Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1[CH:5]2[CH:6]3[CH:10]=[CH:9][CH:8]([CH:4]2C=C1)[CH2:7]3.[C:11](#[N:14])C=C.C1(C=CC(O)=CC=1)O>>[C:11]([C:6]12[CH2:7][CH:8]([CH2:4][CH2:5]1)[CH:9]=[CH:10]2)#[N:14]
Reactant: C=CC#N
Reactant: C1=CC2C3C=CC(C3)C2C1
Agent: Oc1ccc(O)cc1
Product: N#CC12C=CC(CC1)C2
Reaction time: 7 h

Procedure:
Dicyclopentadiene of 54.2%, acrylonitrile of 45.8% and hydroquinone of 500 ppm as a polymerization inhibitor were mixed, and this mixed solution was continuously fed into a tubular reactor (inner diameter: 8 mm) at a rate of 50 ml/hr, wherein the reaction temperature was controlled to 153° C. in a residence time of the reaction solution of up to 5 hours, 170° C. in a residence time of up to 7 hours and 180° C. in a residence time of up to 9 hours. After this reaction reached a steady state, the reaction was further continued for 20 hours to obtain crude cyanonorbornene of about 1 liter having a purity of 95%. This was concentrated under reduced pressure to distill off unreacted cyclopentadiene and acrylonitrile, whereby cyanonorbornene of 950 g having a purity of 99.6% was obtained.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:34])[N:24]([CH:31]([CH3:33])[CH3:32])[CH2:25][CH2:26][S:27](=[O:30])(=[O:29])[NH2:28])[CH:20]=[C:19]([Cl:35])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[Cl:35][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:18]=1)[C:23]([N:24]([CH:31]([CH3:33])[CH3:32])[CH2:25][CH2:26][S:27](=[O:30])(=[O:29])[NH2:28])=[O:34]
Reactant: CC(C)N(CCS(N)(=O)=O)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(CCS(N)(=O)=O)C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1
Reaction time: 64 h

Procedure:
A solution of (2-{3-chloro-5-[isopropyl-(2-sulfamoyl-ethyl)-carbamoyl]-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester (0.012 g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 64 h and then concentrated under reduced pressure to give the title compound (0.011 g) as a colourless gum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].Cl[C:30]1[N:35]=[CH:34][C:33]([C:36]([O:38][CH3:39])=[O:37])=[CH:32][N:31]=1.C1N2CCN(CC2)C1>>[CH3:39][O:38][C:36]([C:33]1[CH:32]=[N:31][C:30]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[N:35][CH:34]=1)=[O:37]
Reactant: COC(=O)c1cnc(Cl)nc1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Agent: C1CN2CCN1CC2
Product: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)nc1

Procedure:
In analogy to Example 62, step 1, 6-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 56, step 4) was react with methyl 2-chloropyrimidine-5-carboxylate and DABCO (1.5 h, r.t.) to give the title compound as a white solid. MS (m/e)=552.2 [M+H+].
Reaction SMILES: [C:1]([N:9]1[C:13]2([CH2:18][CH2:17][CH:16]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=3)=[O:20])[CH2:15][CH2:14]2)[S:12][CH2:11][C@H:10]1[C:31]([O:33]C(C)(C)C)=[O:32])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([N:9]1[C:13]2([CH2:14][CH2:15][CH:16]([C:19]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:26][CH:27]=3)=[O:20])[CH2:17][CH2:18]2)[S:12][CH2:11][C@H:10]1[C:31]([OH:33])=[O:32])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(NC(=O)C2CCC3(CC2)SC[C@@H](C(=O)OC(C)(C)C)N3C(=O)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1ccc(NC(=O)C2CCC3(CC2)SC[C@@H](C(=O)O)N3C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 38.4 %

Procedure:
In 7 ml of methylene chloride was dissolved 0.35 g of tert-butyl (3R)-4-benzoyl-8-[(4-isopropylanilino)-carbonyl]-1-thia-4-azaspiro[4.5]-decane-3-carboxylate. After adding 1.8 ml of trifluoroacetic acid at 0-5° C., the resulting mixture was stirred at ambient temperature for 6 hours. After distilling off the solvent under reduced pressure, the residue was several times subjected to an azeotropic distillation treatment together with toluene and then purified by column chromatography [eluent: chloroform:ethanol=20:1]. The residue was treated with ethyl ether, and the deposited crystal was collected by filtration to obtain 0.12 g of (3R)-4-benzoyl-8-[(4-isopropylanilino)carbonyl]-1-thia-4-azaspiro[4.5]decane-3-carboxylic acid as a colorless crystalline product.
Reaction SMILES: CO[C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH2:25][CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[N:6][CH:5]=1.[CH2:28]([CH2:30][NH2:31])[OH:29]>>[CH2:25]([NH:24][C:23]1[C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3](=[O:27])[NH:31][CH2:30][CH2:28][OH:29])=[CH:5][N:6]=3)=[O:11])[CH2:13][CH2:14]2)=[N:19][CH:20]=[CH:21][CH:22]=1)[CH3:26]
Reactant: NCCO
Reactant: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)OC)cn2)CC1
Product: CCNc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NCCO)cn2)CC1
Yield: 73 %

Procedure:
By the same procedure as described in the example 2, synthesis was carried out starting with 6-[1-[3-(ethylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid methyl ester and using ethanolamine. And then, the product was recrystallized with ethanol and hexane to give a desired compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][O:26][CH2:27][CH2:28][CH2:29][NH:30][CH3:31]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:30]([CH2:29][CH2:28][CH2:27][O:26][CH3:25])[CH3:31])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: CNCCCOC
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: COCCCN(C)C(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3C)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 227 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 3-methoxy-N-methylpropan-1-amine. 1H NMR (400 MHz, DMSO-d6) δ 1.62-1.84 (m, 2H) 2.36 (s, 3H) 2.91 (s, 3H) 3.04 (br. s., 1H) 3.14-3.21 (m, 3H) 7.59 (dd, J=8.1, 1.5 Hz, 1H) 7.65 (s, 1H) 7.72 (d, J=8.1 Hz, 1H) 7.95-8.04 (m, 1H) 8.05-8.09 (m, 1H) 8.30 (d, J=8.3 Hz, 1H) 8.46 (d, J=9.9 Hz, 1H). MS m/z [M+H]+ 406.4.
Reaction SMILES: F[C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[C:22]1[S:26][CH:25]=[N:24][CH:23]=1.[NH:27]1[CH2:31][CH2:30][C@@H:29]([OH:32])[CH2:28]1>CS(C)=O>[OH:32][C@@H:29]1[CH2:30][CH2:31][N:27]([C:2]2[CH:21]=[CH:20][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)=[O:7])=[CH:4][C:3]=2[C:22]2[S:26][CH:25]=[N:24][CH:23]=2)[CH2:28]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(F)c(-c2cncs2)c1
Reactant: O[C@@H]1CCNC1
Solvent: CS(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2CC[C@@H](O)C2)c(-c2cncs2)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 4-fluoro-3-(thiazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 1.1, 50 mg, 0.131 mmol), (R)-pyrrolidin-3-ol (22.8 mg, 0.262 mmol) and TEA (72.9 μL, 0.523 mmol) in DMSO (98 μL) was stirred at 100° C. overnight. The RM was filtered and the filtrate was purified by preparative SFC (Column Diol, isocratic 30% in 6 min) to yield the title compound as a pale brown solid. UPLC-MS (Condition 1) tR=1.05 min, m/z=450.3 [M+H]+, m/z=448.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.68-1.82 (m, 1H) 1.82-1.99 (m, 1H) 2.79 (d, J=10.29 Hz, 1H) 3.06-3.14 (m, 1H) 3.14-3.21 (m, 1H) 3.24-3.33 (m, 1H) 4.24 (br. s, 1H) 4.80-5.00 (m, 1H) 6.98 (d, J=8.78 Hz, 1H) 7.35 (d, J=8.41 Hz, 2H) 7.76-8.02 (m, 5H) 9.17 (s, 1H) 10.18 (s, 1H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[C:14]12([OH:24])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2.N1C=CC=CC=1>O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]([O:24][C:14]12[CH2:21][CH:20]3[CH2:19][CH:18]([CH2:17][CH:16]([CH2:22]3)[CH2:15]1)[CH2:23]2)=[O:12]
Reactant: O=C(Cl)c1cnc2ccccc2n1
Reactant: OC12CC3CC(CC(C3)C1)C2
Solvent: c1ccncc1
Solvent: O
Product: O=C(OC12CC3CC(CC(C3)C1)C2)c1cnc2ccccc2n1
Yield: 16.6 %

Procedure:
Prepared from 2-quinoxaloyl chloride (0.84 g, 4.4 mmol), 1-adamantanol (0.60 g, 3.9 mmol), pyridine (10 mL), and water (100 mL) yielding 0.20 g (16%) of (92):
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:44]12[CH2:51][CH2:50][CH:47]([CH2:48][CH2:49]1)[C@@H:46](O)[CH2:45]2>C1COCC1>[N:44]12[CH2:51][CH2:50][CH:47]([CH2:48][CH2:49]1)[C@@H:46]([O:11][C:10](=[O:12])[CH:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:45]2
Reactant: O=C(O)C(Nc1ccc(Cl)cc1)c1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.5 %

Procedure:
To a solution of (4-chloro-phenylamino)-phenyl-acetic acid (I28) (574 mg, 2.20 mmol) in dry THF (20 mL), are added DCC (543 mg, 2.64 mmol), HOBt (359 mg, 2.64 mmol) and 3(R)-quinuclidinol (558 mg, 4.40 mmol). The resulting mixture is stirred at RT overnight (UPLC-MS monitoring: complete conversion). The solvent is evaporated and the residue is portitioned between EtOAc and 2M K2CO3. The organic phase is dried over Na2SO4, filtered and evaporated to dryness. The resulting crude is purified by flash chromatography (DCM/MeOH=99/1 to 85/15) to obtain the title compound as a white solid (306 mg, 37% yield, mixture of diastereoisomers).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])=[CH:30][C:29]=1[O:40][CH3:41]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([CH2:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])=[CH:30][C:29]=4[O:40][CH3:41])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CCCC(=O)Cc1ccc(OCCCBr)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCC(=O)Cc1ccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)c(OC)c1
Yield: 68.7 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10 mmol), K2CO3 (3 g), 1-[4-(3-bromopropoxy)-3-methoxyphenyl]pentanone (3.7 g, 11.3 mmol) in acetonitrile (140 ml) was heated at reflux for 4 hours. At the end of the reaction, the mixture was cooled and filtered. The filtrate was concentrated to an oil. Purification was performed by flash chromatography over a silica gel column (SiO2, 55 g; eluted with 1% methanol in dichloromethane, 600 ml; 3% methanol:97% dichloromethane, 400 ml). The fractions containing pure product were pooled and concentrated to a solid (4.3 g, 91%). Recrystallization from ethanol (10 ml) gave a powdery solid of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]pentanone (3.22 g), m.p.=79°-80° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:16]=[C:15]([NH:17][C:18](=[O:26])OC3C=CC=CC=3)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=1.[CH3:27][C:28]1[CH:29]=[C:30]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:31]=[C:32]([CH3:34])[CH:33]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:16]=[C:15]([NH:17][C:18]([N:38]3[CH2:39][CH2:40][N:35]([C:30]4[CH:31]=[C:32]([CH3:34])[CH:33]=[C:28]([CH3:27])[CH:29]=4)[CH2:36][CH2:37]3)=[O:26])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=1
Reactant: O=C(Nc1cc(-c2cccnc2)nc2ccccc12)Oc1ccccc1
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Cc1cc(C)cc(N2CCN(C(=O)Nc3cc(-c4cccnc4)nc4ccccc34)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
Phenyl N-[2-(pyridin-3-yl)quinolin-4-yl]carbamate(171 mg, 0.5 mmol) and 1-(3,5-dimethylphenyl)piperazine(95 mg, 0.5 mmol) were dissolved in anhydrous tetrahydrofuran and DBU(117 mg, 0.75 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours, concentrated under the reduced pressure to remove tetrahydrofuran, and purified by column chromatography(ethylacetate:hexane=1:1) to obtain the titled compound.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[N:3]1[CH2:9][CH2:10][NH:11][C:12](=[O:24])[CH2:13][N:14]1[CH2:18][CH2:17][CH:16]([O:19]C(=O)C)[C:15]1=[O:23].N>CO>[CH3:8][C@H:4]1[CH2:5][CH2:6][CH2:7][C@@H:2]([CH3:1])[N:3]1[CH2:9][CH2:10][NH:11][C:12](=[O:24])[CH2:13][N:14]1[CH2:18][CH2:17][CH:16]([OH:19])[C:15]1=[O:23]
Reactant: CC(=O)OC1CCN(CC(=O)NCCN2[C@H](C)CCC[C@@H]2C)C1=O
Agent: N
Solvent: CO
Product: C[C@@H]1CCC[C@H](C)N1CCNC(=O)CN1CCC(O)C1=O

Procedure:
0.3 g of (R/S)-cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetamide is stirred at room temperature for 2 hours in 30 ml of a saturated solution of ammonia in methanol. After evaporation of the methanol, the residue is treated three times with toluene and in each case again evaporated. After trituration in diethyl ether, there is obtained (R/S)-cis-N-[2-(2,6-dimethyl-1-piperidinyl)ethyl]-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide of melting point 129°-130°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH:15]=[N:14][N:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([NH2:9])=O.[OH-].COC(NS([NH3+])(=O)=O)=O.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH:15]=[N:14][N:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]#[N:9]
Reactant: NC(=O)c1cc(Cl)ccc1-n1cnnn1
Agent: COC(=O)NS([NH3+])(=O)=O
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(Cl)ccc1-n1cnnn1
Yield: 89.7 %

Procedure:
To a solution of 5-chloro-2-(1H-tetrazol-1-yl)benzamide (1.0 g, 4.5 mmol) in THF (29 mL) was added (methoxycarbonylsulfamoyl)ammonium hydroxide, inner salt (2.1 g, 8.8 mmol) in five portions over 5 h. Water was added and the reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with brine. Drying and solvent evaporation gave 5-chloro-2-tetrazol-1-yl-benzonitrile (0.83 g, 90%); 1H NMR (400 MHz, CDCl3): δ 9.26 (s, 1H), 7.90 (d, J=1.0 Hz, 1H,), 7.85 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[CH:2].Br[C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH:37]=1)[C:25]([N:27]=[S:28]([CH3:36])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[C:2][C:20]3[CH:21]=[N:22][CH:23]=[C:24]([CH:37]=3)[C:25]([N:27]=[S@@:28]([CH3:36])(=[O:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])=[CH:8][CH:7]=2)=[O:18])=[CH:12][CH:13]=1
Reactant: C#Cc1ccc(NC(=O)c2ccc(F)cc2)cc1
Reactant: CS(=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2ccc(NC(=O)c3ccc(F)cc3)cc2)c1)c1ccccc1
Yield: 72.2 %

Procedure:
In a manner similar to that described in Example 449, N-(4-ethynyl-phenyl)-4-fluoro-benzamide (0.106 g, 0.443 mmol) and 5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (100 mg, 0.295 mmol) were reacted to give the title compound as a solid (106 mg, 72%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.O=S(Cl)Cl>C1(C)C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]=1)=[O:6]
Reactant: Nc1ccc(Br)cc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Nc1ccc(Br)cc1C(=O)Nc1ccccc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 209.2 %

Procedure:
A mixture of 2-amino-5-bromo-benzoic acid (2 g, 9.26 mmol) and SOCl2 (4 mL) in toluene (20 mL) was stirred at 130° C. for 2 h. After being concentrated, the residue was dissolved in tetrahydrofuran (50 mL) and phenylamine was added dropwise at 0° C. Then the reaction mixture was heated to 90° C. for 4 h. The mixture was cooled to room temperature, quenched with saturated aqueous K2CO3 (20 mL) and extracted with ethyl acetate (50 mL*3), the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified with silica gel column chromatograph (PE:EtOAc=4:1) to give 2-amino-5-bromo-N-phenylbenzamide (2.82 g, yield: 99%) as white solid. MS (M+H)+: 291/293.
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:7][N:6]=[C:5]([C:8](O)=O)[CH:4]=1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[NH2:41][C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][C:50]=1[NH2:51])[N:47]([CH2:52][CH3:53])[C:46](=[O:54])[C:45]2([CH3:56])[CH3:55]>CN(C)C=O>[CH2:52]([N:47]1[C:48]2[CH:49]=[C:50]3[NH:51][C:8]([C:5]4[CH:4]=[C:3]([O:2][CH3:1])[NH:7][N:6]=4)=[N:41][C:42]3=[CH:43][C:44]=2[C:45]([CH3:56])([CH3:55])[C:46]1=[O:54])[CH3:53]
Reactant: COc1cc(C(=O)O)n[nH]1
Reactant: CCN1C(=O)C(C)(C)c2cc(N)c(N)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCN1C(=O)C(C)(C)c2cc3nc(-c4cc(OC)[nH]n4)[nH]c3cc21
Temperature: 25 °C
Yield: 28 %

Procedure:
5-Methoxy-1H-pyrazole-3-carboxylic acid (86 mg, 0.61 mmol), 1-hydroxybenzotriazole hydrate (111 mg, 0.73 mmol) and triethylamine (253 μl, 184 mg, 1.82 mmol) were dissolved in N,N-dimethylformamide (DMF) (2 ml) and after the addition of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (139 mg, 0.73 mmol) dissolved in DMF (2 ml) the reaction mixture was stirred at room temperature. After 1 hour a solution of 5,6-diamino-1-ethyl-3,3-dimethyl-1,3-dihydro-indol-2-one in DMF (2 ml) was added and the reaction mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, the residue was quenched with water (20 ml) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (15 ml), dried over sodium sulfate and evaporated. The residue was dissolved in ethanol (5 ml) and after the addition of hydrochloric acid (10 M, 2 ml) it was stirred under reflux for 2 hours. The ethanol was evaporated and the residue was adjusted to pH 9-10 with ammonium hydroxide. After the addition of water (20 ml) the aqueous phase was extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with brine (10 ml), dried over sodium sulfate and evaporated. The crude product was purified by column chromatography on silica gel. Elution with ethyl acetate/n-heptane (9:1) yielded 56 mg (28%) of an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[N:4]([CH2:12][CH2:13][CH3:14])[C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.[CH2:24]([O:26][C:27](=[O:32])[C:28](Br)([CH3:30])[CH3:29])[CH3:25]>>[CH2:24]([O:26][C:27](=[O:32])[C:28]([CH3:30])([O:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([CH2:12][CH2:13][CH3:14])[C:3]([C:15]1[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1)=[C:2]2[CH3:1])[CH3:29])[CH3:25]
Reactant: CCCn1c(-c2ccc([N+](=O)[O-])cc2)c(C)c2cc(O)ccc21
Reactant: CCOC(=O)C(C)(C)Br
Product: CCCn1c(-c2ccc([N+](=O)[O-])cc2)c(C)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
The above compound was prepared from 3-methyl-2-(4-nitro-phenyl)-1-propyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]([CH2:16][CH3:17])=[C:14]([O:18]C)[N:13]=[C:12]([O:20]C)[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:22](Br)(=[O:24])[CH3:23]>>[CH3:8][C:6]1[CH:5]=[C:4]([N:9]([C:10]2[NH:11][C:12](=[O:20])[NH:13][C:14](=[O:18])[C:15]=2[CH2:16][CH3:17])[C:22](=[O:24])[CH3:23])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: CC(=O)Br
Reactant: CCc1c(Nc2cc(C)cc(C)c2)nc(OC)nc1OC
Product: CCc1c(N(C(C)=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Temperature: 25 °C
Yield: 86 %

Procedure:
(3,5-Dimethyl-phenyl)-(5-ethyl-2,6-dimethoxy-pyrimidin-4-yl)-amine (5 g, 17.4 mmol) was refluxed with acetyl bromide (50 mL) for 18 hr. After cooling to room temperature, the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (2:1)) to afford 4.5 g (86%) of a white solid. m.p. 238-239° C.; 1H-NMR (200 MHz, CDCl3) δ 0.93 (3H, t, J=7.5 Hz), 2.05-2.15 (3H, m), 2.24-2.40 (8H, m), 6.94-6.99 (3H, m); m/z (EI) 301(M+).
Reaction SMILES: C[SiH](C)[O:3][CH:4](C(C)(C)C(C)C)[C@H:5]1[N:10]2[C:11]3[CH:12]=[CH:13][C:14]([O:18][CH:19]4[CH2:24][CH2:23][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]4)=[CH:15][C:16]=3[CH:17]=[C:9]2[C:8](=[O:28])[NH:7][CH2:6]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:3][CH2:4][C@H:5]1[N:10]2[C:11]3[CH:12]=[CH:13][C:14]([O:18][CH:19]4[CH2:24][CH2:23][N:22]([CH:25]([CH3:26])[CH3:27])[CH2:21][CH2:20]4)=[CH:15][C:16]=3[CH:17]=[C:9]2[C:8](=[O:28])[NH:7][CH2:6]1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C(O[SiH](C)C)C(C)(C)C(C)C)CNC2=O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](CO)CNC2=O)CC1
Temperature: 25 °C
Yield: 0 %

Procedure:
The solution of 0.2 g (0.40 mmol) (S)-4-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one in 1 ml tetrahydrofuran was cooled down to 0° C. and treated with 0.14 ml (0.126 g, 0.48 mmol) tetra-n-butylammoniumfluoride solution (1M in tetrahydrofuran). The cooling bath was removed and after 1.5 hours stirring at room temperature the solution was poured on saturated aqueous sodium bicarbonate solution and was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash column chromatography on silica gel with dichloromethane:methanol:ammonia (9:1:0.1 v/v) as eluant to give 60 μg (42%) of the desired compound as a colorless semi solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)O)=[CH:4][CH:3]=1.BrC1N=CC(C(OC)C2C3C(=NC=CC=3)NC=2)=CC=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[Br:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Br)nc1)c1c[nH]c2ncccc12
Agent: CC[SiH](CC)CC
Agent: COC(c1ccc(Br)nc1)c1c[nH]c2ncccc12
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Brc1ccc(Cc2c[nH]c3ncccc23)cn1
Yield: 86.8 %

Procedure:
A mixture of (6-bromo-pyridin-3-yl)-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol (89, 1 g, 0.003 mol) and 3-[(6-bromo-pyridin-3-yl)-methoxy-methyl]-1H-pyrrolo[2,3-b]pyridine (90, 2 g, 0.006 mol), triethylsilane (1 mL, 0.006 mol), and trifluoroacetic acid (0.5 mL, 0.006 mol) in acetonitrile (25 mL) was refluxed for 2 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and water. The organic layer was collected, washed with saturated sodium bicarbonate, brine, and dried over sodium sulfate. After removal of the solvent, the residue was purified with silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as an off-white solid (91, 0.75 g, 60%). MS (ESI) [M+H+]+=288.06, 290.00.