Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:5]2=[N:6][C:7]=1Cl.B(O)(O)[C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.O.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:18]1([CH3:21])[CH:17]=[CH:16][C:15]([C:2]2[N:3]=[C:4]3[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:5]3=[N:6][C:7]=2[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:20][CH:19]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=C1CCc2nc(Br)c(Cl)nc2N1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)NC(=O)CC3)cc1
Temperature: 80 °C
Reaction time: 66 h

Procedure:
To a stirrred suspension of 2-bromo-3-chloro-7,8-dihydropyrido[2,3-b]pyrazin-6(5H)-one (Intermediate J) (10 g, 38.1 mmol), p-tolylboronic acid (11.39 g, 84 mmol) in MeCN (400 ml) and water (100 ml) under N2 supply, was added solid K2CO3 (fine mesh) (7.90 g, 57.1 mmol) followed by Pd(PPh3)2Cl2 (1.337 g, 1.905 mmol). The yellow RM was heated to 80° C. and was left stirring for 66 hours. The RM was allowed to cool slowly to RT and then placed in the fridge for 3-4 hours. The fine yellow needles were filtered off under suction and were washed with small quantity of acetonitrile, followed by water. After air drying for 10 min, the solid was transferred, dried in vacuo at 40° C. for 2 hours, to afford the title compound as fine crystalline needles;
Reaction SMILES: [CH3:1][C:2]1([CH3:7])[CH2:6][O:5][CH:4]=[N:3]1.[CH3:8][I:9]>>[I-:9].[CH3:8][N+:3]1[C:2]([CH3:7])([CH3:1])[CH2:6][O:5][CH:4]=1
Reactant: CI
Reactant: CC1(C)COC=N1
Product: C[N+]1=COCC1(C)C
Product: [I-]

Procedure:
To 8-phenyloctylmagnesium bromide (from 24.25 mmol of 8-phenyloctyl bromide and 21.27 mmol of magnesium) in distilled tetrahydrofuran (40 ml) was added 2-(2-methoxyphenyl)-4,4-dimethyloxazoline (17.10 mmol) [A. I. Meyers et al., J. org. Chem., 43, 1372 (1978)] in tetrahydrofuran (20 ml). After stirring for 24 hours, the reaction mixture was worked up to yield 2-12-(8-phenyloctyl)phenyl]-4,4-dimethyloxazoline as an oil. A solution of the oxazoline (11.58 mmol) in methyl iodide (20 ml) was refluxed under argon for 18 hours. Removal of the volatiles afforded the corresponding 3,4,4-trimethyloxazolinium iodide as a white solid (mp 76.5°-78° C.).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Cl[CH2:7][C:8]([OH:10])=[O:9]>CC(OC)(C)C>[CH2:1]([N:3]([CH2:7][C:8]([OH:10])=[O:9])[CH2:4][CH3:5])[CH3:2]
Reactant: O=C(O)CCl
Reactant: CCNCC
Solvent: COC(C)(C)C
Product: CCN(CC)CC(=O)O
Temperature: 3 °C

Procedure:
Diethylamine (9.5 L) was charged into a 20 L glass-lined reactor and cooled to 3° C. Chloroacetic acid (1.21 kg) in MTBE (1.8 L) was added over 1 hour with cooling—the temperature rose to 16° C. during the addition. The mixture was warmed to 20° C., stirred over night and concentrated on rotary evaporator giving yellow oil. This oil was re-concentrated with iPrOAc, mixed with iPrOAc (4.5 L) and stirred over night. The off-white hygroscopic precipitate was filtered, washed with iPrOAc (1.5 L) and immediately placed into a drying cabinet to avoid deliquescence. After drying, titled product was obtained (820 g, Y=49%).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC([N:15]1[C@@H:19]([CH3:20])[CH2:18][CH2:17][C@H:16]1[C:21]1[NH:22][CH:23]=[C:24]([C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[CH:32]=[C:31]([C:36]2[CH:41]=[CH:40][C:39]([C:42]4[N:43]=[C:44]([C@@H:47]5[CH2:51][CH2:50][C@H:49]([CH3:52])[N:48]5C(OC(C)(C)C)=O)[NH:45][CH:46]=4)=[CH:38][CH:37]=2)[CH:30]=[CH:29]3)[N:25]=1)=O)(C)(C)C.C(Cl)Cl>ClCCCl>[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[CH3:52][C@@H:49]1[NH:48][C@H:47]([C:44]2[NH:45][CH:46]=[C:42]([C:39]3[CH:40]=[CH:41][C:36]([C:31]4[CH:30]=[CH:29][C:28]5[C:33](=[CH:34][CH:35]=[C:26]([C:24]6[N:25]=[C:21]([C@@H:16]7[CH2:17][CH2:18][C@H:19]([CH3:20])[NH:15]7)[NH:22][CH:23]=6)[CH:27]=5)[CH:32]=4)=[CH:37][CH:38]=3)[N:43]=2)[CH2:51][CH2:50]1
Reactant: C[C@H]1CC[C@@H](c2nc(-c3ccc(-c4ccc5cc(-c6c[nH]c([C@@H]7CC[C@H](C)N7C(=O)OC(C)(C)C)n6)ccc5c4)cc3)c[nH]2)N1C(=O)OC(C)(C)C
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1CC[C@@H](c2nc(-c3ccc(-c4ccc5cc(-c6c[nH]c([C@@H]7CC[C@H](C)N7)n6)ccc5c4)cc3)c[nH]2)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
TFA (0.500 mL, 6.49 mmol) was added dropwise to a stirred solution of tert-butyl (2S,5S)-2-(4-(4-(6-(2-((2S,5S)-1-(tert-butoxycarbonyl)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-5-methyl-1-pyrrolidinecarboxylate (228 mg, 0.324 mmol) in DCE (6 mL). During the addition, precipitate formed which hindered the stirring. DCM (˜10 mL) was added and the slurry was stirred while the remaining TFA was added. The reaction was stirred at rt for 30 min, additional TFA was added (˜0.5 mL) and the reaction was stirred 3 h. The reaction was concentrated to yield a TFA salt of 2-((2S,5S)-5-methyl-2-pyrrolidinyl)-4-(4-(6-(2-((2S,5S)-5-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazole (102 mg, 113 mg, 114 mg) as an orange solid. LC-MS retention time 2.756 min; m/z 503.14 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where Solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and Solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, MeOD) δ ppm 8.32 (s, 1H), 8.17 (s, 1H), 8.01 (app t, J=8.2 Hz, 2H), 7.85-7.95 (m, 6H), 7.80 (s, 1H), 7.73 (s, 1H), 5.02 (app q, J=8.0 Hz, 2H), 3.92 (dddd, J=8.7, 7.0, 6.9, 4.8 Hz, 2H), 2.52-2.67 (m, 4H), 2.38-2.49 (m, 2H), 1.95-2.07 (m, 2H), 1.55 (app dd, J=6.7, 4.4 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([O:23][CH3:24])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[N:44]1([CH2:49][CH2:50][NH2:51])[CH2:48][CH2:47][CH2:46][CH2:45]1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:51][CH2:50][CH2:49][N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:42])=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: NCCN1CCCC1
Reactant: COc1cc(Oc2ncnc3cc(OC)c(OC)cc23)ccc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc(Oc2ncnc3cc(OC)c(OC)cc23)ccc1NC(=O)NCCN1CCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 18.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-methoxyaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (140 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, 2-tetrahydro-1H-1-pyrrolyl-1-ethanamine (54 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (26 mg, yield 18%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH:29]([F:31])[F:30])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][C:23]([F:26])([F:25])[F:24])[C:17](O)=[O:18])[C:10](=[O:27])[CH:9]=2)[CH:7]=1.[NH2:32][C:33]1[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:35][CH:34]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH:29]([F:30])[F:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][C:23]([F:26])([F:25])[F:24])[C:17]([NH:32][C:33]3[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])=[CH:35][CH:34]=3)=[O:18])[C:10](=[O:27])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CCOC(F)(F)F)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1OC(F)F
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: COc1cn(C(CCOC(F)(F)F)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1OC(F)F

Procedure:
290 mg (purity 93%, 0.57 mmol) of 2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-(trifluoromethoxy)butanoic acid (racemate) and 122 mg (0.63 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 195 mg (50% of theory)
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]=1[C:7]#[N:8].[CH3:13][CH:14]([CH2:18][CH2:19][Cl:20])[C:15](Cl)=[O:16]>C1C=CC=CC=1>[Cl:20][CH2:19][CH2:18][CH:14]([CH3:13])[C:15]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]=1[C:7]#[N:8])=[O:16]
Reactant: CC(CCCl)C(=O)Cl
Reactant: CC(C)(C)c1csc(N)c1C#N
Solvent: c1ccccc1
Product: CC(CCCl)C(=O)Nc1scc(C(C)(C)C)c1C#N
Yield: 56.6 %

Procedure:
A mixture of 4.0 g of 2-amino-3-cyano-4-(1,1-dimethylethyl)thiophene and 4.0 g of 2-methyl-4-chlorobutyryl chloride dissolved with 100 ml benzene was refluxed for about 72 hours. The solvent was evaporated under reduced pressure and the residue was chromatographed while eluting with a 90/10 mixture of Skellysolve B/ethyl acetate. Fractions containing the major component were combined and the solvent was evaporated therefrom to afford 3.75 g of 4-chloro-N-[3-cyano-4-(1,1-dimethylethyl)-2-thienyl]-2-methylbutanamide. mp=115°-116° C. Yield 57%.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Cl[C:10]1[N:19]=[C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.CCN(C(C)C)C(C)C.[OH-].[Na+]>C(#N)CCC.C(OCC)(=O)C>[NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:10]2[N:19]=[C:18]([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH2:5][CH2:4]1
Reactant: CCN(CC)c1nc(Cl)nc2ccccc12
Reactant: NCC1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CCCC#N
Product: CCN(CC)c1nc(N2CCC(CN)CC2)nc2ccccc12

Procedure:
A mixture of 4-(aminomethyl)-piperidine (1.2 g, 11 mmol), 2-chloro-4-diethylaminoquinazoline (2.5 g, 11 mmol) and Hunig's base (2.8 ml, 16 mmol) in 5 ml of butyronitrile was reacted for 12 hours at 100° C. After cooling, ethyl acetate (50 ml) and 50 ml of sodium hydroxide (10%) were added. The phases were separated and the aqueous phase was extracted with ethyl acetate (2×25 ml). The combined organic phases were dried (Na2SO4), concentrated on a rotary evaporator and purified by chromatography on silica gel (eluent: methylene chloride/ethanol/ammonia, 50/10/1) to give the free base as a thick orange-brown oil.
Reaction SMILES: Cl[CH2:2][Si:3]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[O:4]C(C)C.[Na].[NH:23]1[CH:27]=[N:26][CH:25]=[N:24]1>CN(C)C=O>[F:14][C:11]1[CH:12]=[CH:13][C:8]([Si:3]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)([OH:4])[CH2:2][N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)=[CH:9][CH:10]=1
Reactant: c1nc[nH]n1
Reactant: CC(C)O[Si](CCl)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Na]
Solvent: CN(C)C=O
Product: O[Si](Cn1cncn1)(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 2 h
Yield: 30.9 %

Procedure:
A mixture of 10.0 g (30.6 mmol) of chloromethyl[bis(4-fluorophenyl)](2-propoxy)silane and 3.1 g (30.6 mmol) of 1,2,4-triazole sodium salt in dimethylformamide was stirred at 80°-90° under nitrogen for 2 hours. Workup as in Example 37 gave a waxy solid that was washed with 1:1 ether-hexanes to leave 3.0 g (30%) of the title compound. Recrystallization from chlorobutane gave a purer sample: m.p. 130°-131°; nmr (CDCl3) 4.1 (2H, s), 5.8 (1H, broad s), 7.1 (4H, t), 7.7 (4H, d of d), 7.8 (1H, s), 8.0 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(F)cc4)c32)c(C)c1C(=O)NCCn1ccnn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 36.4 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (42.8 mg, 36%).
Reaction SMILES: [OH:1][C:2]1([C:7]#[CH:8])[CH2:6][CH2:5][NH:4][CH2:3]1.[C:9]([C:12]1[CH:13]=[C:14](/[CH:17]=[C:18]2\[C:19](=[O:29])[NH:20][C:21]3[C:26]\2=[C:25](I)[C:24]([F:28])=[CH:23][CH:22]=3)[NH:15][CH:16]=1)(=[O:11])[CH3:10]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[C:9]([C:12]1[CH:13]=[C:14](/[CH:17]=[C:18]2\[C:19](=[O:29])[NH:20][C:21]3[C:26]\2=[C:25]([C:8]#[C:7][C:2]2([OH:1])[CH2:6][CH2:5][NH:4][CH2:3]2)[C:24]([F:28])=[CH:23][CH:22]=3)[NH:15][CH:16]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(I)c32)c1
Reactant: C#CC1(O)CCNC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(C#CC4(O)CCNC4)c32)c1

Procedure:
Using Method C above, rac-3-hydroxy-3-ethynyl-pyrrolidine (35.1 mg, 0.32 mmol) (Example 97C) was coupled with (Z)-3-[(4-acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (50 mg, 0.13 mmol) (see Example 90B) using (Ph3P)4Pd (15 mg) and CuI (3.0 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 85° C. for 5 h. (Yield 10 mg, 21%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:9]([C:10]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[CH2:11])[O:8][CH:7]=[N:6]1)=[O:4].[O:27]1CCCC1>O.C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:4])[CH:5]([NH:6][CH:7]=[O:27])[CH:9]([OH:8])[C:10](=[CH2:11])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]
Reactant: C1CCOC1
Reactant: C=C(CCCCNC(=O)OCc1ccccc1)C1OC=NC1C(=O)OC
Solvent: CCN(CC)CC
Solvent: O
Product: C=C(CCCCNC(=O)OCc1ccccc1)C(O)C(NC=O)C(=O)OC

Procedure:
9.4 g (26.1 mmol) of 5-[6-(N-benzyloxycarbonylamino)hex-1-en-2-yl]-oxazoline-4-carboxylic acid methyl ester are dissolved in 40 ml of tetrahydrofuran and 20 ml of water, a few drops of triethylamine are added and the mixture is heated under reflux for 18 hours. The solvent is removed under reduced pressure and the oil that remains is taken up in a total of 125 ml of methylene chloride, dried over magnesium sulfate and concentrated to dryness by evaporation. 8-(N-benzyloxycarbonylamino)-2-formylamino-3-hydroxy-4-methylene-octanoic acid methyl ester is obtained.
Reaction SMILES: [C:1]([Si:5]([CH3:14])([CH3:13])[O:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[CH2:12][O:11]1)([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:17]=[CH:18][C:19]2[S:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=2[CH:26]=1>CCO.O>[C:1]([Si:5]([CH3:14])([CH3:13])[O:6][CH2:7][CH2:8][CH2:9][C@@H:10]([OH:11])[CH2:12][NH:15][C:16]1[CH:17]=[CH:18][C:19]2[S:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=2[CH:26]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc2c(c1)NC(=O)CS2
Reactant: CC(C)(C)[Si](C)(C)OCCC[C@@H]1CO1
Solvent: O
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCCC[C@@H](O)CNc1ccc2c(c1)NC(=O)CS2
Yield: 28.6 %

Procedure:
A mixture of tert-butyl-dimethyl-((R)-3-oxiranyl-propoxy)-silane (13 g, 60 mmol, prepared according to Org. Lett. 2005, 7, 3997) and 6-amino-4H-benzo[1,4]thiazin-3-one (10.8 g) in EtOH/H2O (9:1, 325 mL) was heated at reflux overnight. The volatiles were removed under reduced pressure and the residue purified by CC (Hept/EA 1:1) to give the desired intermediate (6.8 g, 28% yield) as a brown oil.
Reaction SMILES: Cl[C:2]1[N:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[NH:12]1[CH2:18][CH2:17][CH2:16][C@H:13]1[CH2:14][OH:15].N>CN1C(=O)CCC1.CO.C(Cl)Cl>[F:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([N:12]3[CH2:18][CH2:17][CH2:16][C@H:13]3[CH2:14][OH:15])=[N:3][N:4]=2)[CH:7]=1
Reactant: Fc1ccc2nnc(Cl)n2c1
Reactant: OC[C@@H]1CCCN1
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: CN1CCCC1=O
Product: OC[C@@H]1CCCN1c1nnc2ccc(F)cn12
Temperature: 160 °C
Yield: 51.1 %

Procedure:
A mixture of Intermediate 24b (300 mg, 1.74 mmol) and L-prolinol (704 mg, 9.96 mmol) in NMP (4 mL) was heated in the microwave at 160° C. for 2 h. The reaction mixture was applied to an SCX-2 cartridge (70 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM, gave the title compound (210 mg, 50%). LCMS (Method 4): Rt 1.50 min, m/z 237 [MH+].
Reaction SMILES: C([N:3](CC)CC)C.Cl.[O:9]=[C:10]1[NH:15][C:14]2[C:16]3[CH:17]=[CH:18][C:19]([CH2:23][C:24](O)=[O:25])=[CH:20][C:21]=3[CH2:22][C:13]=2[N:12]2[CH:27]=[CH:28][N:29]=[C:11]12.C(N1C=CN=C1)(N1C=CN=C1)=O.N>CN(C)C=O>[O:9]=[C:10]1[NH:15][C:14]2[C:16]3[CH:17]=[CH:18][C:19]([CH2:23][C:24]([NH2:3])=[O:25])=[CH:20][C:21]=3[CH2:22][C:13]=2[N:12]2[CH:27]=[CH:28][N:29]=[C:11]12
Reactant: CCN(CC)CC
Reactant: O=C(O)Cc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Agent: Cl
Agent: N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: NC(=O)Cc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Temperature: -10 °C
Reaction time: 2 h

Procedure:
1.21 ml of triethylamine are added to a suspension, under nitrogen, of 2.9 g of [4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-8-yl]acetic acid hydrochloride and 108 ml of dimethylformamide. After stirring for 30 minutes at a temperature in the region of 20° C., 3.5 g of 1,1'-carbonyldiimidazole are added to the reaction mixture and stirring is continued for 2 hours at a temperature in the region of 20° C. The reaction mixture is then cooled to -10° C. and a stream of gaseous ammonia is passed into the mixture for 15 minutes. After returning to a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure. The evaporation residue is taken up in 100 ml of distilled water and the suspended solid is filtered, washed with water and then dissolved in 125 ml of dimethyl sulphoxide. The addition of 250 ml of acetone to the solution causes the appearance of a precipitate which is collected by filtration, washed with acetone and dried under reduced pressure (1 mbar) at 60° C. 1.1 g of [4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-8-yl]acetamide are thus obtained in the form of a beige solid with a melting point greater than 260° C. (Analysis; % Calculated C: 64.28, H: 4.32, N: 19.99, O: 11.42; % Found C: 63.9, H: 4.3, N: 19.8, O: 10.9).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[C:10]2[C:11]3[N:22]=[CH:21][S:20][C:12]=3[NH:13][C:14](=[O:19])[C:15]=2[CH:16]=[CH:17][CH:18]=1.[CH2:23]=O>>[CH3:7][O:8][C:9]1[C:10]2[C:11]3[N:22]=[C:21]([CH2:23][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[S:20][C:12]=3[NH:13][C:14](=[O:19])[C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: C1COCCN1
Reactant: COc1cccc2c(=O)[nH]c3scnc3c12
Reactant: C=O
Product: COc1cccc2c(=O)[nH]c3sc(CN4CCOCC4)nc3c12
Temperature: 25 °C

Procedure:
Morpholine (950 μL, 0.011 mmol) was added slowly to solution of 9-methoxythiazolo[5,4-c]isoquinolin-5(4H)-one in 2.6 mL of 37% aqueous formaldehyde and the resulting reaction mixture was refluxed for 7 hours. The reaction was monitored by TLC until all starting material was consumed. After cooling to room temperature, the reaction mixture was partitioned between water and ethyl acetate, the organics were separated, washed with brine, dried over Na2SO4 and solvent was evaporated under reduced pressure to produce the title compound as a pale solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([C:20](=[O:22])[CH3:21])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.CS(O)(=O)=O.C1C(=O)N([Br:42])C(=O)C1>C(#N)C>[Br:42][CH2:21][C:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14](/[CH:13]=[CH:12]/[C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=2)[CH:15]=1)=[O:22]
Reactant: CC(=O)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: CC#N
Product: O=C(CBr)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
To a warm (90° C.) and stirred solution of ketone 57 (5 g, 0.016 mol) in a mixture of 4:1 toluene and acetonitrile (125 ml) was added methane sulfonic acid (2.64 ml, 0.041 mole) and stirred for 1 hour. The reaction mixture was cooled to 68° C., NBS (3.19 g, 0.018 mol) was added at once and stirred the contents at 65° C. for 4 hour followed by stirring at RT for 18 hour. The solid from the reaction mixture was collected by filtration and dissolved in dichloromethane (100 ml). dichloromethane layer was washed with 10% aq. sodium carbonate and subjected to usual workup and concentration to obtain alpha bromo-ketone 58 (3.0 g, 48%) as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[C:13]([CH3:19])=[CH:14][C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][CH2:9]2)=[CH:4][CH:3]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)C.C1(C)C=CC=CC=1>C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:2]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[C:13]([CH3:19])=[CH:14][C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc(C)c2c(c1C)OCC2c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c2c(c1C)OCC2c1ccc(-c2ccccc2)cc1
Yield: 76 %

Procedure:
A mixed solution of 3-(4-bromophenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran obtained in Reference Example 236 (1.0 g, 3.15 mmol), phenylboronic acid (500 mg, 4.10 mmol), tetrakis(triphenylphosphine)palladium(0) (73 mg, 0.063 mmol) in 2 N sodium carbonate aqueous solution (4 mL)-ethanol (4 mL)-toluene (15 mL) was reacted under argon atmosphere at 80° C. for 5 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The combined organic layer was washed with a saturated brine, was dried over anhydrous sodium sulfate, and then was concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain (3-biphenyl-4-yl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran 750 mg (yield 76%). Using this compound, 873 mg of the title compound was synthesized in the same manner as in Reference Example 23. Yield 93%. Melting point: 153-154° C. (methanol).