Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[C:13](=O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.S[CH2:18][CH2:19][C:20]([OH:22])=O>>[OH:16][C:6]1[CH:7]=[CH:12][C:13]([C:13]2([C:1]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:3][CH:2]=3)[C:14]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6](=[O:16])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]2=3)=[CH:14][CH:5]=1
Reactant: O=C(O)CCS
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Product: O=C1c2ccccc2C(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Temperature: 65 °C

Procedure:
Anthraquinone (60 g) phenol (150 g) and 3-mercaptopropionic acid (8 g) were placed in a round-bottom flask. The mixture was heated at 65° C., and then dry hydrogen chloride was bubbled in for about 24 h. The phenol, hydrogen chloride, and cocatalyst were removed by steam distillation. This product was recrystallized from methanol as a slightly yellowish granular mass: MP 320°-322° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.C(N(CC)CC)C.Br[C:25]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[Cl:43])[C:33]2[C:28](=[CH:29][C:30]([CH3:35])=[C:31]([Cl:34])[CH:32]=2)[NH:27][C:26]1=[O:36]>C1COCC1>[C:13]([O:12][C:10]([N:7]1[CH2:6][CH2:5][CH:4]([CH2:3][CH2:2][NH:1][C:25]2([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[Cl:43])[C:33]3[C:28](=[CH:29][C:30]([CH3:35])=[C:31]([Cl:34])[CH:32]=3)[NH:27][C:26]2=[O:36])[CH2:9][CH2:8]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: Cc1cc2c(cc1Cl)C(Br)(c1ccccc1Cl)C(=O)N2
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc2c(cc1Cl)C(NCCC1CCN(C(=O)OC(C)(C)C)CC1)(c1ccccc1Cl)C(=O)N2
Yield: 56.2 %

Procedure:
A solution of 1.35 g of 4-(2-aminoethyl)-1-(tert-butoxycarbonyl)piperidine and 1.75 g of triethylamine in 20 ml of THF is added dropwise at RT to a solution of 2.1 g of 3-bromo-5-chloro-3-(2-chlorophenyl)-1,3-dihydro-6-methylindol-2-one, obtained in step B' of Preparation 71, in 20 ml of THF and the reaction mixture is stirred for 1 hour at RT. It is concentrated under vacuum, the residue is taken up with 400 ml of AcOEt and 50 ml of THF, the resulting suspension is washed twice with a 5% solution of sodium carbonate, with water and with a saturated solution of NaCl and, after decantation, the solid in suspension is filtered off. The solid is dissolved in 400 ml of boiling THF and dried over sodium sulfate and the solvent is partially evaporated off under vacuum. The crystalline product formed is filtered off to give 1.65 g of the expected product. M.p.=245°-248° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C@H:13]3[CH2:15][C@@H:14]3[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][CH:8]=2)[N:4]=[CH:3]1.[I:21]N1C(=O)CCC1=O>ClCCl>[I:21][C:6]1[N:2]([CH3:1])[CH:3]=[N:4][C:5]=1[C:7]1[CH:8]=[CH:9][C:10]([C@H:13]2[CH2:15][C@@H:14]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:12]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)[C@H]1C[C@@H]1c1ccc(-c2cn(C)cn2)cc1
Solvent: ClCCl
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(-c2ncn(C)c2I)cc1
Reaction time: 16 h

Procedure:
To a solution of Ethyl (1S,2S)-2-[4-(1-methyl-1H-imidazol-4-yl)phenyl]cyclopropanecarboxylate (product of Step 1, 2.8 g, 10.36 mmol) in dichloromethane (104 mL) was added N-iodosuccinimide (2.1 g, 9.33 mmol). The reaction mixture was stirred at it for 16 h. The mixture was diluted with dichloromethane and washed with aqueous sodium thiosulfate, followed by three washes with water then dried (MgSO4). The solvent was concentrated to afford the title compound as an orange oil which could be used in the next Step without further purification. LCMS: [M+1]+=396.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>CC#N>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 25 °C
Yield: 60.1 %

Procedure:
To a stirred solution of 5-bromo-2-nitropyridine (4.93 g, 24.3 mmol) and piperazine-1-carboxylic acid tert-butyl ester (4.97 g, 26.7 mmol) in CH3CN (60 ml) is added DIPEA (4.65 mL, 26.7 mmol). The mixture is heated at reflux for 72 hours then cooled to room temperature and the precipitated product collected by filtration. The filtrate is concentrated and purified by flash column chromatography eluting with 30% EtOAc/petrol. The combined products are re-crystallized from EtOAc/petrol to give 4-(6-nitro-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester, (4.50 g, 80% yield). MS (ESI) m/z 308 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:17][NH:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([N:18]([CH3:17])[CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNCCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Product: CN(CCCc1ccccc1)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
By the method of part A of Example 1 N-(tert-butyloxycarbonyl)-L-proline (4.3 g.) was condensed with N-methyl-3-phenylpropylamine hydrochloride (3.71 g.) and the product was purified by high pressure liquid chromatography on silica gel using hexane-ethyl acetate (3:2) as the eluant, affording 1-(tert-butyloxycarbonyl)-N-methyl-N-(3-phenylpropyl)-L-prolinamide as a syrup (2.65 g.).
Reaction SMILES: C[N:2]1CCOCC1.[CH3:8][S:9][C:10]1[N:15]=[C:14]([C:16](O)=[O:17])[CH:13]=[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:11]=1.[Cl-].[NH4+].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH3:8][S:9][C:10]1[N:15]=[C:14]([C:16]([NH2:2])=[O:17])[CH:13]=[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:11]=1
Reactant: CSc1nc(C(=O)O)cc(-c2ccccc2)n1
Reactant: CN1CCOCC1
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CSc1nc(C(N)=O)cc(-c2ccccc2)n1
Yield: 94.1 %

Procedure:
N-Methylmorpholine (2.31 mL, 21 mmol) was added dropwise by syringe to a mixture of 2-methylsulfanyl-6-phenylpyrimidine-4-carboxylic acid (3.45 g, 14 mmol), ammonium chloride (4.27 g, 80 mmol), HOBt (2.84 g, 21 mmol), and EDC (4.0 g, 21 mmol) in DMF (40 mL) at room temperature. The reaction solution was stirred at room temperature for 3 h before the DMF was removed by rotary evaporation. Column chromatography (SiO2, DCM/EtOAc 5:1) afforded 3.23 g of 2-(methylthio)-6-phenylpyrimidine-4-carboxamide as a white solid. 1H NMR (DMSO-d6, 300 MHz) δ 8.25 (m, 2H), 8.13 (s, 1H), 7.59 (m, 3H), 2.62 (s, 3H). HPLC ret. time 2.71 min, 10-100% CH3CN, 5 min gradient. ESI-MS m/z 246.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH:11]([O:14][CH3:15])[O:12][CH3:13].CO.C[O-].[Na+]>>[CH3:13][O:12][CH:11]([O:14][CH3:15])[CH2:10][S:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: Fc1ccc(S)cc1
Reactant: COC(CBr)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(CSc1ccc(F)cc1)OC
Reaction time: 0.17 h
Yield: 89.3 %

Procedure:
In a nitrogen stream, 4-fluorobenzenethiol (2.5 ml, 23.4 mmol) and 2-bromo-1,1-dimethoxyethane (3.0 ml, 25.7 mmol) were added to a sodium methoxide methanol solution (0.5 M, 74.9 ml, 37.4 mmol) under cooling with ice and the reaction mixture was stirred at the same temperature for 10 minutes, and then heated and refluxed for five hours. The reaction mixture was concentrated under reduced pressure, and added with cold water. The mixture was extracted with ether. The organic layer was washed with a saturated sodium chloride aqueous solution, and then dried with sodium sulfate. After filtration, the solvent was distilled under reduced pressure, and the obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:20)] to obtain the title compound (4.52 g, 89%).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:21]([O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH2:35][CH3:36])[CH2:30][NH:29][CH2:28][CH2:27]2)[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:29]1[CH2:28][CH2:27][C:26]2[C:31](=[CH:32][C:33]([O:34][CH2:35][CH3:36])=[C:24]([O:23][CH2:21][CH3:22])[CH:25]=2)[CH2:30]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCCCCCCBr)NOCc1ccccc1
Reactant: CCOc1cc2c(cc1OCC)CNCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc2c(cc1OCC)CN(CCCCCCCC(=O)NOCc1ccccc1)CC2

Procedure:
In a manner analogous to that of example 1(b), 8-bromo-octanoic acid benzyloxy-amide (example 1(a); 0.38 g, 1.2 mmol) was reacted with 6,7-diethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.3 g, 1.2 mmol) in the presence of potassium carbonate (0.16 g, 1.2 mmol) and DMF as solvent to give 8-(6,7-diethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-octanoic acid benzyloxyamide as an almost colorless wax (yield 0.15 g, 27%; purified by column chromatography using silica gel and ethyl acetate: methanol=9:1 as an eluent). MS (M+H+)=469.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)=[O:17].[CH3:24][CH2:25][O:26][C:27](C)=[O:28]>>[O:28]1[C:24]2[CH:22]=[CH:23][C:18]([CH2:16][NH:15][C:19]3[C:18]([C:16]([NH:15][C:3]4[CH:4]=[CH:5][C:6]([O:8][C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=5)=[CH:7][CH:2]=4)=[O:17])=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:19][C:25]=2[O:26][CH2:27]1
Reactant: O=C(Nc1ccc(Oc2ccccc2)cc1Cl)c1cccnc1
Reactant: CCOC(C)=O
Product: O=C(Nc1ccc(Oc2ccccc2)cc1)c1cccnc1NCc1ccc2c(c1)OCO2
Temperature: 110 °C

Procedure:
2-Chloro-(3-pyridyl)-N-(4-phenoxyphenyl)-carboxamide (0.500 g, 1.5 mmol) and 2H-benzo[d]1,3-dioxolan-5-ylmethylamine (0.680 g, 4.5 mmol) were combined and heated neat at 110° C. for 18 h. After cooling to RT, the resulting residue was dissolved in EtOAc and washed with saturated NaACO3 solution and brine, respectively. The organics were dried over Na2SO4 and evaporated. The crude material was purified by column chromatography with EtOAc/hexanes (1:2) as eluant to leave the desired compound as an off-white solid. MS: (ES+) 440 (M +1)+; (ES−): 438 (M−1)−. Calc'd. for C26H21N3O4-439.15.
Reaction SMILES: Cl[C:2]1C=C(C2C3N=CC=CC=3C(=O)NN=2)C=C[CH:7]=1.[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2[C:27]3[CH:36]=[CH:35][CH:34]=[N:33][C:28]=3[C:29](=[O:32])[NH:30][N:31]=2)[CH:23]=[CH:24][CH:25]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2[C:27]3[CH:36]=[CH:35][CH:34]=[N:33][C:28]=3[C:29](=[O:32])[N:30]([CH2:2][CH3:7])[N:31]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: O=c1[nH]nc(-c2cccc(Cl)c2)c2cccnc12
Reactant: O=c1[nH]nc(-c2cccc(Cl)c2)c2ncccc12
Product: CCn1nc(-c2cccc(Cl)c2)c2cccnc2c1=O

Procedure:
Following the procedures of Example 17A and substituting for 8-(3-chlorophenyl)pyrido[2,3-d]pyridazin-5-one with 5-(3-chlorophenyl)pyrido[2,3-d]pyridazin-8-one there is obtained 5-(3-chlorophenyl)-7-ethylpyrido[2,3-d]pyridazin-8-one.
Reaction SMILES: [CH2:1]([S:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[CH:8]=[C:7]([C:15](O)=[O:16])[C:6]1=[O:18])[CH3:2].C(Cl)(=O)C([Cl:22])=O.CN(C)C=O>ClCCl>[CH2:1]([S:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[CH:8]=[C:7]([C:15]([Cl:22])=[O:16])[C:6]1=[O:18])[CH3:2]
Reactant: CCSCn1c(=O)c(C(=O)O)cc2cccnc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCSCn1c(=O)c(C(=O)Cl)cc2cccnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.20 g (8.3 mmol) of 1-(ethylthiomethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid was dissolved in dichloromethane (80 mL), and 5.0 mL (60 mmol) of oxalyl chloride was added thereto. One droplet of N,N-dimethylformamide was added to the above mixture, and the resulting mixture was stirred for one hour at room temperature. The reaction solution was concentrated under reduced pressure, and thus 1-(ethylthiomethyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylic acid chloride was obtained. The acid chloride thus obtained was dissolved in dichloromethane (80 mL), and 1.02 g (9.1 mmol) of 1,3-cyclohexanedione and 1.40 mL (10.0 mmol) of triethylamine were added to the above solution under ice cooling. The resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into an aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with dichloromethane. The organic phase was dried and concentrated. The residue was washed with diisopropyl ether, and 2.99 g of the title compound was obtained as a light yellow solid (yield: quantitative).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([B:9]2[O:13][C:12]([CH3:15])(C)[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:2].C1CCN2C(=NCCC2)CC1.[C:35]([O:39][CH2:40][CH3:41])(=[O:38])[CH:36]=[CH2:37]>C(#N)C>[CH2:1]([C:3]1[C:8]([B:9]2[O:10][C:11]([CH3:16])([CH3:17])[CH:12]([CH3:15])[O:13]2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH:18]1[CH2:23][CH2:22][N:21]([CH2:37][CH2:36][C:35]([O:39][CH2:40][CH3:41])=[O:38])[CH2:20][CH2:19]1)[CH3:2]
Reactant: CCc1c(B2OC(C)(C)C(C)(C)O2)cccc1C1CCNCC1
Reactant: C=CC(=O)OCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCOC(=O)CCN1CCC(c2cccc(B3OC(C)C(C)(C)O3)c2CC)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
To a solution of 4-[2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine (D119) (80 mg, 0.186 mmol) and DBU (0.034 mL, 0.224 mmol) in Acetonitrile (8 mL) was added ethyl 2-propenoate (57 mg, 0.499 mmol). The solution was sealed and stirred at 80° C. for 2 h. The solution was evaporated in vacuo to afford ethyl 3-{4-[2-ethyl-3-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-piperidinyl}propanoate (D123) (46 mg). MS (ES): C24H38BNO4 requires 415.3. found 416.3 (M+H+).
Reaction SMILES: C[O:2][C:3]([C:5]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][C:14]=2[Cl:21])[N:9]2[CH:10]=[N:11][CH:12]=[C:8]2[CH2:7][CH2:6]1)=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[Cl:21][C:14]1[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=1[C:5]1([C:3]([OH:4])=[O:2])[N:9]2[CH:10]=[N:11][CH:12]=[C:8]2[CH2:7][CH2:6]1
Reactant: COC(=O)C1(c2ccc(C#N)cc2Cl)CCc2cncn21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(C2(C(=O)O)CCc3cncn32)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(2-chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid methyl ester (0.6 g, 2.0 mmol) is dissolved in THF/water 3:2 (20 mL) and to it, is added LiOH (0.17 g, 4.0 mmol). The mixture is stirred at room temperature for 2 h before being neutralized to pH 6 with 1M HCl. The solution is evaporated to dryness to give acid, 5-(2-chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid as a solid. MS (ESI) m/z 288.2, 290.2 (M+H); 1H NMR (400 MHz, MeOD) (ammonium salt) δ ppm 2.64-2.74 (m, 1H), 2.77-2.86 (m, 1H), 2.94-3.02 (m, 1H), 3.74 (ddd, J=13.1, 9.1, 8.0 Hz, 1H), 6.74 (d, J=8.1 Hz, 1H), 6.85 (s, 1H), 7.59 (dd, J=8.1, 1.5 Hz, 1H), 7.84 (d, J=1.8 Hz, 1H), 7.91 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([Sn](CCCC)(CCCC)CCCC)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[N:24]1[CH:29]=[CH:28][C:27]([CH:30]([NH:32][C:33]([C:35]2[C:43]3[C:38](=[N:39][CH:40]=[C:41](Br)[N:42]=3)[N:37]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[CH:36]=2)=[O:34])[CH3:31])=[CH:26][CH:25]=1.CN(C=O)C>CCOCC.[Cu]I.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>[N:24]1[CH:29]=[CH:28][C:27]([CH:30]([NH:32][C:33]([C:35]2[C:43]3[C:38](=[N:39][CH:40]=[C:41]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[NH:8][N:7]=4)[N:42]=3)[N:37]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:50])([CH3:52])[CH3:51])[CH:36]=2)=[O:34])[CH3:31])=[CH:26][CH:25]=1
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)c1ccncc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(F)ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(F)ccc34)nc12)c1ccncc1
Temperature: 90 °C
Reaction time: 15 h
Yield: 87.3 %

Procedure:
6-Fluoro-3-tributylstannyl-1H-indazole (0.48 g, 1.13 mmol), copper(I) iodide (16 mg, 0.084 mmol) and 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-pyridin-4-yl-ethyl)-amide (400 mg, 0.84 mmol) were combined with DMF (6 mL) to give a yellow solution. The mixture was degassed for 10 min then tetrakis(triphenylphosphine)palladium (0) (45 mg, 0.039 mmol) was added. The reaction mixture was stirred under nitrogen at 90° C. for 15 h. The reaction mixture was cooled, diluted with ether (60 mL) and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-3% methanol in dichloromethane with 0.5% ammonium hydroxide) to afford 390 mg (87%) of 2-(6-fluoro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-pyridin-4-yl-ethyl)-amide as a yellow solid. MS: (M+H)+=532.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[C:18]([OH:26])(=[O:25])[C:19]([CH2:21][C:22](O)=[O:23])=[CH2:20]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:12]=[CH:13][C:14]([N:17]3[C:22](=[O:23])[CH2:21][CH:19]([C:18]([OH:26])=[O:25])[CH2:20]3)=[CH:15][CH:16]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(/C=C/c2ccc(N)cc2)cc1
Reactant: C=C(CC(=O)O)C(=O)O
Product: COc1ccc(/C=C/c2ccc(N3CC(C(=O)O)CC3=O)cc2)cc1

Procedure:
In an analogous manner to that described in Example 36c), the reaction of (E)-4-[2-(4-methoxy-phenyl)-vinyl]-phenylamine with itaconic acid yields the (RS)-(E)-1-{4-[2-(4-methoxy-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidine-3-carboxylic acid as a brown solid; MS: m/e=336 (M−H)+.
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[CH3:8]CCCCC.[Cl:14][C:15]1[CH:16]=[C:17]([C@@H:21]([OH:25])[C:22]([OH:24])=[O:23])[CH:18]=[CH:19][CH:20]=1.CO>C1C=CC=CC=1>[CH3:8][O:23][C:22](=[O:24])[C@@H:21]([C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([Cl:14])[CH:16]=1)[OH:25]
Reactant: O=C(O)[C@H](O)c1cccc(Cl)c1
Reactant: CCCCCC
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)[C@H](O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.9 %

Procedure:
A solution of trimethylsilyldiazomethane in hexane (2 M, 1.5 mL, 3.0 mmol) was added to a solution of (R)-(3-chloro-phenyl)hydroxy-acetic acid (497 mg, 2.66 mmol) in benzene (2.6 mL)-methanol (1.3 mL) under cooling with ice. Then, the ice bath was removed and the mixture was stirred at room temperature for five minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=3/1) to give the title compound (533 mg, 100%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].[CH3:16][O:17][C:18]([C:20]1[CH:29]=[CH:28][C:23]2[S:24][C:25]([CH3:27])=[CH:26][C:22]=2[CH:21]=1)=[O:19].C(OCC)(=O)C>C(Cl)Cl>[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8]([C:26]1[C:22]2[CH:21]=[C:20]([C:18]([O:17][CH3:16])=[O:19])[CH:29]=[CH:28][C:23]=2[S:24][C:25]=1[CH3:27])=[O:9]
Reactant: COC(=O)c1ccc2sc(C)cc2c1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2sc(C)c(C(=O)c3ccc(Cl)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Aluminum chloride (1.24 g, 9.3 mmol) was dispersed in methylene chloride (10 ml), and 2,4-dichlorobenzoyl chloride (0.97 g, 4.7 mmol) and then 5-(methoxycarbonyl)-2-methylbenzo[b]thiophene (0.8 g, 3.9 ml) were added thereto. The mixture was stirred at room temperature for 4 hr. The reaction mixture was poured into ice water and ethyl acetate was added. The mixture was extracted. The organic layer was washed twice with a saturated aqueous solution of sodium hydrogencarbonate and once with brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to give the objective compound (1.5 g, quantitative) as pale yellow crystals.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([N+:14]([O-])=O)[CH:8]=2)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Ni]>[C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([NH2:14])[CH:8]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc2ccc([N+](=O)[O-])cc2[nH]1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)c1cc2ccc(N)cc2[nH]1
Yield: 88.5 %

Procedure:
To a solution of 2-tert-butyl-6-nitro-1H-indole (1.3 g, 6.0 mmol) in MeOH (10 mL) was added Raney Nickel (0.2 g). The mixture was hydrogenated under 1 atm of hydrogen at room temperature for 3 h. The reaction mixture was filtered and the filtrate was concentrated. The residue washed with petroleum ether to give 2-tert-butyl-1H-indol-6-amine (1.0 g, 89%). 1H NMR (300 MHz, DMSO-d6) δ 10.19 (s, 1H), 6.99 (d, J=8.1 Hz, 1H), 6.46 (s, 1H), 6.25 (dd, J=1.8, 8.1 Hz, 1H), 5.79 (d, J=1.8 Hz, 1H), 4.52 (s, 2H), 1.24 (s, 9H); MS (ESI) m/e (M+H+) 189.1.
Reaction SMILES: S(O[CH2:12][CH:13]1[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]1)(C1C=CC(C)=CC=1)(=O)=O.[I-:24].[Li+]>CC(C)=O.C(OCC)(=O)C>[C:20]([O:19][C:17]([N:15]1[CH2:16][CH:13]([CH2:12][I:24])[CH2:14]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(C(=O)OC(C)(C)C)C2)cc1
Reactant: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CC(CI)C1
Temperature: 35 °C
Reaction time: 16 h
Yield: 94.8 %

Procedure:
To a solution of 1.94 g of tert-butyl 3-[(tosyloxy)methyl]azetidin-1-carboxylate in 15.5 ml acetone were added 837 mg of lithium iodide and the reaction mixture was stirred for 16 hours at 35° C. After cooling, it was diluted with 200 ml ethyl acetate and the organic phase washed twice with 30 ml portions of water and once with 20 ml saturated sodium chloride solution. After drying over sodium sulphate and filtration, this was concentrated in vacuo. In this manner, 1.6 g of tert-butyl-3-(iodomethyl)azetidin-1-carboxylate were obtained, which was further reacted without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[C:3]=1[N+:9]([O-:11])=[O:10].O.[NH2:13][NH2:14]>C1COCC1>[F:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([NH:13][NH2:14])[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1c(F)cccc1F
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Product: NNc1cccc(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.01 M 2,6-difluoronitrobenzene and 0.01 M hydrazine hydrate (99% strength) in 30 ml of THF was stirred overnight at RT (exothermic reaction) and the residue was brought to crystallization after distilling off the solvent by treating with diisopropyl ether. Crystalline substance, m.p.: 93-95° C.
Reaction SMILES: ClCC([NH:5][C:6]1([CH3:14])[CH2:11][CH:10]([CH3:12])[O:9][CH:8]([CH3:13])[CH2:7]1)=O.NC(N)=S>C(O)C.C(O)(=O)C>[CH3:13][CH:8]1[CH2:7][C:6]([NH2:5])([CH3:14])[CH2:11][CH:10]([CH3:12])[O:9]1
Reactant: CC1CC(C)(NC(=O)CCl)CC(C)O1
Agent: NC(N)=S
Solvent: CC(=O)O
Solvent: CCO
Product: CC1CC(C)(N)CC(C)O1

Procedure:
To a solution of 2-chloro-N-(2,4,6-trimethyltetrahydro-2H-pyran-4-yl) acetamide obtained in Example 9-3 (1.85 g) in ethanol/acetic acid (5/1, 15 mL), was added thiourea (705 mg) at room temperature. The reaction mixture was heated at reflux for 2 hrs.