Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH:10]=[O:11].[CH2:12](O)[CH:13]=[CH:14][CH3:15].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>>[CH2:12]([O:11][CH2:10][C:3]1[C:4]([O:8][CH3:9])=[N:5][CH:6]=[CH:7][C:2]=1[I:1])[CH:13]=[CH:14][CH3:15]
Reactant: COc1nccc(I)c1C=O
Reactant: CC=CCO
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC=CCOCc1c(I)ccnc1OC
Temperature: 22 °C
Reaction time: 12 h

Procedure:
A 500 mL 3-necked round-bottom flask is equipped with an overhead mechanical stirrer under nitrogen, the flask is charged with 4-iodo-2-methoxy-pyridine-3-carbaldehyde (Intermediate 1, 75.0 g, 0.29 mol), crotyl alcohol (75 mL, 0.88 mol), and triethylsilane (70 mL, 0.44 mol). To the stirred suspension at 0° C. is added trifluoroacetic acid (175 mL, 2.27 mol) dropwise via an addition funnel. The resulting solution is stirred at about 22° C. for approximately 12 hours. The reaction mixture is slowly poured into a rapidly stirring saturated sodium bicarbonate solution (2 L). The mixture is extracted with 3×500 mL of hexane. The combined organic layers are dried over sodium sulfate, filtered, and concentrated in vacuo to give an oil. Purification of this oil by vacuum distillation (about 0.4 mm Hg, about 120-130° C.) yields 3-(but-2-enyloxymethyl)-4-iodo-2-methoxypyridine as a pale yellow oil: 1 H-NMR (400 MHz, CDCl3d 7.69 (d, J=5 Hz, 1 H), 7.34 (d, J=5 Hz, 1 H), 5.71 (m, 2 H), 4.58 (s, 2 H), 4.02 (d, J=1 Hz, 2 H), 3.94 (s, 3 H), 1.72 (d, J=6 Hz, 3 H); IR (neat) 2948, 2859, 1561, 1459, 1381, 1361, 1301, 1233, 1169, 1094, 1052 cm−1; Elemental analysis: calculated for C11H14NO2I: C 41.40, H 4.42, N 4.39, I 39.76; Found: C 41.31, H 4.45, N 4.37, I 39.71.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5]1[N:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][N:6]=1.[F:17][C:18]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[CH:20][C:19]=1[C:33]1[CH:34]=[N:35][C:36]([NH2:39])=[N:37][CH:38]=1>>[F:17][C:18]1[CH:23]=[C:22]([C:2]2[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=2[O:4][C:5]2[N:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][N:6]=2)[CH:21]=[CH:20][C:19]=1[C:33]1[CH:38]=[N:37][C:36]([NH2:39])=[N:35][CH:34]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: COc1cnc(Oc2ccccc2Br)nc1
Product: COc1cnc(Oc2ccccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)nc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 2-(2-bromophenoxy)-5-methoxypyrimidine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C21H16FN5O2, 389.13; m/z found, 390.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.30-8.26 (m, 3H), 7.96 (d, J=1.5, 1H), 7.78 (m, 1H), 7.52 (dd, J=7.6, 1.7, 1H), 7.46-7.39 (m, 1H), 7.37-7.26 (m, 3H), 7.19 (dd, J=8.1, 1.2, 1H), 6.66 (s, 2H), 3.76 (d, J=1.9, 3H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.O[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.O1CCCC1>[Cl:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][O:8][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: OCc1ccc(CCl)cc1
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1
Temperature: 0 °C
Yield: 54.5 %

Procedure:
4-(Chloromethyl)benzyl alcohol (4.68 g), methyl 3-(4-hydroxyphenyl)propanoate (5.40 g) and triphenylphosphine (9.20 g) were dissolved in a mixed solvent of toluene (60 mL)-tetrahydrofuran (30 mL), cooled to 0° C. and diethyl azodicarboxylate (40% toluene solution, 15.2 g) was added dropwise with stirring. After completion of the dropwise addition, the reaction mixture was allowed to warm to room temperature and further stirred for 1 hr. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19-1:1 in volume ratio) to give the title compound (5.19 g, yield 54%) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.[CH3:14][O:15][C:16]1[CH:31]=[CH:30][C:19]([CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24](SC)=[N:25][CH:26]=2)=[CH:18][CH:17]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:24]2[NH:23][C:22](=[O:29])[C:21]([CH2:20][C:19]3[CH:30]=[CH:31][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)=[CH:26][N:25]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1CCCCN
Reactant: COc1ccc(Cc2cnc(SC)[nH]c2=O)cc1
Solvent: c1ccncc1
Product: COc1ccc(Cc2cnc(NCCCCc3ncc(Br)cc3C)[nH]c2=O)cc1
Yield: 70.8 %

Procedure:
5-Bromo-2-(4-aminobutyl)-3-methylpyridine, (0.875 g) and 5-(4-methoxybenzyl)-2-methylthio-4-pyrimidone (0.786 g) were refluxed in pyridine (3 ml) for 20 hours. The pyridine was evaporated in vacuo. Residual pyridine was removed from the residue by azeotroping with water in vacuo and dried by azeotroping with ethanol. Addition of water (10 ml) and ethanol (1 ml) gave a colourless solid. This was recrystallised from ethanol and then from methanol to give 2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-5-(4-methoxybenzyl)-4-pyrimidone (0.97 g) m.p. 149°-50° C.
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[C:15]([O:18][C:19]3[CH:20]=[N:21][CH:22]=[C:23]([F:25])[CH:24]=3)[CH:16]=[N:17][C:10]=2[N:9]([CH3:34])[C:8]1=[O:35])=O.O[Li].O>C1COCC1.O.CC(=O)OCC>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][C:14]2[C:11]3[C:12](=[O:13])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:8](=[O:35])[N:9]([CH3:34])[C:10]=3[N:17]=[CH:16][C:15]=2[O:18][C:19]2[CH:20]=[N:21][CH:22]=[C:23]([F:25])[CH:24]=2)=[CH:32][CH:31]=1
Reactant: Cn1c(=O)n(CCCOC=O)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3cncc(F)c3)cnc21
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)n(CCCO)c(=O)c2c(Cc3ccc(Cl)cc3)c(Oc3cncc(F)c3)cnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.3 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-6-((5-fluoropyridin-3-yl)oxy)-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (32 mg, 0.064 mmol) in THF (6 mL) and water (6 mL) was added LiOH.H2O (5.38 mg, 0.128 mmol). The reaction was stirred at RT for 30 min then diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep TLC eluted with PE/EA (1:1) and then Prep HPLC to give 5-(4-chlorobenzyl)-6-((5-fluoropyridin-3-yl)oxy)-3-(3-hydroxypropyl)-1-methyl pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (4 mg, 13.2% yield) as a white solid. 1H NMR (CDCl3) δ: 8.47-8.35 (m, 2H), 8.03 (s, 1H), 7.76 (d, J=3.0 Hz, 1H), 7.18 (d, J=8.4 Hz, 2H), 7.12 (d, J=8.4 Hz, 2H), 4.24 (t, J=6.1 Hz, 2H), 4.06 (s, 2H), 3.73 (s, 3H), 3.57 (t, J=5.6 Hz, 2H), 2.01-1.88 (m, 2H). LCMS: MH+ 471 and TR=2.246 min.
Reaction SMILES: [N+](C(C)C(C=C1NC(=O)NC1=O)CCOCCCCC(O)=O)([O-])=O.[O:25]=[C:26]1[NH:30][C:29](=O)[C:28](=[CH:32][C:33]2[CH:34]=[C:35]([CH:46]=[CH:47][C:48]=2[N+:49]([O-])=O)[O:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43]CC)=[O:42])[NH:27]1>>[O:25]=[C:26]1[NH:30][C:29]2=[N:49][C:48]3[CH:47]=[CH:46][C:35]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[CH:34][C:33]=3[CH:32]=[C:28]2[NH:27]1
Reactant: CCOC(=O)CCCCOc1ccc([N+](=O)[O-])c(C=C2NC(=O)NC2=O)c1
Agent: CC(C(C=C1NC(=O)NC1=O)CCOCCCCC(=O)O)[N+](=O)[O-]
Product: O=C(O)CCCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1

Procedure:
This compound was prepared from 5-[[4-nitro-3-[(2,4-dioxoimidazolidin-5-ylidene)methyl]pentyl]oxy]pentanoic acid or ethyl 5-[3-[(2,4-dioxoimidazolidin-5-ylidene)methyl]-4-nitrophenoxy]pentanoate analogous to Example 4, m.p. 317°-318° C.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([NH:23][CH2:24][C:25](=[O:31])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].O[CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>ClCCl.CN(C)C1C=CN=CC=1>[C:16]([NH:23][CH2:24][C:25](=[O:31])[CH2:26][CH2:27][C:28]([O:30][CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:29])([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: CC(C)(C)OC(=O)CCO
Reactant: CC(C)(C)OC(=O)NCC(=O)CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCOC(=O)CCC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 96 %

Procedure:
A solution of N,N′-dicyclohexylcarbodiimide (DCC, 3.34 g; 16.2 mmol) in dry dichloromethane (20 mL) was added using a syringe to a stirred mixture of 5-(Boc-amino)-4-oxopentanoic acid (3.70 g; 16.0 mmol), t-butyl 3-hydroxypropanoate (2.31 g; 15.8 mmol), and 4-dimethylaminopyridine (DMAP, 50 mg) in dichloromethane (40 mL) at ambient temperature under argon. The mild exothermic reaction was moderated with an ice-water bath. After stirring 2 days at ambient temperature, the mixture was suction-filtered on a glass-sinter filter. The residue was washed with dichloromethane (3×20 mL). The combined filtrates were evaporated and the residue was purified by flash chromatography on a 45×55 mm silica gel 60 column eluted with ethyl acetate-hexane (1:1) (500 mL), collecting 7×50 ml fractions. After evaporation of fractions 2-4, 5.45 g (96%) product was obtained (pale yellow oil).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[F:31]>>[Cl:24][C:25]1[CH:26]=[C:27]([C:6]2[N:7]=[C:8]([N:10]3[C:14]4[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=4[N:12]=[CH:11]3)[S:9][C:5]=2[C:3]([OH:2])=[O:4])[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Product: COc1cc2ncn(-c3nc(-c4ccc(F)c(Cl)c4)c(C(=O)O)s3)c2cc1OC
Yield: 18.9 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 3-chloro-4-fluorophenylboronic acid (26.2 mg, 0.15 mmol) gave 4-(3-Chloro-4-fluoro-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (8.2 mg, 19%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.79 (br.s., 1H); 8.84 (s, 1 H,); 8.22 (dd, 1 H); 8.01 (ddd, 1 H); 7.81 (s, 1 H); 7.57 (t, 1H); 7.39 (s, 1 H); 3.87 (s, 3 H); 3.85 (s, 3 H). MS m/z 434 (M+1).
Reaction SMILES: CS(Cl)(=O)=O.[N:6]1[C:15]2[C:10](=[CH:11][C:12]([CH2:16][N:17]3[C:21]4=[N:22][C:23]([C:26]5[CH:27]=[N:28][N:29]([CH2:31][CH2:32]O)[CH:30]=5)=[CH:24][CH:25]=[C:20]4[N:19]=[N:18]3)=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[F-:41].[Cs+]>ClCCl.O.C(O)(C)(C)C>[F:41][CH2:32][CH2:31][N:29]1[CH:30]=[C:26]([C:23]2[N:22]=[C:21]3[N:17]([CH2:16][C:12]4[CH:11]=[C:10]5[C:15](=[CH:14][CH:13]=4)[N:6]=[CH:7][CH:8]=[CH:9]5)[N:18]=[N:19][C:20]3=[CH:25][CH:24]=2)[CH:27]=[N:28]1
Reactant: OCCn1cc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cn1
Reactant: [F-]
Agent: CS(=O)(=O)Cl
Agent: [Cs+]
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Solvent: O
Product: FCCn1cc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10 %

Procedure:
Methane sulphonyl chloride (0.069 g, 0.605 mmol) was added at 0° C. to a solution of example 146 (0.150 g, 0.403 mmol) and triethylamine (0.122 g. 1.21 mmol) in dichloromethane (3 ml) and warmed to RT. After 1 h, the mixture was diluted and washed with sodium bicarbonate solution, washed with brine, dried over sodium sulphate and concentrated. To the residue, cesium fluoride (0.270 g, 1.77 mmol) and tert-butanol (2 ml) were added and heated to 70° C. for 12 h. The reaction mixture was poured in water, extracted with ethyl acetate, washed with brine, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography using dichloromethane:methanol to afford the title compound as an off-white solid (0.015 g, 10%). M.P.: 168-170° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.88 (dd, J=4.2, 1.7 Hz, 1H), 8.57 (s, 1H), 8.53 (d, J=8.7 Hz, 1H), 8.37 (d, J=7.4 Hz, 1H), 8.26 (s, 1H), 8.01 (d, J=8.1 Hz, 1H), 7.99 (s, 1H), 7.83 (m, 2H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 6.11 (s, 2H), 4.88 (dt, J=47.1, 4.5 Hz, 2H), 4.56 (dt, J=27.7, 4.8 Hz, 2H) MS (m/z):: 374.1 (M++1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([O:17][C@@H:18]3[O:44][C@H:43]([CH2:45][O:46][C:47](=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49])[C@@H:35]([O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[C@H:27]([O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C@H:19]3[O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[N:11][NH:12][C:13]=2[CH:14]([CH3:16])[CH3:15])=[C:4]([CH3:53])[CH:3]=1.Br[CH2:55][CH2:56][CH2:57][C:58]([O:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)=[O:59].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>CN(C)C=O.O>[CH2:61]([O:60][C:58]([CH2:57][CH2:56][CH2:55][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10]([O:17][C@@H:18]3[O:44][C@H:43]([CH2:45][O:46][C:47](=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49])[C@@H:35]([O:36][C:37](=[O:42])[C:38]([CH3:39])([CH3:41])[CH3:40])[C@H:27]([O:28][C:29](=[O:34])[C:30]([CH3:31])([CH3:32])[CH3:33])[C@H:19]3[O:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:23])[CH3:24])=[N:11][NH:12][C:13]=2[CH:14]([CH3:16])[CH3:15])=[C:4]([CH3:53])[CH:3]=1)=[O:59])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1
Reactant: O=C(CCCBr)OCc1ccccc1
Reactant: Cc1cc(O)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)n[nH]c1C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCCCC(=O)OCc2ccccc2)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)n[nH]c1C(C)C
Yield: 64.7 %

Procedure:
To a solution of 4-[(4-hydroxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.2 g) in N,N-dimethylformamide (3 mL) were added benzyl 4-bromobutyrate (0.1 g), cesium carbonate (0.18 g) and a catalytic amount of sodium iodide, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1-2/1) to give the title compound (0.16 g).
Reaction SMILES: [F:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([C@@H:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C([O:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[C:41]3[C:36](=[CH:37][C:38]([C:42](O)=[O:43])=[CH:39][CH:40]=3)[C:35]([CH3:45])=[C:34]2[CH3:46])=[CH:28][CH:27]=1)=[O:19])(C)(C)C>>[F:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([C@@H:8]([NH:10][C:42]([C:38]2[CH:37]=[C:36]3[C:41](=[CH:40][CH:39]=2)[N:33]([CH2:32][C:29]2[CH:28]=[CH:27][C:26]([C:21]4[C:20]([C:18]([OH:19])=[O:17])=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:31][CH:30]=2)[C:34]([CH3:46])=[C:35]3[CH3:45])=[O:43])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: COc1c(F)cccc1[C@H](C)N
Product: COc1c(F)cccc1[C@H](C)NC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
The title compound was prepared following the same general protocol as described in Step 1-2, Example 2, using the (S)-1-(3-fluoro-2-methoxyphenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 551 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:18])([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:17])[NH:15][NH2:16])=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].Cl.[C:20](N)(=N)[CH3:21].C(O)(=O)C>CN(C)C=O>[CH3:20][C:21]1[N:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][C:2]([F:18])([F:1])[CH:3]([F:4])[F:5])=[CH:12][CH:11]=2)[C:14](=[O:17])[NH:15][N:16]=1
Reactant: CC(=N)N
Reactant: NNC(=O)Nc1ccc(OC(F)(F)C(F)F)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1n[nH]c(=O)n1-c1ccc(OC(F)(F)C(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
4-[4-(1,1,2,2-Tetrafluoroethoxy)phenyl]semicarbazide (6.0 g) and 10.6 g of acetamidine hydrochloride were dissolved in 100 ml of dimethylformamide. The solution was stirred for one hour at room temperature. After adding 6.6 g of acetic acid, the reaction solution was heated at 80° C. for seven hours and concentrated under reduced pressure. The residue was dissolved in a mixture of 200 ml of ethyl acetate and 40 ml of water. The separated organic layer was washed with water and saturated sodium chloride solution, dried and distilled off to remove the solvent. The residue was recrystallized from ethyl acetate to give 3.6 g of 5-methyl-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-3(2H,4H)-1,2,4-triazolone as colorless needles.
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.[N:20]1[CH:25]=[CH:24][C:23]([C:26]([OH:30])([C:28]#[CH:29])[CH3:27])=[N:22][CH:21]=1>>[F:19][C:3]1[C:2]([C:29]#[C:28][C:26]([OH:30])([C:23]2[CH:24]=[CH:25][N:20]=[CH:21][N:22]=2)[CH3:27])=[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)c1ccncn1
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)c1ccncn1
Yield: 33 %

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-(pyrimidin-4-yl)but-3-yn-2-ol to give the titled compound as a brown solid (60 mg, 33%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Cl[C:26]([O:28][C:29]([CH3:31])=[CH2:30])=[O:27].O>N1C=CC=CC=1>[C:19]([NH:18][C:16](=[O:17])[NH:15][C:12]1[N:13]=[CH:14][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:26](=[O:27])[O:28][C:29]([CH3:31])=[CH2:30])[CH:7]=2)=[CH:10][CH:11]=1)(=[O:24])[C:20]([CH3:21])([CH3:23])[CH3:22]
Reactant: CC(C)(C)C(=O)NC(=O)Nc1ccc(Oc2ccnc(N)c2)cn1
Reactant: C=C(C)OC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: C=C(C)OC(=O)Nc1cc(Oc2ccc(NC(=O)NC(=O)C(C)(C)C)nc2)ccn1
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
A 0° C. suspension of Example C1 (1.2 g, 3.64 mmol) in pyridine (20 mL) was treated with isopropenyl chloroformate (0.398 mL, 3.64 mmol), stirred for 30 min, then treated with water. The resulting solid was collected via filtration and purified via silica gel chromatography (EtOAc/Hex, MeOH/DCM) to afford prop-1-en-2-yl (4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)carbamate (820 mg, 54%). MS (ESI) m/z: 414.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH:14]1(B2OC(C)(C)C(C)(C)O2)[CH2:16][CH2:15]1.C([O-])([O-])=O.[Cs+].[Cs+].C(Cl)Cl>O1CCOCC1.O>[Cl:13][C:5]1[CH:4]=[CH:3][C:2]([CH:14]2[CH2:16][CH2:15]2)=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CC1(C)OB(C2CC2)OC1(C)C
Reactant: CCOC(=O)c1cc(Br)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(C2CC2)ccc1Cl
Yield: 88 %

Procedure:
In a schlenck tube, a mixture of ethyl 5-bromo-2-chlorobenzoate (7.60 mmol, 2 g), 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.59 mmol, 1.3 g), Cs2CO3 (18.97 mmol, 6.18 g), PdCl2dppf.CH2Cl2 (0.76 mmol, 0.620 g) in dioxane (70 ml) and water (15 ml) was heated for 2 hours at 110° C., under argon atmosphere. The solvent was evaporated and the mixture was extracted between ethyl acetate and water. The crude mixture was purified by chromatography over SiO2 eluting hexane/ethyl acetate mixtures and affording 1.5 g (yield 92%) of the expected product.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].C(O)CCCCCCC.C(OC(C)=C)(=O)C.C(OCCCCCCCC)(C)=C.[CH2:35]([O:43][C:44]([O:47]CCCCCCCC)(C)[CH3:45])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>C1(C)C=CC=CC=1>[C:44]([O:43][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])(=[O:47])[CH3:45]
Reactant: CCCCCCCCOC(C)(C)OCCCCCCCC
Agent: C=C(C)OC(C)=O
Agent: C=C(C)OCCCCCCCC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCCCCCCCO
Product: CCCCCCCCOC(C)=O
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To a mixture of di-μ-chlorobis(1,5-cyclooctadiene)diiridium(I) [Ir(cod)Cl]2 (0.01 mmol) and sodium carbonate (0.03 mmol) in toluene (1.0 ml), 1-octanol (130 mg, 1 mmol) and isopropenyl acetate (5 mmol) were added, followed by stirring at 100° C. in an atmosphere of argon gas for 15 hours. The reaction mixture was analyzed by gas chromatography to find that 1-octyl isopropenyl ether, 2,2-bis(1-octyloxy)propane, and octyl acetate were produced in yields of 78%, 4%, and 16%, respectively, with a conversion from 1-octanol of 98%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[C:10]=2Cl)=[C:4]([CH3:18])[N:3]=1.ClC1C=C(CC#N)C=C(Cl)C=1>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:10]=[C:11]([Cl:16])[CH:12]=[C:13]([Cl:15])[CH:14]=2)=[C:4]([CH3:18])[N:3]=1
Reactant: Cc1nc(N)nc(N)c1-c1cc(Cl)cc(Cl)c1Cl
Agent: N#CCc1cc(Cl)cc(Cl)c1
Product: Cc1nc(N)nc(N)c1-c1cc(Cl)cc(Cl)c1

Procedure:
This compound was prepared in a manner analogous to the compound of Example 6 from 3,5-dichlorophenylacetonitrile (Aldrich). mp. 242°-244° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:10][C:11](=[O:20])[C:12]2[N:13]([N:15]=[C:16]([CH:18]=O)[CH:17]=2)[CH:14]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(O)(=O)C.C([BH3-])#N.[Na+].Cl>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:10][C:11](=[O:20])[C:12]2[N:13]([N:15]=[C:16]([CH2:18][N:25]3[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]3)[CH:17]=2)[CH:14]=1
Reactant: CN1CCNCC1
Reactant: O=Cc1cc2c(=O)[nH]c(-c3ccc(Cl)cc3Cl)cn2n1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCN(Cc2cc3c(=O)[nH]c(-c4ccc(Cl)cc4Cl)cn3n2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
145 mg (0.32 mmol) of 6-(2,4-dichlorophenyl)-4-oxo-4,5-dihydropyrazolo[1,5-a]pyrazine-2-carb-aldehyde (Example 18A) were dissolved in 6 ml of methanol, and 64 mg (0.64 mmol) of 1-methylpiperazine, 4 Å molecular sieve and 58 mg (0.96 mmol) of acetic acid were added. Finally, 40.2 mg (0.64 mmol) of sodium cyanoborohydride were added and the mixture was stirred at RT for 15 h. The crude mixture was acidified with 2N hydrochloric acid and the resulting precipitate was filtered off with suction. This gave 120 mg (96% of theory) of the product as a solid which was reacted further without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19]([C:20](O)=[O:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.O[NH:24][C:25](=[NH:36])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([S:32](=[O:35])(=[O:34])[NH2:33])[CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19]([C:20]4[O:21][N:36]=[C:25]([C:26]5[CH:27]=[C:28]([S:32]([NH2:33])(=[O:34])=[O:35])[CH:29]=[CH:30][CH:31]=5)[N:24]=4)=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(Cl)cc3)nc12
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Product: NS(=O)(=O)c1cccc(-c2noc(-c3cnn4c(C(F)F)cc(-c5ccc(Cl)cc5)nc34)n2)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.3) (162 mg, 0.5 mmol) and N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (161 mg, 0.75 mmol) according to general procedure II. Obtained after trituration with water and further purification by crystallization (dichloromethane) as a light yellow solid (170 mg, 68%). MS (ISN) 501.1 [(M−H)−]; mp 231° C.