Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13]CC)=O)[N:10]=2)[N:7]=1.[CH3:16][NH2:17].O1CCCC1>CO>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH:17][CH3:16])=[O:13])[N:10]=2)[N:7]=1
Reactant: CN
Reactant: CCOC(=O)c1cn2nc(I)ccc2n1
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)c1cn2nc(I)ccc2n1
Temperature: 25 °C
Reaction time: 96 h
Yield: 71.6 %

Procedure:
To a suspension of ethyl 6-iodoimidazo[1,2-b]pyridazine-2-carboxylate (4.5 g, 14.8 mmol) in methanol (13.5 mL) was added dropwise a solution of methylamine/tetrahydrofuran (2 mol/L, 37.1 mL, 74.2 mmol), and the mixture was stirred at room temperature for 96 hr. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate, saturated brine and water to give the title compound (3.2 g, 71%) as a dark brown powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]=[C:11]=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH3:14][O:15][C:16](=[O:19])[CH2:17][NH2:18].C(N(CC)CC)C>ClCCl>[CH3:14][O:15][C:16](=[O:19])[CH2:17][NH:18][C:11]([NH:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:12]
Reactant: COC(=O)CN
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CNC(=O)Nc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
To a suspension of 3-nitrophenyl isocyanate (10 g, 61 mmol) and glycine methyl ester hydrochloride (8.4 g, 67 mmol, 1.1 equiv.) in dichloromethane (250 mL) was added triethylamine (10 mL, 72 mmol, 1.2 equiv.) at 0° C. The resulting solution was stirred at room temperature overnight. The resulting dark brown solution was concentrated and triturated in water to give a light yellow suspension. The suspension was filtered and the filter cake was washed with water and air-dried to give [[[(3-nitrophenyl)amino]carbonyl]aminoacetic acid methyl ester (15 g) in quantitative yield.
Reaction SMILES: CC1C2C(=CC=CC=2[N+]([O-])=O)NC=1.[CH3:14][C:15]1[C:23]2[C:18](=[CH:19][C:20]([N+:24]([O-])=O)=[CH:21][CH:22]=2)[NH:17][CH:16]=1>C(O)C.[Pd]>[CH3:14][C:15]1[C:23]2[C:18](=[CH:19][C:20]([NH2:24])=[CH:21][CH:22]=2)[NH:17][CH:16]=1
Reactant: Cc1c[nH]c2cc([N+](=O)[O-])ccc12
Agent: [Pd]
Agent: Cc1c[nH]c2cccc([N+](=O)[O-])c12
Solvent: CCO
Product: Cc1c[nH]c2cc(N)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 0 %

Procedure:
A mixture of 3-methyl-4-nitro-1H-indole and 3-methyl-6-nitro-1H-indole (3 g, 17 mol) and 10% Pd—C (0.5 g) in ethanol (30 mL) was stirred overnight under H2 (1 atm) at room temperature. Pd—C was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give 3-methyl-1H-indol-6-ylamine (B-7) (0.6 g, 24%). 1H NMR (CDCl3) δ 7.59 (br s, 1H), 7.34 (d, J=8.0 Hz, 1H), 6.77 (s, 1H), 6.64 (s, 1H), 6.57 (m, 1H), 3.57 (br s, 2H), 2.28 (s, 3H); ESI-MS 147.2 m/z (MH+).
Reaction SMILES: [CH:1]([O:4][C:5]([CH:7]1[CH:19]([CH2:20][O:21][CH3:22])[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:16]=3)[NH:11][C:10]=2[CH2:9][NH:8]1)=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.ClOC(C)(C)C>C(Cl)Cl>[CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2]
Reactant: COCC1c2c([nH]c3ccc(OCc4ccccc4)cc23)CNC1C(=O)OC(C)C
Agent: CC(C)(C)OCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 32 %

Procedure:
A solution is prepared from 3.3 g (8.5 mmol) of 6-benzyloxy-4-methoxymethyl-l,2,3,4-tetrahydro-β-carboline-3-carboxylic acid isopropyl ester in 150 ml of methylene chloride, combined under argon with 3.9 ml of triethylamine, and cooled to -15° C. At this temperature, a solution of 3.2 ml (25.6 mmol) of tert-butyl hypochlorite in 50 ml of methylene chloride is added dropwise without delay to this solution. After the adding step is completed, the mixture is stirred for another 10 minutes, combined with 2.6 ml of triethylamine, and agitated for 2 hours at room temperature. Subsequently, the mixture is concentrated to one-half thereof and extracted once by shaking with dilute ammonia solution. The organic phase is dried, filtered, and concentrated. The residue is chromatographed over silica gel with methylene chloride:acetone =4:1 as the eluent. Recrystallization from ethyl acetate gives 1.1 g (35% yield) of 6-benzyloxy-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester, mp 150°-151° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.[Br:12]NC(=O)CCC(N)=O>N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][Br:12])=[N:7][C:6]=2[CH:11]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: Cc1nc2cc(Br)ccc2s1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: BrCc1nc2cc(Br)ccc2s1
Temperature: 75 °C
Yield: 63.1 %

Procedure:
To a solution of 5-Bromo-2-methyl-benzothiazole (1.0 g, 4.385 mmol) in 0014 (15 mL) is added N-bromosuccinamide (1.1 g, 6.140 mmol) and azobisisobutyronitrile (0.029 g, 0.175 mmol) at room temperature reaction. The reaction mixture is heated to 75° C. for 16 hours. Reaction mixture is cooled to room temperature, filtered and the solvent evaporated in vacuo to give the crude material, which is then purified by flash chromatography using 3.5% ethyl acetate in hexane as an eluent to afford the title compound (0.85 g). 1H NMR (400 MHz, DMSO-d6) δ: 5.12 (s, 2H), 7.68-7.71 (dd, J1=1.92 Hz, J2=8.76 Hz, 1H), 7.95 (d, J=8.6 Hz, 1H), 8.43 (d, J=1.92 Hz, 1H). LC-MS (m/z): [M+H]=308.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N:11]3[CH2:16][CH2:15][CH:14]([CH:17](O)[CH3:18])[CH2:13][CH2:12]3)=[N:9][N:10]=2)[CH:7]=1.CCN(CC)CC.[CH:27]([Si:30]([O:37]S(C(F)(F)F)(=O)=O)([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])([CH3:29])[CH3:28]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N:11]3[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][O:37][Si:30]([CH:31]([CH3:33])[CH3:32])([CH:34]([CH3:36])[CH3:35])[CH:27]([CH3:28])[CH3:29])[CH2:13][CH2:12]3)=[N:9][N:10]=2)[CH:7]=1
Reactant: CC(O)C1CCN(c2nnc3ccc(F)cn23)CC1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[Si](OCCC1CCN(c2nnc3ccc(F)cn23)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.4 %

Procedure:
To a solution of Intermediate 66a (319 mg, 1.21 mmol) and Et3N (252 μL, 1.82 mmol) in DCM (10 mL) was added triisopropylsilyltrifluoromethane sulfonate (319 μL, 1.45 mmol) and the mixture stirred at RT for 1.5 h. The mixture was washed with sat. aq. NaHCO3 solution, dried and concentrated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, to give the title compound as an orange solid (465 mg, 92%). LCMS (Method 3): Rt 5.35 min, m/z 421 [MH+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)[CH3:2].[CH3:20][C:21]1[O:25][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:23][C:22]=1[CH2:32][CH2:33]OS(C)(=O)=O.[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[CH2:33][CH2:32][C:22]1[N:23]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:25][C:21]=1[CH3:20])[CH3:2]
Reactant: CCOC(=O)C(Cc1cccc2[nH]ccc12)OCC
Reactant: Cc1oc(-c2ccccc2)nc1CCOS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cccc2c1ccn2CCc1nc(-c2ccccc2)oc1C)OCC

Procedure:
In analogy to the procedures described in examples 1 a] and 1 b], rac-2-ethoxy-3-(1H-indol-4-yl)-propionic acid ethyl ester was reacted with methanesulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester in N,N-dimethylformamide in the presence of sodium hydride to yield rac-2-ethoxy-3-{1-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl]-1H-indol-4-yl}-propionic acid ethyl ester, which was subsequently saponified to yield rac-2-ethoxy-3-{1-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl]-1H-indol-4-yl}-propionic acid as light yellow solid.
Reaction SMILES: [CH:1]1([C:4](N)=O)[CH2:3][CH2:2]1.F[B-](F)(F)F.C([O+](CC)CC)C.[NH2:19][C:20]1[C:21]([NH:29][C@H:30]2[CH2:35][CH2:34][C@H:33]([CH2:36][C:37]#[N:38])[CH2:32][CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>O1CCCC1.C(O)C>[CH:1]1([C:4]2[N:29]([C@H:30]3[CH2:31][CH2:32][C@H:33]([CH2:36][C:37]#[N:38])[CH2:34][CH2:35]3)[C:21]3=[C:22]4[S:28][CH:27]=[CH:26][C:23]4=[N:24][CH:25]=[C:20]3[N:19]=2)[CH2:3][CH2:2]1
Reactant: N#CC[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)CC1
Reactant: NC(=O)C1CC1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Product: N#CC[C@H]1CC[C@H](n2c(C3CC3)nc3cnc4ccsc4c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of cyclopropanecarboxamide (65.0 mg, 0.764 mmol) and triethyloxonium tetrafluoroborate (145 mg, 0.763 mmol) in tetrahydrofuran (0.4 mL) was stirred at room temperature for 1 h and then concentrated. A mixture of {trans-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}acetonitrile (22 mg, 0.077 mmol), and the above made reagent in ethanol (0.70 mL) was heated at reflux for 2 h. The mixture was purified on prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (2.5 mg, 9.7%). LCMS calculated for C19H21N4S (M+H)+: m/z=337.1. Found: 337.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:14]C(OC)=O)[C:9]1=[O:19])([CH3:4])([CH3:3])[CH3:2].[C:21]1(=[O:27])[O:26][C:24](=[O:25])[CH2:23][CH2:22]1>CN(C)C=O>[C:1]([O:5][C:6]([CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:24](=[O:25])[CH2:23][CH2:22][C:21]([OH:26])=[O:27])[C@:10]([CH3:14])([C:6]([O:5][CH3:1])=[O:20])[C:9]1=[O:19])=[O:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CCC(=O)O1
Reactant: COC(=O)C[C@@H]1NCCN(CC(=O)OC(C)(C)C)C1=O
Solvent: CN(C)C=O
Product: COC(=O)[C@]1(C)C(=O)N(CC(=O)OC(C)(C)C)CCN1C(=O)CCC(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 192.7 %

Procedure:
A mixture of (S)-(3-methoxycarbonylmethyl-2-oxo-piperazin-1-yl)acetic acid tert-butyl ester (1.0 g) and succinic anhydride (0.7 g) in dimethylformamide (15 ml) was stirred for 5 hours at room temperature. The reaction mixture was concentrated under reduced pressure. The concentrate was dissolved in water (10 ml) and purified by means of CHP-20 column chromatography (H2O→30% acetonitrile aqueous solution) to give the titled compound (1.3 g) as a colorless oily product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:18]=1[NH2:19]>>[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:18]=1[NH:19][C:9](=[O:11])[C:8]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[C:12]([NH2:14])=[O:13]
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: COc1ccc(OC)c(N)c1
Product: COc1ccc(OC)c(NC(=O)c2cc(C(N)=O)ccc2OC)c1

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2,5-dimethoxyaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:10]Br>CC(O)=O>[NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][C:5]([Br:10])=[CH:4][N:3]=1
Reactant: Nc1ncccc1CO
Reactant: BrBr
Solvent: CC(=O)O
Product: Nc1ncc(Br)cc1CO
Reaction time: 1 h
Yield: 75.1 %

Procedure:
To a stirred solution of 2-amino-3-(hydroxymethyl)pyridine (15.0 g, 121 mmole) in HOAc (300 mL) at RT was added bromine (6.2 mL, 121 mmole) dropwise over 1 hr. A suspension formed after approximately 15 min. After the addition, the reaction was stirred for an additional 1 hr, then was concentrated under vacuum. The residue was taken up in 1.0 M Na2CO3 (500 mL), and the solution was extracted with ethyl acetate (2×250 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to dryness. The resulting residue was triturated with a small volume of petroleum ether, filtered and dried under vacuum to give the title compound (18.45 g, 75%) as a beige solid: LCMS (ES) m/e 203.2 (M+H)+; 1H NMR (400 MHz, DMSO-d$) δ 7.89 (d, J=2.3 Hz, 1H), 7.52 (s, 1H), 5.92 (br s, 2H), 5.29 (br s, 1H), 4.30 (s, 2H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Br:4][C:5]1[C:13]2[S:12][C:11]([CH2:14]Br)=[CH:10][C:9]=2[C:8]([F:16])=[C:7]([F:17])[CH:6]=1>C1COCC1.C(#N)C>[Br:4][C:5]1[C:13]2[S:12][C:11]([CH2:14][N:2]([CH3:3])[CH3:1])=[CH:10][C:9]=2[C:8]([F:16])=[C:7]([F:17])[CH:6]=1
Reactant: CNC
Reactant: Fc1cc(Br)c2sc(CBr)cc2c1F
Solvent: C1CCOC1
Solvent: CC#N
Product: CN(C)Cc1cc2c(F)c(F)cc(Br)c2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetonitrile (1 mL) was added to a solution (0.5 mL) of 2.0 M dimethylamine in THF, and a solution (2 mL) of the compound (121 mg, 0.354 mmol) of Step 1 of Example 65 in acetonitrile was added dropwise under ice-cooling, and stirred at room temperature overnight. The solvent was distilled away under reduced pressure. The resulting residue was diluted with ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution, and then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure to thus obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([O:9][CH:10]2[CH2:14][CH2:13][N:12]([C:15](=[O:18])[CH2:16][CH3:17])[CH2:11]2)[N:3]=1.[CH:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])[CH3:20]>N1C=CC=CC=1.ClCCl.[OH-].[Na+]>[CH:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:8][C:7]2[C:2]([CH3:1])=[N:3][C:4]([O:9][CH:10]3[CH2:14][CH2:13][N:12]([C:15](=[O:18])[CH2:16][CH3:17])[CH2:11]3)=[CH:5][CH:6]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])[CH3:20]
Reactant: CCC(=O)N1CCC(Oc2ccc(N)c(C)n2)C1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)N1CCC(Oc2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)c(C)n2)C1

Procedure:
2-Methyl-6-[(1-propionylpyrrolidin-3-yl)oxy]pyridin-3-amine (340 mg) was dissolved in pyridine (3.3 mL) and 4-isopropylbenzenesulfonyl chloride (358 mg) was slowly added under stirring. After 19 h stirring at room temperature, the reaction mixture was diluted with dichloromethane and 2 M aqueous NaOH was added. After stirring for 1 h at room temperature the phases were separated. The organic phase was dried (sodium sulfate), concentrated and the crude product purified by flash chromatography (silica, dichloromethane, 0.5 to 5% methanol gradient). Yield: 460 mg (78%, pale yellow oil).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH:10]1([C:13](Cl)=[O:14])[CH2:12][CH2:11]1.[NH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([N:26]2[CH2:35][CH2:34][C:33]3[N:32]=[C:31]([CH3:36])[N:30]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:29]=3[C:28]3[CH:44]=[CH:45][CH:46]=[CH:47][C:27]2=3)=[O:25])=[CH:20][C:19]=1[CH3:48]>ClCCl>[CH2:37]([N:30]1[C:29]2[C:28]3[CH:44]=[CH:45][CH:46]=[CH:47][C:27]=3[N:26]([C:24]([C:21]3[CH:22]=[CH:23][C:18]([CH2:17][NH:16][C:13]([CH:10]4[CH2:12][CH2:11]4)=[O:14])=[C:19]([CH3:48])[CH:20]=3)=[O:25])[CH2:35][CH2:34][C:33]=2[N:32]=[C:31]1[CH3:36])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1cc(C(=O)N2CCc3nc(C)n(Cc4ccccc4)c3-c3ccccc32)ccc1CN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCc3nc(C)n(Cc4ccccc4)c3-c3ccccc32)ccc1CNC(=O)C1CC1
Reaction time: 20 h
Yield: 90 %

Procedure:
DIEA (0.176 ml, 1.02 mmol) and cyclopropanecarbonyl chloride (0.033 ml, 0.36 mmol) were added to a solution of (4-aminomethyl-3-methyl-phenyl)-(1-benzyl-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone from Example E121.2 (150 mg, 0.34 mmol) in dichloro-methane (5 ml) at room temperature. The mixture was stirred for 20 h, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give the title compound (155 mg, 90%).
Reaction SMILES: [S:1](Cl)([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[CH2:18]([NH:22][S:1]([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2])[CH2:19][CH2:20][CH3:21]
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: CCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCCNS(=O)(=O)c1cccc2c(N(C)C)cccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
One equivalent of dansyl chloride (7) was added to a solution containing 2 equivalents of both butylamine and potassium carbonate in 1:1 acetonitrile:water. Solution was stirred at room temperature for 1.5 hrs. Acetonitrile was then removed and water residue extracted with ethyl acetate. The organic solution washed with 5% sodium bicarbonate, 2M citric acid and brine. Solution was dried over magnesium sulfate, filtered and solvent removed by flash evaporation. Crude was dissolved in minimal amount of ethyl acetate and hexane was added until cloudiness. Solution was stored in the refrigerator for 2 hrs. The precipitate was collected by suction filtration, washed with hexane and dried on the pump. ESI-MS and 1H-NMR were consistent with structure 8, which is (n-butyl dansylamide; BDA): 1H-NMR (CDCl3, =ppm): 8.55 (1H, d); 8.30 (2H, dd); 7.55 (2H, m); 7.20 (1H, d); 4.80 (1H, t); 2.90 (8H, m); 1.35 (2H, m). 1.20 (2H, m); 0.70 (3H, t). ESI-MS: Calc. m/z=306.4. Found m/z+H+=307.4.
Reaction SMILES: [CH:1]1[C:13]2[C:12]3[CH2:11][CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][C:7]=3[CH:6]=[N:5][C:4]=2[NH:3][N:2]=1.[Br:21]N1C(=O)CCC1=O>ClCCl>[Br:21][C:1]1[C:13]2[C:12]3[CH2:11][CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][C:7]=3[CH:6]=[N:5][C:4]=2[NH:3][N:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCc2c(cnc3[nH]ncc23)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2c(cnc3[nH]nc(Br)c23)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxylate (0.301 g, 1.09 mmol) in dichloromethane (10 mL) was added N-bromosuccinimide (0.293 g, 1.64 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding aqueous Na2CO3. The organic layer was separated, washed with brine (10 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to give a residue. The crude product was purified by flash column chromatography (SiO2, 30% EtOAc in hexanes) to give the desired product. tert-butyl 1-bromo-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxylate (0.258 g, 67%) as a foamy white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.94 (s, 1H), 8.40 (s, 1H), 4.63 (s, 2H), 3.67 (m, 2H), 3.28 (m, 2H), 1.44 (s, 9H); LCMS [M+H]: 353.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[C:19]([O:23][C:24]([N:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([CH2:36][O:37][CH3:38])[CH:32]=2)[CH:27]1[C:39](O)=[O:40])=[O:25])([CH3:22])([CH3:21])[CH3:20].[F:42][C:43]1[CH:44]=[C:45]([NH2:54])[CH:46]=[C:47]2[C:51]=1[C:50]([CH3:53])([CH3:52])[CH2:49][CH2:48]2.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[F:42][C:43]1[CH:44]=[C:45]([NH:54][C:39]([CH:27]2[C:28]3[C:33](=[CH:32][C:31]([CH2:36][O:37][CH3:38])=[CH:30][CH:29]=3)[CH2:34][CH2:35][N:26]2[C:24]([O:23][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:25])=[O:40])[CH:46]=[C:47]2[C:51]=1[C:50]([CH3:52])([CH3:53])[CH2:49][CH2:48]2
Reactant: COCc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2C(=O)O
Reactant: CC1(C)CCc2cc(N)cc(F)c21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COCc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Temperature: 60 °C
Reaction time: 48 h
Yield: 71.1 %

Procedure:
T3P (8.24 mL, 14.00 mmol) was added to a mixture of 2-(tert-butoxycarbonyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (1.5 g, 4.67 mmol), 7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-amine (0.837 g, 4.67 mmol), DIEA (4.08 mL, 23.34 mmol), DMAP (0.570 g, 4.67 mmol) and ethyl acetate (5 mL) at 60° C., and the mixture was stirred at 60° C. for 2 days. To the reaction mixture was added ethyl acetate, and the mixture was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 32→40% ethyl acetate/hexane) to give tert-butyl 1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2 (1H)-carboxylate (1.600 g, 3.32 mmol, 71.0%) as a white solid.
Reaction SMILES: O[C:2]1[CH:7]=C[C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])/[C:13]/3=[CH:20]\[C:21]2[NH:22][CH:23]=[CH:24][CH:25]=2)=[CH:4][CH:3]=1.C(C1C=C2C(=CC=1)[NH:33]C(=O)/C/2=C\C1NC=CC=1)#C.BrC1C=CC=CN=1.C(N(CC)CC)C>[Cu]I.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.CN(C=O)C>[N:33]1[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=1[C:8]#[C:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[NH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C#Cc1ccc2c(c1)/C(=C/c1ccc[nH]1)C(=O)N2
Reactant: O=C1Nc2ccc(C#Cc3ccc(O)cc3)cc2/C1=C/c1ccc[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Brc1ccccn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1Nc2ccc(C#Cc3ccccn3)cc2/C1=C/c1ccc[nH]1

Procedure:
This compound was also prepared in a manner analogous to the preparation of (Z)-1,3-dihydro-5-(4-hydroxyphenyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one in Example 83 above. In this example, (Z)-1,3-dihydro-5-ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (40 mg, 0.17 mmol) (Example 82) was coupled with 2-bromopyridine (25 mg, 0.17 mmol) (Aldrich) using CuI (8 mg, 0.042 mmol) (Aldrich) and (Ph3P)2PdCl2 (14 mg, 0.020 mmol) (Aldrich) as catalyst in 1 mL DMF and 1 mL triethylamine at 70° C. for 14 hours to give (Z)-1,3-dihydro-5-(2-pyridinyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a red powder. (Yield 42 mg, 80%).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH2:28]([N:30]([CH2:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1)[CH2:31][CH3:32])[CH3:29]>>[CH2:28]([N:30]([CH2:33][C:34]1[CH:35]=[CH:36][C:37]([NH:38]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:39][CH:40]=1)[CH2:31][CH3:32])[CH3:29]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CCN(CC)Cc1ccc(N)cc1
Product: CCN(CC)Cc1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)OC)ccc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(diethylamino-methyl)-aniline Rf value: 0.4 (silica gel, methylene chloride/methanol=10:1) C28H29N3O3
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH3:11])([CH3:10])[CH2:5]1)(=[O:3])[CH3:2].[CH2:12](O)[CH:13]=[CH2:14].C([O-])(=O)C.[Na+]>>[C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][C:6]([CH3:11])([CH3:10])[CH2:5]1)(=[O:3])[CH2:2][CH2:14][CH:13]=[CH2:12]
Reactant: C=CCO
Reactant: CC(=O)C1CCCC(C)(C)C1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: C=CCCC(=O)C1CCCC(C)(C)C1

Procedure:
Into a 2 liter autoclave is placed 700 grams of the diethyl ketal of 1-acetyl-3,3-dimethyl cyclohexane prepared according to Example II; 360 grams of allyl alcohol; and 10 grams of sodium acetate. The autoclave is sealed and heated to 150° and maintained at that temperature for a period of five hours. At the end of the five hour period, the autoclave is opened and the contents are filtered, washed with water and distilled on a 12" Goodloe column yielding the following fractions: