Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(CO[C:6]2[N:11]=[C:10]([C:12](O)=O)[CH:9]=[CH:8][C:7]=2OC(F)(F)F)CC1.[Cl:20][C:21]1[N:26]=[C:25]([C:27]([OH:29])=O)[CH:24]=[CH:23][C:22]=1[O:30][CH2:31][CH:32]1[CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.CC1(C)CCCN1.[OH-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[Cl:20][C:21]1[N:26]=[C:25]([C:27]([N:11]2[CH2:6][CH2:7][CH2:8][C:10]2([CH3:9])[CH3:12])=[O:29])[CH:24]=[CH:23][C:22]=1[O:30][CH2:31][CH:32]1[CH2:34][CH2:33]1
Reactant: O=C(O)c1ccc(OC(F)(F)F)c(OCC2CC2)n1
Reactant: O=C(O)c1ccc(OCC2CC2)c(Cl)n1
Agent: CC1(C)CCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)CCCN1C(=O)c1ccc(OCC2CC2)c(Cl)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31 %

Procedure:
The mixture of 6-cyclopropylmethoxy-5-trifluoromethoxy-pyridine-2-carboxylic acid and 6-chloro-5-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 47 a, 50 mg, 180 μmol) was dissolved in DMF (2 mL). TBTU (63.7 mg, 198 μmol), DIEA (154 μl, 902 μmol) and 2,2-dimethylpyrrolidine (CAN 35018-15-6, 24 μl, 198 μmol) were added and the reaction mixture was stirred at room temperature for 16 hours. Ethyl acetate (3 mL) and 1 N sodium hydroxide solution (2 mL) were added; the mixture was dried by passage through ChemElut® and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, ethyl acetate/n-heptane gradient) to give the title compound (17 mg, 31%) as off-white wax; LC-MS (UV peak area, ESI) 97%, 309.1367 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[C:7]2[C:3]=1[C:4](=[O:13])[C:5](=[O:12])[NH:6]2.[H-].[Na+].[Si:16]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]I)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].OS([O-])(=O)=O.[K+]>O>[Si:16]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:6]1[C:7]2[C:3](=[C:2]([Br:1])[CH:10]=[C:9]([I:11])[CH:8]=2)[C:4](=[O:13])[C:5]1=[O:12])([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:17])[CH3:18]
Reactant: O=C1Nc2cc(I)cc(Br)c2C1=O
Reactant: CC(C)(C)[Si](C)(C)OCCCCCI
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCCCN1C(=O)C(=O)c2c(Br)cc(I)cc21
Temperature: 50 °C
Reaction time: 4 h
Yield: 84.4 %

Procedure:
To a mixture of 4-bromo-6-iodoisatin (450 mg, 1.32 mmol) and 60% NaH (60 mg, 1.5 mmol) was added 5-t-butyldimethylsilyloxy-1-iodopentane (600 mg, 1.83 mmol). The mixture was stirred for 4 h at 50° C. and water and 5% KHSO4 was added. The mixture was extracted with toluene-ethyl acetate and the extracts were washed with 5% KHSO4, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography with 6:1 hexane/ethyl acetate to give the title compound (615 mg, 86%).
Reaction SMILES: C(O[CH:4](OCC)[N:5]([CH3:7])[CH3:6])C.[C:11]([O:14][CH2:15][C:16]1[CH2:23][S:22][CH:21]2[N:18]([C:19](=[O:28])[CH:20]2[NH:24][C:25]([NH2:27])=[S:26])[C:17]=1[C:29]([O:31][CH:32]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])(=[O:13])[CH3:12]>ClCCl>[C:11]([O:14][CH2:15][C:16]1[CH2:23][S:22][C@H:21]2[N:18]([C:19](=[O:28])[C@H:20]2[NH:24][C:25]([N:27]=[CH:4][N:5]([CH3:7])[CH3:6])=[S:26])[C:17]=1[C:29]([O:31][CH:32]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:30])(=[O:13])[CH3:12]
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(N)=S)C2SC1
Reactant: CCOC(OCC)N(C)C
Solvent: ClCCl
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=S)N=CN(C)C)[C@H]2SC1
Reaction time: 0.33 h

Procedure:
A 650 mg portion of N,N-dimethylformamide diethylacetal in 10 ml of dichloromethane was added dropwise to a solution of 2 g of (6R-trans)-3-[(acetyloxy)methyl-7-[(aminothioxomethyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester in 35 ml of dichloromethane. The mixture was stirred for 20 minutes, then filtered, evaporated and the residue purified by flash chromatography using the system ethyl acetate:petroleum ether (1:1) and giving 1.08 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:31])[N:4]([C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=2[O:29][CH3:30])[C:22]([O:24]C)=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].O1CCCC1.CO.[OH-].[Na+]>O>[Br:1][C:2]1[C:3](=[O:31])[N:4]([C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=2[O:29][CH3:30])[C:22]([OH:24])=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: COC(=O)c1ccc(OC)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)cc1-n1c(C)cc(OCc2ccc(F)cc2F)c(Br)c1=O
Reaction time: 0.5 h

Procedure:
A 100 mL round bottomed flask was charged with the product of Step 4 (0.77 g, 1.55 mmol), tetrahydrofuran (10 mL), methanol (5 mL), and water (5 mL). To this slurry was added 2.5 N NaOH (1.2 mL, 3.1 mmol). The reaction mixture became clear after 30 minutes and the reaction was complete in 1 h by LC-MS. The organics were removed on the rotary evaporator and the remaining solution was acidified to pH 2-3 with 6N HCl. The desired compound was precipitated by the addition of water and diethyl ether and subsequent filtration. The title compound was isolated as a white powder (0.60 g, 81w). 1H NMR (400 MHz, CD3OD) δ 8.17 (dd, J=2.2 and 8.8 Hz, 1H), 7.82 (d, J=2.2 Hz, 1H), 7.64 (q, 1H), 7.29 (d, J=8.8 Hz, 1H), 7.34 (t, J=8.8 Hz, 2H), 6.60 (s, 1H), 5.34 (s, 2H), 3.87 (s, 3H), 2.01 (s, 3H) ppm. ES-HRMS m/z 480.0259 (M+H calcd for C21H17BrF2NO5 requires 480.0253).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2C(=O)C3=CC=CC=C3C2=O)[CH:5]=[N:6][CH:7]=1.CN.[OH-].[Na+]>Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH2:9])[CH:5]=[N:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cncc(Br)c1
Agent: CN
Agent: Cl
Agent: [Na+]
Product: NCc1cncc(Br)c1
Yield: 59.9 %

Procedure:
5-Bromo-3-(phthalimidomethyl)pyridine (7.9 g, 25 mmol) is then hydrolyzed by treatment with aqueous methylamine (40%, 50 mL) and refluxing the mixture for 3 h. The solvents were removed by rotary evaporation to yield a pale yellow-colored solid, which was then taken up into concentrated hydrochloric acid (50 mL) and refluxed for 15 h. The reaction mixture was basified (pH=10–11) with aqueous sodium hydroxide (50%), extracted with chloroform (5×40 mL) and dried (K2CO3). The solvent was removed by rotary evaporation and the product purified by column chromatography to yield (5-bromo-3-pyridyl)methylamine (2.80 g, 59.8% yield).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].[C:6]([O:11]CC)(=O)[CH:7]([CH3:9])[OH:8]>C(O)C>[C:6]([NH:1][CH2:2][CH:3]([OH:5])[CH3:4])(=[O:11])[CH:7]([CH3:9])[OH:8]
Reactant: CC(O)CN
Reactant: CCOC(=O)C(C)O
Solvent: CCO
Product: CC(O)CNC(=O)C(C)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
22.6 g 1-amino-2-propanol was added to 56.5 g ethyl lactate at room temperature. The mixture was heated to reflux and stirred for 4 hours. The reaction mixture was cooled and left to stand overnight at room temperature. The following day the ethanol formed and the excess of ethyl lactate were removed from the reaction mixture by distillation, using a 20 cm vigreux column 43 g of N-lactoyl 1-amino-2-propanol (pale brown viscous liquid) was collected as residue and cooled to room temperature. The purity of the obtained product was confirmed by NMR analysis.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].P(Cl)(Cl)(Cl)=O.[C:22]1([CH3:31])[C:23]([C:28](O)=O)=[CH:24][CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:14][C:31]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])=[N:16][N:15]=1
Reactant: Cc1ccccc1C(=O)O
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.9 %

Procedure:
To a suspension of 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) in phosphorus oxychloride (1.68 mL, 18.4 mmol) was added o-toluic acid (188 mg, 1.38 mmol) and was stirred for 30 min at ambient temperature. The suspension was heated for 2 h at 90° C. whereupon it became homogeneous. After cooling to ambient temperature it was then poured onto a mixture of ethyl acetate (20 mL) and aqueous sodium carbonate (saturated, 20 mL). The aqueous phase was then separated and extracted with ethyl acetate (20 mL). The combined organic extracts were then washed with aqueous sodium carbonate and brine. Concentration and trituration in tert-butylmethylether (3 mL) afforded the title compound (99 mg, 34%) as a white solid. MS: m/e=318.1 [M+H]+.
Reaction SMILES: [NH3:1].[N:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([CH3:16])[CH:12]=2)=[C:7]([O:17][CH3:18])[CH:6]=1)=[C:3]=[S:4]>CO>[CH3:18][O:17][C:7]1[CH:6]=[C:5]([NH:2][C:3]([NH2:1])=[S:4])[CH:10]=[CH:9][C:8]=1[C:11]1[O:15][N:14]=[C:13]([CH3:16])[CH:12]=1
Reactant: N
Reactant: COc1cc(N=C=S)ccc1-c1cc(C)no1
Solvent: CO
Product: COc1cc(NC(N)=S)ccc1-c1cc(C)no1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.4 %

Procedure:
Step H (4): Methanolic ammonia (1.3 mL, 9.28 mmol) was added to a flask charged with 5-(4-isothiocyanato-2-methoxyphenyl)-3-methylisoxazole (508 mg, 2.063 mmol) in MeOH (4.6 mL). After stirring at rt for 24 h, the reaction mixture was concentrated to dryness in vacuo to afford 1-(3-methoxy-4-(3-methylisoxazol-5-yl)phenyl)thiourea (540 mg, 2.051 mmol, 99% yield). LC-MS (M+H)+ 264.2. 1H NMR (400 MHz, methanol-d4) δ ppm 7.82 (d, J=8.56 Hz, 1 H) 7.49-7.54 (m, 1 H) 6.99 (dd, J=8.56, 2.01 Hz, 1 H) 6.67 (s, 1 H) 3.96 (s, 3 H) 2.30 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[C:10]([O:20]CC)=[C:11]([O:17]CC)[C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:7]=2[CH:6]=1)=[O:4].Cl>[Cl-].[Zn+2].[Cl-].O>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[C:10]([OH:20])=[C:11]([OH:17])[C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:7]=2[CH:6]=1)=[O:4]
Reactant: CCOc1c([N+](=O)[O-])cc2cc(C(=O)OC)sc2c1OCC
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Product: COC(=O)c1cc2cc([N+](=O)[O-])c(O)c(O)c2s1
Temperature: 100 °C

Procedure:
6,7-Diethoxy-5-nitro-benzo[b]thiophene-2-carboxylic acid methyl ester (0.77 g), zinc chloride (5.0 g) and conc. HCl (1.3 ml) were mixed and heated at 100° C. for 2 hours. The reaction mixture was cooled. Water (20 ml) was added and the precipitate was filtered. The crude product was recrystallized twice from methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][C:19](=[CH2:22])[CH2:20]O>CC(=O)CC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH2:20][C:19]([CH3:22])=[CH2:18])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1O
Reactant: C=C(C)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=C(C)COc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 84 %

Procedure:
A mixture of 30.0 g (0.17 mole) of 5-chloro-2-nitrophenol, 30.49 g (0.221 mole) of potassium carbonate, and 18.47 g (0.204 mole) of 2-methyl-2-propen-1-ol in 200 mL of 2-butanone was heated at 80° C. for approximately 16 hours. During this period the reaction changed color from orange to pale yellow. At the conclusion of this period the reaction mixture was filtered, and the filtrate was evaporated under reduced pressure, leaving 32.50 g of 4-chloro-2-(2-methyl-2-propen-1-yloxy)nitrobenzene as a solid residue, m.p. 47°-49° C.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:12][O:13][CH2:14][CH2:15][NH2:16].C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:16][CH2:15][CH2:14][O:13][CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: COCCN
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COCCNc1ccc2ncc(Br)n2n1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and 2-methoxyethylamine according to general procedure 1 providing the amino compound (432 mg, 74%) as a yellow solid; Rf=0.71 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 7.57 (d, J=9.7 Hz, 1H), 7.42 (s, 1H), 6.75 (d, J=9.7 Hz, 1H), 3.68 (t, J=5.4 Hz, 2H), 3.59 (t, J=5.6 Hz, 2H), 3.43 (s, 3H); ES-MS: (M+H)=271, 273 m/z.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].C([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[C:40]3[C:35](=[CH:36][C:37]([C:41](O)=[O:42])=[CH:38][CH:39]=3)[C:34]([CH3:44])=[C:33]2[CH3:45])=[CH:27][CH:26]=1)=[O:18])(C)(C)C>>[CH3:45][C:33]1[N:32]([CH2:31][C:28]2[CH:29]=[CH:30][C:25]([C:20]3[C:19]([C:17]([OH:18])=[O:16])=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:26][CH:27]=2)[C:40]2[C:35]([C:34]=1[CH3:44])=[CH:36][C:37]([C:41](=[O:42])[NH:8][CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[CH:38][CH:39]=2
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3cccc([N+](=O)[O-])c3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 3-nitrobenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][NH:11][C:10]2[N:15]=[CH:16][C:17](I)=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)=[O:24])[CH3:21]>>[CH2:20]([O:22][C:23](=[O:24])[C:25]1[CH:30]=[CH:29][C:28]([C:17]2[CH:16]=[N:15][C:10]3[NH:11][CH2:12][C:13](=[O:14])[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:9]=3[CH:18]=2)=[CH:27][CH:26]=1)[CH3:21]
Reactant: O=C1CNc2ncc(I)cc2N1Cc1ccccc1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Product: CCOC(=O)c1ccc(-c2cnc3c(c2)N(Cc2ccccc2)C(=O)CN3)cc1
Yield: 72 %

Procedure:
1-Benzyl-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (509 mg) was reacted with 4-ethoxycarbonyl phenyl boronic acid as in General Procedure 4B to give the title compound as a brown solid (72% yield). M.p.=178° C., LCMS: m/z=388.23 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 1.32 (3H, t, J=7.1 Hz), 4.20 (2H, d, J=1.5 Hz), 4.31 (2H, q, J=7.1 Hz), 5.26 (2H, s), 7.23 (2H, m), 7.32 (2H, s), 7.34 (2H, m), 7.39 (1H, d, J=1.8 Hz), 7.63 (2H, d, J=8.6 Hz), 7.94 (2H, d, J=8.3 Hz), 8.06 (1H, d, J=2.0 Hz).
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[Br:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][N:11]=[CH:12]2>>[Br:6][C:7]1[CH:16]=[CH:15][C:14]([S:1]([OH:3])(=[O:5])=[O:2])=[C:13]2[C:8]=1[CH:9]=[CH:10][N:11]=[CH:12]2
Reactant: Brc1cccc2cnccc12
Reactant: O=S(=O)(O)O
Product: O=S(=O)(O)c1ccc(Br)c2ccncc12
Temperature: 25 °C
Yield: 90 %

Procedure:
To fuming sulfuric acid at 0° C. was added 5-bromoisoquinoline (20.0 g, 96 mmol), The resultant mixture was warmed to 200° C. for 4 h and was then cooled to rt and poured into 500 mL of ice water. The product was removed via filtration, washed with water and acetone, and dried to give 25 g (90%) of a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:13])[C:4]2[CH:5]=[CH:6][CH:7]=[N:8][C:9]=2[C:10](=[O:12])[CH:11]=1.[CH3:14][N:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1>C(O)(=O)C>[Cl:1][C:2]1[C:3](=[O:13])[C:4]2[CH:5]=[CH:6][CH:7]=[N:8][C:9]=2[C:10](=[O:12])[C:11]=1[C:16]1[N:15]([CH3:14])[CH:19]=[CH:18][CH:17]=1
Reactant: Cn1cccc1
Reactant: O=C1C(Cl)=CC(=O)c2ncccc21
Solvent: CC(=O)O
Product: Cn1cccc1C1=C(Cl)C(=O)c2cccnc2C1=O
Yield: 40 %

Procedure:
A solution of 2.58 mmol of 6-chloroquinoline-5,8-dione with 20.7 mmol of 1-methylpyrrole in 50 ml of acetic acid is stirred at room temperature for 24 hours. The medium is subsequently concentrated under reduced pressure, the residue is extracted with chloroform and the combined organic phases are washed in succession with aqueous sodium carbonate solution and then water before being dried over magnesium sulphate, filtered and concentrated under vacuum. The crude product obtained is purified by chromatography on a silica gel column to give 6-chloro-7-(1-methyl-1H-pyrrol-2-yl)quinoline-5,8-dione with a yield of 40%.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:23]=[C:22]([CH2:24][OH:25])[CH:21]=[CH:20][C:6]=1[O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=1)#[N:4].Cl[C:27]1[CH:28]=[C:29]2[N:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:35][CH2:34][N:30]2[C:31](=[O:33])[N:32]=1>>[C:3]([C:5]1[CH:23]=[C:22]([CH:21]=[CH:20][C:6]=1[O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:18])([F:17])[F:19])[CH:9]=1)[CH2:24][O:25][C:27]1[CH:28]=[C:29]2[N:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:35][CH2:34][N:30]2[C:31](=[O:33])[N:32]=1)#[N:4]
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(C#N)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3ccc(C#N)c(C(F)(F)F)c3)c(C#N)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from NaH, 4-(2-cyano-4-(hydroxymethyl)phenoxy)-2-(trifluoromethyl)benzonitrile and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [IH:1].[CH3:2][N:3]=[C:4](SC)[NH:5][NH2:6].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O>[IH:1].[NH2:6][NH:5][C:4]([NH:3][CH3:2])=[N:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCc1ccccc1
Reactant: CN=C(NN)SC
Agent: I
Solvent: O
Product: CNC(=NCc1ccccc1)NN
Reaction time: 8 h

Procedure:
A solution of 36.0 g. of methyl N-methylthiocarbazimidate hydroiodide and 16.1 g. of benzylamine in 100 ml. of water is heated on a steam bath for one hour and then allowed to stand at room temperature overnight. The reaction mixture is concentrated under reduced pressure. The residue is dissolved in ethanol, treated with activated charcoal and filtered. The filtrate is concentrated to a small volume under reduced pressure and the residual solution is diluted with diethyl ether. The resultant crystals are recovered by filtration and recrystallized from a mixture of ethanol and diethyl ether, giving the desired product as pale pink crystals, m.p. 118°-119° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:9]([CH:11]=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])=[C:4]([CH:23]([OH:40])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:26][C:25]=2[O:38][CH3:39])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:31]([O:30][C:27]1[CH:28]=[CH:29][C:24]([C@@H:23]2[C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=3[N:8]([CH2:18][C:19]([CH3:21])([CH3:22])[CH3:20])[C:9](=[O:10])[C@@H:11]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:40]2)=[C:25]([O:38][CH3:39])[CH:26]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCOC(=O)C=CC(=O)N(CC(C)(C)C)c1ccc(Cl)cc1C(O)c1ccc(OCc2ccccc2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C[C@H]1O[C@H](c2ccc(OCc3ccccc3)cc2OC)c2cc(Cl)ccc2N(CC(C)(C)C)C1=O
Reaction time: 24 h
Yield: 81.7 %

Procedure:
To a mixture of ethyl 3-[N-[4-chloro-2-(4-benzyloxy-α-hydroxy-2-methoxybenzyl)-phenyl]-N-neopentylcarbamoyl]acrylate (12 g), potassium carbonate (5.9 g) and ethanol (150 ml) was stirred for 24 h. After the mixture was concentrated in vacuo, the residue was diluted with water (200 ml) and extracted with ethyl acetate (200 ml). The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give ethyl trans-5-(4-benzyloxy-2-methoxyphenyl)-7-chloro-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate (9.8 g) as needles (mp=130°-131° C.).
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[C@@H:3]([NH:20]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:19])[NH:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[CH:6][CH:5]=1.N1CCCCC1>C(O)C>[NH2:20][C@@H:3]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([NH:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[O:19])=[CH:8][CH:9]=1)[CH:2]([CH3:38])[CH3:1]
Reactant: CC(C)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1ccc(C(=O)NOC2CCCCO2)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)[C@@H](N)c1ccc(C(=O)NOC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.3 %

Procedure:
To a 1-L round-bottom flask was added (9H-fluoren-9-yl)methyl (1R)-2-methyl-1-(4-(tetrahydro-2H-pyran-2-yloxycarbamoyl)phenyl)propylcarbamate (10.0 g, 0.0195 mol), ethanol (588 mL), and piperidine (51.7 mL). The solution was stirred at rt for 16 h, then concentrated to give a solid. Flash column chromatography gave 4-((R)-1-amino-2-methylpropyl)-N-(tetrahydro-2H-pyran-2-yloxy)benzamide (2.3 g, 41%). 1H NMR (CDCl3, 400 MHz) δ7.59 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 5.00 (m, 1H), 3.95 (m, 1H), 3.59 (m, 2H), 1.83 (m, 4H), 1.57 (m, 3H), 1.20 (m, 1H), J=6.8 Hz, 3H), 0.67 (t, J=6.8 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]3[CH2:13][CH2:12]3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Br[CH2:15][C:16]1[CH:37]=[CH:36][C:19]2/[C:20](=[C:30](/[CH:33]3[CH2:35][CH2:34]3)\[C:31]#[N:32])/[C:21]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=3[O:23][CH2:24][C:18]=2[CH:17]=1>>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]3[CH2:13][CH2:12]3)[N:7]([CH2:15][C:16]3[CH:37]=[CH:36][C:19]4/[C:20](=[C:30](/[CH:33]5[CH2:34][CH2:35]5)\[C:31]#[N:32])/[C:21]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=5[O:23][CH2:24][C:18]=4[CH:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc2[nH]c(C3CC3)nc12
Reactant: N#C/C(=C1\c2ccc(CBr)cc2COc2cc(F)ccc21)C1CC1
Product: N#C/C(=C1\c2ccc(Cn3c(C4CC4)nc4c(Cl)cccc43)cc2COc2cc(F)ccc21)C1CC1
Yield: 74.8 %

Procedure:
Using 4-chloro-2-cyclopropyl-1H-benzo[d]imidazole (EP1988091, 60 mg, 0.31 mmol) and (E)-2-(8-bromomethyl-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)-2-cyclopropylacetonitrile (120 mg, 0.31 mmol) obtained in Reference Example 6, and in the same manner as in Reference Example 1A, the title compound (115 mg, 74%) was obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([F:13])[CH:4]=1.[CH3:14][NH2:15]>CO>[F:13][C:5]1[CH:4]=[C:3]([CH2:2][NH:15][CH3:14])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: CN
Reactant: Fc1cc(CBr)cc(C(F)(F)F)c1
Solvent: CO
Product: CNCc1cc(F)cc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To a solution of 1-(bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene (257 mg, 1 mmol) in MeOH (5 mL) was added methanamine in MeOH (5 mL). The reaction was stirred at 50° C. for 16 h and then concentrated in high vacuum. The residue was purified by silica gel chromatography (DCM/MeOH=20/1 to 10/1) to give the title compound (200 mg, yield: 90%); m/z (ES+): 222 [M+H]+.