NC2C=CC=C[C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.CNOC.[O:39]1[CH2:44][CH2:43][CH2:42][O:41][CH:40]1[C:45]1[CH:50]=[CH:49][C:48]([C:51]2[S:52][C:53]3[CH:59]=[C:58]([C:60]([OH:62])=O)[CH:57]=[CH:56][C:54]=3[N:55]=2)=[C:47]([F:63])[CH:46]=1>CN(C=O)C.O>[O:39]1[CH2:44][CH2:43][CH2:42][O:41][CH:40]1[C:45]1[CH:50]=[CH:49][C:48]([C:51]2[S:52][C:53]3[CH:59]=[C:58]([C:60]([N:9]([O:8][CH3:4])[CH3:10])=[O:62])[CH:57]=[CH:56][C:54]=3[N:55]=2)=[C:47]([F:63])[CH:46]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2c1
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2c1
Reaction time: 0.5 h

Procedure:
HBTU (0.80 g, 2.11 mmol) was added to a solution of di-isopropylethylamine (0.61 mL, 3.52 mmol), N,O-dimethylhydroxylamine hydrochloride (0.21 g, 2.11 mmol), and 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)benzo[d]thiazole-6-carboxylic acid (0.51 g, 1.41 mmol) in DMF (7 mL). The reaction mixture was stirred for 30 min, diluted with water, and extracted with EtOAc three times. The combined extracts were dried (MgSO4), concentrated under vacuum, and purified by silica gel chromatography to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-N-methoxy-N-methylbenzo[d]thiazole-6-carboxamide as an oil. MS (ESI) m/z: Calculated: 402.1; Observed: 403.1 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([S:17][CH2:18][CH2:19][CH3:20])=[C:15]([C:21]([OH:23])=O)[CH:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:4].Cl.[CH:25]12[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH:26]1[NH2:35])[CH2:32]2>>[CH:25]12[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH:26]1[NH:35][C:21]([C:15]1[CH:14]=[N:13][N:12]([C:9]3[CH:8]=[CH:7][C:6]([CH2:5][C:3]([O:2][CH3:1])=[O:4])=[CH:11][CH:10]=3)[C:16]=1[S:17][CH2:18][CH2:19][CH3:20])=[O:23])[CH2:32]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: CCCSc1c(C(=O)O)cnn1-c1ccc(CC(=O)OC)cc1
Agent: Cl
Product: CCCSc1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccc(CC(=O)OC)cc1

Procedure:
Prepared from 1-[4-(methoxycarbonylmethyl)phenyl]-5-propylsulfanyl-pyrazole-4-carboxylic acid (Intermediate#35) and 2-adamantylamine hydrochloride by the same procedure as used for Intermediate #6.
Reaction SMILES: C([O:4][C@H:5]([C@:16]12[CH2:51][C:50](=[O:52])[C:49]([CH:53]([CH3:55])[CH3:54])=[C:17]1[C@@H:18]1[C@@:31]([CH3:34])([CH2:32][CH2:33]2)[C@@:30]2([CH3:35])[C@@H:21]([C@:22]3([CH3:48])[C@@H:27]([CH2:28][CH2:29]2)[C:26]([CH3:37])([CH3:36])[C@@H:25]([O:38][C:39](=[O:47])[CH2:40][C:41]([CH3:46])([CH3:45])[C:42]([OH:44])=[O:43])[CH2:24][CH2:23]3)[CH2:20][CH2:19]1)[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)(=O)C.[C:56]([O-:59])([O-])=O.[Na+].[Na+].[CH3:62]O>>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][N:7]([CH2:6][C@@H:5]([C@:16]23[CH2:51][C:50](=[O:52])[C:49]([CH:53]([CH3:54])[CH3:55])=[C:17]2[C@@H:18]2[C@@:31]([CH3:34])([CH2:32][CH2:33]3)[C@@:30]3([CH3:35])[C@@H:21]([C@:22]4([CH3:48])[C@@H:27]([CH2:28][CH2:29]3)[C:26]([CH3:36])([CH3:37])[C@@H:25]([O:38][C:39](=[O:47])[CH2:40][C:41]([CH3:46])([CH3:45])[C:42]([OH:44])=[O:43])[CH2:24][CH2:23]4)[CH2:20][CH2:19]2)[OH:4])[C:56](=[O:59])[CH3:62])=[CH:14][CH:13]=1
Reactant: CC(=O)O[C@@H](CNCc1ccc(Cl)cc1)[C@@]12CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)C1=C(C(C)C)C(=O)C2
Reactant: CO
Reactant: O=C([O-])[O-]
Agent: [Na+]
Product: CC(=O)N(Cc1ccc(Cl)cc1)C[C@H](O)[C@@]12CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)C1=C(C(C)C)C(=O)C2
Yield: 30 %

Procedure:
A mixture of 4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-1-acetoxy-2-((4-chlorobenzyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (49) (150 mg, 0.192 mmol), Na2CO3 (20.37 mg, 0.192 mmol), in methanol (3 mL) was stirred for 3 h, then purified by preparative-HPLC to afford 4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((R)-2-(N-(4-chlorobenzyl)acetamido)-1-hydroxyethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (74) (45 mg, 30%) as a white solid. Compound exists as a mixture of rotomers; 1H NMR (500 MHz, METHANOL-d4) δ=7.43-7.27 (m, 2H), 7.28-7.11 (m, 2H), 5.30-4.09 (m, 6H), 3.55-2.09 (m, 11H), 2.09-0.78 (m, 44H); LC/MS: m/z calculated 779.5. found 780.4 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:23])=[CH:4][C:5]2[O:21][C:20](=[O:22])[C:9]3[CH2:10][N:11]([CH2:14][CH:15]([NH:17][CH2:18][CH3:19])[CH3:16])[CH2:12][CH2:13][C:8]=3[C:6]=2[CH:7]=1.[BH4-].[Na+].[C:26](O)(=O)[CH3:27]>>[Cl:1][C:2]1[C:3]([CH3:23])=[CH:4][C:5]2[O:21][C:20](=[O:22])[C:9]3[CH2:10][N:11]([CH2:14][CH:15]([N:17]([CH2:26][CH3:27])[CH2:18][CH3:19])[CH3:16])[CH2:12][CH2:13][C:8]=3[C:6]=2[CH:7]=1
Reactant: CC(=O)O
Reactant: CCNC(C)CN1CCc2c(c(=O)oc3cc(C)c(Cl)cc23)C1
Agent: [BH4-]
Agent: [Na+]
Product: CCN(CC)C(C)CN1CCc2c(c(=O)oc3cc(C)c(Cl)cc23)C1

Procedure:
Prepared by the method described for Example 59 from 9-chloro-3-[2-(ethylamino)propyl]-1,2,3,4-tetrahydro-8-methyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one (0.9 g, 0.003 moles), glacial acetic acid (5 ml), and sodium borohydride (0.6 g, 0.016 moles). Recrystallization from isopropyl ether gave the product (0.45 g), mp 78°-80° C.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:33]3[N:41]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C:36]4=[N:37][CH:38]=[CH:39][CH:40]=[C:35]4[N:34]=3)[CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:33]3[N:41]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C:36]4=[N:37][CH:38]=[CH:39][CH:40]=[C:35]4[N:34]=3)[CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCCCCn1c(-c2ccc3nc(CCC)n(Cc4ccc(-c5ccccc5C(=O)OC(C)(C)C)cc4)c3c2)nc2cccnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCn1c(-c2ccc3nc(CCC)n(Cc4ccc(-c5ccccc5C(=O)O)cc4)c3c2)nc2cccnc21

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4 '-[[2-n-propyl-6-(3-n-hexyl-imidazo[4,5-b ]pyridin-2-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: C([C:3](CC)(CC)[CH:4](P(O)(O)=O)[C:5]([O-:7])=[O:6])C.[CH2:16]([Li])[CH2:17]CC.[I:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.C(OCC)(=O)C>O1CCCC1.CCCCCC>[CH2:16]([O:7][C:5](=[O:6])/[C:4](/[CH3:3])=[CH:26]/[C:25]1[CH:28]=[CH:29][C:22]([I:21])=[CH:23][CH:24]=1)[CH3:17]
Reactant: CCC(CC)(CC)C(C(=O)[O-])P(=O)(O)O
Reactant: O=Cc1ccc(I)cc1
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)/C(C)=C/c1ccc(I)cc1
Reaction time: 0.17 h
Yield: 99 %

Procedure:
A stirred, cooled (−78° C.) solution of triethyl-2-phosphonopropionate (10 g, 41.9 mmol) in anhydrous tetrahydrofuran (100 mL) was treated with a 1.6M solution of n-butyl lithium in hexanes (25 mL, 40 mmol). After 10 min, the reaction mixture was cannulated into a cooled (−78° C.) solution of 4-iodo-benzaldehyde (4.66 g, 20 mmol) in tetrahydrofuran (25 mL). After 30 minutes, it was quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford an oil that was subjected to flash column chromatography over silica gel (230–400 mesh) using 9–10% ethyl acetate in hexane as the eluent to afford the title compound (6.3 g, 99%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[CH3:13])=[CH:8][CH:7]=1.[S:15]([NH:25][NH2:26])(C1C=CC(C)=CC=1)(=O)=O.S(Cl)(Cl)=O>C(O)C>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:26]=[N:25][S:15][CH:13]=2)=[CH:8][CH:7]=1
Reactant: CC(=O)c1ccc(CCCCCl)cc1
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: ClCCCCc1ccc(-c2csnn2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 125 ml round-bottomed flask equipped with condenser and N2 inlet were added 6.25 g (29.65 mmol) p-(4-chlorobutyl)acetophenone, 5.57 g (29.65 mmol) tosylhydrazine, and 50 ml ethanol. The reaction was refluxed 3.5 hours, cooled, and evaporated. The residue was taken up in 23.4 ml (326 mmol) thionyl chloride and stirred at room temperature for 3 hours. The reaction mixture was evaporated and the residue chromatographed on silica gel using hexane/methylene chloride as eluent to afford an oil, 6.1 g (81.5%). NMR (CDCl3): 1.84 (m, 4H), 2.73 (m, 2H), 3.58 (m, 2H), 7.3 and 7.95 (m, 4H), 8.59 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]4[O:25][C:26]([CH2:29][CH2:30][NH2:31])=[CH:27][CH:28]=4)[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:9][C:8]=1[Cl:32].[CH3:36][S:37]([CH2:40][C:41](O)=[O:42])(=[O:39])=[O:38].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>>[F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]4[O:25][C:26]([CH2:29][CH2:30][NH:31][C:41](=[O:42])[CH2:40][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:27][CH:28]=4)[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:9][C:8]=1[Cl:32]
Reactant: CS(=O)(=O)CC(=O)O
Reactant: NCCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)CC(=O)NCCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1

Procedure:
Preparation according to Procedure (I) utilizing (4-(3-fluorobenzyloxy)-3-chlorophenyl)-(6-(5-(2-aminoethyl)-furan-2-yl)-quinazolin-4-yl)-amine (26 mg, 0.0537 mmol), methanesulfonylacetic acid (22.2 mg, 0.161 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30.0 mg, 0.161 mmol) and N,N-diisopropylethylamine (0.028 mL, 0.161 mmol). 1H (DMSO) 9.84 (s, 1H), 8.65 (s, 1 H), 8.49 (s, 1 H), 8.10 (d, 1 H), 7.96 (d, 1 H), 7.73 (d, 1 H), 7.69 (m, 1 H), 7.41 (m, 1 H), 7.22–7.29 (m, 3 H), 7.13 (m, 1 H), 6.98 (d, 1 H), 6.35 (d, 1 H), 5.21 (s, 2 H), 4.02 (s, 2 H), 3.07 (t, 2 H), 3.05 (s, 3 H), 2.87 (t, 2 H). Electrospray m/z 609 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH2:28][CH3:29])[N:16]=[C:17]([C@H:18]4[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:30]([O:34][CH2:35][CH3:36])(=[O:33])[CH:31]=[CH2:32].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:24]([C@@H:21]1[CH2:20][CH2:19][C@H:18]([C:17]2[N:10]3[C:11]([C:12](=[O:14])[NH:13][C:8]([C:4]4[CH:3]=[C:2](/[CH:32]=[CH:31]/[C:30]([O:34][CH2:35][CH3:36])=[O:33])[CH:7]=[CH:6][CH:5]=4)=[N:9]3)=[C:15]([CH2:28][CH3:29])[N:16]=2)[CH2:23][CH2:22]1)([CH3:25])([CH3:27])[CH3:26]
Reactant: C=CC(=O)OCC
Reactant: CCc1nc([C@H]2CC[C@@H](C(C)(C)C)CC2)n2nc(-c3cccc(Br)c3)[nH]c(=O)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cccc(-c2nn3c(c(CC)nc3[C@H]3CC[C@@H](C(C)(C)C)CC3)c(=O)[nH]2)c1
Temperature: 25 °C

Procedure:
740 mg (1.62 mmol) cis-2-(3-bromophenyl)-7-(4-tert-butylcyclohexyl)-5-ethylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (Example 27A), 1.6 g (16.2 mmol) ethyl acrylate, 327 mg (3.24 mmol) triethylamine and 227 mg (0.32 mmol) dichlorobis(triphenylphosphine)palladium(II) are stirred at 120° C. in 20 ml DMF in an argon atmosphere for 18 hours. After cooling down to room temperature, the mixture is filtrated over Celite, and the product is isolated by column chromatography or preparative HPLC.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.C1(C)C=CC=CC=1.[NH2:30][C:31]1[C:32]2[C:57]([CH3:64])([C:58]([NH:60][NH:61][CH:62]=O)=O)[C:56](=[O:65])[NH:55][C:33]=2[N:34]=[C:35]([C:37]2[C:45]3[C:40](=[N:41][CH:42]=[CH:43][CH:44]=3)[N:39]([CH2:46][CH2:47][C:48]([F:54])([F:53])[C:49]([F:52])([F:51])[F:50])[N:38]=2)[N:36]=1>C1COCC1>[NH2:30][C:31]1[C:32]2[C:57]([CH3:64])([C:58]3[S:10][CH:62]=[N:61][N:60]=3)[C:56](=[O:65])[NH:55][C:33]=2[N:34]=[C:35]([C:37]2[C:45]3[C:40](=[N:41][CH:42]=[CH:43][CH:44]=3)[N:39]([CH2:46][CH2:47][C:48]([F:54])([F:53])[C:49]([F:52])([F:51])[F:50])[N:38]=2)[N:36]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C(=O)NNC=O)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(N)c21
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1(c2nncs2)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(N)c21
Temperature: 100 °C

Procedure:
Lawesson's reagent (133 mg, 0.328 mmol) was added to a toluene (5 mL) solution of the intermediate from Step B (170 mg, 0.298 mmol). THF (0.5 mL) was added to improve solubility and the reaction was heated to 100° C. for 1 hour in a screw cap vial. The reaction was then cooled and concentrated in vacuo. The crude product was purified by silica gel column chromatography using a hexanes/EtOAc gradient to give the title compound. Chiral separation using SFC on a Chiralcel OD column provided both enantiomers of the title compound. 1H NMR (600 MHz, CD3OD): δ 9.45 (s, 1H); 9.04 (dd, J=7.8, 1.2 Hz, 1H); 8.60 (dd, J=4.2, 1.2 Hz, 1H); 7.36 (dd, J=7.8, 4.2 Hz, 1H); 4.94 (t, J=8.4 Hz, 2H); 4.56 (bs, 2H), 3.01-2.92 (m, 2H); 1.98 (s, 3H). m/z=511.95 (M+H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C@@:20]([OH:45])([CH2:43][OH:44])[C@H:21]([N:23]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]([F:41])([F:40])[CH:37]([F:39])[F:38])=[CH:30][CH:29]=2)[C:24]1=[O:42])[CH3:22]>C(OCC)(=O)C>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C@@:20]([OH:45])([CH2:43][O:44][S:2]([CH3:1])(=[O:4])=[O:3])[C@H:21]([N:23]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]([F:41])([F:40])[CH:37]([F:38])[F:39])=[CH:30][CH:29]=2)[C:24]1=[O:42])[CH3:22]
Reactant: C[C@@H](N1CCN(c2ccc(OCC(F)(F)C(F)F)cc2)C1=O)[C@](O)(CO)c1ccccc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@@H](N1CCN(c2ccc(OCC(F)(F)C(F)F)cc2)C1=O)[C@](O)(COS(C)(=O)=O)c1ccccc1F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 99.8 %

Procedure:
Metanesulfonyl chloride (2.12 g) and triethylamine (1.87 g) were added dropwise to an ice-cooled solution of 1-[(1R,2S)-2-(2-fluorophenyl)-2,3-dihydroxy-1-methylpropyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-imidazolidinone (5.85 g) in ethyl acetate (60 ml). The resulting mixture was stirred for 20 minutes at 0° C. and then washed with water (20 ml×2) and an aqueous sodium chloride solution (20 ml) successively. The organic layer was dried over magnesium sulfate and evaporated in vacuo to give 1-[(1R,2S)-2-(2-fluorophenyl)-2-hydroxy-3-methanesulfonyloxy-1-methylpropyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-imidazolidinone (6.8 g) as a colorless oil. This compound (6.8 g) was dissolved in N,N-dimethylformamide (130 ml). 1H-1,2,4-Triazole (4.24 g) and potassium carbonate (16.9 g) were added to the solution. The resulting mixture was heated at 80° C. for 5 hours, and then concentrated in vacuo. The residue was diluted with ethyl acetate (200 ml) and the mixture was washed with water (40 ml×2), 1N-hydrochloric acid (40 ml×2) and an aqueous sodium chloride solution successively. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by chromatography on silica gel (100 g; eluent, hexane-ethyl acetate, 2:1 to 1:2) followed by recrystallization from a mixture of ethyl acetate and diisopropyl ether to give 1-[(1R,2R)-2-(2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-imidazolidinone (4.4 g, 68%) as colorless prisms.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]([OH:15])[CH:12]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])([CH3:26])[CH3:25].N1C=CN=C1>CN(C=O)C.O.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:14][CH:13]([O:15][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:30])[CH3:29])[CH:12]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[O:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1CN(Cc2ccccc2)CCOC1c1ccc(Cl)c(Cl)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC1CN(Cc2ccccc2)CCOC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
To a solution of (6RS,7SR)-4-benzyl-7-(3,4-dichlorophenyl)-1,4-oxazepan-6-ol (27.7 g) in DMF (154 mL) were added tert-butylchlorodimethylsilane (17.8 g) and imidazole (10.7 g), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with water-ethyl acetate for partitioning, and the organic layer was washed with distilled water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (37.0 g).
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[F:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([C:27]([OH:31])([C:29]#[CH:30])[CH3:28])[CH:22]=1>>[F:19][C:3]1[C:2]([C:30]#[C:29][C:27]([C:23]2[CH:22]=[C:21]([F:20])[CH:26]=[CH:25][N:24]=2)([OH:31])[CH3:28])=[CH:18][C:6]2[C:7]3[N:8]([CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Reactant: C#CC(C)(O)c1cc(F)ccn1
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)c1cc(F)ccn1
Yield: 12 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-(4-fluoropyridin-2-yl)but-3-yn-2-ol to give the titled compound as a brown solid (16 mg, 12%).
Reaction SMILES: [CH2:1](Cl)/[CH:2]=[CH:3]\[OH:4].C[OH:7].[OH-].[CH3:9][N+:10]([CH3:19])([CH3:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O.C(O)(=O)C=CC1C=CC=CC=1.C1C=CC=CC=1>[C:3]([O-:4])(=[O:7])[CH:2]=[CH:1][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:9][N+:10]([CH3:19])([CH3:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O/C=C\CCl
Reactant: CO
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C(O)C=Cc1ccccc1
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=C([O-])C=Cc1ccccc1

Procedure:
A 6.5 g amount of polyepichlorohydrin was dissolved in 227 ml of dimethylformamide while heated under a nitrogen atmosphere. In addition, 13.6 g of cinnamic acid was dissolved in 177 ml of benzene and then 38.3 g of a 40% methanol solution of trimethylbenzyl ammonium hydroxide was admixed with the solution. Trimethylbenzyl ammonium cinnamate was isolated when the benzene solvent was evaporated in addition to the methanol and the water formed by the neutralization reaction. The product obtained was admixed with the solution of polyepichlorohydrin and the mixture was reacted at 80° C for 6.5 hours. The reaction mixture was mixed with methanol and 12 g of a rubber-like white polymer was obtained. Infrared spectrum analysis and elemental analysis of the product indicated that the polymer was a photosensitive resin having units 1 and 2 wherein the ratio of 1 to 2 was 71% to 29%. ##STR6##