Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:18][C:19](O)=[O:20])[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.[C:22](N1C=CN=C1)([N:24]1C=CN=C1)=O>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:18][C:19]([NH:24][CH3:22])=[O:20])[C:9]([C:11]3[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=3)=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2ccc(Cl)nc21
Solvent: C1CCOC1
Product: CNC(=O)Cn1c(-c2ccc(Cl)cc2)nc2ccc(Cl)nc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.4 %

Procedure:
A solution of 5-chloro-2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0155 mole) and 1,1'-carbonyldiimidazol (2.52 g, 0.0155 mole) in dry tetrahydrofuran (100 ml) was refluxed under nitrogen for two hours. The solution was cooled to room temperature and a stream of nitrogen was bubbled through it for thirty minutes. A solution of methylamine in tetrahydrofuran (36 ml of a 2.59M solution, 0.0932 mole) was added and the suspension was stirred at room temperature under nitrogen for three days. The solvents were evaporated under reduced pressure and the resulting solid was triturated in water (100 ml), collected by filtration, and rinsed twice with water, twice with a 5% potassium hydroxide solution and twice again with water. The solid was dissolved in hot isopropyl alcohol, dried over magnesium sulfate, treated with charcoal and filtered while hot. The filtrate was reduced to one-half its original volume and isopropyl ether was added. Upon cooling to room temperature, solid precipitated, which was collected by filtration, rinsed with isopropyl ether and dried under high vacuum at 60° C. to give 3.45 g (66% yield) of title compound, mp >250° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:20]3[C:19]([CH3:21])=[C:18]([CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[S:17][C:16]=3[C:15]([Br:28])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:29])[C:3]=1[OH:30].O[C@@H:32]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:33]([O:35]C)=[O:34].BrBr>C(#N)C>[Br:29][C:4]1[CH:5]=[C:6]([C:8]2[C:20]3[C:19]([CH3:21])=[C:18]([CH2:22][N:23]([CH2:24][CH3:25])[CH2:26][CH3:27])[S:17][C:16]=3[C:15]([Br:28])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=[C:2]([Br:1])[C:3]=1[O:30][C@H:32]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:33]([OH:35])=[O:34]
Reactant: CCN(CC)Cc1sc2c(Br)c3ccccc3c(-c3cc(Br)c(O)c(Br)c3)c2c1C
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Agent: BrBr
Solvent: CC#N
Product: CCN(CC)Cc1sc2c(Br)c3ccccc3c(-c3cc(Br)c(O[C@H](Cc4ccccc4)C(=O)O)c(Br)c3)c2c1C

Procedure:
Prepared from 2,6-dibromo-4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-phenol (Example 18) and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (Example 25) according to the procedure of Example 30. White solid: NMR (DMSO-d6); δ13.3 (broad band, 1H), 8.20 (d, J=8 Hz, 1H), 7.70(s, 2H), 7.66 (ddd, J=8, 7, 1 Hz, 1H), 7.51(ddd, J=8, 7, 1 Hz, 1H), 7.40-7.25(m, 6H), 5.21(t, J=7 Hz, 1H), 3.75(s, 2H), 3.32(dd, J=4, 3 Hz, 2H), 2.55 (q, J=7 Hz, 4H), 1.63(s, 3H), 1.02 (t, J=7 Hz, 6H) MS [(+)FAB]: [M+H]+@ 758, 3 bromine isotope pattern, 758(25%), 760(80%), 762(75%), 764(35%), 689(100%); Anal HPLC, Primesphere 5C-18 column, eluent 62% acetonitrile for 15 minutes indicated 97.8%purity; High Resolution MS (FAB)+ve: Calculated Sample Mass: 759.95556 for formula C33H31NO3Br3 as [M+H], Measured Mass 759.97370 mass deviation: 18.14 mmu.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[O:25]1[CH2:26][CH2:27][N:22]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:32]3[CH:33]=[CH:34][C:29]([NH2:28])=[N:30][CH:31]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4ccc(N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with 2-amino-pyridine-5-boronic acid pinacol ester in General Procedure A. Purification on silica and ether trituration gave 240. NMR (CDCl3): 2.67-2.71 (4H, m), 2.81 (3H, s), 3.29-3.33 (4H, m), 3.89 (2H, s), 3.89-3.93 (4H, m), 4.08-4.12 (4H, m), 4.60-4.65 (2H, br. s), 6.57 (1H, d, J=8.6), 7.40 (1H, s), 8.45 (1H, dd, J=8.6, 2.2), 9.17 (1H, d, J=2.2). MS (ESI+): MH+490.18 (100%)
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([S:17]([O-:20])(=O)=[O:18])[CH:11]=[CH:10]2.O>CN(C=O)C>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([S:17]([Cl:3])(=[O:20])=[O:18])[CH:11]=[CH:10]2
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2cc(S(=O)(=O)[O-])ccc2c1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2cc(S(=O)(=O)Cl)ccc2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Sodium hydroxide (0.7 g) was added to a solution of sodium 6-hydroxynapthalene-2-sulfonate (9 mmol) in water (20 ml). Dimethyl sulfate (1.1 eq.) was added to this solution at 50-55° C. over 1 h, followed by sodium chloride (3.3 g). The solid that was formed was filtered off, washed with saturated NaCl solution and toluene and dried. Yield: 75% 2. Thionyl chloride (0.25 ml) was added to a cooled solution of 6-methoxynaphthalene-2-sulfonate (2 mmol) in dry DMF (1 ml) under N2. The reaction mixture was stirred for 3 h at 0° C. Iced water (20 ml) was added to the mixture, the solid was filtered off and washed with iced water. The solid was taken up in DCM (25 ml), the solution dried over Na2SO4, filtered and concentrated under reduced pressure. Yield: 75%
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.N12CCN(CC1)CC2.[CH3:20][N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH2:23][CH2:22]1>C(O)(C)C>[Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:35][C:32]2[CH:31]=[CH:30][C:29]([O:28][CH2:27][CH:24]3[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]3)=[CH:34][CH:33]=2)=[N:4][CH:3]=1
Reactant: CN1CCC(COc2ccc(N)cc2)CC1
Reactant: Brc1ncc(Br)n2ccnc12
Agent: C1CN2CCN1CC2
Solvent: CC(C)O
Product: CN1CCC(COc2ccc(Nc3ncc(Br)n4ccnc34)cc2)CC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of 5,8-dibromo-imidazo[1,2-a]pyrazine (0.100 g, 0.36 mmol) in isopropanol (5 mL) are added 1,4-diazabicyclo[2,2,2]octane (DABCO) (0.036 mL, 0.36 mmol) and 4-(1-methyl-piperidin-4-ylmethoxy)-phenylamine (79.6 mg, 0.36 mmol). The reaction mixture is stirred at 90° C. overnight. The solvent is evaporated and the residue chromatographed on silica gel column eluting with 97:3 followed by 94:6 and 90:10 DCM:MeOH. The title compound is obtained as a solid (20 mg, 13%). LCMS: Rt 2.30min (94%), m/z (APCI) 417.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)[CH:26]=[CH:25][C:3]=1[C:4]([NH:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:14]=2)[NH:9][N:8]=1)=[O:5].C(N(CC)C(C)C)(C)C.[NH:45]1[CH:49]=[CH:48][CH:47]=[C:46]1[C:50](Cl)=[O:51]>ClCCl>[C:19]1([S:16]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[NH:9][N:8]=[C:7]3[NH:6][C:4]([C:3]2[CH:25]=[CH:26][C:27]([N:29]3[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]3)=[CH:28][C:2]=2[NH:1][C:50]([C:46]2[NH:45][CH:49]=[CH:48][CH:47]=2)=[O:51])=[O:5])(=[O:18])=[O:17])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(S(=O)(=O)c5ccccc5)cc34)c(N)c2)CC1
Reactant: O=C(Cl)c1ccc[nH]1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(S(=O)(=O)c5ccccc5)cc34)c(NC(=O)c3ccc[nH]3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.6 %

Procedure:
2-Amino-N-(5-benzenesulfonyl-1H-indazol-3-yl)-4-(4-methyl-piperazin-1-yl)-benzamide (245 mg, 0.5 mmol) was suspended in dichloromethane (10 mL), treated first with neat N,N-diisopropylethylamine (0.35 mL, 2 mmol) then with solid 1H-pyrrole-2-carbonyl chloride (258 mg, 2 mmol). The reaction was stirred at room temperature overnight then treated with additional acid chloride (258 mg) and N,N-diisopropylethylamine (0.35 mL). After two hours the solvent was removed under reduced pressure and the crude was taken up with tetrahydrofuran (30 mL) and treated with 2N NaOH (10 mL). After stirring overnight the solvent was removed and the solid was filtered and washed thoroughly with water. The crude was purified by flash chromatography over silica gel (eluent: ethyl acetate/methanol/aq.33% NH4OH in 9:1:0.1 ratio) to give 60 mg of title compound.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[C:5]([O:13][C@H:14]1[C@@H:20]2[C@@H:18]([O:19]2)[CH2:17][C@:16]([OH:25])([C:21]([O:23][CH3:24])=[O:22])[CH2:15]1)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.B(F)(F)F.CCOCC>C1COCC1.[Cu]I>[C:5]([O:13][C@@H:14]1[CH2:15][C@@:16]([OH:25])([C:21]([O:23][CH3:24])=[O:22])[CH2:17][C@@H:18]([CH:1]=[CH2:2])[C@@H:20]1[OH:19])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)[C@@]1(O)C[C@@H]2O[C@@H]2[C@H](OC(=O)c2ccccc2)C1
Reactant: C=C[Mg]Br
Agent: [Cu]I
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C[C@@H]1C[C@](O)(C(=O)OC)C[C@@H](OC(=O)c2ccccc2)[C@H]1O
Reaction time: 1 h

Procedure:
Vinylmagnesium bromide can be added to a −78° C. suspension of CuI in THF. After stirring for 1 hour, a solution of Example 17D and BF3.Et2O in THF can be added. After stirring for 2 hours at −78° C., the reaction mixture can be quenched with saturated NH4Cl. The reaction mixture can be extracted several times with dichloromethane and the combined dichloromethane layers are washed with brine, dried (MgSO4), filtered and concentrated. The concentrate can be purified by flash column chromatography to afford the desired product.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30].C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CCCC(OC)=O)N=2)CC1)=O)(C)(C)C>>[CH3:32][O:31][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][N:14]1[C:15]2[CH2:16][CH2:17][NH:8][CH2:9][CH2:10][C:11]=2[C:12]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[N:13]1
Reactant: COC(=O)CCCCl
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: COC(=O)CCCn1nc2c(c1-c1ccc(Cl)cc1)CCN(C(=O)OC(C)(C)C)CC2
Product: COC(=O)CCCn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2

Procedure:
The title compound (0.003 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.1 g) using methyl 4-chlorobutyrate (0.8 mL) in place of benzyl chloride. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-(3-methoxycarbonyl-propyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C18H22ClN3O2, 347.14; found, m/z 348.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.37-7.31 (m, 4H), 4.07 (t, J=6.6 Hz, 2H), 3.52 (s, 3H), 2.97-2.94 (m, 2H), 2.88-2.84 (m, 4H), 2.70-2.66 (m, 2H), 2.25 (t, J=6.6 Hz, 2H), 1.98-1.95 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]1[CH:34]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:41]([F:44])([F:43])[F:42])[C:32]([C:45]([O:47][CH3:48])=[O:46])=[CH:31][CH:30]=1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:28][C:29]3[CH:34]=[C:33]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[C:41]([F:42])([F:43])[F:44])[C:32]([C:45]([O:47][CH3:48])=[O:46])=[CH:31][CH:30]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(CBr)cc1-c1ccccc1C(F)(F)F
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)n(C[C@H](O)C(F)(F)F)c2=O)cc1-c1ccccc1C(F)(F)F

Procedure:
179 mg (0.58 mmol) of the compound from Example 5A and 285 mg (0.88 mmol) of cesium carbonate were suspended in 5 ml of acetonitrile, and 340 mg (0.58 mmol) of the compound from Example 108A were added. The mixture was stirred under reflux for 4 h. The precipitated solid was then filtered off and the filtrate was concentrated under reduced pressure to a volume of about 1.5 ml. After addition of 0.5 ml of 1 N hydrochloric acid, the mixture was directly purified chromatographically [Method 19]. This gave 231 mg (65% of theory) of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:22][C:23]1[C:27]([CH3:29])([CH3:28])[O:26][C:25](=O)[CH:24]=1.Cl>C1COCC1.O>[Br:22][C:23]1[C:27]([CH3:29])([CH3:28])[O:26]/[C:25](=[C:5]2/[C:6](=[O:11])[NH:7][C:8]3[C:4]/2=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)/[CH:24]=1
Reactant: CC1(C)OC(=O)C=C1Br
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)O/C(=C2/C(=O)Nc3ccc(F)cc32)C=C1Br
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 81.3 %

Procedure:
To a solution of 5-fluorooxindole (7.5 g, 49 mmol) in THF (80 mL) at 0° C., was added 1M LHMDS in THF (100 mL, 100 mmol). The reaction mixture was stirred at 0° C. for 20 minutes. A solution of 4-bromo-5,5-dimethyl-5H-furan-2-one (6.4 g, 33 mmol) in THF (20 mL) was added to the reaction mixture. The reaction was stirred at 0° C. for 30 minutes and then allowed to warm to room temperature over 5 hours. To the reaction mixture was added aqueous 2 M HCl (100 mL). The resulting mixture was stirred at 60-65° C. for 1 hour, cooled to room temperature, poured into water (3000 mL) and stirred at room temperature for 2 hours. The precipitates separated and were collected, washed with water, and dried in vacuo to provide 3-[4-bromo-5,5-dimethyl-5H-furan-(2E)-ylidene]-5-fluoro-1,3-dihydro-indol-2-one as a yellow solid (8.7 g, yield 80%), which was used for the next reaction without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].O=[CH:26][CH2:27][CH:28]1[CH2:32][CH2:31][CH2:30][N:29]1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>ClCCl>[Br:21][C:20]([Br:24])=[CH:26][CH2:27][CH:28]1[CH2:32][CH2:31][CH2:30][N:29]1[C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34]
Reactant: CC(C)(C)OC(=O)N1CCCC1CC=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1CC=C(Br)Br
Temperature: -15 °C
Reaction time: 0.33 h

Procedure:
Into a 10 L 3-necked roundbottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of triphenylphosphine (516.6 g, 1.970 mol) in dichloromethane (2,000 ml). The solution was cooled to −15° C. and a solution of carbontetrabromide (327.3 g, 985.8 mmol) in dichloromethane (1,000 ml) was added over a period of 120 minutes. Then a solution of tert-butyl 2-(2-oxoethyl)pyrrolidine-1-carboxylate (105 g, 493 mmol) in dichloromethane (1,000 ml) was added dropwise over a period of 120 minutes. The resulting solution was allowed warm to warm to 0° C., and stir for 20 minutes. The resulting solution was diluted with 4,000 ml of petroleum ether. The mixture was filtered and concentrated. The residue was purified by flash column chromatography (ethylacetate/petroleum ether gradient) to afford tert-butyl 2-(3,3-dibromoprop-2-en-1-yl)pyrrolidine-1-carboxylate.
Reaction SMILES: Cl[C:2]1[NH:3][S:4](=[O:17])(=[O:16])[C:5]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:6]=2[N:7]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][C:29]=1[O:30][CH3:31])[CH2:26][NH:25][CH2:24][CH2:23]2>COC(O)C>[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][C:29]=1[O:30][CH3:31])[CH2:26][N:25]([C:2]1[NH:3][S:4](=[O:17])(=[O:16])[C:5]3[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:6]=3[N:7]=1)[CH2:24][CH2:23]2
Reactant: COc1cc2c(cc1OC)CNCC2
Reactant: COc1cc2c(cc1OC)S(=O)(=O)NC(Cl)=N2
Agent: COC(C)O
Product: COc1cc2c(cc1OC)CN(C1=Nc3cc(OC)c(OC)cc3S(=O)(=O)N1)CC2
Yield: 50.3 %

Procedure:
3-Chloro-6,7-dimethoxy-2H-benzo[1,2,4]thiadiazine-1,1-dioxide 1a (154 mg, 0.55 mmol) and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 2a (wherein R1 and R4 are hydrogen, and R2 and R3 are methoxy)(138 mg, 0.6 mmol) were dissolved in 20 ml of methoxyethanol and heated at reflux for 72 h. The solvent was removed under reduced pressure. The gummy residue was triturated with isopropanol and the resulting crystals filtered. Recrystallization from dichloromethane afforded 120 mg of 3-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-6,7-dimethoxy-2H-benzo[1,2,4]thiadiazine-1,1-dioxide 101, [M+H]+=434.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH:3]=1.Cl.[NH2:20][CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=2)=[O:8])=[C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH:3]=1
Reactant: O=C(O)c1ccc(F)cc1Oc1ccc(F)cc1
Reactant: COC(=O)c1ccc(CN)cc1
Agent: Cl
Product: COC(=O)c1ccc(CNC(=O)c2ccc(F)cc2Oc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 4-fluoro-2-(4-fluorophenoxy)benzoic acid (step 1) and methyl 4-(aminomethyl)benzoate hydrochloride: 1H-NMR (CDCl3) δ 7.99–7.89 (2H, m), 7.38–7.28 (4H, m), 7.12–7.00 (4H, m), 6.41 (1H, dd, J=2.7, 8.1 Hz), 4.63 (2H, br.s), 3.86 (3H, s); MS (ESI) m/z 398 (M+H)+, 396 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][C@H:4]([N:8]1[CH2:12][C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[CH:10][C:9]1=[O:21])[C:5]([OH:7])=O.[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([NH2:29])=[N:25]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH3:23][N:24]1[CH:28]=[CH:27][C:26]([NH:29][C:5](=[O:7])[C@@H:4]([N:8]2[CH2:12][C:11]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])=[CH:10][C:9]2=[O:21])[CH2:3][CH:2]([CH3:1])[CH3:22])=[N:25]1
Reactant: Cn1ccc(N)n1
Reactant: Cc1ccccc1OC1=CC(=O)N([C@@H](CC(C)C)C(=O)O)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccccc1OC1=CC(=O)N([C@@H](CC(C)C)C(=O)Nc2ccn(C)n2)C1
Temperature: 0 °C
Yield: 18.9 %

Procedure:
To a solution of (S)-4-methyl-2-(2-oxo-4-o-tolyloxy-2,5-dihydro-pyrrol-1-yl)-pentanoic acid (0.208 g, 0.69 mmol) in N,N-dimethylformamide (4 mL) was added 1-methyl-1H-pyrazol-3-ylamine (0.080 g, 0.82 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.620 g, 1.40 mmol). The mixture was stirred at 0° C. and triethylamine (0.150 g, 1.48 mmol) was added. The mixture was stirred at room temperature for 3 h and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 25 g, 20% to 100% ethyl acetate/hexanes) which afforded (S)-4-methyl-2-(2-oxo-4-o-tolyloxy-2,5-dihydro-pyrrol-1-yl)-pentanoic acid (1-methyl-1H-pyrazol-3-yl)-amide (0.050 g, 19%) as a tan solid: HR-ES-MS m/z calculated for C21H26N4O3 [M+H]+ 383.2078, observed 383.2077, 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00-0.90 (d, J=6.3 Hz, 3H), 0.94 (d, J=6.3 Hz, 3H), 1.20-1.92 (m, 3H), 2.19 (s, 3H), 3.73 (s, 3H), 4.20 (d, J=18.1 Hz, 1H), 4.57 (d, J=18.1 Hz, 1H), 4.63 (s, 1H), 4.87 (dd, J=10.3, 4.8 Hz, 1H), 6.40 (d, J=1.8 Hz, 1H), 7.17-7.33 (m, 3H), 7.36 (d, J=7.2 Hz, 1H), 7.55 (d, J=1.8 Hz, 1H), 10.72 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:12]([O:14][CH2:15]/[CH:16]=[C:17](\[C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=2)/[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:11]=[CH:10][C:3]=1[O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)#[CH:33]>O1CCCC1.C(N(CC)CC)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH3:1][C:2]1[CH:13]=[C:12]([O:14][CH2:15]/[CH:16]=[C:17](/[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)\[C:25]2[CH:26]=[CH:27][C:28]([C:33]#[C:32][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)=[CH:29][CH:30]=2)[CH:11]=[CH:10][C:3]=1[O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: C#Cc1ccccn1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(C)cc2)c2ccc(I)cc2)cc1C
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(C)cc2)c2ccc(C#Cc3ccccn3)cc2)cc1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of methyl (Z)-[2-methyl-4-[3-(4-iodophenyl)-3-(4-methylphenyl)allyloxy]-phenoxy]acetate (310 mg, 0.587 mmol; example 3) in a mixture of tetrahydrofuran (9 mL) and triethylamine (9 mL) was degassed and 2-ethynylpyridine (121 mg, 1.17 mmol) was added in argon atmosphere. The solution was cooled down; tetrakis(triphenylphosphine)-palladium (55 mg, 0.047 mmol) and copper(I) iodide (17.8 mg, 0.094 mmol) were added. The reaction mixture was stirred at ambient temperature for 48 h, then evaporated in vacuo and the residue was dissolved in ethyl acetate (20 mL). The solution was washed with water (3×15 mL), dried with anhydrous magnesium sulphate and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 7:3) yielding methyl (Z)-[2-methyl-4-[3-(4-methylphenyl)-3-[4-(pyridin-2-ylethynyl)phenyl]allyloxy]-phenoxy]acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:17][C:18]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=O>>[Cl:27][C:25]1[CH:26]=[C:18]2[C:19]([C:20](=[O:22])[N:14]([S:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)(=[O:13])=[O:12])[C:15](=[O:16])[NH:17]2)=[CH:23][CH:24]=1
Reactant: COc1ccc(S(=O)(=O)N=C=O)cc1OC
Reactant: Nc1cc(Cl)ccc1C(=O)O
Product: COc1ccc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)cc1OC
Yield: 35 %

Procedure:
897 mg (3.69 mmol) of 3,4-dimethoxybenzenesulfonylisocyanate and 633 mg (3.69 mmol) of 2-amino-4-chlorobenzoic acid were treated in the same way as in Example 1 to obtain 512 mg of the above-identified compound (yield 35.0%). Properties: colorless crystal, Melting point: >250° C., PMR (δppm, DMSO-d6): 3.85 (3H,s), 3.88 (3H,s), 7.12 (1H,s), 7.22 (2H,d), 7.67 (1H,s), 7.77 (1H,d), 7.86 (1H,d), 11.63 (1H,br).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1C(O)=O.C(O)(=O)C.C(=O)=O>[Zn].O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1c(C(=O)O)ccc2c1C(=O)c1ccccc1C2=O
Agent: O=C=O
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Yield: 112 %

Procedure:
To a three-necked round-bottomed flask equipped with stirrer and reflux condenser was added 5 g (0.014 mole) 1-aminoanthraquinone-2-carboxylic acid, 1 g (0.0037 mole) zinc powder, and 40 ml of 90% acetic acid. The mixture was refluxed gently for 4 hours during which time carbon dioxide was evolved. The reaction mixture was then poured into 200 ml of water and the resulting mixture was heated on a steam bath for 30 minutes. The red solid which precipitated was collected by filtration and washed with water to give 3.5 g (82% yield) of more than 90% pure 1-aminoanthraquinone.