Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:14][CH:15]=2)[N:7]=[C:6]([C:27](O)=[O:28])[CH:5]=1)[CH2:2][CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN(C=O)C.[NH2:68][C@H:69]([CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=1[F:81])[CH2:70][C:71]([OH:73])=[O:72].Cl>>[F:81][C:76]1[CH:77]=[CH:78][CH:79]=[CH:80][C:75]=1[CH2:74][C@@H:69]([NH:68][C:27]([C:6]1[CH:5]=[C:4]([CH2:1][CH2:2][CH3:3])[N:8]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:14][CH:15]=2)[N:7]=1)=[O:28])[CH2:70][C:71]([OH:73])=[O:72]
Reactant: N[C@@H](CC(=O)O)Cc1ccccc1F
Reactant: CCCc1cc(C(=O)O)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCc1cc(C(=O)N[C@@H](CC(=O)O)Cc2ccccc2F)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)nc1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A solution of 5-propyl-1-{6-[2-(1H-tetrazol-5-yl)phenyl]pyridin-3-ylmethyl}-1H-pyrazole-3-carboxylic acid (40 mg, 103 μmol), HATU (39.0 mg, 0.103 mmol) and DIPEA (89.4 μL, 514 μmol) in DMF (3.2 mL, 41.1 mmol) was stirred to pre-activate the acid. After 30 minutes, (R)-3-amino-4-(2-fluorophenyl)butanoic acid.HCl (24.0 mg, 103 μmol) was added. The resulting solution was stirred overnight. The mixture was concentrated, re-dissolved in water/MeCN/TFA and purified using reverse phase liquid chromatography to yield the title compound (15.7 mg; 100% purity) as a TFA salt. MS m/z: [M+H]+ calcd for C30H29FN8O3, 569.23; found 569.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH2:15][CH2:14][CH2:13][CH2:12][C:8]=2[S:9][C:10]=1[NH2:11])=[O:5])[CH3:2].C[C:17]1([CH3:25])[C:19]([CH3:21])([CH3:20])[CH:18]1[C:22]([OH:24])=O>>[CH2:20]1[CH:19]2[C:18]3([C:22]([NH:11][C:10]4[S:9][C:8]5[CH2:12][CH2:13][C:14]6[C:15]([C:7]=5[C:6]=4[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:8][CH:7]=[CH:6][CH:4]=6)=[O:24])[CH2:17][CH:25]([CH2:14][CH:13]1[CH2:12]3)[CH2:21]2
Reactant: CC1(C)C(C(=O)O)C1(C)C
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Product: CCOC(=O)c1c(NC(=O)C23CC4CC(CC2C4)C3)sc2c1-c1ccccc1CC2

Procedure:
The title compound was prepared as described in Example 12, substituting Example 278A for 2-amino-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester and 2-hexahydro-2,5-methano-pentalene-3a-carboxylic acid for 2,2,3,3-tetramethylcyclopropanecarboxylic acid. 1H NMR (300 MHz, CD3OD) δ ppm 1.35 (t, J=7.0 Hz, 3H) 1.60-1.73 (m, 4H) 1.77-1.87 (m, 2H) 1.92 (dd, J=10.2, 2.7 Hz, 2H) 2.00-2.10 (m, 2H) 2.68 (t, J=6.8 Hz, 1H) 2.85-2.94 (m, 2H) 2.99-3.08 (m, 2H) 4.36 (q, J=7.1 Hz, 2H) 7.09-7.31 (m, 4H) 11.44 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:11]([OH:13])=[O:12].[C:14](Cl)(=O)C(Cl)=O.CO>CN(C=O)C.C1COCC1>[CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: Cc1c(C(=O)O)oc2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1oc2ccccc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a solution of 3-methyl-benzofuran-2-carboxylic acid (0.98 g, 5.6 mmol) and catalytic amount of DMF (5 drops) in THF (25 ml) was added oxalyl chloride (0.53 ml, 6.1 mmol). After stirring the solution for 1 h at room temperature, methanol (20 ml) and TEA (7.0 ml) were added. The reaction mixture was stirred overnight at room temperature, then concentrated and dissolved in ethyl acetate (100 ml) and washed with aqueous sodium bicarbonate solution (100 ml). The organic layer was dried over sodium sulfate and concentrated to provide crude methyl 3-methylbenzofuran-2-carboxylate (1.0 g, 5.3 mmol) as a tan solid, which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]=[N:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([F:16])[CH:3]=1.C([N-]C(C)C)(C)C.CN([CH:27]=[O:28])C.O>C1COCC1>[Br:1][C:2]1[C:3]([CH:27]=[O:28])=[C:4]([F:16])[C:5]([N:9]=[N:10][N:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)=[C:6]([F:8])[CH:7]=1
Reactant: CN(C)C=O
Reactant: Fc1cc(Br)cc(F)c1N=NN1CCCC1
Agent: CC(C)[N-]C(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1c(Br)cc(F)c(N=NN2CCCC2)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
In a 200 ml three necked flask fitted with a magnetic stirrer, under inert atmosphere, (4-bromo-2,6-difluoro-phenyl)-pyrrolidin-1-yl-diazene a8 (6.06 g, 0.021 mol.) in THF (50 ml) is added to a solution of diisopropylamide (2 M in THF, 12.5 ml) cooled at −78° C. After 2 h at this temperature, dry DMF (3.2 ml) is added to the green solution. After 1 h, it is poured into water (200 ml), extracted with ether (3×200 ml) and the organic phase is dried over MgSO4, filtered and concentrated in vacuo to give the crude aldehyde a9 (6.62 g, 99%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[N:17][C:18]([N:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)=[N:19][CH:20]=1)=[CH:11][C:10]([C:34]1[CH:39]=[C:38]([F:40])[C:37]([OH:41])=[C:36]([Cl:42])[CH:35]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>>[Cl:42][C:36]1[CH:35]=[C:34]([C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[C:13]3[NH:14][C:15]2[CH:20]=[N:19][C:18]([N:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]3)=[N:17][CH:16]=2)[CH:39]=[C:38]([F:40])[C:37]=1[OH:41]
Reactant: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1Nc1cnc(N2CCNCC2)nc1
Yield: 26.6 %

Procedure:
Following procedure A-2 tert-butyl 4-(5-(3-acetyl-6-(3-chloro-5-fluoro-4-hydroxyphenyl)quinolin-4-ylamino)pyrimidin-2-yl)piperazine-1-carboxylate (50 mg, 0.084 mmol) was treated with TFA (2 mL) to afford the desired product (11 mg, 26%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 9.29 (s, 1H), 8.55 (s, 2H), 8.23 (dd, J=11, 2 Hz, 1H), 8.02 (m, 2H), 7.12 (m, 2H), 4.21 (t, J=10 Hz, 4H), 3.35 (t, J=10.5 Hz, 4H) 2.80 (s, 3H); ESI MS m/z 493, [C25H22ClFN6O2+H]+; HPLC 99.0% (AUC), tR=9.90 min.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11]C)[C:5]=2[N:4]=[C:3]1[CH3:13].B(Br)(Br)Br.ClCCl.C(=O)(O)[O-].[Na+]>ClCCl>[OH:11][C:10]1[C:5]2[N:4]=[C:3]([CH3:13])[N:2]([CH3:1])[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc2c1nc(C)n2C
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc2c(O)cccc2n1C
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
To a solution of 1,2-dimethyl-4-methoxy-1H-benzimidazole (560 mg) in dichloromethane (2 ml) was added 1M boron tribromide-dichloromethane solution (6.36 ml) under ice-cooling, and the mixture was stirred for 30 minutes at the same temperature and then for 2 hours at ambient temperature, and refluxed for 14 hours. After cooling, the solution was adjusted to pH 7 with saturated sodium bicarbonate solution, and extracted with dichloromethane twice. The organic layers were combined, washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized with ethyl acetate to give 4-hydroxy-1,2-dimethyl-1H-benzimidazole (297 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1.[C:13]([OH:21])(=[O:20])[C:14]([CH2:16][C:17](O)=[O:18])=[CH2:15]>C1(C)C(C)=CC=CC=1>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([N:1]2[C:17](=[O:18])[CH2:16][CH:14]([C:13]([OH:21])=[O:20])[CH2:15]2)=[CH:3][C:4]=1[CH3:12])=[O:7]
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: COC(=O)c1ccc(N)cc1C
Solvent: Cc1ccccc1C
Product: COC(=O)c1ccc(N2CC(C(=O)O)CC2=O)cc1C
Temperature: 25 °C

Procedure:
10 g (60.5 mmol) methyl 4-amino-2-methyl-benzoate and 7.9 g (60.5 mmol) itaconic acid are suspended in 50 ml xylene and refluxed for seven hours. The reaction mixture is cooled to ambient temperature and evaporated to dryness. The residue is suspended in methanol. The undissolved solid is filtered off and dried until the weight remains constant.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH2:15]O)[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:19][CH2:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1cccc(Oc2cccc(CO)c2)n1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccc(Oc2cccc(CCl)c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.7 %

Procedure:
(3-(6-Methylpyridin-2-yloxy)phenyl)methanol from Step 1 (3.7 g, 17 mmol), in dichloromethane (50 mL), was cooled to 0° C., and treated dropwise with thionyl chloride (1.50 mL, 20.6 mmol). The reaction mixture was allowed to warm to ambient temperature and was stirred for 3 h. Saturated aqueous sodium bicarbonate (20 mL) was added and the mixture was stirred at RT for 5 min. The organic layer was separated, dried over sodium sulfate, filtered and concentrated by evaporation to afford the title compound (4.0 g, 99% yield) as an oil.
Reaction SMILES: [NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([C:6]([NH:8][C@H:9]([C:19](O)=[O:20])[CH2:10][CH2:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:7])[CH:3]([CH3:5])[CH3:4].CN1CCOCC1.ClC(OCC(C)C)=O.[NH:44]1[CH2:79][CH2:78][CH2:77][C@H:45]1[C:46]([NH:48][C@H:49]([C:54]([N:56]1[CH2:76][CH2:75][CH2:74][C@H:57]1[C:58]([NH:60][C@H:61]([C:70]([O:72][CH3:73])=[O:71])[CH2:62][C:63]1[CH:68]=[CH:67][C:66]([OH:69])=[CH:65][CH:64]=1)=[O:59])=[O:55])[C@H:50]([CH2:52][CH3:53])[CH3:51])=[O:47]>O1CCCC1.CN(C)C=O>[NH:1]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C@H:2]([C:6]([NH:8][C@H:9]([C:19]([N:44]1[CH2:79][CH2:78][CH2:77][C@H:45]1[C:46]([NH:48][C@H:49]([C:54]([N:56]1[CH2:76][CH2:75][CH2:74][C@H:57]1[C:58]([NH:60][C@H:61]([C:70]([O:72][CH3:73])=[O:71])[CH2:62][C:63]1[CH:68]=[CH:67][C:66]([OH:69])=[CH:65][CH:64]=1)=[O:59])=[O:55])[C@H:50]([CH2:52][CH3:53])[CH3:51])=[O:47])=[O:20])[CH2:10][CH2:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:7])[CH:3]([CH3:5])[CH3:4]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H]1CCCN1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OC
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OC
Temperature: -15 °C
Reaction time: 0.03 h

Procedure:
0.8 g of Boc-Val-Glu(OBut)-OH (1.9 mmol) is dissolved in 5 cm3 of tetrahydrofuran cooled to -15° C. 0.21 cm3 of N-methylmorpholine (1.9 mmol) and 0.25 cm3 of isobutyl chloroformate are added in succession. After 2 minutes, the solution of Pro-Ile-Pro-Tyr-OMe in 5 cm3 of dimethylformamide, prepared earlier, is added. The reaction mixture is stirred for 1 hour at -15° C. and then for 2 hours at 20° C. The solvents are removed under reduced pressure. The 1.2 g of crude product obtained are purified by chromatography on silica gel by eluting with mixtures of ethyl acetate and petroleum ether (1-1; 7-2 and 8-2 by volume). The main fraction is purified by chromatography on silica gel by eluting with methylene chloride containing 3% of methanol (by volume). In this way, 0.6 g of Boc-Val-Glu(OBut)-Pro-Ile-Pro-Tyr-OMe is obtained, the properties of which are as follows:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[CH:5]=[C:4]([Cl:11])[N:3]=1.ClC1C=CC=C(C(OO)=[O:20])C=1>C(O)C>[NH2:1][C:2]1[N+:7]([O-:20])=[C:6]([NH:8][CH2:9][CH3:10])[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: CCNc1cc(Cl)nc(N)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCO
Product: CCNc1cc(Cl)nc(N)[n+]1[O-]
Reaction time: 2 h
Yield: 34.9 %

Procedure:
8 g of 2-amino-4-ethylamino-6-chloropyrimidine are suspended in 150 ml of ethanol. 21.80 g of meta-chloroperbenzoic acid are added dropwise as solution in 150 ml of ethanol. After 2 hours' stirring, the reaction mixture is concentrated to a third in a rotary evaporator. The precipitate is filtered off on sintered glass, washed with 2×50 ml of ethyl ether and is then recrystallized from 60 ml of a 9/1 acetonitrile-ethanol mixture. 3.05 g of 2-amino-4-ethylamino-6-chloropyrimidine 3-oxide are obtained.
Reaction SMILES: [Cl:1][C:2](Cl)([O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].[Sb](Cl)(Cl)(Cl)(Cl)Cl.[FH:22]>>[Cl:1][C:2]([F:22])([O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: F
Reactant: FC(F)(F)C(Cl)(Cl)Oc1ccc(Cl)cc1
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Product: FC(F)(F)C(F)(Cl)Oc1ccc(Cl)cc1
Reaction time: 0.33 h
Yield: 89.8 %

Procedure:
A 500 ml polytetrafluoroethylene reactor equipped with stirrer, thermometer and reflux condenser is charged with 55.9 g (0.2 mol) of 4-(1,1-dichloro-2,2,2-trifluoroethoxy)chlorobenzene in 100 ml of hydrogen fluoride. 3.0 g (0.01 mol; corresponding to 5 mol%) of antimony pentachloride are added at a temperature in the range from -5° C. to 0° C. The resultant hydrogen chloride is removed from the reactor through the reflux condenser. After 20 minutes at 0° C., the evolution of hydrogen chloride ceases. Excess hydrogen fluoride is removed by distillation, the residue is dissolved in 200 ml of methylene chloride and the solution is extracted with water. The organic phase is separated by distillation, affording 47.3 g (89.8% of theory) of 4-(1-chloro-1,2,2,2-tetrafluoroethoxy)chlorobenzene. Boiling point 181° C., nD25 =1.4362.
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:10]=[CH:9][C:8](/[C:11](/[C:28]3[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=3)=[CH:12]/[CH2:13][O:14][C:15]3[CH:26]=[CH:25][C:18]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:17]([CH3:27])[CH:16]=3)=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.[CH3:35][N:36]([CH2:38][C:39]#[CH:40])[CH3:37].C(NC(C)C)(C)C>O1CCCC1.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.[Cu]I>[CH:1]1([S:4][C:5]2[CH:10]=[CH:9][C:8](/[C:11](/[C:28]3[CH:33]=[CH:32][C:31]([C:40]#[C:39][CH2:38][N:36]([CH3:37])[CH3:35])=[CH:30][CH:29]=3)=[CH:12]/[CH2:13][O:14][C:15]3[CH:26]=[CH:25][C:18]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:17]([CH3:27])[CH:16]=3)=[CH:7][CH:6]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(SC3CC3)cc2)cc1C
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN(C)C)cc2)c2ccc(SC3CC3)cc2)cc1C
Temperature: 25 °C

Procedure:
To a degassed solution of methyl (Z)-[4-[3-(4-cyclopropylsulfanylphenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (480 mg, 0.818 mmol; prepared as described in example 53), N,N-dimethylpropargylamine (0.175 mL, 1.64 mmol) and diisopropylamine (0.539 mL, 3.85 mmol) in anhydrous tetrahydrofuran (10 mL), bis(triphenylphosphine)palladium(II) dichloride (29 mg, 0.041 mmol) and copper(I) iodide (13 mg, 0.068 mmol) were added. The reaction mixture was stirred at ambient temperature over night under nitrogen. The solvents were evaporated in vacuo and the residue was purified by flash column chromatography (silica gel Fluka 60, dichloromethane/methanol 99:1-98:2) yielding methyl (E)-[4-[3-(4-cyclopropylsulfanylphenyl)-3-[4-[3-(N,N-dimethylamino)propynyl]phenyl]allyloxy]-2-methylphenoxy]acetate as yellow oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[CH3:19][CH2:20][O:21][C:22]([CH2:24][CH:25]1[C:30](=O)[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:23]>>[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:26]3[CH:25]([CH2:24][C:22]([O:21][CH2:20][CH3:19])=[O:23])[CH2:30][CH2:29][CH2:28][C:27]=3[C:15]3[C:10]2=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=3)=[CH:5][CH:4]=1
Reactant: NN(Cc1ccc(Cl)cc1)c1ccc(F)cc1
Reactant: CCOC(=O)CC1CCCCC1=O
Agent: Cl
Product: CCOC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1ccc(F)cc21
Yield: 57.8 %

Procedure:
To 3.50 g of 1-(4-chlorobenzyl)-1-(4-fluorophenyl)hydrazine hydrochloride in 70 cc of iso-propan. (was added 2.23 g of ethyl 2-cyclohexanone acetate. The reaction was refluxed under nitrogen for 16 hours. The resulting reaction mixture was then evaporated to dryness and the residue suspended in ether. The solid material was then filtered. The ether filtrate was washed with water, dried and evaporated. The resulting syrup was chromatographed on silica gel to give 2.8 g (42%) of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]2[CH:13]([OH:17])[NH:14][C:15](=O)[CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[SiH](C)C>ClCCl.FC(F)(F)C(O)=O>[CH2:1]([N:8]1[CH2:9][CH:10]2[CH2:15][NH:14][C:13](=[O:17])[CH:11]2[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(O)C2CN(Cc3ccccc3)CC12
Agent: C[SiH](C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCC2CN(Cc3ccccc3)CC12
Temperature: 3 °C
Reaction time: 16 h

Procedure:
5-Benzyl-3-hydroxyhexahydropyrrolo[3,4-c]pyrrole-1-one, (7 g; 30 mmol) in suspension in dichloromethane (50 ml) is placed in a 1000 ml three-necked flask and is then cooled in an ice bath. Trimethylsilane (7.1 g; 60 mmol) is run in slowly at 3° C. The reaction mixture is homogeneous and is left to react at 25° C. for 10 minutes, and is then cooled to 3° C. in order to run in trifluoro-acetic acid (50 ml). The reaction mixture is agitated at 20° C. for 16 hours and then evaporated under reduced pressure. The residue is taken up in a mixture of ethyl acetate (100 ml) and 4 N aqueous sodium peroxide (50 ml), separated by settling out and washed with water (100 ml). After drying over magnesium sulfate and evaporation under reduced pressure, a yellow-colored oil is isolated, which is purified by chromatography on silica gel (silica: 40-63 μm eluent: 90/10 ethyl acetate/methanol). The fractions containing the expected compound are combined and then evaporated under reduced pressure, giving 5-benzylhexahydropyrrolo[3,4-c]pyrrole-1-one, (7.2 g) which is used directly in the following step.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].C(O[C:34]([N:36]1[CH2:41][CH2:40][CH:39]([C:42]2[CH:47]=[CH:46][C:45]([C:48](O)=O)=[CH:44][CH:43]=2)[CH2:38][CH2:37]1)=O)(C)(C)C>>[CH2:1]([N:3]([CH2:48][C:45]1[CH:44]=[CH:43][C:42]([CH:39]2[CH2:40][CH2:41][N:36]([CH3:34])[CH2:37][CH2:38]2)=[CH:47][CH:46]=1)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCNc1ccc(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Product: CCN(Cc1ccc(C2CCN(C)CC2)cc1)c1ccc(OC)cc1C1CCc2cc(O)ccc2C1
Yield: 78.7 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-5-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (50 mg) and 4-(4-carboxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (100 mg) according to an analogous synthetic method to Example 337 described below, the title compound (50 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15](I)[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1.[Cu][C:28]#[N:29]>O1CCCC1.C(OCC)(=O)C.[Cu]I>[Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([C:28]#[N:29])[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1
Reactant: N#C[Cu]
Reactant: Cc1cc(I)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12

Procedure:
To a solution of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-iodo-8-methyl-4H-3,1-benzoxazin-4-one (i.e. the benzoxazinone product of Step E) (600 mg, 1.1 mmol) in tetrahydrofuran (15 mL) was added copper(I) iodide (126 mg, 0.66 mmol), tetrakis(triphenyphosphine)palladium(0) (382 mg, 0.33 mmol) and copper(I) cyanide (800 mg, 8.8 mmol) sequentially at room temperature. The reaction mixture was then heated at reflux overnight. The reaction turned black in color, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The reaction mixture was diluted with ethyl acetate (20 mL) and filtered through Celite®, followed by washing three times with 10% sodium bicarbonate solution and once with brine. The organic extract was dried (MgSO4) and concentrated under reduced pressure to afford 440 mg of the title compound as a crude yellow solid.
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:6]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:10]([F:19])[C:9]([O:20][CH:21]([CH3:23])[CH3:22])=[C:8]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([N:31]4[CH:36]=[CH:35][C:34]([C:37]([O:39]C)=[O:38])=[C:33]([CH2:41][CH3:42])[C:32]4=[O:43])[CH2:27][CH2:26]3)[CH:7]=2)[CH2:5][CH2:4]1.Cl>CO>[CH:3]1([C:6]2[C:11]([C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)=[C:10]([F:19])[C:9]([O:20][CH:21]([CH3:23])[CH3:22])=[C:8]([CH2:24][N:25]3[CH2:26][CH2:27][CH:28]([N:31]4[CH:36]=[CH:35][C:34]([C:37]([OH:39])=[O:38])=[C:33]([CH2:41][CH3:42])[C:32]4=[O:43])[CH2:29][CH2:30]3)[CH:7]=2)[CH2:5][CH2:4]1
Reactant: CCc1c(C(=O)OC)ccn(C2CCN(Cc3cc(C4CC4)c(-c4ccc(F)cc4)c(F)c3OC(C)C)CC2)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1c(C(=O)O)ccn(C2CCN(Cc3cc(C4CC4)c(-c4ccc(F)cc4)c(F)c3OC(C)C)CC2)c1=O
Reaction time: 1 h
Yield: 70.7 %

Procedure:
A 2 M aqueous sodium hydroxide solution (1.54 mL) was added at room temperature to a methanol (3 mL) solution of methyl 1-(1-((6-cyclopropyl-2,4′-difluoro-3-isopropoxybiphenyl-4-yl)methyl)piperidin-4-yl)-3-ethyl-2-oxo-1,2-dihydropyridine-4-carboxylate (348 mg), and the mixture was stirred at 50 C for 1 hour. The reaction mixture was cooled to room temperature and neutralized with 2 M hydrochloric acid, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from water, and the obtained solid was recrystallized (ethanol/diisopropyl ether) to obtain the title compound (240 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([NH2:22])[CH2:13][C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:30][CH3:31]>C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([NH:22][CH2:30][CH3:31])[CH2:13][C:12]2=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: NC1CCc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCNC1CCc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 18.2 %

Procedure:
To a solution of 0.225 gm (0.77 mMol) 6-benzyloxy-3-amino-1,2,3,4-tetrahydro-9H-carbazole in 20 mL acetonitrile were added 0.223 gm (1.617 mMol) potassium carbonate followed by 130 μL (1.617 mMol) iodoethane and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was then heated at 60° C. for 4 hours and then at 50°-45° C. for 3 hours. The reaction mixture was then concentrated under reduced pressure and the residue partitioned between dichloromethane and water. The organic phase was then dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to radial chromatography (silica gel, 2 mm), eluting with 97:3:1 dichloromethane:methanol:ammonium hydroxide. Fractions shown to contain the desired compound were concentrated under reduced pressure to give 0.045 gm (6%) of the desired compound.