Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:26][NH:25][CH2:24]4)[C:15]=3[O:27][CH2:28][CH3:29])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.C(N(CC)CC)C.Br[CH2:38][CH2:39][OH:40].C(=O)(O)[O-].[Na+]>O1CCCC1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[CH:21]=[C:20]([Cl:22])[C:17]([C:18]#[N:19])=[C:16]([CH:23]4[CH2:24][N:25]([CH2:38][CH2:39][OH:40])[CH2:26]4)[C:15]=3[O:27][CH2:28][CH3:29])[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: OCCBr
Reactant: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(CCO)C1
Temperature: 60 °C
Reaction time: 6 h
Yield: 44.5 %

Procedure:
A solution of 4-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-2-azetidin-3-yl-6-chloro-3-ethoxybenzonitrile (300 mg, 0.74 mmol, chiral intermediate from Example 212) in tetrahydrofuran (14 mL) was treated with triethylamine (260 μL, 1.8 mmol) followed by 2-bromoethanol (63 μL, 0.89 mmol) dropwise and stirred at 60° C. for 6 h. The reaction mixture was treated with additional 2-bromoethanol (26 μL, 0.37 mmol) and stirred at 60° C. for another 6 h. The reaction mixture was poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was concentrated and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (0.15 g, 44%). The product was isolated as a single enantiomer. 1H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.56 (s, 1H), 6.36-6.25 (m, 1H), 4.48 (br s, 1H), 4.19-4.07 (m, 1H), 4.04-3.94 (m, 2H), 3.91-3.82 (m, 1H), 3.81-3.72 (m, 1H), 3.20-3.08 (m, 2H), 2.62 (s, 2H), 2.57 (s, 3H), 1.79 (d, J=6.8 Hz, 3H), 1.40 (t, J=6.6 Hz, 3H). LCMS for C22H27ClN7O2 (M+H)+: m/z=456.2; Found: 456.1.
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:15][CH2:16][CH3:17])[NH:8][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH3:4])[CH3:3].[O-]CC.[Na+].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1.[Cl-].[Na+]>C1(C)C=CC=CC=1.CN(C)C(=O)C>[C:36]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:8]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([C:2]([OH:1])([CH3:4])[CH3:3])[N:6]=[C:7]2[CH2:15][CH2:16][CH3:17])=[CH:29][CH:28]=1)#[N:37]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
Ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylate (8.09 g) obtained in Example 6 was dissolved in a mixture of toluene (28.3 ml) and N,N-dimethylacetamide (18 ml) under a nitrogen atmosphere, and to the reaction solution, sodium ethoxide (2.43 g) was added. After the reaction solution was stirred at room temperature for 1 hour, 4′-(bromomethyl)biphenyl-2-carbonitrile (9.70 g) was added, and the reaction solution was stirred at 40° C. for 4 hours. After the reaction solution was cooled to room temperature, it was poured into aqueous sodium chloride solution (5.4 wt %), and the aqueous layer was extracted with toluene. The organic layers were combined and concentrated under reduced pressure to approximately half the volume, subsequently Isopar E was added, then the mixture was stirred at room temperature for 16 hours, followed by further stirring for 1 hour under ice cooling. The precipitated crystals were collected by filtration, and subsequently dried under reduced pressure to afford the title compound (13.1 g) as white crystals.
Reaction SMILES: C[O-].[Na+].[CH3:4][N:5]1[CH:9]=[C:8]([CH2:10][S:11]C(=O)C2C=CC=CC=2)[CH:7]=[N:6]1.[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:60]/[O:61][C:62]([C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=2)([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)/[C:27]([NH:29][C@@H:30]2[C:58](=[O:59])[N:32]3[C:33]([C:42]([O:44][CH:45]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[O:43])=[C:34](OS(C)(=O)=O)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1>C1COCC1.CN(C=O)C>[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:60]/[O:61][C:62]([C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)([C:75]2[CH:76]=[CH:77][CH:78]=[CH:79][CH:80]=2)[C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)/[C:27]([NH:29][C@@H:30]2[C:58](=[O:59])[N:32]3[C:33]([C:42]([O:44][CH:45]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)=[O:43])=[C:34]([S:11][CH2:10][C:8]4[CH:7]=[N:6][N:5]([CH3:4])[CH:9]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1
Reactant: CS(=O)(=O)OC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(N)n3)[C@H]2SC1
Reactant: Cn1cc(CSC(=O)c2ccccc2)cn1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1cc(CSC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)/C(=N\OC(c4ccccc4)(c4ccccc4)c4ccccc4)c4csc(N)n4)[C@H]3SC2)cn1
Temperature: -65 °C
Reaction time: 1 h
Yield: 47.6 %

Procedure:
Under nitrogen atmosphere, 1.35 ml of sodium methoxide (6.5 m mol) was added slowly to a solution of 1.50 g of 1-methyl-4-benzoylthiomethylpyrazole (6.5 m mol) in THF (6 ml) and DMF (18 ml) at 0° C. Stirring was continued for 1 hour. The mixture was cooled to −65° C. with dry ice/ethanol bath, and added to a solution of 4.36 g of diphenylmethyl 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(trityloxyimino)acetamido]-3-methanesulfonyloxy-3-cephem-4-carboxylate (5 m mol) in a mixture of THF (15 ml) and DMF (25 ml) at the same temperature. After stirring for 1 hour, the reaction was quenched with 10% hydrochloric acid, and the mixture was poured into water-ethyl acetate. The organic layer was separated washed with brine, dried over magnesium sulfate. After filtration, the filtrate was concentrated in vacuo, the residue was purified on silica gel (eluent: dichloromethane-acetone) to afford a diphenylmethyl 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(trityloxyimino)acetamido]-3-[(1-methylpyrazol-4-yl)methylthio]-3-cephem-4-carboxylate (2.15 g).
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]1[N:22]([NH2:23])[C:21]([OH:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Cl:32])[CH:19]=2)[N:14]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[Cl:33][CH2:34][C:35](Cl)=[O:36].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>CN(C)C=O>[C:1]([NH:11][CH2:12][C:13]1[N:22]([NH:23][C:35](=[O:36])[CH2:34][Cl:33])[C:21]([OH:31])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Cl:32])[CH:19]=2)[N:14]=1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(Cl)CCl
Reactant: NN1C(CNC(=O)OCc2ccccc2)=Nc2ccc(Cl)cc2C1(O)c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CCl)NN1C(CNC(=O)OCc2ccccc2)=Nc2ccc(Cl)cc2C1(O)c1ccccc1Cl
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a solution of 2-carbobenzoxyaminomethyl-3-amino-4-hydroxy-4-(2-chlorophenyl)-6-chloro-3,4-dihydroquinazoline (18.84 g) in dimethylformamide (100 ml), chloroacetyl chloride (8.48 g) is added, and the resultant mixture is stirred at room temperature for 1 hour and allowed to stand overnight. The reaction mixture is neutralized with aqueous sodium bicarbonate and shaken with ethyl acetate. The ethyl acetate layer is evaporated under reduced pressure to remove the solvent, and the residue is washed with ether to give 2-carbobenzoxyaminomethyl-3-(2-chloroacetamido)-4-hydroxy-4-(2-chlorophenyl)-6-chloro-3,4-dihydroquinazoline (18.9 g). This product is recrystallized from ethyl acetate to give crystals melting at 130° to 134° C.
Reaction SMILES: [O:1]=[C:2](Cl)OC(Cl)(Cl)Cl.[NH2:9][CH:10]([CH2:15][CH:16]=[CH2:17])[C:11]([O:13][CH3:14])=[O:12].C>O1CCOCC1>[N:9]([CH:10]([CH2:15][CH:16]=[CH2:17])[C:11]([O:13][CH3:14])=[O:12])=[C:2]=[O:1]
Reactant: C=CCC(N)C(=O)OC
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: C=CCC(N=C=O)C(=O)OC

Procedure:
0.35 mol diphosgene is added dropwise over 1 hour to a mixture of 0.28 mol of methyl 2-amino-4-pentenoate, prepared as described by D. Ferroud, J. P.Genet, and R. Kiolle in Tetrahedron Letters, 1986, 27, 23-26, and 0.4 g activated charcoal in 400 mL dioxane under N2. The reaction mixture is then heated and stirred at reflux for 21/2 hours. The reaction mixture is then cooled, filtered, and concentrated to dryness by rotary evaporator, keeping exposure to moisture to a minimum. The crude product is re-dissolved in 100 mL THF, and the pH of the solution is adjusted to 5.5-6.0 by addition of pyridine. The product mixture is again filtered, and the product is purified by fractional distillation to give methyl 2-isocyanato-4-pentenoate.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[CH2:8][CH2:7][CH:6]=1.[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[K].CN(C=O)C>O>[CH3:16][O:15][C:12]1[CH:13]=[C:14]2[C:9]([CH2:8][CH2:7][CH:6]=[C:5]2[CH2:4][CH2:3][CH2:2][N:21]2[C:17](=[O:27])[C:18]3[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:20]2=[O:22])=[CH:10][CH:11]=1
Reactant: COc1ccc2c(c1)C(CCCBr)=CCC2
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)C(CCCN1C(=O)c3ccccc3C1=O)=CCC2
Temperature: 100 °C
Yield: 95.4 %

Procedure:
A mixture of 4-(3-bromopropyl)-6-methoxy-1,2-dihydronaphthalene (10 g, 35.6 mmol), potassium phthalimide (7.9 g, 42.7 mmol) and DMF (50 ml ) was heated at 100° C. for 1 hour and then cooled. The mixture was diluted with water and the product was extracted with ethyl acetate. The extract was washed with brine and water, dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. The residue was purified by a silica gel column chromatography (ethyl acetate:hexane=2:8) to afford the titled compound (11.8 g, yield 95%, oil).
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:14][C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2.N1C=CC=CC=1>O>[N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[C:15]([NH:14][C:11]([C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)=[O:12])[CH:16]=1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: Nc1cnc2ccccc2c1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cnc2ccccc2c1)C12CC3CC(CC(C3)C1)C2
Yield: 28.3 %

Procedure:
Prepared from 1-adamantanecarbonyl chloride (0.75 g, 3.8 mmol), 3-aminoquinoline (0.60 g, 4.2 mmol), pyridine (10 mL), and water (100 mL) yielding 0.33 g (29%) of (86):
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]([CH2:9][O:10][C:11]3[CH:19]=[CH:18][CH:17]=[C:16]4[C:12]=3[CH:13]=[C:14]([C:20](O)=[O:21])[NH:15]4)=[CH:7][O:8][C:4]=2[CH:3]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][C:29]([CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][C@H:38]([OH:41])[C@@H:37]([CH3:42])[CH2:36]2)([OH:32])[CH2:28][CH2:27]1>>[OH:32][C:29]1([CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][C@H:38]([OH:41])[C@@H:37]([CH3:42])[CH2:36]2)[CH2:30][CH2:31][CH:26]([NH:25][C:20]([C:14]2[NH:15][C:16]3[C:12]([CH:13]=2)=[C:11]([O:10][CH2:9][C:6]2[C:5]4[CH:23]=[CH:24][C:2]([F:1])=[CH:3][C:4]=4[O:8][CH:7]=2)[CH:19]=[CH:18][CH:17]=3)=[O:21])[CH2:27][CH2:28]1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Reactant: O=C(O)c1cc2c(OCc3coc4cc(F)ccc34)cccc2[nH]1
Product: C[C@H]1CN(CCC2(O)CCC(NC(=O)c3cc4c(OCc5coc6cc(F)ccc56)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized analogously to example 1 from 4-(6-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (synthesis described in WO2005077932A2, cmpd 106) and amine 14.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Cl.[Cl:11][C:12]([NH2:14])=[NH:13].C1COCC1>C1C=CC=CC=1>[ClH:11].[N:1]1[N:2]([C:12]([NH2:14])=[NH:13])[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2
Reactant: N=C(N)Cl
Reactant: c1ccc2[nH]ncc2c1
Agent: Cl
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: N=C(N)n1cc2ccccc2n1
Yield: 52.8 %

Procedure:
940 mg of indazole and 920 mg of chloroformamidine hydrochloride were heated under reflux in 30 ml of benzene of THF for 5 hours, and the crystals formed were removed by filtration. These were recrystallized from ethanol ether to obtain 826 mg of 2H-indazole-2-carboxamidine hydrochloride.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][S:10]([CH:13]=[CH2:14])(=[O:12])=[O:11].[C:16](=O)([O-])[O-].[Na+].[Na+].CI>CC(C)=O>[C:1]1([CH3:15])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[N:9]([CH3:16])[S:10]([CH:13]=[CH2:14])(=[O:12])=[O:11]
Reactant: O=C([O-])[O-]
Reactant: C=CS(=O)(=O)Nc1c(C)cc(C)cc1C
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CI
Product: C=CS(=O)(=O)N(C)c1c(C)cc(C)cc1C
Yield: 100.3 %

Procedure:
22.5 g (0.1 mole) N-mesitylethenesulphonamide, 37.2 g anhydrous sodium carbonate, 52 ml methyl iodide and 1000 ml acetone were mixed and refluxed for 6 hours. The mixture was then filtered and evaporated to dryness. The residue was dissolved in diethyl ether and extracted with 2 N sodium hydroxide solution (to remove remaining starting material). The ether solution was dried over magnesium sulphate and evaporated to dryness. 24.0 g of the crude title compound was obtained as an oil, which solidifies slowly. M.p. c.a. 25° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH2:12]([NH2:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:12]([NH:28][C:2]1[N:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCCCCCN
Reactant: COC(=O)c1ccc(Cl)nc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC)cn1

Procedure:
A mixture of 5.13 g. of methyl 6-chloronicotinate, 7.23 g. of hexadecylamine and 150 ml. of hexamethylphosphoramide is stirred at 130° for 6 hours. Cooling and dilution with water affords a precipitate which is collected by filtration and recrystallized from ethyl acetate and then from acetone to yield methyl 6-hexadecylamino-3-pyridinecarboxylate as a tan solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][CH3:25])=[C:20]([N+:26]([O-])=O)[CH:19]=3)[CH:14]=[CH:13][N:12]=2)=[O:9])[CH2:4][CH2:3]1>CO.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[NH2:26][C:20]1[CH:19]=[C:18]([O:17][C:15]2[CH:14]=[CH:13][N:12]=[C:11]([NH:10][C:8]([CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:9])[CH:16]=2)[CH:23]=[CH:22][C:21]=1[NH:24][CH3:25]
Reactant: CNc1ccc(Oc2ccnc(NC(=O)C3CCN(C)CC3)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Product: CNc1ccc(Oc2ccnc(NC(=O)C3CCN(C)CC3)c2)cc1N

Procedure:
The mixture containing 1-methyl-N-(4-{[4-(methylamino)-3-nitrophenyl]oxy}-pyridin-2-yl)piperidine-4-carboxamide in methanol with catalytic amount of Lindlar's catalyst was hydrogenated to yield N-(4-{[3-amino-4-(methylamino)phenyl]oxy}pyridin-2-yl)-1-methylpiperidine-4-carboxamide. MS: MH+=356.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=O)[CH:18]=2)=[CH:13][CH:12]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:18]=2)=[CH:15][CH:16]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=Cc1cccc(-c2ccc(Cl)cc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Fc1ccc(CNCc2cccc(-c3ccc(Cl)cc3)c2)cc1
Reaction time: 4 h
Yield: 62.7 %

Procedure:
To a homogeneous mixture of (4-fluorophenyl)methanamine (2.5 mL, 21.8 mmol) and 4′-chlorobiphenyl-3-carbaldehyde (Aldrich, 3.6 g, 16.8 mmol) in anhydrous dichloroethane (25 mL), under nitrogen atmosphere, was added acetic acid (1.2 mL, 21.0 mmol). The mixture was stirred at room temperature for 13.5 h before sodium triacetoxyborohydride (5.0 g, 23.5 mmol) was added. After 4 h, (4-fluorophenyl)methanamine (2.5 mL, 21.8 mmol) was added and the stirring continued. After an additional 5 h of stirring, the reaction was quenched with 1 N aq. NaOH solution (50 mL) then extracted twice with chloroform. The organic extracts were combined, washed with saturated aqueous NaHCO3 and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (Merck KGaA, 230-400 mesh particle size) eluting with 0-70% ethyl acetate in hexane, to afford the title compound (3.43 g, 59%) as a colorless oil. MS (ESI): 326.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]1[C:20]([F:21])=[C:19]([C:22]([F:25])([F:24])[F:23])[C:18]([F:26])=[C:17]([F:27])[C:14]=1[CH2:15]Br>CN(C=O)C>[Cl:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:15][C:14]2[C:17]([F:27])=[C:18]([F:26])[C:19]([C:22]([F:23])([F:25])[F:24])=[C:20]([F:21])[C:13]=2[F:12])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Fc1c(F)c(C(F)(F)F)c(F)c(F)c1CBr
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Solvent: CN(C)C=O
Product: O=C(O)c1cc(NCc2c(F)c(F)c(C(F)(F)F)c(F)c2F)ccc1Cl
Yield: 85.5 %

Procedure:
According to the similar procedure in Synthesis Example 1, by using 5-amino-2-chlorobenzoic acid (1.02 g, 5.94 mmole) (ACROS, 32525-5000), DMF (50 ml) and 2,3,5,6-tetrafluoro-4-trifluoromethylbenzyl bromide (1.16 g, 6.99 mmole), 2.04 g (85.5% yield) of 2-chloro-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino) benzoic acid was obtained as a pale brown solid.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[CH2:17][C@H:16]3[NH:18]C(=O)OC(C)(C)C)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].O.[OH-].[Na+]>O1CCOCC1.OS(O)(=O)=O>[NH2:18][C@@H:16]1[CH2:17][C@H:15]1[C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:27][CH:26]=2)=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(OCc2ccc(C#N)cc2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccc(COc2ccc([C@@H]3C[C@H]3N)cc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 84.6 %

Procedure:
tert-butyl(trans)-2-{4-[(4-cyanobenzyl)oxy]phenyl}cyclopropylcarbamate (0.31 g, 0.85 mmol) was dissolved in a mixture of 1,4-dioxane/H2SO4 (15 mL, 10:1, v/v) and stirred at room temperature for 45 min. The reaction mixture was poured into water (15 mL), basified by addition of 15 mL of aqueous NaOH (10%) and extracted with EtOAc (2×15 mL); the organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and filtered. After removal of the solvent, the crude residue was purified by column chromatography on silica gel (0%-3% MeOH/CH2Cl2) to afford 0.19 g of 4-({4-[(trans)-2-aminocyclopropyl]phenoxy}methyl)benzonitrile [Rf=0.2 (5% MeOH/CH2Cl2), beige solid, 85% yield].
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=2[N+:19]([O-])=O)[CH2:4]1>CO.[Pd]>[NH2:19][C:10]1[CH:11]=[C:12]([C:15]([F:16])([F:17])[F:18])[CH:13]=[CH:14][C:9]=1[N:5]1[CH2:6][CH2:7][CH2:8][C@H:3]([N:2]([CH3:22])[CH3:1])[CH2:4]1
Reactant: CN(C)[C@H]1CCCN(c2ccc(C(F)(F)F)cc2[N+](=O)[O-])C1
Agent: [Pd]
Solvent: CO
Product: CN(C)[C@H]1CCCN(c2ccc(C(F)(F)F)cc2N)C1

Procedure:
(S)—N,N-Dimethyl-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-amine (0.82 g, 2.6 mmol) was reduced with Pd/C (10%, 0.27 g) in 10 ml methanol in a manner similar to Example 124-Step 3 to give the title compound as an orange-red oil. MS (m/z): 288.2 (M+H)+. Calc'd for C14H20F3N3: 287.32.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[I:12]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:12])=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:9])=[O:10]
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: O=C1CCC(=O)N1I
Solvent: ClC(Cl)Cl
Product: Nc1ccc(I)cc1S(N)(=O)=O
Temperature: 25 °C
Yield: 77.6 %

Procedure:
2-Amino-benzenesulfonamide (5.15 g, 29.3 mmol) was dissolved in chloroform (87 mL), and N-iodosuccinimide (7.29 g, 30.77 mmol) was added under a nitrogen atmosphere. The mixture was heated at reflux for 24 h, allowed to cool to 25° C., and filtered through a sinter funnel. The solid was washed with chloroform and 10% methanol/chloroform (3-8 times) to afford the desired product, 2-amino-5-iodo-benzenesulfonamide (6.78 g, 22.75 mmol, 78% yield) as a brown crystalline solid. 1H NMR (400 MHz, DMSO-d6): 5.98 (s, 2H), 6.62 (d, 1H, J=8.8 Hz), 7.31 (s, 2H), 7.45 (dd, 1H, J=8.8, 2.4 Hz), 7.73 (d, 1H, J=2.0 Hz).
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[NH:19][C:20](=[O:22])[CH3:21])C(=O)C2=CC=CC=C12.O.NN>C(O)CC>[NH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[NH:19][C:20](=[O:22])[CH3:21]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1OCCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCCO
Solvent: O
Product: CC(=O)Nc1cc([N+](=O)[O-])ccc1OCCCN
Temperature: 0 °C

Procedure:
0.03 mol (11.5 g) of 2-acetylamino-4-nitrophenyl γ-phthalimidopropyl ether and 3 cm3 of 98% pure hydrazine hydrate in 120 cm3 of normal propyl alcohol are heated for 15 minutes on a boiling waterbath. After hot filtration, the filtrate is cooled to 0° C. The expected product precipitates. It is taken up in a dilute solution of sodium hydroxide, and the sodium hydroxide phase is extracted with chloroform. By concentrating the solvent in vacuo, the expected product, which melts at 110°-120° C., is obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]12CCCC1C1CC2(CN)CC1.[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C=O>C(Cl)(Cl)Cl>[O:21]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:3][CH2:2][NH:1]1
Reactant: NCC12CCC(C1)C1CCCC12CN
Reactant: Oc1ccccc1
Agent: C=O
Solvent: ClC(Cl)Cl
Product: c1ccc2c(c1)CCNO2
Temperature: 60 °C

Procedure:
One mole of 3(4),8(9),-bis(aminomethyl)tricyclo[5,2,1,02,6]decane as saturated alicyclic hydrocarbon diamine compound having a condensed ring structure, two moles of phenol as the phenol compound represented by Formula (1), as well as, 4 moles of paraformaldehyde as aldehyde compound and 1500 g of chloroform were mixed. This mixture was heated to 60° C. under stirring, and the reaction was carried out for 6 hours since chloroform started circulating. After the end of the reaction, the reaction mixture was washed with an aqueous solution of 1 N sodium hydroxide, and then rinsed with ion exchanged water. Then, after the chloroform phase was dried with anhydrous sodium sulfate, chloroform was evaporated with a rotary evaporator to obtain a bifunctional dihydro benzoxazine compound in which R14 of Formula (2) is the amino residue of 3(4),8(9),-bis(aminomethyl)tricyclo[5,2,1,02,6]decane.