Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]([O-:12])(O)=O.[Na+].O.[C:15]([C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1C(Cl)=O)([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:9](=[O:12])[C:25]1[CH:26]=[CH:27][C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:20][CH:24]=1
Reactant: CC(C)(C)c1ccccc1C(=O)Cl
Reactant: Nc1ccccc1Br
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2Br)cc1
Temperature: 35 °C

Procedure:
2-Bromoaniline (98%, Oakwood 005347, 214 g, 1.25 mol), NaHCO3 (270 g, 3.2 mol), THF (500 mL) and water (500 mL) were placed into a 5-L round-bottom flask equipped with an overhead stirrer, thermometer and a 500-mL addition funnel. Solution of t-butyl benzoyl chloride (>98%, Fluka 19660, 250 mL, 1.37 mol) in 250 mL of THF was placed into the addition funnel and was added slowly (in 25 min) to the stirred mixture of reagents in the flask. (No external heating or cooling was administered, slight exotherm was observed raising the temperature inside the flask to 35° C.).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[F:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:18])=[C:13]([N:15]=[C:16]=[S:17])[CH:14]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([N:3]1[CH2:4][C:5](=[O:7])[N:15]([C:13]2[CH:14]=[C:9]([F:8])[CH:10]=[CH:11][C:12]=2[CH3:18])[C:16]1=[S:17])[CH3:2]
Reactant: CCNCC(=O)O
Reactant: Cc1ccc(F)cc1N=C=S
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN1CC(=O)N(c2cc(F)ccc2C)C1=S
Yield: 41.3 %

Procedure:
A mixture of the crude N-ethyl glycine (11.5 g), 5-fluoro-2-methylphenyl-isothiocyanate (10.42 g), triethyl amine (12.5 g) and chloroform (300 mL) was heated at reflux for 6 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (500 mL) and washed with water (500 mL). The organic phase was evaporated to dryness. The residue was dissolved in ethanol (50 mL), then diluted with diethyl ether (200 mL). The solution was saturated with hydrogen chloride. The mixture was filtered. The solid was discarded. The filtrate was evaporated to dryness. The residue was dissolved in diethyl ether (300 mL) and washed with water (200 mL). The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. Crystallization from ethanol afforded the title compound (6.5 g) as a pink solid, m.p. 98°-100° C. Anal. Calcd. for. C12H13F N2O S: C, 57.13; H, 5.19; N, 11.10. Found: C, 56.88; H, 5.17; N, 11.05. Mass spectrum (EI, M.+) m/z 252.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N@:11]1[CH2:13][CH:12]1[C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:18][CH2:17]1)=[O:15])(=[O:10])=[O:9].[I-].[Na+].[CH:34]([N:37]=[C:38]=[O:39])([CH3:36])[CH3:35]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:13][CH:12]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([C:28]([F:30])([F:29])[F:31])=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])[N:37]([CH:34]([CH3:36])[CH3:35])[C:38]1=[O:39])(=[O:9])=[O:10]
Reactant: O=C(C1C[N@@]1S(=O)(=O)c1ccccc1Cl)N1CCN(c2ncccc2C(F)(F)F)CC1
Reactant: CC(C)N=C=O
Agent: [I-]
Agent: [Na+]
Product: CC(C)N1C(=O)N(S(=O)(=O)c2ccccc2Cl)CC1C(=O)N1CCN(c2ncccc2C(F)(F)F)CC1

Procedure:
In analogy to example 2, [(S)-1-(2-chloro-benzenesulfonyl)-aziridin-2-yl]-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone (example 72, step 3) was reacted with sodium iodide and isopropylisocyanate to give the title compound as a colorless foam. MS: 560.2 ([M+H]+)
Reaction SMILES: [F:1][C:2]1[C:14]([N:15]=[C:16]=[O:17])=[CH:13][C:5]2[N:6]([CH2:10][C:11]#[CH:12])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.F[C:19]1[C:31](N=C=S)=[CH:30][C:22]2[N:23](CC#C)[C:24](=O)[S:25]C=2C=1.FC1C(N=C=O)=CC2[N:40](CC#C)C(=O)COC=2C=1>>[F:1][C:2]1[C:14]([N:15]2[C:24](=[S:25])[N:23]3[CH2:22][CH:30]=[CH:31][CH2:19][N:40]3[C:16]2=[O:17])=[CH:13][C:5]2[N:6]([CH2:10][C:11]#[CH:12])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1
Reactant: C#CCn1c(=O)sc2cc(F)c(N=C=O)cc21
Reactant: C#CCN1C(=O)COc2cc(F)c(N=C=O)cc21
Reactant: C#CCn1c(=O)sc2cc(F)c(N=C=S)cc21
Product: C#CCn1c(=O)sc2cc(F)c(-n3c(=O)n4n(c3=S)CC=CC4)cc21

Procedure:
In place of 6-fluoro-5-isocyanato-3-propargyl-2-benzothiazolone in the foregoing Example 1, use was made of 6-fluoro-5-isothiocyanato-3-propargyl-2-benzothiazolone and 7-fluoro-6-isocyanato-4-propargyl-4H-1,4-benzoxazin-3-one so as to obtain 5,8-dihydro-2-(6-fluoro-3-propargyl-2-benzothiazolon-5-yl)-1H-[1,2,4]triazolo-[1,2-a]pyridazine-1-thion-3(2H)-one and 5,8-dihydro-2-(7-fluoro-4-propargyl-4H-1,4-benzoxazin-3(4H)-on-6-yl)-1H-[1,2,4]triazolo-[1,2-a]pyridazine-1,3(2H)-dione, respectively.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[OH2:13]>>[CH2:11]([OH:12])[C@H:9]1[O:10][C@H:2]([O:1][C@H:7]2[C@H:5]([OH:6])[C@@H:3]([OH:4])[C@H:2]([OH:1])[O:13][C@@H:9]2[CH2:11][OH:12])[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@@H:7]1[OH:8]
Reactant: O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 90 °C

Procedure:
A liquefied starch solution having a DE (Dextrose Equivalent) of about 0.5 was prepared by adding to a suspension of 1 part by weight of potato starch in 10 parts by weight of water a commercial bacterial liquefying alpha-amylase (EC 3.2.1.1), heating the mixture to 90° C. to effect gelatinization, and further heating it quickly to 130° C. to suspend enzymatic reaction. To the solution was added 100 units/g starch of isoamylase (EC 3.2.1.68) prepared from a culture of Pseudomonas amyloderamosa ATCC 21262, and 50 units/g starch of "#1500", a beta-amylase (EC 3.2.1.2) derived from soybean, commercialized by Nagase & Company, Ltd., Osaka, Japan, and the resultant mixture was saccharified at pH 5.0 for 40 hours to obtain a high-purity maltose having a maltose content of 92.5% DS. The high-purity maltose was then purified by carbon decolorization and resin refining, and concentrated in vacuo to obtain a high-concentration syrup having a moisture content of 6.5 w/w %. The syrup was then placed in a kneader, and added with 1% DS crystalline alpha-maltose and 1% DS crystalline beta-maltose hydrate while keeping at 95° C. The resultant mixture was then kneaded for 3 minutes at this temperature, extruded in sheet shape, aged at 80° C. for 3 hours, further aged at 40° C. for 48 hours, and pulverized to obtain a maltose powder containing crystalline beta-maltose hydrate, moisture content of about 6.0 w/w %, in the yield of about 94% DS against the starting starch.
Reaction SMILES: [I:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([I:10])[C:5]([CH2:11][OH:12])=[C:4]([I:13])[C:3]=1[CH2:14][OH:15].C(N(CC)CC)C.N1C=CC=CC=1>CS(C)=O>[I:1][C:2]1[C:3]([CH:14]=[O:15])=[C:4]([I:13])[C:5]([CH:11]=[O:12])=[C:6]([I:10])[C:7]=1[CH:8]=[O:9]
Reactant: OCc1c(I)c(CO)c(I)c(CO)c1I
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: O=Cc1c(I)c(C=O)c(I)c(C=O)c1I
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1,3,5-Triiodo-2,4,6-trihydroxymethylbenzene (4.5 g, 8.2 mmol) was dissolved in DMSO (80 ml). Triethylamine (51.7 ml, 371 mmol) and pyridine.SO3 (11.8 g, 74.2 mmol) were added and the mixture was stirred for two hours. The two phases were separated and the lower phase was cooled to 0° C., poured into water (150 ml) and stirred for 30 min at 0° C. The white solid was collected by filtration, washed with water and dried. Yield: 3.0 g (67%).
Reaction SMILES: I[C:2]1[C:3]2[CH:17]=[CH:16][NH:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)[N:7]=1.[Br:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23](B(O)O)[CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:18][C:19]1[CH:24]=[C:23]([C:2]2[C:3]3[CH:17]=[CH:16][NH:15][C:4]=3[N:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=3)[N:7]=2)[CH:22]=[N:21][CH:20]=1
Reactant: OB(O)c1cncc(Br)c1
Reactant: Cc1cccc(-c2nc(I)c3cc[nH]c3n2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: Cc1cccc(-c2nc(-c3cncc(Br)c3)c3cc[nH]c3n2)n1
Temperature: 25 °C

Procedure:
To a solution of 4-iodo-2-(6-methyl-pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 3) (1 eq, 1.50 mmol, 530 mg) and 3-bromopyridine-5-boronic acid (ABCR GmbH & Co. KG, Karlsruhe, Germany) (1.1. eq, 1.65 mmol, 339 mg) in DME/EtOH (1:1, 6 ml) are added aqueous Na2CO3 solution (2 M, 3 eq, 4.50 mmol, 2.2 ml) and Pd(PPh3)4 (0.05 eq, 0.075 mmol, 89 mg). The resulting mixture is heated using microwave radiation at 120° C. for 20 min. After cooling down to r.t., the mixture is filtered and the resulting precipitate is washed with EtOH. The residue is suspended in DCM, filtered, and dried to give the title compound; [M+H]+=366/368; 1H-NMR (400 MHz, DMSO): δ 12.58 (s, 1H), 9.40 (m, 1H), 8.89 (m, 1H), H), 8.79 (m, 1H), 8.37 (t, 1H), 7.87-7.77 (m, 2H), 7.33 (t, 1H), 7.00 (m, 1H), 2.56 (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:8]=1)([O-])=O.[H][H]>[Pd].CO>[S:9]([N:7]1[CH:8]=[C:4]([NH2:1])[CH:5]=[N:6]1)([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)n2cc([N+](=O)[O-])cn2)cc1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2cc(N)cn2)cc1
Yield: 71.5 %

Procedure:
4-nitro-1-tosyl-1H-pyrazole (example 9-1c) (3 g, 11.2 mmol) and 10% palladium on carbon (800 mg) in MeOH (150 mL) were stirred under 2 atmospheres of hydrogen on the Parr hydrogenator for 3 hours. The mixture was filtered through celite, concentrated and purified by silica gel chromotography (80% ethyl acetate in hexanes) to afford 1-tosyl-1H-pyrazol-4-amine (1.9 g, 71%) as a pink solid. 1H NMR (CDCl3, 400 MHz, 2.40 (s, 3H), 3.01 (bs, 2H), 7.29 (d, 2H, J=8 Hz), 7.41 (d, 1H, J=1.2 Hz), 7.53 (d, 1H, J=1.2 Hz), 7.81 (d, 2H, J=8 Hz).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.Cl.O.[NH:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:12][C:11]([F:14])([F:13])[C:8]1[N:6]2[N:7]=[C:2]([N:17]3[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 90 °C
Yield: 82.8 %

Procedure:
6-Chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (10.0 g, 44.93 mmol), 4-piperidone monohydrate hydrochloride (8.48 g, 49.43 mmol) and DIPEA (16.3 mL, 98.85 mmol) in DMF (100 mL) were stirred and heated at 90° C. for 1 hour. The DMF was then evaporated in vacuo and the residue purified by flash silica chromatography, eluting with 2% MeOH in DCM. Pure fractions were concentrated to give a pale yellow precipitate. The precipitate was collected by filtration, washed with ether and air dried to afford 1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-one (10.61 g, 83%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14](=[O:31])[O:15][CH:16]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:32][CH3:33]>CCOC(C)=O>[I-:32].[CH2:1]([N+:8]1([CH3:33])[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]([O:15][CH:16]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[O:31])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H]1CCN(Cc2ccccc2)C1)OC(c1cccc(F)c1)c1cccc(F)c1
Reactant: CI
Solvent: CCOC(C)=O
Product: C[N+]1(Cc2ccccc2)CC[C@@H](NC(=O)OC(c2cccc(F)c2)c2cccc(F)c2)C1
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.2 %

Procedure:
To a solution of (R)-bis(3-fluorophenyl)methyl 1-benzylpyrrolidin-3-ylcarbamate (300 mg, 0.71 mmol) in EtOAc (9 ml), iodomethane (44.2 μl, 0.71 mmol) was added, and the reaction was stirred at room temperature overnight. The solvent was then removed under vacuum, and the residue was triturated with diethyl ether. The product was purified by flash chromatography (DCM/MeOH=99/1) and then by preparative HPLC to give (3R)-1-benzyl-3-((bis(3-fluorophenyl)methoxy)carbonylamino)-1-methylpyrrolidinium iodide (25 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]1(=O)[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1>C(O)C>[OH:14][C:11]1[CH:12]=[CH:13][C:8]([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)=[CH:9][CH:10]=1
Reactant: O=C1CCC(=O)CC1
Reactant: OC1CCNCC1
Solvent: CCO
Product: Oc1ccc(N2CCC(O)CC2)cc1
Yield: 56.5 %

Procedure:
202 mg of 4-hydroxypiperidine and 448 mg of 1,4-cyclohexanedione were heated under reflux in 10 ml of ethanol and reacted for 9 hours with introducing air with a pump. During the reaction, ethanol was added as needed. After the completion of the reaction, the resultant was separated by silica gel column chromatography (n-hexane:ethyl acetate=2:1) and 0.218 g of 1-(4-hydroxyphenyl)-4-hydroxypiperidine was obtained (yield 56.48%).
Reaction SMILES: Cl.O[C:3]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[CH:11]=[CH:10][C:4]=1C(=N)OCC.Cl.[NH2:23][CH2:24][C:25]([NH:31]Cl)([CH3:30])[C:26]([O:28][CH3:29])=[O:27].CCN(CC)CC.[CH3:40][OH:41]>>[OH:41][C:40]1[C:12]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:13][CH:3]=[CH:4][C:10]=1[C:11]1[NH:23][CH2:24][C:25]([CH3:30])([C:26]([O:28][CH3:29])=[O:27])[N:31]=1
Reactant: CCOC(=N)c1ccc(OCCOCCOC)cc1O
Reactant: CO
Reactant: COC(=O)C(C)(CN)NCl
Agent: Cl
Solvent: CCN(CC)CC
Product: COCCOCCOc1cccc(C2=NC(C)(C(=O)OC)CN2)c1O
Yield: 25 %

Procedure:
To a solution of ethyl 2-hydroxy-4-(2-(2-methoxyethoxy)ethoxy)benzimidate hydrochloride (0.35 g, crude, ˜1.0 mmol) in MeOH (10 mL) was added methyl 3-amino-2-(chloroamino)-2-methylpropanoate hydrochloride (0.24 g, crude, ˜1.0 mmol). Et3N (1 mL) was added dropwise at 0° C. The resulting solution was refluxed overnight. The solvent was evaporated under vacuum and the residue was purified by prep-HPLC to obtain the title compound as colorless oil (90 mg, 25%). LC-MS (ES, m/z): 353 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH:13][C@H:14]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]3)[N:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2)#[N:2].[NH:26]([C:28](OCC)=[O:29])[NH2:27]>CN1C(=O)CCC1.CCOC(C)=O>[O:29]=[C:28]1[NH:26][N:27]=[C:1]([C:3]2[CH:4]=[C:5]3[C:10](=[C:11]([NH:13][C@H:14]4[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]4)[N:12]=2)[N:9]=[CH:8][CH:7]=[CH:6]3)[NH:2]1
Reactant: CCOC(=O)NN
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C#N)cc3cccnc23)C1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3n[nH]c(=O)[nH]3)cc3cccnc23)C1
Temperature: 175 °C
Yield: 32.5 %

Procedure:
To (S)-tert-butyl 3-((6-cyano-1,7-naphthyridin-8-yl)amino)pyrrolidine-1-carboxylate (210 mg, 0.619 mmol) in NMP (1.5 mL) was added ethyl hydrazinecarboxylate (258 mg, 2.475 mmol). The reaction mixture was heated at 175° C. for 2 days and was then cooled, diluted with EtOAc, and washed with aqueous NH4Cl. The organic phase was dried and concentrated. The crude product was purified by preparative HPLC eluting with a gradient of 35-60% ACN in water (acid mode) to give the title compound (80 mg, 33%).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[C:14]2[CH2:18][C@H:19]([NH:21]C(=O)OC(C)(C)C)[CH3:20])(=[O:4])=[O:3].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:21][C@H:19]([CH3:20])[CH2:18][C:14]1[C:13]2[C:17](=[C:9]([O:8][CH2:7][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:29])[CH:10]=[CH:11][CH:12]=2)[NH:16][CH:15]=1
Reactant: C[C@H](Cc1c[nH]c2c(OCC(=O)NS(C)(=O)=O)cccc12)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](N)Cc1c[nH]c2c(OCC(=O)NS(C)(=O)=O)cccc12

Procedure:
A solution of tert-butyl (R)-{2-[7-(2-methanesulfonylamino-2-oxoethoxy)-1H-indol-3-yl]-1-methylethyl}carbamate (0.14 g, 0.33 mmol) and trifluoroacetic acid (1 mL) in methylene chloride (4 mL) is stirred at room temperature for 8 hours. The mixture is concentrated to give the desired (R)—N-{2-[3-(2-aminopropyl)-1H-indol-7-yloxy]acetyl}methane-sulfonamide.trifluoroacetate (0.13 g, yield: 90%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]([CH3:20])([CH3:19])[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:21]([O:23][CH3:24])=[O:22])[CH:15]=3)[NH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)C(C)C)(C)C.[C:34](Cl)(=[O:38])[CH:35]([CH3:37])[CH3:36].C(OCC)(=O)C>ClCCl>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([CH:9]2[C:18]([CH3:19])([CH3:20])[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:21]([O:23][CH3:24])=[O:22])[CH:15]=3)[NH:10]2)=[CH:3][C:2]=1[NH:1][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(Cl)c(N)c1)N2
Reactant: CC(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(Cl)c(NC(=O)C(C)C)c1)N2
Yield: 109.1 %

Procedure:
To a solution of methyl 2-(3-amino-4-chlorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (182 mg, 0.53 mmol) in dichloromethane (5 mL) was added N,N-diisopropyle thylamine (136 mg, 1.06 mmol) with ice cooling, followed by the addition of isobutyryl chloride (84 mg, 0.8 mmol) in dichloromethane (2 mL) via syringe. The resultant mixture was stirred at room temperature overnight. Thin layer chromatography (petroleum ether: ethyl acetate=10:1) showed the reaction was complete. The mixture was separated by Preparative Thin layer chromatography to afford 240 mg of methyl 2-(4-chloro-3-isobutyramidophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate, which was used in next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][CH:24]4[CH2:26][O:25]4)=[CH:17][CH:18]=3)[O:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:27]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(O)C>[CH:27]1([NH:33][CH2:26][CH:24]([OH:25])[CH2:23][O:22][C:16]2[CH:15]=[C:14]3[C:19]([C:20](=[O:21])[C:11]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)=[CH:12][O:13]3)=[CH:18][CH:17]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NC1CCCCC1
Reactant: COc1ccc(-c2coc3cc(OCC4CO4)ccc3c2=O)cc1OC
Solvent: CCO
Product: COc1ccc(-c2coc3cc(OCC(O)CNC4CCCCC4)ccc3c2=O)cc1OC
Yield: 52.9 %

Procedure:
A mixture of compound 4 (obtained from example 2) (0.35 g, 1 mmol), cyclohexylamine (0.50 g, 5 mmol), and ethanol (30 mL) was refluxed for 6 hrs (TLC monitoring). After removal of solvent in vacuo, the residue was treated with H2O (50 mL). The resulting precipitate was collected and purified by column chromatography (MeOH/CH2Cl2=1:25) to give the title compound 6c (0.24 g, 54% yield). M.p.: 70-71° C.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:17][CH2:16][C:15]2[C:14]3[CH:13]=[C:12]([CH3:18])[CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[CH2:6][CH2:5]1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([CH3:29])[CH2:28][O:27]2)=[CH:22][CH:21]=1.C(O)(=O)C(O)=O>CN(C=O)C.C1COCC1.O>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([OH:27])([CH3:28])[CH2:29][N:8]2[C:9]3[CH:10]=[CH:11][C:12]([CH3:18])=[CH:13][C:14]=3[C:15]3[CH2:16][CH2:17][N:4]([CH3:3])[CH2:5][CH2:6][C:7]2=3)=[CH:24][CH:25]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Reactant: CC1(c2ccc(F)cc2)CO1
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccc(F)cc2)CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
The title compound was prepared by following general procedure 5. To a stirred suspension of sodium hydride (67 mg, 0.28 mmol) in 5 mL of DMF, 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.2 g, 0.934 mmol) was added and stirred at RT for 5 min. 2-(4-Fluorophenyl)-2-methyloxirane (212 mg, 1.39 mmol) was added slowly dropwise and stirred at RT for 14 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, water was added, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, evaporated under reduced pressure and purified by column chromatography using 10% methanol-DCM. The freebase (30 mg, 0.082 mmol) was dissolved in THF (1.0 mL) and oxalic acid (10 mg, 0.082 mmol) in THF (1.0 mL) was added slowly, the mixture was stirred at RT for 20 min. and the formed solid was filtered, washed with ether and dried to afford the product as oxalate salt (15 mg, brown solid).
Reaction SMILES: I[CH2:2][CH:3]1[CH2:14][C:13]2[C:15]3[C:5](=[N:6][CH:7]=[N:8][C:9]=3[CH:10]=[C:11]([O:18][CH3:19])[C:12]=2[O:16][CH3:17])[N:4]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:17][O:16][C:12]1[C:11]([O:18][CH3:19])=[CH:10][C:9]2=[C:15]3[C:13]=1[CH:14]=[C:3]([CH3:2])[N:4]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:5]3=[N:6][CH:7]=[N:8]2
Reactant: COc1cc2ncnc3c2c(c1OC)CC(CI)N3c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc2ncnc3c2c(c1OC)C=C(C)N3c1ccccc1
Temperature: 120 °C

Procedure:
To a solution 5-iodomethyl-7,8-dimethoxy-4-phenyl-5,6-dihydro-4H-1,3,4-triaza-phenalene (0.1 g, 0.22 mmol) (from Example 15, Step F, supra) in toluene (20 mL) was added DBU (73 μL, 0.49 mmol) (Fluka). The reaction mixture was heated at 120° C. for 1 hour. The mixture was then diluted with chloroform (100 mL), and washed with H2O. The organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:1:0.05) as eluent to give the desired 7,8-dimethoxy-5-methyl-4-phenyl-4H-1,3,4-triaza-phenalene as a pale yellow solid. (Yield 50 mg, 71%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[O:30]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31]1>>[C:18]([N:13]1[C:12]([C:32]2[CH:33]=[CH:34][O:30][CH:31]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:19])([CH3:20])[CH3:21]
Reactant: OB(O)c1ccoc1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C(C)(C)C)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: CC(C)(C)n1nc2c(c1-c1ccoc1)CCNCC2
Yield: 50.3 %

Procedure:
The title compound (60 mg) was prepared according to Example 215 using 203 mg of 2-(tert-butyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 215, Step A) and 154 mg of 3-furanboronic acid. MS (ESI): exact mass calculated for C15H21N3O, 259.17; found, m/z 260.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.69-7.68 (m, 1H), 7.61 (br s, 1H), 6.50-6.49 (m, 1H), 3.38-3.36 (m, 2H), 3.27-3.25 (m, 2H), 3.13-3.11 (m, 2H), 2.63-2.61 (m, 2H), 1.50 (s, 9H).