Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([CH2:21][OH:22])[O:11][CH2:12][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:42]([O:46][C:47]([N:49]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[C:50]1[N:58]=[C:57]2[C:53]([N:54]=[CH:55][N:56]2O)=[C:52]([O:60][CH3:61])[N:51]=1)=[O:48])([CH3:45])([CH3:44])[CH3:43].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:65]([O:64][C:62]([N:49]([C:47]([O:46][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:48])[C:50]1[N:58]=[C:57]2[C:53]([N:54]=[CH:55][N:56]2[O:22][CH2:21][C@@H:10]([O:11][CH2:12][P:13]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])=[O:20])[CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:52]([O:60][CH3:61])[N:51]=1)=[O:63])([CH3:68])([CH3:67])[CH3:66]
Reactant: CCOP(=O)(CO[C@H](CO)COCc1ccccc1)OCC
Reactant: COc1nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc2c1ncn2O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOP(=O)(CO[C@@H](COCc1ccccc1)COn1cnc2c(OC)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc21)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.6 %

Procedure:
To a stirred solution of diethyl (R)-[2-benzyloxy-1-(hydroxymethyl)ethoxy]methylphosphonate (1.0 g, 3 mmol), triphenylphosphine (1.18 g, 4.5 mmol) and 2-[bis-(t-butoxycarbonyl)amino]-9-hydroxy-6-methoxypurine (1.15 g, 3 mmol) in dry THF (20 ml), cooled in ice and under a mitrogen atmosphere, was added, dropwise, diethyl azodicarboxylate (0.71 ml, 4.5 mmol). The resulting solution was allowed to warm to ambient temperature and left stirring for 16 hours. The solvent was evaporated under reduced pressure and the residue obtained chromatographed on silica gel using hexane/ethyl acetate 2:1 as eluant. The eluant was changed as follows: hexane/ethyl acetate 1:1, hexane/ethyl acetate 1:2 and finally to ethyl acetate to give (S)-2-[bis-(t-butoxycarbonyl)amino]-9-[3-benzyloxy-2-(diethoxyphosphorylmethoxy)propoxy]-6-methoxypurine as a colourless oil (1.85 g, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[CH3:12][NH:13][CH2:14][CH2:15][OH:16]>CO>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([NH:6][C:7]([N:13]([CH3:12])[CH2:14][CH2:15][OH:16])=[O:9])=[C:4]([OH:8])[CH:3]=1
Reactant: CNCCO
Reactant: O=c1[nH]c2ccc(Cl)cc2o1
Solvent: CO
Product: CN(CCO)C(=O)Nc1ccc(Cl)cc1O
Temperature: 65 °C

Procedure:
6-Chlorobenzoxazolinone (20 g) and N-methylethanolamine (17.7 g) in methanol (40 ml) were stirred and heated at 65° C. for 3 hours. The mixture was cooled to ambient temperature, filtered, and the residue was washed with diethyl ether to give the desired urea which melted at 178° C. (decomp.).
Reaction SMILES: [CH2:1]([O:8][N:9]1[CH2:13][C:12]([CH2:14][CH3:15])=[C:11]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.C(O)(=O)C>[CH2:1]([O:8][N:9]1[CH2:13][C@H:12]([CH2:14][CH3:15])[C@H:11]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC1=C(NCc2ccc(OC)cc2)C(=O)N(OCc2ccccc2)C1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC[C@H]1CN(OCc2ccccc2)C(=O)[C@H]1NCc1ccc(OC)cc1
Yield: 99.1 %

Procedure:
1-Benzyloxy-4-ethyl-3-(4-methoxybenzylamino)-2-oxo-2,5-dihydropyrrole (72 mg, 205 μmol) was hydrogenated on platinum (IV) oxide (9.6 mg) in ethyl acetate (10 ml) and acetic acid (100 μl) at atmospheric pressure for 20 h. The mixture was filtered, washed with sodium hydrogen carbonate solution and brine, dried (MgSO4), and evaporated in bacuo to give cis-1-benzyloxy-4-ethyl-3-(4-methoxybenzylamino)pyrrolidin-2-one (72 mg, 100%) as an oil. 1H NMR (250 MHz, CDCl3) δ7.3-7.5 (5 H, m, Ph), 7.26 (2 H, d, J=9 Hz, MeOCCH), 6.84 (2 H, d, J=9 Hz MeOCCHCH), 4.98 (2 H, s, OCH2), 3.80 (2 H, s, CH2NH), 3.78 (3 H, s, OMe), 3.30 (1 H, d, J=8.5 Hz, NCH), 3.25 (1 H, dd, J=6 and 10 Hz, CHAHBNO), 2.95 (1 H, dd, J=3 and 10 Hz, CHAHBNO), 2.0-2.1 (1 H, m, CHCH2), 1.5-1.6 and 1.0-1.1 (2 H, m, CH2CH3), 0.74 (3 H, t, J=7.5 Hz, CH3), m/z (CI, NH3) 249 (M-MeOC6H4 +H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4]C1CCCCO1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24](=[N:26][OH:27])[CH3:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24](=[N:26][O:27][CH2:2][CH2:3][OH:4])[CH3:25])=[CH:20][CH:19]=2)=[CH:16][CH:17]=1
Reactant: BrCCOC1CCCCO1
Reactant: CC(=NO)c1ccc(-c2ccc(F)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(=NOCCO)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
The target compound (3.84 g) was obtained as white crystals by carrying out the reaction and the post-treatment according to Reference examples 1(c) and 1(d) of WO 97/37970(EP 916651A) using 2-(2-bromoethoxy)tetrahydropyran (6.84 g), 4′-(4-fluorophenyl)acetophenone oxime (5.00 g), potassium carbonate (6.02 g) and a catalytic amount of p-toluenesulfonic acid monohydrate.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5]O)[CH2:3][OH:4].[CH2:8](Br)[CH2:9][CH2:10][CH3:11].O=S(Cl)[Cl:15]>>[CH2:8]([O:4][CH2:3][C:2]([CH2:5][Cl:15])([CH3:7])[CH3:1])[CH2:9][CH2:10][CH3:11]
Reactant: CC(C)(CO)CO
Reactant: CCCCBr
Reactant: O=S(Cl)Cl
Product: CCCCOCC(C)(C)CCl

Procedure:
The alkylation of 2,2-dimethyl-1,3-propanediol with n-butyl bromide carried out essentially as in Example 8 gave the crude mono-alkylated product, which was treated with SOCl2 to give C4H9—O—CH2C(CH3)2CH2Cl, b. 80-90° C./20-30 torr. This compound was then fluorinated as in Example 1 to give C4F9—O—CF2C(CF3)2CF2Cl. 20.0 g of the latter chloride was mixed with 5.3 g water-wet Raney Ni and 50 mL of NH3-saturated methanol. The mixture was left shaking on a Parr hydrogenation apparatus for 3 days at about 25° C., with most of the 21 kPa (3 psig) hydrogen pressure drop occurring in the first day. The product was recovered by filtration and quenched in water, yielding 7.9 g with some mechanical loss. 19F-nmr confirmed the product to be C4F9—O—CF2C(CF3)2CF2H. A scaleup to 100 g gave 47 g, distilled to b.p 135° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([C:12]3[N:13]([C:21]4[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=4)[N:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=3)[O:8][C:7](=[O:28])[C:6]=2[CH:5]=[C:4]2[NH:29][CH:30]=[N:31][C:3]=12.[CH:32]([NH2:35])([CH3:34])[CH3:33]>>[CH:32]([NH:35][C:7]([C:6]1[C:11]([NH:10][C:9]([C:12]2[N:13]([C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[N:14]=[C:15]([C:17]([F:19])([F:20])[F:18])[CH:16]=2)=[O:8])=[C:2]([Cl:1])[C:3]2[N:31]=[CH:30][NH:29][C:4]=2[CH:5]=1)=[O:28])([CH3:34])[CH3:33]
Reactant: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2c(Cl)c3nc[nH]c3cc12
Reactant: CC(C)N
Product: CC(C)NC(=O)c1cc2[nH]cnc2c(Cl)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
See step f) of example H2 with 4-chloro-6-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-1H-7-oxa-1,3,5-triaza-cyclopenta[b]naphthalen-8-one as starting material and 2 equivalents of isopropylamine. After overnight stirring at ambient temperature, 2 equivalents of amine were added and the reaction is stopped after 5 hours. After purification by flash chromatography on silica gel, a white solid is obtained in 50% yield. m.p.: 200-203° C.; LC/MS: 526/528 (M+1)+.
Reaction SMILES: C([O:8][C:9]1C=CC=C[C:10]=1[C:11]([OH:13])=[O:12])C1C=CC=CC=1.C1C([N+:24]([O-])=O)=CC=C(O)C=1.C1(N=C=NC2CCCCC2)CCCCC1.[N+:43]([C:46]1[CH:51]=[CH:50][C:49]([C:52]2[C:53]([O:61][CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)=[C:54]([CH:58]=[CH:59][CH:60]=2)[C:55]([O-:57])=[O:56])=[CH:48][CH:47]=1)([O-:45])=[O:44]>C(OCC)(=O)C.O1CCCC1.C(N(CC)CC)C>[N+:43]([C:46]1[CH:51]=[CH:50][C:49]([C:52]2[C:53]([O:61][CH2:62][C:63]3[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=3)=[C:54]([CH:58]=[CH:59][CH:60]=2)[C:55]([O-:57])=[O:56])=[CH:48][CH:47]=1)([O-:45])=[O:44].[NH2:24][C@H:10]([C:11]([OH:13])=[O:12])[CH2:9][OH:8]
Reactant: O=C(O)c1ccccc1OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])c1cccc(-c2ccc([N+](=O)[O-])cc2)c1OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: N[C@@H](CO)C(=O)O

Procedure:
2-Benzyloxybenzoic acid 4 was then reacted with p-nitrophenol 5 and dicyclohexylcarbodiimide (DCC) in ethyl acetate to produce, after work-up, 4-nitrophenyl-2-(benzyloxy)benzoate 6 in 45% yield. Treatment of the benzoate 6 with L-serine 7 and triethylamine (TEA) in tetrahydrofuran (THF)/water gave the protected E/D fragment 8 of Exochelin 786SM(R) in 79% yield. This segment undergoes subsequent reaction with a protected form of the C/F fragment to generate the largest subunit of the target compound.
Reaction SMILES: [CH:1]1([C:4](=[N:6][OH:7])[NH2:5])[CH2:3][CH2:2]1.[C:8]1(C)C=CC=C[CH:9]=1.C([C:17]([CH2:24]C)([C:21]([O-:23])=[O:22])C([O-])=O)C>C(O)C.O>[CH2:8]([O:23][C:21](=[O:22])[CH2:17][C:24]1[O:7][N:6]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[N:5]=1)[CH3:9]
Reactant: CCC(CC)(C(=O)[O-])C(=O)[O-]
Reactant: NC(=NO)C1CC1
Reactant: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1nc(C2CC2)no1
Temperature: 25 °C

Procedure:
A 20 gallon glass-lined vessel was charged with cyclopropylcarboxamide oxime (5) (5.39 kg, 53.9 Mol), toluene (Shell Chem, 324, 54.0 l) and diethylmalonate (Lancaster B/N 52068785, 24.5 kg, 160 Mol) under nitrogen at room temperature. The stirred reaction mixture was heated at gentle reflux for 21 h. The ethanol/water produced during the reaction was periodically drawn off to maintain a high reflux temperature (i.e 105°-110° C.). The reaction mixture was cooled to room temperature, washed with 25% saturated brine (3×5 l) and the toluene removed under reduced pressure. The residue was distilled using a small fractionating column to give: a) recovered diethylmalonate b.p. 60°-70° C. at 2 mbar; and b) oxadiazole-ester (6) b.p. 90°-120° C., at ~ 2 mbar.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][C:36](=[O:39])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>C1COCC1>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][C:36]([OH:39])([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCC[Sn](CCCC)(CCCC)C1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 49 %

Procedure:
Scheme IIb, step A: Diisopropylamine (25.2 mL, 0.18 mol) in anhydrous THF (500 mL) was cooled to 0° C. and n-butyllithium (112.5 mL of a 1.6 M solution in THF, 0.18 mol) was added dropwise over 20 minutes to the cooled solution. The reaction mixture was stirred for an additional 15 minutes at 0° C. and then tri-n-butyltinhydride (48.4 mL, 0.18 mol) was added dropwise over 30 minutes. The reaction mixture was then stirred for one hour and then cooled to −78° C. N-(t-butoxycarbonyl)-4-piperidone (30.0 g, 0.15 mol) in THF (500 mL) was then added dropwise to the cooled solution over one hour. After addition was complete, the reaction was stirred for 2 hours at −78° C. and then quenched with buffer (pH 6). The mixture was extracted with ethyl acetate, the organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography (5% ethyl acetate/hexane to provide 1-(t-butoxycarbonyl)-4-hydroxy-4-tributylstannyl piperidine (36.06 g).
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])=[CH2:2].[C:14]([O:18][CH3:19])(=[O:17])[CH:15]=[CH2:16].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.O>CN(C=O)C.C(OCC)(=O)C>[CH3:19][O:18][C:14](=[O:17])[CH2:15][CH2:16][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:4]([C:1]([CH3:3])=[CH2:2])[C:5]1=[O:13]
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Reactant: C=CC(=O)OC
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C(C)n1c(=O)n(CCC(=O)OC)c2ccccc21
Temperature: 25 °C
Yield: 64.3 %

Procedure:
To a stirred solution of 1-Isopropenyl-1,3-dihydro-benzimidazol-2-one (5 g, 28.7 mmol) in DMF (20 ml) was added methyl acrylate (2.8 ml, 31.6 mmol) followed by benzyltrimethylammonium hydroxide (Triton B, 40 wt % in MeOH, 3.2 ml). The resulting solution was stirred at ambient temperature until the reaction was complete. After this time the reaction was poured into water and ethyl acetate. The layers were separated and the aqueous phase was extracted twice more with ethyl acetate. The combined organic layers were dried (MgSO4), filtered and concentrated to give the crude product which was purified via column chromatography (silica gel, 30% ethyl acetate/hexanes). The product-containing fractions were combined and concentrated to give 4.8 g (64%) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8](=[O:35])[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)(=[O:28])=[O:27])=[CH:22][CH:21]=1)=[C:10]([CH2:17][CH3:18])[NH:11]2.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[C:49](OC(=O)C)([F:51])[F:50]>O>[CH3:1][O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:35][CH:49]([F:51])[F:50])=[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)(=[O:28])=[O:27])=[CH:24][CH:25]=1)[C:10]([CH2:17][CH3:18])=[N:11]2
Reactant: CC(=O)OC(F)(F)Cl
Reactant: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(S(=O)(=O)N2CCOCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(S(=O)(=O)N2CCOCC2)cc1
Temperature: 80 °C
Reaction time: 17 h

Procedure:
A mixture of {2-ethyl-8-fluoro-3-[4-(morpholine-4-sulfonyl)benzyl]-4-oxo-1,4-dihydroquinolin-5-yloxy}acetic acid methyl ester (0.14 g), N,N-dimethylformamide (3.0 mL), potassium carbonate (0.12 g) and acetic acid chlorodifluoromethyl ester (0.15 mL) was stirred at 80° C. for 17 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and dichloromethane (1:1 by volume) gave title compound, 0.092 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]2[C:16]3=[CH:17][N:18]=[CH:19][CH:20]=[C:15]3[C:14]([CH2:21][CH2:22][NH:23]C(=O)OC(C)(C)C)=[CH:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]2[C:16]3=[CH:17][N:18]=[CH:19][CH:20]=[C:15]3[C:14]([CH2:21][CH2:22][NH2:23])=[CH:13]2)(=[O:10])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(S(=O)(=O)n2cc(CCNC(=O)OC(C)(C)C)c3ccncc32)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(S(=O)(=O)n2cc(CCN)c3ccncc32)c1
Reaction time: 2 h

Procedure:
A solution of t-Butyl [2-{1-(3-methoxybenzene-sulfonyl)-1H-pyrrolo[2,3-c]pyridin-3-yl}-ethyl]carbamate in CH2Cl2 is treated with trifluoroacetic acid, stirred for 2 h and concentrated in vacuo. The resultant residue is purified by preparative reverse phase HPLC to afford the title final product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[N:10]=[C:11]=[O:12])[CH:3]=1.C(N(CCCC)CCCC)CCC.O(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[C:11](=[O:12])[NH:10][CH:9]=[CH:8]2
Reactant: O=C=N/C=C/c1cccc(Br)c1
Solvent: CCCCN(CCCC)CCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=c1[nH]ccc2cc(Br)ccc12
Temperature: 210 °C
Yield: 30.4 %

Procedure:
A solution of (E)-1-bromo-3-(2-isocyanatovinyl)benzene (100 g, 0.44 mol) in toluene (200 mL) was added dropwise to a mixture of tributylamine (100 mL) and oxydibenzene (500 mL) at 190° C. After the addition, the mixture was heated at 210° C. for another two hours. Thin layer chromatography (petroleum ether/ethyl acetate=1:1) indicated the reaction was complete. The mixture was cooled to room temperature, filtered, and the solid was washed with ethyl acetate (50 mL×3). The solid was dried under vacuum to give crude 6-bromoisoquinolin-1(2H)-one (30 g, 30%) as a light yellow solid, which was used in the next step directly.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([F:10])[C:3]=1[SH:11].[CH3:12][O:13][C:14]([CH2:16][C:17]1[CH:18]=[C:19]([CH2:23][C:24](Cl)=O)[CH:20]=[CH:21][CH:22]=1)=[O:15]>CN1CCCC1=O.O>[F:8][C:7]1[C:2]2[N:1]=[C:24]([CH2:23][C:19]3[CH:18]=[C:17]([CH2:16][C:14]([O:13][CH3:12])=[O:15])[CH:22]=[CH:21][CH:20]=3)[S:11][C:3]=2[C:4]([F:10])=[CH:5][C:6]=1[F:9]
Reactant: Nc1c(F)c(F)cc(F)c1S
Reactant: COC(=O)Cc1cccc(CC(=O)Cl)c1
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)Cc1cccc(Cc2nc3c(F)c(F)cc(F)c3s2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
To a solution of monomethyl 1,3-phenylene diacetate (531 mg, 2.6 mmol) in benzene (5 ml) was gradually added thionyl chloride (607 mg, 5.2 mmol). The mixture was heated to reflux for 2 hours. An excess of thionyl chloride was then distilled off in vacuo leaving 3-methoxycarbonylmethylphenylacetyl chloride. 2-Amino-3,4,6-trifluorothiophenol (507 mg, 2.8 mmol) was dissolved in N-methylpyrrolidone (NMP, 5 ml) under a nitrogen stream. To the resultant solution was gradually added the product 3-methoxycarbonylmethylphenylacetyl chloride thus obtained and the mixture was stirred at 100° C. for 2 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried and then evaporated to yield a residue, which was purified on a silica gel column to give methyl 3-[(4,5,7-trifluorobenzothiazol-2-yl)methyl]phenylacetate (267 mg, 27%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][NH:7][CH3:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:18](Br)[C:19]#[CH:20]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][N:7]([CH2:20][C:19]#[CH:18])[CH3:8])=[CH:4][CH:3]=1
Reactant: CNCc1ccc(Cl)cc1
Reactant: C#CCBr
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C#CCN(C)Cc1ccc(Cl)cc1

Procedure:
To a solution of 31.1 g (0.2 mole) N-(4-chlorobenzyl)-methylamine and 30.3 g (0.3 mole) triethylamine in 150 ml dry benzene are added in portions at room temperature while stirring 23.8 g (0.2 mole) propargyl bromide. The solution is heated for 17 hours with reflux. After filtering off the solid phase, the the solvent is distilled under vacuum and the remaining residue fractionally distilled under reduced pressure. One thus obtains 30.9 g N-(4-chlorobenzyl)-N-methyl-2-propinylamine (79% of the theory as colorless liquid of the boiling point 86°-106° C./2 Torr.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([OH:9])=O)[CH2:5][C:4]([CH3:10])=[N:3]1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:31]=[CH:32][C:33]=1[F:34])[O:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH:22]=[C:23]([NH:25][C:26]([CH:28]3[CH2:30][CH2:29]3)=[O:27])[N:24]=2)[N:21]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:28]1([C:26]([NH:25][C:23]2[N:24]=[C:19]3[CH:18]=[CH:17][C:16]([O:15][C:14]4[CH:31]=[CH:32][C:33]([F:34])=[C:12]([NH:11][C:7]([CH:6]5[N:2]([CH3:1])[N:3]=[C:4]([CH3:10])[CH2:5]5)=[O:9])[CH:13]=4)=[N:21][N:20]3[CH:22]=2)=[O:27])[CH2:29][CH2:30]1
Reactant: CC1=NN(C)C(C(=O)O)C1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1=NN(C)C(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2F)C1
Yield: 63.3 %

Procedure:
In the same manner as in Example 278 and using 1,3-dimethyl-4,5-dihydro-1H-pyrazole-5-carboxylic acid (170 mg, 1.2 mmol), N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (280 mg, 0.84 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (450 mg, 1.2 mmol), N,N-diisopropylethylamine (330 mg, 2.5 mmol) and N,N-dimethylformamide (7 mL) as starting materials, the title compound (240 mg, 63%) was obtained as a white solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[N:13]2[C:8]([C:9]([NH2:14])=[N:10][CH:11]=[N:12]2)=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=3[F:35])=[O:23])=[CH:17][CH:16]=2)[CH:6]=1)=[O:4].[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>C1COCC1.CCOC(C)=O.C1(C)C=CC=CC=1>[NH2:14][C:9]1[C:8]2=[C:7]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=4[F:35])=[O:23])=[CH:17][CH:16]=3)[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[N:13]2[N:12]=[CH:11][N:10]=1
Reactant: C1COCCN1
Reactant: Nc1ncnn2c(C(=O)CBr)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)c12
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Nc1ncnn2c(C(=O)CN3CCOCC3)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)c12
Reaction time: 0.25 h

Procedure:
A solution of N-[4-(7-bromoacetyl-4-aminopyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]urea (65 mg, 0.12 mmol) in 2 mL THF was treated with morpholine (53 uL, 0.59 mmol) and allowed to stir for 15 min. The reaction was then diluted with 50 mL EtOAc and 5 mL toluene & washed with sodium carbonate solution (1×). The organic layer dried with sodium sulfate and concentrated to give a yellow oil. Trituration with Et2O:hexanes (1:1) gave the title compound as a faintly yellow powder (52.4 mg, 79% Yield). 1H-NMR (DMSO-d6) 9.28 (s, 1H), 8.84 (s, 1H), 8.43 to 8.47 (m, 1H). 7.95 (s, 1H), 7.42 (d, J=8.7 Hz, 2H), 7.19 to 7.31 (m, 3H) 7.25 (d, J=8.7 Hz, 2H), 7.17 (s, 1H), 3.76 (s, 2H), 3.38 to 3.43 (m, 4H), 2.35 to 2.41 (m, 4H); MS [M+H]+=557.9; LCMS RT=2.57.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.Cl[CH2:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)=O.C([O:33]CC)C>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][CH:20]2[CH2:21][CH2:22][N:17]([CH:15]([NH:1][C:2]3[CH:12]=[CH:11][C:5]4[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=4[CH:3]=3)[CH:14]=[O:33])[CH2:18][CH2:19]2)=[CH:25][CH:26]=1
Reactant: Nc1ccc2c(c1)OCC(=O)N2
Reactant: O=C(CCl)N1CCC(Cc2ccc(F)cc2)CC1
Reactant: CCOCC
Product: O=CC(Nc1ccc2c(c1)OCC(=O)N2)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from 7-amino-4H-benzo[1,4]oxazine-3-one and 2-chloro-1-[4-(4-fluoro-benzyl)-piperidin-1-yl]-ethanone (Example 197a) according to the method described in Example 142b. Melting Point: 156-161° C. (diethylether).