Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)[NH:5][C:6](=[O:23])[C@H:7]([C@H:19]([CH2:21][CH3:22])[CH3:20])[NH:8]C(OCC1C=CC=CC=1)=O.C1COCC1.[C:40]1([S:50](Cl)(=[O:52])=[O:51])[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][CH:41]=1>CN(C)C=O.CN(C1C=CN=CC=1)C.[C].[Pd]>[CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)[NH:5][C:6](=[O:23])[C@H:7]([C@H:19]([CH2:21][CH3:22])[CH3:20])[NH:8][S:50]([C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][CH:41]=1)(=[O:52])=[O:51]
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: [Pd]
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](NS(=O)(=O)c1cccc2ccccc12)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Temperature: 0 °C
Reaction time: 3 h
Yield: 77.4 %

Procedure:
A mixture of N-benzyloxycarbonyl-(L)-isoleucyl-(L)-tryptophan methyl ester (11.3 g), palladium-carbon (5%, 50% wet, 3.0 g) and THF (50 ml) was subjected to catalytic hydrogenation at room temperature and atomospheric pressure. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure to yield an oily substance. The oil was dissolved in N,N-dimethylformamide (50 ml), and 1-naphthalenesulfonyl chloride (5.8 g) and 4-(N,N-dimethylamino)pyridine (DMAP) (3.2 g) were added to the ice-cooling mixture. After stirring at 0° C. for 3 hours, the reaction mixture was concentrated under reduced pressure. The residue was suspended in ethyl acetate and the mixture was successively washed with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate and brine, and dried (MgSO4). The organic solvent was evaporated off to yield N-(1-naphthylsulfonyl)-(L)-isoleucyl-(L)-tryptophan methyl ester (9.8 g, 77%) as crystals. Melting point: 172°-174° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([CH2:18][O:19][CH2:20][C:21]4([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)[CH:17]=2)[N:14]([CH3:40])[N:13]=[CH:12]3)=[CH:5][CH:4]=1)#[N:2]>FC(F)(F)C(O)=O>[CH3:40][N:14]1[C:15]2[C:11](=[CH:10][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)=[CH:17][C:16]=2[CH2:18][O:19][CH2:20][C:21]2([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]2)[CH:12]=[N:13]1
Reactant: Cn1ncc2cc(-c3ccc(C#N)cc3)cc(COCC3(c4ccccc4)CCN(C(=O)OC(C)(C)C)CC3)c21
Solvent: O=C(O)C(F)(F)F
Product: Cn1ncc2cc(-c3ccc(C#N)cc3)cc(COCC3(c4ccccc4)CCNCC3)c21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
tert-Butyl 4-(((5-(4-cyanophenyl)-1-methyl-1H-indazol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (63 mg, 0.117 mmol) was dissolved in trifluoroacetic acid (25% in dichloromethane, 4 mL) and stirred at room temperature for 45 min. The reaction was concentrated, and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol to give 47.3 mg (92%) as a colorless film. 1H-NMR (CDCl3, 500 MHz) δ 7.98 (s, 1H), 7.85 (d, J=1.5 Hz, 1H), 7.70 (m, 4H), 7.35 (d, J=1.5 Hz, 1H), 7.25 (m, 4H), 7.17 (m, 1H), 4.72 (s, 2H), 3.93 (s, 3H), 3.48 (s, 2H), 2.83 (m, 2H), 2.69 (m, 2H), 2.11 (m, 2H), 1.81 (m, 2H), 1.78 (bs, 1H); 13C-NMR (CDCl3, 126 MHz) δ 145.7, 144.2, 138.5, 133.5, 132.7, 131.4, 128.4, 127.9, 127.8, 127.2, 126.24, 126.20, 121.2, 120.2, 119.1, 110.5, 79.5, 71.1, 42.7, 41.7, 38.2, 33.7. Mass spec.: 437.19 (MH)+. Accurate mass spec.: m/z 437.2354 [MH]+, Δ=2.9 ppm.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:13][OH:14])[CH:10]=2)[C:5]([CH3:21])([CH3:20])[CH2:4][CH2:3]1.O[C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(OCC)(=O)C>[CH3:30][O:29][C:27](=[O:28])[C:26]1[CH:31]=[CH:32][C:23]([O:14][CH2:13][CH:12]([C:9]2[CH:10]=[C:11]3[C:6]([C:5]([CH3:20])([CH3:21])[CH2:4][CH2:3][N:2]3[CH3:1])=[CH:7][CH:8]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CCCCCC(CO)c1ccc2c(c1)N(C)CCC2(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCC(COc1ccc(C(=O)OC)cc1)c1ccc2c(c1)N(C)CCC2(C)C
Yield: 62.6 %

Procedure:
A solution of 2-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-heptan-1-ol (1.2 g, 4.15 mmole) in 20 mL of THF was treated with 0.69 g of methyl 4-hydroxybenzoate, 1.2 g of triphenylphosphine and 0.72 mL of diethyl azodicarboxylate (DEAD) and heated at reflux for 6 hours. The mixture was diluted with 100 mL of ethyl acetate and washed with two 50 mL portions of water and 50 mL of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The product was purified by flash chromatography (SiO2, 10% ethyl acetate in hexanes) to yield 1.1 g of 4-[2-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-heptyloxy]-benzoic acid methyl ester, as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([O:13]CC)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].[CH2:16]([O:19][C:20]1[C:29]2[C:28]([CH3:31])([CH3:30])[CH2:27][CH2:26][C:25]([CH3:33])([CH3:32])[C:24]=2[CH:23]=[C:22](B(O)O)[CH:21]=1)[CH2:17][CH3:18]>>[OH:8][C:7]1[CH:6]=[CH:5][C:4]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[CH:3][C:2]=1[C:22]1[CH:21]=[C:20]([O:19][CH2:16][CH2:17][CH3:18])[C:29]2[C:28]([CH3:31])([CH3:30])[CH2:27][CH2:26][C:25]([CH3:32])([CH3:33])[C:24]=2[CH:23]=1
Reactant: CCCOc1cc(B(O)O)cc2c1C(C)(C)CCC2(C)C
Reactant: CCOC(=O)C=Cc1ccc(O)c(Br)c1
Product: CCCOc1cc(-c2cc(C=CC(=O)O)ccc2O)cc2c1C(C)(C)CCC2(C)C
Yield: 42.3 %

Procedure:
In a manner similar to that of Example 1(c), by reaction of 1.0 g (3.7 mmol) of ethyl 3-(3-bromo-4-hydroxyphenyl)acrylate obtained in Example 34(d) with 1.61 g (5.5 mmol) of 4-propyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylboronic acid obtained in Example 43(c), 640 mg (40%) of the expected compound were obtained in the form of a white powder having a melting point of 114°-116° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([NH:15][C:16]3[CH:17]=[N:18][C:19]([O:28][CH3:29])=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:21]=3)=[C:8]([CH:14]=2)[C:9]([O:11]CC)=[O:10])[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C.O.CO.N>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([NH:15][C:16]3[CH:17]=[N:18][C:19]([O:28][CH3:29])=[C:20]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:21]=3)=[C:8]([CH:14]=2)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(C2CC2)ccc1Nc1cnc(OC)c(-c2ccccc2)c1
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CO
Product: COc1ncc(Nc2ccc(C3CC3)cc2C(=O)O)cc1-c1ccccc1
Temperature: 60 °C
Yield: 77 %

Procedure:
The solid residue obtained in step A was dissolved in 2.5 ml of ethanol and 0.180 ml of aqueous solution 2N NaOH were added. The mixture was heated at 60° C. for 2 hours, the solvent was evaporated and the solid obtained was suspended in water. The pH was taken to 6.5 and extracted with CHCl3. The crude mixture was purified over a SCX cartridge eluting with MeOH/NH3 10:1 affording 0.025 g (yield 77%) of the expected product.
Reaction SMILES: [S:1]1[C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][NH:8]2)=[CH:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]1=2.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[S:28][C:27]([CH3:29])=[N:26][C:25]=2[C:30](O)=[O:31])=[CH:20][CH:19]=1>>[S:1]1[C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][N:8]2[C:30]([C:25]2[N:26]=[C:27]([CH3:29])[S:28][C:24]=2[C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)=[O:31])=[CH:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]1=2
Reactant: c1ccc2sc(CC3CCCCN3)cc2c1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Product: Cc1nc(C(=O)N2CCCCC2Cc2cc3ccccc3s2)c(-c2ccc(F)cc2)s1
Yield: 15.5 %

Procedure:
The title compound (40 mg) was prepared from 2-benzo[b]thiophen-2-ylmethyl-piperidine D83(133 mg) and 5-(4-fluoro-phenyl)2-methyl-thiazol-4-carboxylic acid (136 mg) according to a procedure similar to that described for Example 4.
Reaction SMILES: Cl[C:2](=[C:6]([C:9]#[N:10])[C:7]#[N:8])[CH:3]([CH3:5])[CH3:4].[Cl:11][C:12]1[C:13]([NH:19][NH2:20])=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=1.C(N(CC)CC)C>C1COCC1>[NH2:8][C:7]1[N:19]([C:13]2[C:12]([Cl:11])=[CH:17][C:16]([Cl:18])=[CH:15][N:14]=2)[N:20]=[C:2]([CH:3]([CH3:5])[CH3:4])[C:6]=1[C:9]#[N:10]
Reactant: NNc1ncc(Cl)cc1Cl
Reactant: CC(C)C(Cl)=C(C#N)C#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)c1nn(-c2ncc(Cl)cc2Cl)c(N)c1C#N
Temperature: 25 °C
Yield: 82.2 %

Procedure:
A solution of (1-chloro-2-methylpropylidene)methane-1,1-dicarbonitrile (35.6 g, 230 mmole) in THF (875 mL) was treated with 3,5-dichloropyridylhydrazine (40.9 g, 230 mmole) followed by triethylamine (23 g, 230 mmole). The reaction was then heated to reflux for 18 hours. The reaction was then cooled to room temperature and partitioned between EtOAc (1 L) and 1M aqueous NaOH (500 mL). The aqueous layer was extracted with EtOAc (2×500 mL), and the combined organic layers were washed with 10% citric acid (500 mL), saturated aqueous NaHCO3 (750 mL). The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure to yield the desired product (56 g, 82% yield).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][C:16]=3[F:28])=[N:6]2)[CH2:2]1.[C:29]([C:31](=[CH:35][CH:36]([CH3:38])[CH3:37])[C:32](O)=[O:33])#[N:30].C1CN([P+](ON2N=NC3C=CC=NC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH2:14][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[N:5]([CH:3]3[CH2:2][N:1]([C:32]([C:31](=[CH:35][CH:36]([CH3:38])[CH3:37])[C:29]#[N:30])=[O:33])[CH2:4]3)[N:6]=[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][C:16]=3[F:28])[C:8]=12
Reactant: CC(C)C=C(C#N)C(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1F)nn2C1CNC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Product: CC(C)C=C(C#N)C(=O)N1CC(n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of 1-(azetidin-3-yl)-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-amine (80 mg, 0.210 mmol, 2-cyano-4-methyl-pent-2-enoic acid (44.4 mg, 0.320 mmol), PyAOP (121.9 mg, 0.230 mmol) and TEA (0.09 mL, 0.640 mmol) in DCM (3 mL), were stirred overnight at room temperature. The solvent was removed and the residue was purified on a silica gel plate using 6:94 MeOH:CH2Cl2 to get 2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]azetidine-1-carbonyl]-4-methyl-pent-2-enenitrile (34 mg) as white powder. LC-MS (ES, m/z): 498 [M+H].
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH:8]([CH3:9])[CH2:7][N:6](C(OCC)=O)[CH2:5][CH:4]1[CH3:15]>[OH-].[Na+].C(O)C>[CH3:1][NH:2][CH:3]1[CH:8]([CH3:9])[CH2:7][NH:6][CH2:5][CH:4]1[CH3:15]
Reactant: CCOC(=O)N1CC(C)C(NC)C(C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CNC1C(C)CNCC1C

Procedure:
Mixtures A+B of 4-methylamino-1-carbethoxy-3,5-dimethylpiperidine (1.3 g, 0.6 mmol) was stirred in a mixture of 10% NaOH solution (20 ml) and ethyl alcohol (10 ml) at 100° C. for 120 hr, cooled, extracted with ethyl acetate, dried (Na2SO4) and concentrated to afford a Mixtures A+B of 4-methylamino-3,5-dimethylpiperidine. Yield 0.61 g (70%), C8H18N2, m/z 143 (M+1).
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([NH:10][CH:11]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[OH:25])[C:12]([O:14]C)=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl>O1CCCC1>[C:3]([O:7][C:8]([NH:10][CH:11]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[OH:25])[C:12]([OH:14])=[O:13])=[O:9])([CH3:5])([CH3:6])[CH3:4]
Reactant: COC(=O)C(Cc1ccc(OC)cc1O)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(CC(NC(=O)OC(C)(C)C)C(=O)O)c(O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.3 %

Procedure:
5 ml of a 1N aqueous solution of sodium hydroxide are added to a solution of 850 mg (2.6 mmol) of methyl 2-tert-butoxycarbonylamino-3-(2-hydroxy-4-methoxyphenyl)-propanoate in 10 ml of tetrahydrofuran. The reaction medium is stirred for 4 hours at ambient temperature and then a 1N aqueous solution of hydrochloric acid is added until the pH is 1, and the medium is extracted with dichloromethane. The organic phase is dried over magnesium sulphate, filtered and evaporated. 820 mg of 2-tert-butoxycarbonylamino-3-(2-hydroxy-4-methoxy-phenyl)propanoic acid are obtained in the form of a beige powder with a quantitative yield.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14]([C:17]2[CH:22]=[C:21]([N+]([O-])=O)[C:20]([OH:26])=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=2)([CH3:16])[CH3:15])[CH:7]=[C:8]([N+]([O-])=O)[C:9]=1[OH:10])([O-:3])=[O:2].[N+](C1C(O)=C([N+]([O-])=O)C([N+]([O-])=O)=C(C(C2C=CC(O)=CC=2)(C)C)C=1[N+]([O-])=O)([O-])=O.OC1C=CC(C(C2C=CC(O)=CC=2)(C)C)=CC=1.[N+]([O-])(O)=O.ClC(Cl)C>>[OH:26][C:20]1[CH:21]=[CH:22][C:17]([C:14]([C:6]2[CH:7]=[CH:8][C:9]([OH:10])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)([CH3:16])[CH3:15])=[CH:18][C:19]=1[N+:27]([O-:29])=[O:28]
Reactant: CC(C)(c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1)c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Agent: CC(C)(c1ccc(O)cc1)c1c([N+](=O)[O-])c([N+](=O)[O-])c(O)c([N+](=O)[O-])c1[N+](=O)[O-]
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: O=[N+]([O-])O
Solvent: CC(Cl)Cl
Product: CC(C)(c1ccc(O)c([N+](=O)[O-])c1)c1ccc(O)c([N+](=O)[O-])c1

Procedure:
This invention uses 2,2-bis(3,5-dinitro-4-hydroxyphenyl) propane as a polymerization inhibitor. For the sake of convenience, this compound will also be called tetranitrobisphenol A. A method of synthesizing said compound is described in Stroganov et al, Zh. Org. Khim 1973, 9(8), 1713-17, and Smirnov and Stroganov USSR Pat. No. 237,860 (1969). Thus, 2,2-bis(4-hydroxyphenyl)propane is nitrated with a concentrated nitric acid (for instance 70% HNO3) in a suitable solvent such as dichloroethane to afford primarily 2,2-bis(4-hydroxy-3-nitro-phenyl)propane. A typical reaction condition for this step is 20°-30° C. for 2 hours. Without isolating the product, a mixture of sulfuric acid and nitric acid (for instance, 42% H2SO4, 50% HNO3, and 8% H2O) is added to the reaction mixture and nitration continued to afford tetranitrobisphenol A. A typical reaction condition for the second step is 40° C. for 2 hours. The desired product is isolated by a routine procedure.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:17][C:18]([F:32])([F:31])[C:19]([F:30])([F:29])[C:20]([F:28])([F:27])[O:21][C:22]([F:26])=[C:23]([F:25])[F:24].C(C1C=CC=C(OC(F)(F)C(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C=1)#C>O1CCCC1>[F:25][C:23]([F:24])([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)[CH:22]([F:26])[O:21][C:20]([F:27])([F:28])[C:19]([F:29])([F:30])[C:18]([F:17])([F:31])[F:32]
Reactant: FC(F)=C(F)OC(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(=O)c1ccc(O)cc1
Agent: C#Cc1cccc(OC(F)(F)C(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OC(F)(F)C(F)OC(F)(F)C(F)(F)C(F)(F)F)cc1

Procedure:
In the dry box, tetrahydrofuran (50 mL) and 1-(4-hydroxyphenyl)ethanone (0.68 g, 0.005 mol) were added to a round bottom flask equipped with a stirrer. Potassium carbonate (0.175 g, 0.00126 mol) was then added to the flask. 1,1,1,2,2,3,3-heptafluoro-3-((1,2,2-trifluorovinyl)oxy)propane (1.99 g, 0.0075 mol) was then added via the addition funnel and the reaction was placed in an oil bath and heated to a gentle reflux for 5.5 hours. The content was analyzed by proton NMR and shown to be 1-ethynyl-3-(1,1,2-trifluoro-2-(1,1,2,3,3,3-hexafluoro-2-(perfluoropropoxy)propoxy)ethoxy)benzene.
Reaction SMILES: [Cl-].[NH4+].[CH3:3][O:4][C:5](=[O:20])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][CH2:14][C:15]#[N:16])=[C:8]([N+:17]([O-])=O)[CH:7]=1>O.[Zn]>[CH3:3][O:4][C:5](=[O:20])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][CH2:14][C:15]#[N:16])=[C:8]([NH2:17])[CH:7]=1
Reactant: COC(=O)c1ccc(NCCC#N)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Product: COC(=O)c1ccc(NCCC#N)c(N)c1
Temperature: 60 °C
Yield: 76.3 %

Procedure:
To a solution of ammonium chloride (21.7 g, 406.3 mmol) in water (200 mL) was added 4-(2-cyanoethylamino)-3-nitro-benzoic acid methyl ester (6.1 g, 24.5 mmol) followed by zinc powder (42.8 g, 655.9 mmol). The mixture was heated to 60° C. for 3 h. It was filtered hot and washed with EtOAc. The filtrate was further extracted with EtOAc and the combined organic phase washed with brine solution. The organic layer was evaporated to give 4.1 g (75%) of 3-amino-4-(2-cyano-ethylamino)-benzoic acid methyl ester. MS-ESI m/z 220 (M+1); 1H NMR (300 MHz, CDCl3) δ 2.7 (t, 2H), 3.6 (m, 2H), 3.8 (s, 3H), 4.3 (bs, 1H), 6.6 (d, 1H), 7.45 (d, 1H), 7.6 (d, 1H)
Reaction SMILES: O[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:14]2[C:15](=[O:31])[N:16]([CH3:30])[C:17](=[O:29])[C:18]=2[C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH3:28])[CH:20]=2)[C:8]2[O:12][CH:11]=[CH:10][C:9]=2[CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:52]>ClCCl>[Br:52][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:14]2[C:15](=[O:31])[N:16]([CH3:30])[C:17](=[O:29])[C:18]=2[C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH3:28])[CH:20]=2)[C:8]2[O:12][CH:11]=[CH:10][C:9]=2[CH:13]=1
Reactant: CN1C(=O)C(c2cn(C)c3ccccc23)=C(c2cc(OCCO)cc3ccoc23)C1=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN1C(=O)C(c2cn(C)c3ccccc23)=C(c2cc(OCCBr)cc3ccoc23)C1=O

Procedure:
Add to a solution of 3-[5-(2-hydroxyethoxy)benzofur-7-yl]-1-methyl-4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-dione (1.87 g, 4.49 mmol) in dichloromethane (30 ml), triphenylphosphine (1.41 g, 5.39 mmol) and carbon tetrabromide (1.79 g, 5.39 mmol). Stir the reaction for 15 minutes under nitrogen atmosphere. Add another 2.2 mmol of triphenylphosphine and 2.2 mmol of carbon tetrabromide and stir for 15 more minutes. Diluted with dichloromethane, wash with water, brine, dry over magnesium sulfate, filter and concentrate. Flash chromatography over silica gel (1% methanol:dichloromethane) affords the title compound as an orange solid. MS(ES+): 479.0, 481.0.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10](OC)[CH:11]=2)[NH:6][CH:5]=1.[CH3:15][O:16]C1C=C2C(C=CN2)=CC=1>>[Br:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([O:16][CH3:15])=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: COc1ccc2[nH]cc(CCBr)c2c1
Reactant: COc1ccc2cc[nH]c2c1
Product: COc1ccc2c(CCBr)c[nH]c2c1

Procedure:
The title compound was synthesized according to above mentioned procedure for 3-(2-bromoethyl)-5-methoxy-1H-indole, starting with 6-methoxyindole yielding a brown oil which was stored in the freezer. LC-MS conditions B: tR=0.81 min, [M+H]+=254.13.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[CH:15]1[CH:16]=[CH:17][N:18]2[CH2:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[NH:21][CH2:20][C:19]=12.CN(C)C1C=CC=CC=1.O>O1CCOCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:21]2[C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[CH2:24][N:18]3[CH:17]=[CH:16][CH:15]=[C:19]3[CH2:20]2)=[O:7])=[CH:4][C:3]=1[S:11]([NH2:12])(=[O:14])=[O:13]
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CN(C)c1ccccc1
Product: NS(=O)(=O)c1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1Cl
Reaction time: 2 h
Yield: 43.5 %

Procedure:
A solution containing 1.02 g (0.004 mol) of 4-chloro-3-sulfamoylbenzoyl chloride, 0.74 g (0.004 mol) of 10,11-dihydro-5H-pyrolo[2,1-c][1,4]benzodiazepine and 0.48 g (0.004 mol) of N,N-dimethylaniline in 50 ml of 1,4-dioxane was allowed to stand at room temperature for 2 hours. The reaction mixture was then poured into 500 mL of water with stirring. The precipitate was collected, washed and dried to provide the title compound (0.7 g), m.p. 137° C. dec.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[CH2:32]([NH2:40])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH:40][CH2:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[O:24])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: NCCc1ccccc1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(NCCc1ccccc1)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with phenethylamine as in General Procedure 10 to give the title compound. LCMS: m/z=550.96 (M+H+); retention time=0.94 minutes.
Reaction SMILES: [CH2:1]([N:8]1[CH2:29][CH2:28][CH2:27][C:10]2([CH2:15][N:14]([C:16]3[CH:21]=[C:20]([N+:22]([O-])=O)[C:19]([NH2:25])=[C:18]([CH3:26])[CH:17]=3)[CH2:13][CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[Cl:34][C:35]1[C:40]([CH:41]=O)=[C:39]([I:43])[CH:38]=[CH:37][N:36]=1>CO.[Pd]>[CH2:1]([N:8]1[CH2:29][CH2:28][CH2:27][C:10]2([CH2:11][CH2:12][CH2:13][N:14]([C:16]3[CH:17]=[C:18]([CH3:26])[C:19]4[N:25]=[C:41]([C:40]5[C:35]([Cl:34])=[N:36][CH:37]=[CH:38][C:39]=5[I:43])[NH:22][C:20]=4[CH:21]=3)[CH2:15]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(N2CCCC3(CCCN(Cc4ccccc4)C3)C2)cc([N+](=O)[O-])c1N
Reactant: O=Cc1c(I)ccnc1Cl
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(N2CCCC3(CCCN(Cc4ccccc4)C3)C2)cc2[nH]c(-c3c(I)ccnc3Cl)nc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 9 %

Procedure:
To a solution of 4-(8-benzyl-2,8-diaza-spiro[5.5]undec-2-yl)-2-methyl-6-nitro-phenylamine (394 mg, 1.0 mmol) in MeOH (47.5 mL) were added Pd/C (10%, 40 mg) and acetic acid (2.5 mL). The mixture was stirred under atmospheric hydrogen (balloon) at the room temperature for 3 h and filter over Celite. The filtrate was mixed with 2-chloro-3-formyl-4-iodopyridine (267.5 mg, 1.0 mmol), stirred at the room temperature for 18 h, and evaporated to dryness under reduced pressure. The residue was dissolved in MeOH (10 mL) and 28% aqueous NH4OH solution (0.5 mL) was added. After it was stirred for 5 min, the mixture was concentrated and chromatographed (330:10:1 CH2Cl2/MeOH/28% aqueous NH4OH) to afford the title compound (55 mg, 9%). 1H NMR (CDCl3) δ 1.22-1.36 (2H), 1.49-1.84 (6H), 1.95-2.59 (6H), 2.59 (s, 3H), 2.94-3.45 (6H), 6.82 (s, 1H), 6.87 (s, 1H), 7.16-7.33 (5H), 7.72 (d, J=6 Hz, 1H), 7.99 (d, J=6 Hz, 1H). ESI-MS m/z 612 (MH+).