Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[C:21]([C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH2:26])(=[O:23])[CH3:22]>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[C:21](=[O:23])[CH3:22])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: CC(=O)c1ccccc1N
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)c1ccccc1NC(=O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 16.4 %

Procedure:
A procedure similar to that described in Example 51 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (170 mg, 1 mmol) and o-acetylaniline (90 mg, 0.67 mmol) to give 50 mg of the title compound (21%) after chromatography of the crude product on a silica gel column with 1% acetic acid/ethyl acetate as an eluent: mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.06 (bs, 1H), 11.12 (s, 1H), 8.20 (bd, 1H, J=8.1 Hz), 7.96 (d, 2H, J=8.1 Hz), 7.60 (t, 1H, J=8.1 Hz), 7.23 (t, 1H, J=8.1 Hz), 7.23 (d, 1H, J =2 Hz), 7.17 (d, 1H, J=2 Hz), 5.14~5.26 (m, 1H), 3.04 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.83 (dm, 1H, J=17.1 Hz), 2.64~2.76 (m, 2H), 2.60 (s, 3H), 2.16 (dm, 1H, J=13.5 Hz), 1.82~1.97 (m, 1H).
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([OH:15])=O)=[CH:4]2.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[NH2:38][CH2:39][C:40]([N:42]1[CH2:48][CH2:47][CH2:46][N:45]([CH2:49][CH2:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:44][CH2:43]1)=[O:41].C1CCN2C(=NCCC2)CC1.C(N(CC)CC)C>C(#N)C>[C:52]1([CH2:51][CH2:50][CH2:49][N:45]2[CH2:46][CH2:47][CH2:48][N:42]([C:40]([CH2:39][NH:38][C:13]([C:5]3[S:6][C:7]4[N:12]5[C:3](=[CH:2][N:1]=[C:11]5[CH:10]=[CH:9][CH:8]=4)[CH:4]=3)=[O:15])=[O:41])[CH2:43][CH2:44]2)[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: O=C(O)C1=Cc2cnc3cccc(n23)S1
Reactant: NCC(=O)N1CCCN(CCCc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(NCC(=O)N1CCCN(CCCc2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1
Reaction time: 1 h

Procedure:
To a suspension of 1.0 g (4.58 mmol.) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid and 1.05 g (9.12 mmol.) of N-hydroxysuccinimide in acetonitrile (20 ml) was added, at room temperature, 1.76 g (9.18 mmol.) of N-ethyl-N′-3-(N,N-dimethylamino)propylcarbodimide hydrochloride. The mixture was stirred for one hour. To the reaction system was added a solution of 1.91 g (5.48 mmol.) of 1-(aminoacetyl)-4-(3-phenylpropan-1-yl)-2,3,5,6-tetrahydro-7H-1,4-diazepine dihydrochloride, 1.67 g (10.97 mmol.) of 1,8-diazabicyclo[5.4.0]unde-7-cene (DBU) and 0.7 ml (5.0 mmol.) of triethylamine in acetonitrile (20 ml). The mixture was stirred for further one hour. The solvent was distilled off under reduced pressure. To the residue was added water. The mixture was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, followed by drying over magnesium sulfate. The solvent was distilled off under reduced pressure to leave a crude product, which was purified by means of a column chromatography (methanol/ethyl acetate 30-50%) to afford the object compound as an amorphous substance.
Reaction SMILES: [CH3:1][C:2]1([CH2:19][C:20]([F:23])([F:22])[F:21])[C@@:7]2([C:8]3[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=3)[CH:5]([O:6]2)[C:4](=[O:18])[O:3]1.[K].[Br:25][C:26]1[CH:27]=[CH:28][C:29](O)=[N:30][CH:31]=1.[OH-].[K+]>CN(C)C=O.C(O)(C)C>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([O:6][C:5]2[C:4](=[O:18])[O:3][C@:2]([CH3:1])([CH2:19][C:20]([F:23])([F:22])[F:21])[C:7]=2[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[N:30][CH:31]=1
Reactant: Oc1ccc(Br)cn1
Reactant: CC1(CC(F)(F)F)OC(=O)C2O[C@]21c1ccc(S(C)(=O)=O)cc1
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: C[C@]1(CC(F)(F)F)OC(=O)C(Oc2ccc(Br)cn2)=C1c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C

Procedure:
To a 0° C. mixture of the epoxide(0.930 g) from step 1 in dimethylformamide(3 mL) and isopropanol(12 mL) was added the potassium salt of 5-bromo-2-hydroxypyridine, prepared from 5-bromo-2-hydroxypyridine and one equivalent of 8N KOH followed by evaporation to dryness with toluene and high vacuum drying, (0.742 g, 3.5 mmol) and the mixture was warmed up slowly to reflux for 16 hrs. It was then cooled to room temperature and poured on icy dilute ammonium chloride and ethyl acetate; the organic layer was separated and the aquous further extracted ounce with ethyl acetate. The combined organic layers were washed with brine, dried with MgSO4 and the solvents were removed in vacuo to yield after purification on silica gel(10% acetone/toluene) the title compound (0.380 g).
Reaction SMILES: C[Si](C)(C)O[Si](C)(C)C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=O)[CH2:33][CH:34]2[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36][CH2:35]2)=[C:27]([OH:48])[CH:26]=1.O>ClCCCl>[Br:24][C:25]1[CH:30]=[CH:29][C:28]2[N:31]=[C:32]([CH2:33][CH:34]3[CH2:35][CH2:36][NH:37][CH2:38][CH2:39]3)[O:48][C:27]=2[CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)Nc2ccc(Br)cc2O)CC1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: C[Si](C)(C)O[Si](C)(C)C
Solvent: ClCCCl
Solvent: O
Product: Brc1ccc2nc(CC3CCNCC3)oc2c1
Yield: 45.4 %

Procedure:
Hexamethyldisiloxane (1.068 g, 6.58 mmol) was added to a solution of P2O5 (0.786 g, 5.54 mmol) in dry 1,2-Dichloroethane (2.9 mL) under argon and then heated to reflux for 10 min. A solution of tert-butyl 4-(2-(4-bromo-2-hydroxyphenylamino)-2-oxoethyl)piperidine-1-carboxylate (0.41 g, 0.992 mmol) in 1,2-Dichloroethane (2.9 mL) was added and the mixture was heated to reflux for 3 h. The mixture was poured into cool water (5 mL), extracted with CH2Cl2 (3×3 mL). The organic layers were discarded. The aqueous layer and the remaining solid were brought to pH=12 using aqueous NaOH (1 N). The mixture was extracted with CH2Cl2 (3×6 mL). The combined organic layers were dried (K2CO3), filtered, and concentrated to afford desired product as an orange oil (0.133 g, HPLC purify 95%, 43% yield). 1H NMR (500 MHz, chloroform-d) δ ppm 7.65 (d, J=1.7 Hz, 1H), 7.48-7.56 (m, 1H), 7.38-7.46 (m, 1H), 3.01-3.15 (m, 2H), 2.80-2.89 (m, 2H), 2.63 (td, J=12.2, 2.1 Hz, 2H), 1.96-2.14 (m, J=15.0, 7.7, 7.6, 3.6, 3.4 Hz, 1H), 1.74 (d, J=12.7 Hz, 2H), 1.57 (br. s., 1H), 1.20-1.36 (m, 2H). LCMS (m/z)=295 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][N:7]([CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]([CH2:24][CH2:25][CH3:26])[C:16]=1[C:27]([OH:29])=O)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[CH:39]1([CH2:42][NH:43][CH2:44][CH:45]2[CH2:47][CH2:46]2)[CH2:41][CH2:40]1.FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)CN(CC1C2C(=CC=CC=2)NC=1C(O)=O)C1N=NN(C)N=1.C(NCC)C>>[CH:39]1([CH2:42][N:43]([CH2:44][CH:45]2[CH2:47][CH2:46]2)[C:27]([C:16]2[N:17]([CH2:24][CH2:25][CH3:26])[C:18]3[C:23]([C:15]=2[CH2:14][N:7]([CH2:6][C:5]2[CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=[C:3]([C:2]([F:38])([F:1])[F:37])[CH:4]=2)[C:8]2[N:9]=[N:10][N:11]([CH3:13])[N:12]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:29])[CH2:41][CH2:40]1
Reactant: CCCn1c(C(=O)O)c(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2ccccc21
Reactant: C1CC1CNCC1CC1
Agent: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2c(C(=O)O)[nH]c3ccccc23)n1
Solvent: CCNCC
Product: CCCn1c(C(=O)N(CC2CC2)CC2CC2)c(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2ccccc21

Procedure:
3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-1-propyl-1H-indole-2-carboxylic acid (0.16 g, 0.29 mmol) and bis cyclopropylmethylamine (0.37 g, 0.29 mmol) were used to synthesize the title compound instead of using 3-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-1H-indole-2-carboxylic acid and diethylamine in step (ii) of example 131 (0.08 g, 42%)
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[C:4](OC)=[O:5].[BH4-].[Na+].O.C(OCC)(=O)C>C(O)C>[F:1][C:2]([F:18])([F:19])[CH:3]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[CH2:4][OH:5]
Reactant: COC(=O)C(Nc1cccc([N+](=O)[O-])c1)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cccc(NC(CO)C(F)(F)F)c1
Reaction time: 4 h
Yield: 73.8 %

Procedure:
To a solution of methyl 3,3,3-trifluoro-2-((3-nitrophenyl)amino)propanoate (C13, 297 mg) in ethanol (10 mL), sodium borohydride (121 mg) was added at room temperature, and the mixture was stirred at the same temperature for 4 hours. To the reaction mixture, water and ethyl acetate were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 100 to 50% hexane in ethyl acetate) to obtain 3,3,3-trifluoro-2-((3-nitrophenyl)amino)propan-1-ol (C14, 197 mg).
Reaction SMILES: [OH:1][C:2]1[C:3]([O:5][C@H:6]([CH3:12])[C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[O:4].[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([O-:15])=[O:14].CN1CCOCC1.O>C1(C)C=CC=CC=1>[N+:13]([C:16]1[CH:17]=[CH:18][C:19]([S:22]([O:1][C:2]2[C:3]([O:5][C@H:6]([CH3:12])[C:7]=2[C:8]([O:10][CH3:11])=[O:9])=[O:4])(=[O:24])=[O:23])=[CH:20][CH:21]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C1=C(O)C(=O)O[C@@H]1C
Solvent: CN1CCOCC1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C(=O)O[C@@H]1C
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
34.44 g of (R)-2-hydroxy-3-methoxycarbonyl-2-penten-4-olide are dissolved in 170 ml of toluene at 40° C., 49.4 g of p-nitrobenzenesulphonyl chloride in 160 ml of toluene are added and the whole is cooled to 5° C. Within a period of 30 minutes, 20.3 g of N-methylmorpholine are metered in at from 0 ° to 5° C. 350 ml of water are added, the toluene product phase is removed, and the aqueous phase is re-extracted twice with 100 ml of toluene. The toluene phases are washed with sodium chloride solution and with water, filtered over a small amount of silica gel and concentrated by evaporation. The residue is crystallised from ethyl acetate/cyclohexane. [α]D20 =+12.4° (3% in CHCl3), m.p. 123°-124° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(O[CH:15](OC(C)C)[N:16]([CH3:18])[CH3:17])(C)C>>[CH3:15][N:16]([CH3:18])/[CH:17]=[CH:9]/[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:10]
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: CC(C)OC(OC(C)C)N(C)C
Product: CN(C)/C=C/C(=O)c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
A solution of 1-(4-chlorophenyl)ethan-1-one (3.0 g, 19.3 mmol) and N,N, dimethylformamide diisopropylacetal (20 ml) was heated at 150° C. for 16 hours. The reaction mixture was cooled to 0° C. and treated with hexanes (20 ml). The resulting solid was collected via filtration and washed with hexanes to provide the title compound: EI-MS (m/z) 209 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:18])[CH:12]=2)=[C:4]([OH:20])[CH:3]=1.Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]2[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:18])[CH:12]=3)[O:20][C:4]=2[CH:3]=1
Reactant: O=C(Nc1cc(O)c(Cl)cc1O)c1ccc(O)c(F)c1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccc(-c2nc3cc(O)c(Cl)cc3o2)cc1F

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, step b, from N-(4-chloro-2,5-dihydroxyphenyl)-3-fluoro-4-hydroxybenzamide and pyridine hydrochloride and was obtained as a white solid, m.p. 258–260° C.; MS m/e 278 (M−H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:16])[O:9][CH2:8][C:7]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)([OH:10])[CH2:6][O:5]1.Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:10][C:7]2([C:11]3[S:12][CH:13]=[CH:14][N:15]=3)[CH2:8][O:9][C:4]([CH3:16])([CH3:3])[O:5][CH2:6]2)=[CH:20][CH:21]=1
Reactant: CC1(C)OCC(O)(c2nccs2)CO1
Reactant: COc1ccc(CCl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1ccc(COC2(c3nccs3)COC(C)(C)OC2)cc1
Reaction time: 0.5 h

Procedure:
To an ambient suspension of sodium hydride (1.136 g, 47.3 mmol) in N,N-dimethylformamide (126 ml) was added 2,2-dimethyl-5-(thiazol-2-yl)-1,3-dioxan-5-ol (Example 11A) (8.15 g, 37.9 mmol) as a solution in N,N-dimethylformamide (20 mL). The reaction was stirred for 30 minutes, and tetrabutylammonium iodide (0.699 g, 1.893 mmol) and 1-(chloromethyl)-4-methoxybenzene (6.42 ml, 47.3 mmol) were sequentially added. The reaction was stirred overnight and then quenched by the addition of saturated aqueous ammonium chloride solution and ethyl acetate. The layers were separated, and the aqueous layer was extracted with additional ethyl acetate (2×). The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 40% ethyl acetate in hexane, to give the title product. MS ESI(+) m/z 336.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B(O)O)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:18]1[CH:19]=[CH:20][C:21]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[C:22]([CH:32]=1)[C:23]([NH:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)=[O:24]>O.COCCOC.C(OCC)(=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>[F:1][C:2]1[CH:7]=[C:6]([C:18]2[CH:19]=[CH:20][C:21]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:22]([CH:32]=2)[C:23]([NH:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[O:24])[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Nc1cccnc1)c1cc(-c2ccnc(F)c2)ccc1OCc1ccccc1

Procedure:
(2-Fluoro-4-pyridinyl)boronic acid (425 mg, 3.02 mmol), bis(triphenylphosphine)palladium(II) chloride (70.6 mg, 0.10 mmol) and sodium carbonate (1066 mg, 10.06 mmol) as a solution in 2 ml of water was added to a solution of 5-bromo-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in example 2; 771 mg, 2.01 mmol) in 1,2-dimethoxyethane (20 ml). The mixture was heated to reflux for 2 hours. The mixture was diluted with ethyl acetate (50 ml) and water (50 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×50 ml). The organics were combined and evaporated. The residue was purified by chromatography on silica eluting with 0-10% methanol/dichloromethane 1% ammonia to yield the title compound as an off-white solid. 500 mg.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][N:15]=[C:14]2[N:23]1[CH2:28][CH2:27][CH:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]1.O>CS(C)=O.CCOCC>[CH3:30][C:29]1([CH:26]2[CH2:27][CH2:28][N:23]([C:14]3[C:13]4[C:18](=[CH:19][C:20]([O:21][CH3:22])=[C:11]([O:10][CH3:9])[CH:12]=4)[N:17]=[CH:16][N:15]=3)[CH2:24][CH2:25]2)[CH2:2][O:31]1
Reactant: COc1cc2ncnc(N3CCC(C(C)=O)CC3)c2cc1OC
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2ncnc(N3CCC(C4(C)CO4)CC3)c2cc1OC

Procedure:
Trimethylsulphoxonium iodide (2.25 g) was added portionwise to a stirred suspension of sodium hydride (0.5 g of a 50% dispersion in oil) in dimethylsulphoxide (20 cm3) and the mixture was stirred for 1 hour after which time 6,7-dimethoxy-4-[4-(1-oxoethyl)piperid-1-yl]quinazoline (3.15 g) was added in DMSO (10 cm3). After 1 hour the mixture was poured into water (50 cm3), extracted with dichloromethane (3×50 cm3) and the dried extracts (MgSO4) were evaporated to give an oil which was chromatographed on silica (Merck 60.9385) eluting with chloroform to give a viscous oil. Trituration with ether gave 2-methyl-2-[1-(6,7-dimethoxyquinazolin-4-yl)piperid-4-yl]oxirane slightly contaminated with the starting ketone (2.0 g).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:35])[C@@H:24]([NH:26][C:27](=[O:34])[C@H:28]([CH:30]4[CH2:33][CH2:32][CH2:31]4)[OH:29])[CH3:25])[NH:18]3)=[O:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[CH3:36][C:37]([CH3:43])([CH:41]=[CH2:42])[C:38]([OH:40])=[O:39].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH:30]1([C@H:28]([OH:29])[C:27]([NH:26][C@@H:24]([CH3:25])[C:23]([N:19]2[CH2:20][CH2:21][CH2:22][C@@H:17]([C:15]([NH:14][C@@H:12]([C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2](/[CH:42]=[CH:41]/[C:37]([CH3:43])([CH3:36])[C:38]([OH:40])=[O:39])=[CH:3][CH:4]=4)[N:9]=3)[CH3:13])=[O:16])[NH:18]2)=[O:35])=[O:34])[CH2:33][CH2:32][CH2:31]1
Reactant: C=CC(C)(C)C(=O)O
Reactant: C[C@H](NC(=O)[C@@H](O)C1CCC1)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C[C@H](NC(=O)[C@@H](O)C1CCC1)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(/C=C/C(C)(C)C(=O)O)cc3n2)N1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
A solution of (S)-1-[(S)-2-((S)-2-cyclobutyl-2-hydroxy-acetylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide (427.5 mg, 0.782 mmol), 2,2-dimethyl-but-3-enoic acid (89.3 mg, 0.782 mmol), tri(o-tolyl)phosphine (47.6 mg, 0.156 mmol) and triethylamine (0.33 mL, 2.346 mmol) in 1,4-dioxane (10 mL) was degassed by bubbling nitrogen through for 5 minutes then warmed to 50° C. and treated with tris(dibenzylideneacetone)dipalladium(0) (71.6 mg, 0.078 mmol). After stirring at 100° C. for 1.5 h, tris(dibenzylideneacetone) dipalladium(0) (71.6 mg, 0.078 mmol) and tri(o-tolyl)phosphine (47.6 mg, 0.156 mmol) were added. After stirring for 40 minutes at 100° C., the reaction was cooled to room temperature, filtered through a pad of Celite, which was rinsed with ethyl acetate. The volatiles were removed in vacuo to provide crude title compound as an orange foam that was used without further purification. LCMS (m/z) 580.2 [M+H], Tr=2.01 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][CH:5]=1)[CH3:2].[F:16][C:17]([F:41])([F:40])[CH2:18][NH:19][C:20]([C:22]1([CH2:35][CH2:36][CH2:37][CH2:38]Br)[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:21]>>[F:16][C:17]([F:40])([F:41])[CH2:18][NH:19][C:20]([C:22]1([CH2:35][CH2:36][CH2:37][CH2:38][N:13]2[CH2:12][CH2:11][N:10]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([O:3][CH2:1][CH3:2])[N:9]=3)[CH2:15][CH2:14]2)[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:21]
Reactant: CCOc1cccc(N2CCNCC2)n1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: CCOc1cccc(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)n1

Procedure:
Prepared analogously to Example 2 b from 1-(6-ethoxy-pyridin-2-yl)-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]1[N:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:14]=1[C:15]([OH:17])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C)C=O>[CH2:1]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]1[N:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:14]=1[C:15]([NH:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1)=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: O=C(O)c1cc(Cl)cnc1N1CCCC1Cc1ccccc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CCCC3Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
A mixture of 2-(2-benzylpyrrolidin-1-yl)-5-chloronicotinic acid (D100) (70 mg, 0.22 mmol), methyl 4-(1-aminocyclopropyl)benzoate (D7) (50.31 mg, 0.22 mmol) and N,N-Diisopropylethylamine (0.115 ml, 0.66 mmol) in dimethylformamide (5 ml) was stirred at room temperature for 1 h. (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP) (137.9 mg, 0.265 mmol) was added and the resulting mixture was stirred overnight at room temperature. The reaction mixture was poured into ice-water and extracted with diethyl ether (3×15 ml). The combined organic layers were washed with brine (2×10 ml), dried over Na2SO4, filtered and concentrated. The crude residue was purified by Biotage column (10 g) eluting with a mixture dichloromethane/ethylacetate from 100/0 to 90/10. Collected fractions, after solvent evaporation, afforded the title compound (D144) (66 mg)