Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]([NH2:4])=[O:3].CN1CCOCC1.ClC(OCC)=O.[CH:20]1([O:25][C:26]2[CH:27]=[C:28]([CH2:34][CH2:35][NH2:36])[CH:29]=[CH:30][C:31]=2[O:32][CH3:33])[CH2:24][CH2:23][CH2:22][CH2:21]1.[Cl-].[NH4+]>COCCOC>[CH:20]1([O:25][C:26]2[CH:27]=[C:28]([CH2:34][CH2:35][NH:36][C:1]([C:2]([NH2:4])=[O:3])=[O:6])[CH:29]=[CH:30][C:31]=2[O:32][CH3:33])[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: COc1ccc(CCN)cc1OC1CCCC1
Reactant: NC(=O)C(=O)O
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: COCCOC
Solvent: CN1CCOCC1
Product: COc1ccc(CCNC(=O)C(N)=O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
To a suspension of oxamic acid (1.76 g, 20 mmol) in 1,2-dimethoxyethane (75 mL) under an argon atmosphere was added dropwise N-methylmorpholine (2.55 mL, 23 mmol) followed by ethyl chloroformate (2.20 mL, 23 mmol). After stirring for 1 h at room temperature, a solution of 2-(3-cyclopentyloxy-4-methoxy-phenyl)ethylamine (4.65 g, 20 mmol) in 1,2-dimethoxyethane (30 mL) was added over 5 min, and the resulting mixture was stirred for 2 h. Saturated aqueous ammonium chloride was added and the solvent was removed under reduced pressure. The solid residue was dissolved in methanol/methylene chloride, washed successively with water, 10% hydrochloric acid, aqueous sodium bicarbonate and water and dried (potassium carbonate). The solvent was removed in vacuo and the residue was purified by flash chromatography, eluting with 1% i-propanol/methylene chloride to provide the oxamide (1.82 g, 30%): m.p. 175°-175.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:14][O:15][C:16]1[C:17]([S:28](F)(=[O:30])=[O:29])=[CH:18][C:19]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21][C:20]=2[CH:27]=1>O1CCCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([S:28]([C:17]2[C:16]([O:15][CH3:14])=[CH:27][C:20]3[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25][C:19]=3[CH:18]=2)(=[O:29])=[O:30])=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: COc1cc2c(cc1S(=O)(=O)F)CCN(C)CC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc2c(cc1S(=O)(=O)c1ccc(Br)cc1)CCN(C)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1,4-dibromobenzene (0.665 g, 2.82 mmol, 2.0 eq) in dry tetrahydrofuran (7 mL) under argon at −78° C. was added butyllithium (1.25 mL 2.5M in hexanes, 3.10 mmol, 2.2 eq) dropwise over 10 min. After a further 30 min. a suspension of sulfonyl fluoride D4 (0.385 g, 1.41 mmol, 1.0 eq) was added portionwise. The resultant mixture was allowed to warm to room temperature then stirred for 2 h. The mixture was quenched with water (40 mL) then extracted twice with ethyl acetate (2×40 mL). The organic layer was washed sequentially with water (50 mL) and brine (50 mL) then dried over MgSO4 and evaporated to dryness. Purification by Biotage chromatography, eluting with 1-6% MeOH—CH2Cl2 containing 0.5% NH3 afforded the desired product D13 as a solid, 0.289 g (50%). MH+411. 1H NMR δ (CDCl3) 2.37 (3H, s), 2.55 (4H, m), 2.93 (4H, m), 3.75 (3H, s), 6.65 (1H, s), 7.60 (2H, d), 7.80 (3H, m).
Reaction SMILES: [F:1][CH:2]([F:32])[O:3][C:4]1[C:9]2[O:10][C:11]3[C:12](=[O:19])[N:13]([CH2:17][CH3:18])[N:14]=[CH:15][C:16]=3[C:8]=2[C:7]([C:20]([O:22]C2C=CC([N+]([O-])=O)=CC=2)=O)=[CH:6][CH:5]=1.[NH2:33][C:34]1[C:39]([Cl:40])=[CH:38][N:37]=[CH:36][C:35]=1[Cl:41].[H-].[Na+].Cl>CN(C)C=O.O>[Cl:41][C:35]1[CH:36]=[N:37][CH:38]=[C:39]([Cl:40])[C:34]=1[NH:33][C:20]([C:7]1[C:8]2[C:16]3[CH:15]=[N:14][N:13]([CH2:17][CH3:18])[C:12](=[O:19])[C:11]=3[O:10][C:9]=2[C:4]([O:3][CH:2]([F:32])[F:1])=[CH:5][CH:6]=1)=[O:22]
Reactant: Nc1c(Cl)cncc1Cl
Reactant: CCn1ncc2c(oc3c(OC(F)F)ccc(C(=O)Oc4ccc([N+](=O)[O-])cc4)c32)c1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ncc2c(oc3c(OC(F)F)ccc(C(=O)Nc4c(Cl)cncc4Cl)c32)c1=O
Temperature: 5 °C
Yield: 210.7 %

Procedure:
A suspension of 4-nitrophenyl 6-difluoromethoxy-3-ethyl-4-oxo-3,4-dihydrobenzo[4,5]furo[2,3-d]pyridazine-9-carboxylate (from step III) (81 mg, 0.18 mmol) and 4-amino-3,5-dichloro pyridine (32 mg, 0.19 mmol) in dimethyl formamide (3 ml) was cooled to −30-40° C. under nitrogen. Then sodium hydride (15 mg, 0.36 mmol) was added lotwise at the same temp. under nitrogen. Progress of reaction was monitored by TLC. At the end, reaction mixture was cooled to 0-10° C. Water (100 ml) was added dropwise to the reaction mixture at 0-10° C. and acidified with dilute HCl. the precipitate obtained was filtered and dried in oven. The solid was purified by column chromatography using 20% acetone in chloroform. 178 mg pure product was obtained as off white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(Cl)CCl.C1C=CC2N(O)N=[N:24]C=2C=1.N>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:24])=[O:13])[CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cc(Br)cc2cc[nH]c12
Agent: N
Solvent: ClCCCl
Solvent: ClCCl
Product: NC(=O)c1cc(Br)cc2cc[nH]c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
To a solution of 5-bromo-1H-indole-7-carboxylic acid (10.0 g, 42 mmol) in CH2Cl2 (100 mL) at room temperature, EDC (9.66 g, 50.4 mmol), HOBt (6.81 g, 50.4 mmol) and NH3 (2.0 M in MeOH, 84 mL, 168 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the residue partitioned between ethyl acetate (100 mL) and water (100 mL). The water layer was extracted with ethyl acetate (100 mL×2) and the combined organic phase was dried over MgSO4 and concentrated to give the crude product (10 g, 98%). This crude product was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][C:18](O)=[O:19])=[CH:14][CH:13]=1)=[O:11].S(Cl)([Cl:25])=O.Cl.S(=O)(O)O>O1CCOCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][C:18]([Cl:25])=[O:19])=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(O)COc1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Reactant: O=S(Cl)Cl
Agent: Cl
Agent: O=S(O)O
Solvent: C1COCCO1
Product: O=C(Cl)COc1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of 3.54 g of 4-(2,3-dichlorophenyl-carbamoyl)-phenoxyacetic acid, 3.57 g of thionyl chloride and 30 ml of dioxane was stirred at a temperature of 80° C. for 4 hours. An excess amount of thionyl chloride and dissolved hydrochloric acid gas, sulfurous acid gas and dioxane were distilled off by a rotary evaporator to obtain 4-(2,3-dichlorophenyl-carbamoyl)-phenoxyacetyl chloride as the residue after distillation.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:4]([CH:17](O)[CH3:18])[CH:3]=1.CCN(C(C)C)C(C)C.CS([Cl:33])(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:4]([CH:17]([Cl:33])[CH3:18])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)c1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(Cl)c1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the product of step b) (0.34 g) in DCM (5 ml) was added Hunigs base (1 ml) followed by methanesulfonyl chloride (0.46 ml) and the reaction stirred at room temperature for 2 h followed by heating at 45° C. for 2 h. After cooling to 0° C. the bulk of the volatiles were removed in vacuo. Diethyl ether and water were added and the organic layer separated.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH2:18])[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>O1CCOCC1>[C:1]1([C:7]2[N:8]=[C:9]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1nc(-c2ccccc2)c(-c2ccccc2)s1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(Nc1nc(-c2ccccc2)c(-c2ccccc2)s1)c1ccccc1

Procedure:
4,5-Diphenyl-thiazol-2-ylamine (50.5 mg, 0.200 mmol) and benzoyl chloride (28.1 mg, 0.200 mmol) were dissolved in 1,4-dioxane (2 mL) containing triethylamine (84.1 μL, 0.600 mmol). The reaction mixture was subjected to microwave irradiation for 5 minutes at 200° C. The crude product was filtered, evaporated to dryness, dissolved in 1 mL of dimethylsulfoxide and purified by reverse-phase preparative liquid chromatography (7.21 mg, 0.0202 mmol, 10.1%). ESI-MS m/z calc. 356.1. found 357.2 (M+1)+ Retention time 3.95 minutes.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]3[CH:17]=[C:16]([C:18](O)=[O:19])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[C:22]1([NH2:29])[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1>>[C:22]1([NH:29][C:18]([C:16]2[CH:15]=[CH:14][C:12]3[NH:13][C:9]([C:6]4[CH:5]=[CH:4][C:3]([N:2]([CH3:21])[CH3:1])=[CH:8][CH:7]=4)=[N:10][C:11]=3[CH:17]=2)=[O:19])[CH:27]=[CH:26][C:25]([NH:28][C:18]([C:16]2[CH:15]=[CH:14][C:12]3[NH:13][C:9]([C:6]4[CH:5]=[CH:4][C:3]([N:2]([CH3:21])[CH3:1])=[CH:8][CH:7]=4)=[N:10][C:11]=3[CH:17]=2)=[O:19])=[CH:24][CH:23]=1
Reactant: Nc1ccc(N)cc1
Reactant: CN(C)c1ccc(-c2nc3ccc(C(=O)O)cc3[nH]2)cc1
Product: CN(C)c1ccc(-c2nc3cc(C(=O)Nc4ccc(NC(=O)c5ccc6[nH]c(-c7ccc(N(C)C)cc7)nc6c5)cc4)ccc3[nH]2)cc1

Procedure:
Compound 283 was prepared according to the procedure similar to that described in Scheme V from 2-(4-dimethylaminophenyl)benzimidazole-5-carboxylic acid and 1,4-phenylenediamine. [M+H]+ calcd for C38H34N8O2: 635.28; found: 635.05.
Reaction SMILES: [N:1]1([C:7]2[C:12]([C:13]#[N:14])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl[CH2:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-:37])=[O:36])[CH:30]=1)=[O:27]>C1(C)C=CC=CC=1>[C:13]([C:12]1[C:7]([N:1]2[CH2:2][CH2:3][N:4]([CH2:25][C:26]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-:37])=[O:36])[CH:30]=3)=[O:27])[CH2:5][CH2:6]2)=[N:8][CH:9]=[CH:10][CH:11]=1)#[N:14]
Reactant: O=C(CCl)Nc1cccc([N+](=O)[O-])c1
Reactant: N#Cc1cccnc1N1CCNCC1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccnc1N1CCN(CC(=O)Nc2cccc([N+](=O)[O-])c2)CC1
Temperature: 90 °C
Yield: 24.6 %

Procedure:
2-(1-Piperazinyl)-3-pyridinecarbonitrile (640 mg, 3.40 mmol) and N,N-diisopropylethylamine (1.0 mL) in toluene (15 mL) at room temperature were treated with N-chloroacetyl-3-nitroaniline (Lancaster, 610 mg, 2.84 mmol) and the reaction was heated at 90° C. for 18 hours. The mixture was allowed to cool to room temperature, transferred to a separatory funnel and washed with saturated aqueous sodium bicarbonate. The organic phase was dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (elution with 85% hexanes:ethyl acetate) to provide 256 mg (25% yield) of the title compound as a light tan solid. mp 143-145° C.; 1H NMR (300 MHz, DMSO-d6) δ 2.69 (m, 4H), 3.27 (s, 2H), 3.70 (m, 4H), 6.93 (dd, 1H, J=7.4, 5.0 Hz), 7.61 (dd, 1H, J=8.1, 8.1 Hz), 7.93 (br d, 1H, J=8.2 Hz), 8.06 (dd, 2H, J=7.8, 7.8 Hz), 8.42 (m, 1H), 8.70 (br s, 1H), 10.28 (br s, 1H); MS (DCI/NH3) m/e 367 (M+H)+; Anal. calcd for C18H18N6O3: C, 59.01; H, 4.95; N, 22.94. Found: C, 59.31; H, 5.25; N, 22.66.
Reaction SMILES: [Cl-].[NH2:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[K+].[C:11]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)#[N:12].C(O)C>O>[N:16]1[CH:17]=[CH:18][C:13]([C:11]2[N:12]=[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][N:3]3[N:2]=2)=[CH:14][CH:15]=1
Reactant: N#Cc1ccncc1
Reactant: N[n+]1ccccc1
Agent: [Cl-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: c1ccn2nc(-c3ccncc3)nc2c1
Reaction time: 66 h
Yield: 53.1 %

Procedure:
1-Aminopyridinium chloride (7.9g) was added to potassium hydroxide (6.72g) in water (60 ml). 4-Cyanopyridine (31.2g) was added to ethanol (63 ml). The two solutions were then admixed at room temperature and left for 66 hours. The ethanol was then evaporated off in vacuo, and the residue extracted with chloroform (100 ml). The chloroform extract was dried over magnesium sulphate, filtered, and evaporated in vacuo. Recrystallisation of the product from ethanol gave 2-(4-pyridyl)-s-triazolo[1,5-a]pyridine (6.3g), mp 188°-190° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH2:11]Br)[CH:5]=1.[C:14]([O-:17])(=[O:16])[CH3:15].[K+].O>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH2:11][O:17][C:14](=[O:16])[CH3:15])[CH:5]=1
Reactant: COC(=O)c1cc(C)cc(CBr)c1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(C)cc(COC(C)=O)c1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
In a 5 liter flask were combined 507 g (2.09 mole) of methyl-3-bromomethyl-5-methylbenzoate with 615 g (6.3 mole) of potassium acetate in 2850 ml of glacial acetic acid and refluxed for 3 hours. The contents of the flask were then cooled down to room temperature and divided in 3 equal portions for work up. Each portion was poured into 2 liter of water and extracted with ethyl ether (3×300 ml). The combined organic layers were washed with water (3×600 ml) and then with 2% aqueous sodium hydroxide (5×200 ml) and then dried over sodium sulfate. The solvent was then eliminated in the rotavap to give 420.8 g (90% yield) of crude product, used as such in the next step.
Reaction SMILES: [C:1]1([CH3:8])[C:2]([CH3:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.C(Cl)(Cl)Cl.[C:13]1(C)C=CC=C[CH:14]=1>>[CH2:7]1[C:2]2[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:8][CH2:14][CH2:13]1
Reactant: Cc1ccccc1
Reactant: Cc1ccccc1C
Solvent: ClC(Cl)Cl
Product: c1ccc2c(c1)CCCC2

Procedure:
Compound I, II or III is then dissolved in toluene, xylene, tetralin, or chloroform to form a solution of concentration around 1-2 mol L−1. This solution may be inkjet printed to provide an effective organic semiconductor (OSC).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:7])[S:5][CH:6]=1.[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O)=[O:9].C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH3:7][C:4]1[S:5][CH:6]=[C:2]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:8]=[O:9])[CH:3]=1
Reactant: Cc1cc(Br)cs1
Reactant: O=Cc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cc(-c2ccccc2C=O)cs1
Temperature: 150 °C
Yield: 80.9 %

Procedure:
In a microwave vial, 4-bromo-2-methyl-thiophene (653 mg, 3.69 mmol), 2-formyl phenylboronic acid (500 mg, 3.36 mmol) and 7 ml of actonitrile were mixed. 6.7 ml of 1N aqueous sodium carbonate was added to above solution, followed by 5 mole percent of dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated at 150° C. for 5 minutes with microwave irradiation. After cooling, 50 ml of ethyl acetate was added, the organic layer was separated, washed with water, dried with sodium sulfate, the organic solvent was evaporated and the residue was purified by ISCO to give 550 mg of 2-(5-methyl-thiophen-3-yl)benzaldehyde, yield 81%.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][S:11]([CH2:14][CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)(=[O:13])=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].NN.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C.C1COCC1>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][S:11]([CH2:14][CH2:15][NH2:16])(=[O:12])=[O:13])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(NS(=O)(=O)CCN2C(=O)c3ccccc3C2=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NN
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)N1CCC(NS(=O)(=O)CCN)CC1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
2.48 g (6.53 mmol) crude 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid (1-isopropyl-piperidin-4-yl)-amide were dissolved in 100 ml ethanol. 65.3 ml (10 equiv.) of a 1M hydrazine-solution in THF and 124 mg (0.1 equiv.) p-toluenesulfonic acid were added. The resulting mixture was stirred at 60° C. for 72 h. The formed precipitate was filtered off. The filtrate was concentrated under reduced pressure. The resulting residue was co-distilled three times with 200 ml DMF to remove the excess hydrazine. Crude 2-amino-ethanesulfonic acid (1-isopropyl-piperidin-4-yl)-amide was obtained as a colorless oil. Yield: 2.00 g
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]=[C:5]3[N:15]4[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]4[CH2:13][O:12][C:6]3=[N:7][C:8]=2[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:16]1[N:15]2[C:5]3[C:6]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17]1)=[N:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:2]([NH:1][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:3]=1[N:4]=3
Reactant: Nc1cccc2nc3c(nc12)N1CCCCC1CO3
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(Nc1cccc2nc3c(nc12)N1CCCCC1CO3)c1ccccc1
Reaction time: 8 h

Procedure:
A mixture of 5.1 g. of 11-amino-1,2,3,4,4a,5-hexahydropyrido[1',2':4,5][1,4]oxazino[2,3-b]quinoxaline, 100 ml. of methylene chloride and 20 ml. of 1 N sodium hydroxide is stirred and 2.8 g. of benzoyl chloride is added. The reaction mixture is stirred overnight and the layers are separated. The methylene chloride layer is washed with water and concentrated and N-(1,2,3,4,4a,5-hexahydropyrido[1',2':4,5][1,4]oxazino[2,3-b] quinoxalin-11-yl)benzamide is obtained.
Reaction SMILES: [CH2:1]([O:4][CH3:5])[C:2]#[CH:3].I[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1/[C:9](=[CH:17]/[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24])/[C:10](=[O:16])[NH:11]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:5][O:4][CH2:1][C:2]#[C:3][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1/[C:9](=[CH:17]/[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24])/[C:10](=[O:16])[NH:11]2
Reactant: C#CCOC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCC#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, methyl propargyl ether (34 mg, 0.49 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (150 mg, 0.41 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (20 mg) and CuI (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 18 h to yield (Z)-1,3-dihydro-4-(3-methoxy-1-propynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 69 mg, 55%).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17]C[CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.N1C=C(B(O)O)C=NC=1>>[CH:14]([N:13]([C@H:11]1[CH2:10][C@H:9]([C:7]2[S:8][C:4]3[CH:3]=[C:2]([C:26]4[CH:27]=[N:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=4)[CH:20]=[CH:19][C:5]=3[N:6]=2)[CH2:12]1)[CH3:17])([CH3:18])[CH3:15]
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: COc1ccc(B(O)O)cn1
Agent: OB(O)c1cncnc1
Product: COc1ccc(-c2ccc3nc([C@H]4C[C@H](N(C)C(C)C)C4)sc3c2)cn1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, substituting the product of Example 52A for the product of Example 1E and substituting 6-methoxypyridine-3-boronic acid for pyrimidine-5-boronic acid. 1H NMR (300 MHz, CDCl3) δ ppm 8.00 (d, J=8.48 Hz, 1H) 7.87 (d, J=1.70 Hz, 1H) 7.68 (dd, J=9.16, 2.71 Hz, 1H) 7.49 (dd, J=8.48, 1.70 Hz, 1H) 7.39-7.44 (m, 1H) 6.70 (d, J=9.49 Hz, 1H) 3.75-3.88 (m, 1H) 3.65 (s, 3H) 3.56-3.63 (m, 1H) 3.00-3.16 (m, 1H) 2.66-2.80 (m, 2H) 2.52-2.65 (m, 2H) 2.18 (s, 3H) 1.05 (d, J=6.44 Hz, 6H). MS: (M+H)+=368.
Reaction SMILES: [CH2:1]([N:4]([CH3:20])[CH2:5][CH:6]=[CH:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH2:15][CH2:14][CH2:13]2)[CH:2]=[CH2:3].CCN(C(C)C)C(C)C.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>C(Cl)Cl>[CH2:1]([N:4]([CH2:5][CH:6]=[CH:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([S:37]([C:34]1[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=1)(=[O:39])=[O:38])[CH2:15][CH2:14][CH2:13]2)[CH3:20])[CH:2]=[CH2:3]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: C=CCN(C)CC=CCOc1ccc2c(c1)CCCN2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCN(C)CC=CCOc1ccc2c(c1)CCCN2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
To 54 mg (0.2 mmol) Allyl-methyl-[4-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-but-2-enyl]-amine in 2 ml CH2Cl2 3 drops of Huenig's base and 527 mg (0.25 mmol) 4-chlorobenzene sulfonylchloride were added. The solution was stirred at RT for 2 h, concentrated and purified by column chromatography on silica gel with CH2Cl2/MeOH 19:1 to yield 70 mg (78%) Allyl-{4-[1-(4-chloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinolin-6-yloxy]-but-2-enyl}-methyl-amine as yellow oil, MS: 447 (MH+, 1Cl).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:27]=[CH:26][C:8]([O:9][C:10]2[C:18]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=2[N+:23]([O-:25])=[O:24])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[C:1]([NH:4][C:5]1[CH:27]=[CH:26][C:8]([O:9][C:10]2[C:18]([S:19](=[O:21])(=[O:22])[NH:20][C:28](=[O:30])[CH3:29])=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=2[N+:23]([O-:25])=[O:24])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(Oc2c([N+](=O)[O-])cc(C(=O)O)cc2S(N)(=O)=O)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(Oc2c([N+](=O)[O-])cc(C(=O)O)cc2S(=O)(=O)NC(C)=O)cc1

Procedure:
The starting material is prepared as follows: The mixture of 12.5 g of 4-(4-acetamidophenoxy)-3-nitro-5-sulfamoylbenzoic acid and 125 ml of acetic anhydride is refluxed for 2 hours under nitrogen and evaporated under reduced pressure. The residue is taken up in 125 ml of 2N aqueous sodium hydroxide and 25 ml of water, the solution washed with diethyl ether, filtered and the filtrate acidified with concentrated hydrochloric acid and the precipitate recrystallized from 33 and 50% aqueous ethanol, to yield the 4-(4-acetamidophenoxy)-3-nitro-5-acetylsulfamoylbenzoic acid decomposing at about 240°. The solution of 10.5 g thereof in 100 ml of water and 22 ml of 2N aqueous sodium hydroxide is hydrogenated over 2.5 g of 10% palladium on charcoal until the theoretical amount of hydrogen has been absorbed. The mixture is filtered, the filtrate acidified with concentrated hydrochloric acid and the precipitate recrystallized from aqeuous ethanol, to yield the 4-(4-acetamidophenoxy)-3-amino-5 -acetylsulfamoylbenzoic acid melting at 305°-306° with decomposition.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=2)[N:4]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[N:3]=1.[O:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH:24]=[C:23]1B(O)O.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC>[O:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH:24]=[C:23]1[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=2)[N:4]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[N:3]=1
Reactant: CCOC(=O)c1ccc2c(c1)c(Br)nn2C1CCCCO1
Reactant: OB(O)c1cc2ccccc2o1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)c(-c1cc3ccccc3o1)nn2C1CCCCO1
Temperature: 90 °C
Reaction time: 8 h
Yield: 363.3 %

Procedure:
A solution of ethyl 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxylate (500 mg, 1.41 mmol), 2-benzofuran boronic acid (454 mg, 2.82 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium (II) complex with dichloromethane (163 mg, 0.141 mmol), and potassium phosphate (1.5 g, 7.05 mmol) in ethylene glycol dimethyl ether (12 mL) was allowed to stir under a nitrogen atmosphere at 90° C. overnight. The reaction was extracted with ethyl acetate and purified by silica gel chromatography to yield the title compound (2.0 g, 90% yield). ES-MS (m/z) 391 [M+1]+.