Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][CH:12]([C@H:14]1[CH2:19][O:18][C:16](=[O:17])[CH2:15]1)[CH3:13].[CH2:20](I)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH2:20]([C@@H:15]1[C@@H:14]([CH:12]([CH3:13])[CH3:11])[CH2:19][O:18][C:16]1=[O:17])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ICc1ccccc1
Reactant: CC(C)[C@H]1COC(=O)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)[C@H]1COC(=O)[C@@H]1Cc1ccccc1
Reaction time: 1 h
Yield: 58 %

Procedure:
Lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 92 mL, 92 mmol) was added in 3-5 minutes to a solution of (S)-β-(2-propyl)-γ-butyrolactone 175 (11.68 g, 91.25 mmol) in dry THF 100 mL at −78° C. under argon atmosphere. It was stirred for 1 h and a solution of benzyl iodide (21.87 g, 100.37 mmol )in dry THF was added rapidly. Stirring was continued for 1.5 hours and quenched at −78° C. by the addition of a solution of brine followed by ethyl acetate. The organic phase was separated and the aqueous was further extracted with ether. Chromatography on silica gel first eluted with 5% methylene chloride in pet ether, and finally with 10% ether in pet ether gave desired compound 11.6 g, 58%. NMR (CDCl3) δ 7.19 (m, 5H, C6H5), 4.02 (app. t, 1H, CHaHbO), 3.87 (dd, 1H, CHaHbO), 2.98 (d, 2H, ArCH2), 2.57 (q, 1H, BnCHC═O), 2.05 (m, 1H, CHCH(Me)2, 1.55 (m, 1H, CH(Me)2), 0.81 (d, 3H, CH3) and 0.72 (d, 3H, CH3).
Reaction SMILES: [C:1]([O:6][C:7]1[CH:12]=[CH:11][C:10](Cl)=[CH:9][CH:8]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].[Mg].B(OC)(OC)[O:16]C.OO>C(O)(=O)C.O1CCCC1>[CH3:5][CH2:4][C:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:16])=[CH:9][CH:8]=1)([CH3:3])[CH3:2]
Reactant: COB(OC)OC
Reactant: CCC(C)(C)Oc1ccc(Cl)cc1
Agent: OO
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCC(C)(C)Oc1ccc(O)cc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
A Grignard reagent was previously prepared using 99.3 g of 1-tert-amyloxy-4-chlorobenzene, 12.76 g of magnesium, and 200 mL of tetrahydrofuran. To the Grignard reagent, 57.1 g of trimethyl borate was added dropwise at an internal temperature below −50° C. At a reaction temperature of 5° C., stirring was continued for 3 hours. Thereafter, at an internal temperature below 30° C., 45.0 g of acetic acid and 145.7 g of 35% hydrogen peroxide solution were added. At room temperature, stirring was continued for 3 hours. Standard work-up and purification by silica gel chromatography gave 62.2 g of 4-tert-amyloxy-1-phenol (yield 69%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1.[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][O-:32].[Na+].O>O1CCCC1>[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31][O:32][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1
Reactant: CN(C)CC[O-]
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(Oc2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCOc1cc2c(Nc3ccc(Oc4ccccc4)cc3)c(C#N)cnc2cn1
Yield: 85 %

Procedure:
To 250 mg of 6-fluoro-4-(4-phenoxy-phenylamino)-[1.7]naphthyridine-3-carbonitrile under an inert atmosphere was added 8 mL of 1 M sodium (2-dimethylamino-ethoxide) in tetrahydrofuran. After refluxing for 2 hours, the reaction was stripped of tetrahydrofuran and water was added. The product was filtered, washed with water, dried, and recrystallized from chloroform/ether/hexanes to give 266 mg (85%) of 6-(2-dimethylamino-ethoxy)-4-(4-phenoxy-phenylamino)-[1.7]naphthyridine-3-carbonitrile as a yellow solid: melting point 159-161° C.; mass spectrum (m/e): M+H 426.0
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.C[N:14](C)C=O.C1(C)C=CC=CC=1.N>O>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH2:14])=[O:12])=[CH:5][CH:4]=1
Reactant: O=C(O)Cc1ccc(CBr)cc1
Reactant: CN(C)C=O
Agent: N
Solvent: O
Solvent: Cc1ccccc1
Product: NC(=O)Cc1ccc(CBr)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 393 %

Procedure:
To a solution of (4-bromomethyl-phenyl)-acetic acid (9.23 g, 40.30 mmol) and N,N-dimethylformamide (0.5 ml, 6.47 mmol) in toluene (100 ml) thionyl chloride (3.1 ml, 42.31 mmol) was added. The mixture was heated at 80° C. for 1 h. At 0° C., this mixture was added to a solution of ammonia in water (25%, 200 ml). After stirring for 30 min the precipitate was collected, washed with water and pentane, and dried in a vacuum oven at 50° C. to give the product as white crystals (5.8 g, 63%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].[CH2:14]([C:19]1[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=1)[CH2:15][CH2:16][CH2:17][CH3:18]>C1COCC1.C(N(CC)CC)C.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([O:7][C:22]1[CH:21]=[CH:20][C:19]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:24][CH:23]=1)=[O:6]
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: CCCCCc1ccc(O)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCc1ccc(OC(=O)c2ccc([N+](=O)[O-])c(C)c2)cc1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
9.50 g of 3-methyl-4-nitrobenzoic acid (52.5 mM) were dissolved in 400 ml of THF and 53.1 g of triethylamine (525.0 mM). The solution was cooled to −30° C. and 6.01 g of methansulfochloride (52.5 mM) were added. The mixture was stirred for 1 h at this temperature, then a solution of 8.21 g of 4-pentylphenol (50.0 mM) in 20 ml of THF was added, followed by 100 mg of DMAP. The reaction mixture was stirred for 1 h at −30° C. and was allowed to warm to room temperature while stirred overnight. The next day, the mixture was filtered through a pad of celite filter aid, evaporated to dryness. The residue was flash chromatographed on silica gel using cyclohexane/ethyl acetate: 1/1 as eluent to afford 4-pentylphenyl 3-methyl-4-nitrobenzoate as a yellow oil. Yield: 16.2 g (49.5 mM, 99%).
Reaction SMILES: [C:1]1([C:14](O)=[O:15])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[N:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:35]=[C:36]([NH2:40])[CH:37]=[CH:38][CH:39]=2)=[CH:30][N:29]=1>ClCCl.N1C=CC=CC=1>[N:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:35]=[C:36]([NH:40][C:14]([C:1]3[C:13]4[CH2:12][C:11]5[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=5)[C:5]=4[CH:4]=[CH:3][CH:2]=3)=[O:15])[CH:37]=[CH:38][CH:39]=2)=[CH:30][N:29]=1
Reactant: O=C(O)c1cccc2c1Cc1ccccc1-2
Reactant: Nc1cccc(-c2ccnnc2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cccc(-c2ccnnc2)c1)c1cccc2c1Cc1ccccc1-2
Reaction time: 2 h
Yield: 64.1 %

Procedure:
To a suspension of 1-fluorenecarboxylic acid (120 mg) and oxalyl chloride (0.12 ml) in dichloromethane (2.5 ml) was added N,N-dimethylformamide (0.01 ml) and the mixture was stirred for 2 hours. The resultant solution was evaporated to give a crude acid chloride. To a suspension of 3-(pyridazin-4-yl)phenylamine (98 mg) and pyridine (0.14 ml) in dichloromethane (2 ml) was dropwise added a solution of the acid chloride obtained above in dichloromethane (5 ml), and the mixture was stirred for an hour. The mixture was diluted with dichloromethane and washed with an aqueous solution of sodium hydrogen carbonate and brine. The separated organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by a silica gel column chromatography eluting with 2% methanol in dichloromethane to give N-(3-(pyridazin-4-yl)-phenyl)-9H-fluorene-1-carboxamide (133 mg, 63.9%)
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[OH-].[Na+].Cl[C:11]1[N:16]=[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Cl:26])[CH:19]=2)[N:14]=[C:13]([NH:27][CH:28]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[N:12]=1>C1C=CC=CC=1>[Cl:26][C:20]1[CH:19]=[C:18]([NH:17][C:15]2[N:14]=[C:13]([NH:27][CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)[N:12]=[C:11]([N:5]3[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]3)[N:16]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Reactant: OC1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(N3CCC(O)CC3)n2)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 4-hydroxypiperidine (0.198 g, 1.96 mmol) and sodium hydroxide (79 mg, 1.96 mmol) in benzene (10 mL) was heated to reflux for 2 hours with stirring under nitrogen atmosphere and then cooled to 25° C. followed by the addition of compound 133 (0.25 g, 0.65 mmol) at same temperature. The mixture was heated to reflux for 6 hours, concentrated under vacuum and diluted with water (10 mL). The precipitated solid was filtered off and purified by column chromatography (1-2% MeOH—CHCl3) to afford the title compound E24 as an off-white solid (0.20 g, 58%). mp 142-144° C.; HPLC: Hichrom RPB (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4 (pH 5.5); solvent B=CH3CN], Gradient elution program: T/% B=0/20, 10/20, 25/80, 40/80, 55/60, 65/20, 70/20; 270 nm, Rt 40.56 min, 98.60% purity; MS (CI): m/z 447 (M+H, 100).
Reaction SMILES: [C:1]([SiH:4]([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])=[CH2:2].[Br:11]N1C(=O)CCC1=O>ClCCl>[C:1]([SiH:4]([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])=[CH2:2].[C:1]([Si:4]([CH:8]([CH3:10])[CH3:9])([CH:5]([CH3:7])[CH3:6])[Br:11])([CH3:3])=[CH2:2]
Reactant: O=C1CCC(=O)N1Br
Agent: C=C(C)[SiH](C(C)C)C(C)C
Solvent: ClCCl
Product: C=C(C)[Si](Br)(C(C)C)C(C)C

Procedure:
Crude isopropenyldiisopropylsilane (10 g), which was prepared as described in “Preparation of Isopropenyldiisopropylsilane—Method 2” was taken up in dichloromethane (120 mL) and cooled in an ice bath. N-Bromosuccinimide (13.7 g, 77 mmol, 1.2 eq. assuming silane purity of 100%) was added scoopwise over 1 hour, followed by an additional hour of stirring while maintaining the temperature. The suspension was filtered and the solid rinsed with pentane (50 mL). Solvent was removed by rotary evaporation and the suspension again taken up in pentane (70 mL), and filtered through quantitative filter paper, that was then rinsed with additional pentane (50 mL). Removal of solvent by rotary evaporation yielded crude isopropenyldiisopropylbromosilane (15 g) as a hazy, pale brown liquid.
Reaction SMILES: O.[OH-].[Li+].O.C[O:6][C:7]([C:9]1[CH:13]=[CH:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[N:16][CH:15]=2)[CH:10]=1)=[O:8].[K+].[Br-]>O1CCCC1>[C:7]([C:9]1[CH:13]=[CH:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[N:16][CH:15]=2)[CH:10]=1)([OH:8])=[O:6]
Reactant: COC(=O)c1ccn(-c2cncc3ccccc23)c1
Agent: [Br-]
Agent: [K+]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccn(-c2cncc3ccccc23)c1
Reaction time: 15 h

Procedure:
0.63 g (15.02 mmol) of lithium hydroxide monohydrate and 20 mL of water are added to a solution, at a temperature in the region of 22° C., of 0.95 g (376 mmol) of 3-methoxycarbonyl-1-(isoquinol-4-yl)-1H-pyrrole in 20 mL of tetrahydrofuran. After stirring at the reflux point of the solvent for 15 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is dissolved in water. The solution is extracted with ethyl acetate and the organic phase is discarded. The aqueous phase is adjusted to pH 6 with N hydrochloric acid and extracted with ethyl acetate. The organic phase is washed successively with water and with saturated aqueous sodium chloride solution and then it is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa), resulting in 0.75 g of 3-carboxy-1-(isoquinol-4-yl)-1H-pyrrole in the form of a beige-coloured solid. IR spectrum (KBr): 3153, 2518, 1855, 1690, 1495, 1276, 1188, 933, 808, 783, 757, 712 and 675 cm−1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-])=O)[CH:25]=2)[C:7]2[C:12]([C:13](=[O:22])[C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:11][CH:10]=[C:9]([CH3:23])[N:8]=2)=[O:4]>CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=2)[C:7]2[C:12]([C:13](=[O:22])[C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:11][CH:10]=[C:9]([CH3:23])[N:8]=2)=[O:4]
Reactant: COC(=O)c1c(Cc2ccccc2)c(=O)c2ccc(C)nc2n1-c1cccc([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Product: COC(=O)c1c(Cc2ccccc2)c(=O)c2ccc(C)nc2n1-c1cccc(N)c1
Yield: 17.2 %

Procedure:
Compound 104 (15 mg) was dissolved in EtOAc (10 mL) with Pc/C (10%, 5 mg), and hydrogenated using H2 (balloon) for 2 h. The product was filtered, concentrated, and purified by prep TLC (50/50 EtOAc/hexane), then 10% MeOH/DCM to provide 1-(3-amino-phenyl)-3-benzyl-7-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-2-carboxylic acid methyl ester (Compound 105, 2.4 mg). M+H=478.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[O:12][N:11]=[C:10]([CH3:13])[C:9]=1[C:14]([O:16]C)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:18]>O>[C:1]([NH:5][C:6]([C:8]1[O:12][N:11]=[C:10]([CH3:13])[C:9]=1[C:14]([NH2:18])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: COC(=O)c1c(C)noc1C(=O)NC(C)(C)C
Solvent: O
Product: Cc1noc(C(=O)NC(C)(C)C)c1C(N)=O

Procedure:
4.0 g of methyl 5-tert-butylaminocarbonyl-3-methylisoxazole-4-carboxylate and 50 ml of concentrated ammonia are refluxed for 3 hours. After cooling, the mixture is diluted with water and extracted with dichloromethane and the organic phase is evaporated down. 5-tert-butylaminocarbonyl-3-methylisoxazole-4-carboxamide is obtained as colorless crystals of melting point 155°-158° C. (compound No. 1).
Reaction SMILES: NC12CC3CC(CC(N[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=4)=[O:14])(C3)C1)C2.Cl.[CH3:23][O:24][C:25]([C:27]12[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:35][C:29]([NH2:37])([CH2:30]3)[CH2:28]1)[CH2:34]2)=[O:26].CC1N=C(C(O)=O)C=CC=1>>[CH3:23][O:24][C:25]([C:27]12[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:35][C:29]([NH:37][C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=4)=[O:14])([CH2:30]3)[CH2:28]1)[CH2:34]2)=[O:26]
Reactant: Cc1cccc(C(=O)NC23CC4CC(CC(N)(C4)C2)C3)n1
Reactant: COC(=O)C12CC3CC(CC(N)(C3)C1)C2
Agent: Cc1cccc(C(=O)O)n1
Agent: Cl
Product: COC(=O)C12CC3CC(CC(NC(=O)c4cccc(C)n4)(C3)C1)C2
Yield: 75 %

Procedure:
Intermediate 1 was also made via the same synthetic procedures for Intermediate 2 (see below). Starting from 3-amino-adamantane-1-carboxylic acid methyl ester hydrochloride (14.9 g, 60.8 mmol), coupling with 6-methyl-pyridine-2-carboxylic acid afforded 3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantane-1-carboxylic acid methyl ester (14.9 g, 75%). The methyl ester was then hydrolyzed to give 3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantane-1-carboxylic acid (12.2 g, 86%). Finally, the Curtius rearrangement of 3-[(6-methyl-pyridine-2-carbonyl)-amino]-adamantane-1-carboxylic acid (10.0 g, 31.8 mmol) yielded Intermediate 1 (8.48 g, 93%).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[C:23]3[C:29]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[O:36][CH3:37])=[CH:28][NH:27][C:24]3=[N:25][CH:26]=2)=[CH:17][C:16]=1[C:38](=[O:42])[N:39]([CH3:41])[CH3:40])=[O:13])C)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[CH3:37][O:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:29]1[C:23]2[C:24](=[N:25][CH:26]=[C:21]([C:18]3[CH:19]=[CH:20][C:15]([NH:14][C:12]([NH:11][CH2:10][CH2:9][NH:7][CH3:6])=[O:13])=[C:16]([CH:17]=3)[C:38]([N:39]([CH3:41])[CH3:40])=[O:42])[CH:22]=2)[NH:27][CH:28]=1
Reactant: COc1ccccc1-c1c[nH]c2ncc(-c3ccc(NC(=O)NCCN(C)C(=O)OC(C)(C)C)c(C(=O)N(C)C)c3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCNC(=O)Nc1ccc(-c2cnc3[nH]cc(-c4ccccc4OC)c3c2)cc1C(=O)N(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[2-(3-{2-dimethylcarbamoyl-4-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenyl}-ureido)-ethyl]-methyl-carbamic acid tert-butyl ester (61 mg, 0.103 mmol) was dissolved in 5% trifluoroacetic acid in dichloromethane (15 mL). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated and the residue was purified by preparative HPLC to give 13 mg (26%) of (5-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-2-[3-(2-methylamino-ethyl)-ureido]-benzamide. 1H-NMR (250 MHz, d6-DMSO) δ 11.90 (broad s, 1H), 11.04 (s, 1H), 9.15 (s, 1H), 8.64 (d, J=2.0 Hz, 1H), 8.43 (d, J=8.8 Hz, 1H), 8.24 (d, J=2 Hz, 1H), 8.06 (d, J=2.0 Hz, 1H), 7.81 (dd, J=8.8, 2.0 Hz, 1H), 7.72 (s, 1H), 7.61 (dd, J=7.4, 1.6 Hz, 1H), 7.28 (d, J=7.0 Hz, 1H), 7.13 (d, J=7.6 Hz, 1H), 7.06 (t, J=7.5 Hz, 1H), 3.84 (s, 3H), 2.92 (s, 6H), 2.42 (s, 3H); MS: m/z 487.1 (M+H+).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH:17]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[C:18]([O:20][CH3:21])=[O:19])[CH3:16])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.[I-].[Na+]>CC(C)=O.O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]([CH3:16])[CH:17]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:37][CH2:38][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:26][CH:27]=2)[C:18]([O:20][CH3:21])=[O:19])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)OC)c2ccc(O)cc2)cc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CC(C)=O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)OC)c2ccc(OCCN3CCOCC3)cc2)cc1
Yield: 48.7 %

Procedure:
To a solution of 0.25 g (0.620 mmol) of methyl [{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino](4-hydroxyphenyl)acetate in 10 mL of acetone was added 0.342 g of potassium carbonate, 0.231 g (1.241 mmol) of 4-(2-chloroethyl)morpholine hydrochloride and 1 equivalent of sodium iodide. The reaction was heated to reflux for 5 h, diluted with water and extracted with chloroform. The organics were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with chloroform/methanol (9:1) to provide 0.156 g of methyl 2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-2-{4-[2-(4-morpholinyl)ethoxy]phenyl}acetate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:11]=1)[C:5]([O:7]C)=[O:6].[OH-].[Li+].O1CCCC1.Cl>O>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(S(C)(=O)=O)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cc(Br)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of methyl 3-bromo-5-(methylsulfonyl)benzoate (0.65 g, 2.2 mmol), lithium hydroxide (0.26 g, 11 mmol), tetrahydrofuran (25 mL) and water (5 mL) was stirred at room temperature for 3 h. Water (50 mL) was added and the mixture was acidified with 1N aq. HCl to pH 2-3 and extracted with EtOAc (100 mL). The organic layer was separated, washed with brine, dried (Na2SO4), and concentrated to yield a white solid. LC-MS: 278.6 [M−1]−; 1H NMR (400 MHz, CDCl3): 8.59 (m, 1H), 8.50 (m, 1H), 8.33 (m, 1H), 3.13 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]2[C:13]1[CH:22]=[CH:21][C:20]2[CH2:19][CH2:18][CH2:17][CH:16]([OH:23])[C:15]=2[N+:14]=1[O-])#[N:2].P(Cl)(Cl)Cl>C(OCC)(=O)C.C(#N)C>[OH:12][C:7]1[NH:8][C:9]2[C:5]([C:6]=1[C:13]1[CH:22]=[CH:21][C:20]3[CH2:19][CH2:18][CH2:17][CH:16]([OH:23])[C:15]=3[N:14]=1)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2
Reactant: N#Cc1ccc2c(c1)C(c1ccc3c([n+]1[O-])C(O)CCC3)C(=O)N2
Solvent: ClP(Cl)Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1ccc2[nH]c(O)c(-c3ccc4c(n3)C(O)CCC4)c2c1
Temperature: 25 °C
Yield: 18 %

Procedure:
To a suspension of crude 2-(5-cyano-2-oxoindolin-3-yl)-8-hydroxy-5,6,7,8-tetrahydroquinoline 1-oxide (263 mg, 0.819 mmol) in ethyl acetate (12 mL) and acetonitrile (12 mL) was added dropwise a solution of phosphorous trichloride (0.644 mL, 7.37 mmol) in ethyl acetate (4 mL). The resulting suspension was stirred at RT. After 24 h the mixture was diluted with ethyl acetate and washed with a saturated sodium bicarbonate solution (2×). The aqueous phase was re-extracted with ethyl acetate (1×) and the combined organic extracts were dried over sodium sulfate, filtered, and evaporated to dryness (52 mg). The crude was dissolved in a mixture of water (2 mL) and dimethylformamide (3 mL) and the solution was heated in a microwave oven at 120° C. for 5 min. After cooling to RT the reaction mixture was diluted with ethyl acetate was washed with brine (5×). The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness. The crude was purified by flash chromatography (silica gel, dichloromethane/methanol) yielding yellow solid. Amount 8.6 mg. Yield 18%.
Reaction SMILES: [C:1]([NH:9][NH:10][C:11]1[C:23]([Cl:24])=[CH:22][C:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:13][N:12]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>C1(C)C=CC=CC=1>[Cl:24][C:23]1[C:11]2[N:12]([C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:9][N:10]=2)[CH:13]=[C:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:22]=1
Reactant: CC(C)(C)OC(=O)c1cnc(NNC(=O)c2ccccc2)c(Cl)c1
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1cc(Cl)c2nnc(-c3ccccc3)n2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 45.4 %

Procedure:
To a solution of tert-butyl 6-(2-benzoylhydrazino)-5-chloronicotinate (3.3 g, 9.49 mmol) in toluene (40 mL) was added Lawesson's reagent (1.92 g, 4.74 mmol). The mixture was stirred at 80° C. After 2 h, the mixture was concentrated. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate (3×). The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→60% dichloromethane/ethyl acetate) gave the title compound (1.42 g): LC-MS [M+1]=330.1.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl[Ni](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.[Zn].CN(C=O)C>[CH3:9][O:8][C:5]1[N:4]=[N:3][C:2]([C:2]2[N:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=2)=[CH:7][CH:6]=1
Reactant: COc1ccc(Cl)nn1
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(OC)nn2)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
In a 100 ml two-necked flask, 1.55 g (2.1 mmol) of dichlorobis(triphenylphosphine)nickel(II), 452 mg (6.95 mmol) of zinc and 2.23 g (6.95 mmol) of tetrabutylammonium bromide are solubilized in 40 ml of freshly distilled DMF. After degassing, the solution is stirred at ambient temperature for 30 min (the green starting solution turns brown). 1 g (6.95 mmol) of 3-chloro-6-methoxypyridazine 14 is added to this solution, and the reaction mixture is heated at 55° C. for 8 hours. After the solvent has been evaporated off under reduced pressure, the residue is taken up in a saturated solution of ammonium chloride, the suspension is extracted with 4×40 ml of dichloromethane and the organic phase is dried over MgSO4 and then concentrated under reduced pressure. The reaction crude is chromatographed on silica gel (eluent:ethyl acetate/petroleum ether=4/6), to give the bipyridazine 15 with a yield of 96%.