Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][NH:4][C:5](=S)[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][C:17]#[N:18])[N:8]=1.[NH3:22]>CCO>[F:1][C:2]([F:21])([F:20])[CH2:3][N:4]=[C:5]([NH2:22])[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][C:17]#[N:18])[N:8]=1
Reactant: N
Reactant: N#CCCCSc1cccc(NC(=S)NCC(F)(F)F)n1
Solvent: CCO
Product: N#CCCCSc1cccc(NC(N)=NCC(F)(F)F)n1

Procedure:
A mixture of 4-[2-(3-[2,2,2-trifluoroethyl]thioureido)pyrid-6-ylthio]butyronitrile (29 g.), yellow mercuric oxide (29 g.) and a saturated solution of ammonia in EtOH (100 ml.) was stirred at room temperature for 24 hours and then filtered. The filtrate was evaporated to dryness and the residue triturated with petroleum ether (b.p. 60°-80°) and collected to give 4-[2-(2-[2,2,2-trifluoroethyl]guanidino)pyrid-6-ylthio]butyronitrile (24 g.), m.p. 89°-91°.
Reaction SMILES: [O:1]([CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O(CCN1CCOCC1)C1C=CC=CC=1.[Cl:32][S:33](O)(=[O:35])=[O:34]>ClCCl>[N:10]1([CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][C:5]([S:33]([Cl:32])(=[O:35])=[O:34])=[CH:4][CH:3]=2)[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1
Reactant: c1ccc(OCCN2CCOCC2)cc1
Reactant: O=S(=O)(O)Cl
Agent: Cl
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc(OCCN2CCOCC2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
[2-(Morpholin-4-yl)ethoxy]benzene-4-sulfonyl chloride was prepared using N-(2-phenoxyethyl) morpholine by similar reaction described above. For example, 7.2 g of N-(2-phenoxyethyl)morpholine HCl salt was resuspended in 20 ml of dichloromethane and 7 ml of chlorosulfonic acid was slowly introduced with cooling by ice-jacket. The reaction mixture was stirred at 0° C. for 2 hr, then, at room temperature overnight. Dichloromethane (350 ml) was added to the reaction mixture and excess chlorosulfonic acid was destroyed by adding icy water(about 100 g). Aqueous layer was adjusted to pH 8.5 by concentrated sodium carbonate solution with cooling by ice. Dichloromethane was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give 8.1 g of [2-(morpholin-4-yl)ethoxy]benzene-4-sulfonyl chloride. M.P. 48-50° C.
Reaction SMILES: [H-].[Na+].C(S)C.[F:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[CH2:10][N:11]1[CH:16]=[CH:15][C:14]([O:17]C)=[C:13]([C:19]#[N:20])[C:12]1=[O:21].Cl>CN(C=O)C>[F:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][CH:24]=1)[CH2:10][N:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([C:19]#[N:20])[C:12]1=[O:21]
Reactant: COc1ccn(Cc2cccc(F)c2)c(=O)c1C#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCS
Product: N#Cc1c(O)ccn(Cc2cccc(F)c2)c1=O
Temperature: 100 °C
Yield: 92 %

Procedure:
To a solution of sodium hydride (92 mg of a 60% dispersion in mineral oil, 2.3 mmol) in DMF (7 mL) was added ethanethiol (0.14 g, 2.2 mmol), followed by a solution of 1-(3-fluorobenzyl)-4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile (0.23 g, 0.89 mmol) in DMF (2 mL), and the reaction mixture was heated to 100° C. The reaction mixture was cooled to room temperature, acidified with 3 N HCl, and washed with EtOAc. The organic solution was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to give 1-(3-fluorobenzyl)-4-hydroxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrile as an off-white solid (0.20 g, 91%): 1H NMR (300 MHz, MeOD) δ 8.00 (s, 1H), 7.82 (d, J=8 Hz, 1H), 7.40-7.30 (m, 1H), 7.15-7.00 (m, 2H), 6.13 (d, J=8 Hz, 1H), 5.11 (s, 2H).
Reaction SMILES: [C:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13](B(O)O)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([O:3][C:4]([CH3:7])(C)C)=[O:2].N1C=CC=CC=1.[C:26]([C:30]1[CH:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[NH:32][N:31]=1)([CH3:29])([CH3:28])[CH3:27].B(O)O>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[C:26]([C:30]1[CH:34]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:32]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([C:1]([O:3][CH2:4][CH3:7])=[O:2])[CH:9]=[CH:10]3)[N:31]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(B(O)O)ccc21
Reactant: CCOC(=O)c1cc(C(C)(C)C)n[nH]1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: OBO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(C(C)(C)C)nn1-c1ccc2c(ccn2C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
Commercially available N-Boc-5-indoleboronic acid (0.30 g, 1.1 mmol) was dissolved in CH2Cl2 (20 mL) and pyridine (1 mL) with molecular sieves (activated 4 A) and stirred overnight at RT. Commercially available ethyl 3-t-butyl-1 H-pyrazole-5-carboxylate, Cu(OAc)2 and molecular sieves (4 A activated, powder) were added to the boronic acid solution and the whole stirred at RT open to the atmosphere for 2d. The reaction mixture was filtered through a pad of Celite®, concentrated and purified by column chromatography to yield ethyl 5-(3-t-butyl-5-(ethoxycarbonyl)-1H-pyrazol-1-yl)-1H-indole-1-carboxylate (0.18 g, 38% yield). LC-MS (EI) m/z: 412.3 (M+H+).
Reaction SMILES: I[C:2]1[N:3]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16].[CH2:29]([OH:33])[CH2:30][C:31]#[CH:32]>>[OH:33][CH2:29][CH2:30][C:31]#[C:32][C:2]1[N:3]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(I)n(Cc3cccc4ccccc34)cc21
Reactant: C#CCCO
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C#CCCO)n(Cc3cccc4ccccc34)cc21

Procedure:
The title compound was prepared from 5-iodo-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione and 3-butyn-1-ol in a manner analogous to the method of Example 13 above.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[NH2:11][CH2:12][CH2:13][S:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[CH:22][N:23]=2)[N:20]=1>O1CCCC1>[CH:1]([NH:11][CH2:12][CH2:13][S:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[CH:22][N:23]=2)[N:20]=1)=[O:3]
Reactant: O=CO
Reactant: NCCSc1ccc2nccn2n1
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: O=CNCCSc1ccc2nccn2n1
Reaction time: 1 h

Procedure:
On the other hand, 5.52 g of formic acid is added to 12.25 g of acetic anhydride at room temperature and the mixture is stirred at 45°-50° C. for 1 hour. After cooling, 60 ml of tetrahydrofuran and 5.83 g of the above-prepared crystals of 6-(2-aminoethylthio)imidazo[1,2-b]pyridazine are added and the mixture is stirred at room temperature for 1 hour. The solvent is distilled off under reduced pressure and the residue made basic with a saturated aqueous solution of sodium hydrogen carbonate. The precipitated crystals are collected by filtration to give 2.83 g of 6-(2-formylaminoethylthio)imidazo[1,2-b]pyridazine as colorless crystals melting at 148° to 151° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([I:9])[C:6]([CH:10]([O:12]COC)[CH3:11])=[CH:5][N:4]=1.C(Cl)(Cl)Cl>CO.C(=O)([O-])[O-].[Na+].[Na+]>[F:2][C:3]1[N:4]=[CH:5][C:6]([CH:10]([OH:12])[CH3:11])=[C:7]([I:9])[CH:8]=1
Reactant: COCOC(C)c1cnc(F)cc1I
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(O)c1cnc(F)cc1I
Reaction time: 8 h
Yield: 87.8 %

Procedure:
Add 1 N HCl (5 mL) to a solution of 2-fluoro-4-iodo-5-(1-methoxymethoxy-ethyl)-pyridine (1 g, 3.2 mmol) in methanol (10 mL). Stir the mixture overnight. Dilute the reaction mixture with 2 N sodium carbonate. Abstract the product into chloroform. Dry the organic phase over sodium sulfate. Concentrate the solution in vacuo to a give the crude. Purify the crude by column chromatography (10% methanol in dichloromethane) to afford the product as a white solid (0.75 g, 87%). MS (ES) m/z 268 [M+1]+.
Reaction SMILES: Br[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:23][O:24][C:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:23][O:24][C:25]1[CH:30]=[C:29]([C:2]2[C:3]([O:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=4)=[CH:11][CH:10]=3)=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:28]=[CH:27][N:26]=1
Reactant: Cc1ccc(Nc2ccc(Oc3ncccc3Br)cc2)nc1
Reactant: COc1cc(B(O)O)ccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2cccnc2Oc2ccc(Nc3ccc(C)cn3)cc2)ccn1
Temperature: 100 °C

Procedure:
To a glass microwave vial was added N-(4-(3-bromopyridin-2-yloxy)phenyl)-5-methylpyridin-2-amine (0.2017 g, 0.566 mmol), 2-methoxypyridin-4-ylboronic acid, trans-dichlorobis(triphenylphosphine) palladium (II) (0.032 g, 0.045 mmol), and sodium carbonate (0.300 g, 2.83 mmol) in DME (0.906 mL) and water (0.226 mL). The reaction mixture was stirred and heated in a Biotage Initiator microwave reactor at 100° C. for 30 min. The crude product was purified by chromatography to give the title compound. MS (ESI, pos. ion) m/z: 356 (M+1). IC50 (uM) 0.003548.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[C:11](=S)=[S:12].[OH-].[K+]>O.C(O)C>[SH:12][C:11]1[O:8][C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[N:9][N:10]=1
Reactant: S=C=S
Reactant: NNC(=O)c1cccnc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Sc1nnc(-c2cccnc2)o1

Procedure:
13.7 g (0.1 mol) of nicotinic acid hydrazide and 8 g (0.105 mol) of carbon disulfide are added dropwise to a solution of 56 g (0.1 mol) of potassium hydroxide in 20 g of water and 350 ml of 95% ethanol. The reaction mixture is refluxed for 3 hours, then the solvent is evaporated off under vacuum and the residue is dried under a high vacuum. The dry residue is stirred in 75 ml of water, filtered, and the filtrate is neutralised with 1N hydrochloric acid. The precipitated product is isolated by filtration, washed in succession with acetone and hexane and vacuum dried, affording 9.9 g (55% of theory) of the title compound with a melting point of 237° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:23])[N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][CH2:21][OH:22])[CH2:15][CH2:14]2)[CH3:11])=[CH:4][CH:3]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]([N:10]([CH2:12][C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][CH2:21][O:22][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:15][CH2:14]2)[CH3:11])=[O:23])=[CH:6][CH:7]=1
Reactant: CN(C[C@H]1CC[C@H](CCCO)CC1)C(=O)Oc1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Product: CN(C[C@H]1CC[C@H](CCCOS(C)(=O)=O)CC1)C(=O)Oc1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 3.4, trans-[4-(3-hydroxy-propyl)-cyclohexylmethyl]-methyl-carbamic acid 4-chloro-phenyl ester was treated with methanesulfonyl chloride to yield trans-methanesulfonic acid 3-(4-{[(4-chloro-phenoxycarbonyl)-methyl-amino]-methyl}-cyclohexyl)-propyl ester as colorless solid, MS: 418 (MH+, 1Cl).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21]([OH:23])=O)=[CH:15][CH:16]=2)[NH:11][N:10]=1.Cl.[CH:29]([O:32][NH2:33])([CH3:31])[CH3:30].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:29]([O:32][NH:33][C:21](=[O:23])[C:20]1[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=1[NH:18][C:14]1[CH:13]=[C:12]2[C:17]([C:9](/[CH:8]=[CH:7]/[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:10][NH:11]2)=[CH:16][CH:15]=1)([CH3:31])[CH3:30]
Reactant: CC(C)ON
Reactant: O=C(O)c1ccccc1Nc1ccc2c(C=Cc3ccccn3)n[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)ONC(=O)c1ccccc1Nc1ccc2c(/C=C/c3ccccn3)n[nH]c2c1
Reaction time: 8 h
Yield: 50.1 %

Procedure:
A solution of 2-[3-(2-Pyridin-2-yl-vinyl)-1H-indazol-6-ylamino]-benzoic acid (50.0 mg, 0.084 mmol), O-isopropyl-hydroxylamine hydrochloride (18.7 mg, 0.17 mmol), triethylamine(58 μl, 0.42 mmol), dissolved in DMF (0.8 mL), was treated with HATU (48 mg, 0.13 mmol). The mixture was stirred overnight, then purified by reverse phase HPLC yielding 17.4 mg (50%) of the title compound as a yellow solid. 1H NMR (DMSO-d6): δ 9.23 (1H, s), 8.69 (H, d, J=2.1), 8.03 (4H, m), 7.50 (5H, m), 7.23 (1H, s), 7.04 (1H, d, J=6.7 Hz), 6.92 (1H, m), 5.98 (1H, m), 4.13 (1H, m), 1.29 (6H, d, J=8.1). ESIMS (M+H+): 414.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][S:8](=[O:22])(=[O:21])[C:9]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:10]=2[C:11]=1[OH:12])=[O:5])[CH3:2].[CH3:23]I>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:23])[S:8](=[O:21])(=[O:22])[C:9]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:10]=2[C:11]=1[OH:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1
Reactant: CI
Product: CCOC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Yield: 82 %

Procedure:
4-Hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid ethyl ester-1,1-dioxide was prepared analogous to Example 1c from 4-hydroxy-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid ethyl ester-1,1-dioxide and methyl iodide. Yield: 82% of theory; m.p. 163°-165° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[O:11][CH2:10][CH:9]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:8][C:5]2=[N:6][CH:7]=1.[F:17][C:18]([F:31])([F:30])[O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl.N1C=CC=CC=1>[F:31][C:18]([F:17])([F:30])[O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:1][C:2]2[CH:3]=[C:4]3[O:11][CH2:10][CH:9]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[CH2:8][C:5]3=[N:6][CH:7]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: CCC(=O)NC1COc2cc(N)cnc2C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)NC1COc2cc(NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)cnc2C1
Temperature: 25 °C
Yield: 46.9 %

Procedure:
A portion of the raw N-(7-amino-3,4-dihydro-2H-pyrano[3,2-b]pyridin-3-yl)propionamide (100 mg, 0.45 mmol) was dissolved in CH2Cl2/pyridine 9/1 (20 ml) and 4-(trifluoromethoxy)benzenesulfonyl chloride (100 μl, 0.58 mmol) was added dropwise. After stirring at room temperature over night, the reaction mixture was concentrated and the purification of the residue by chromatography on silica gel (CH2Cl2:CH3OH, 97:3) gave the title compound (94 mg, 47% for steps 31.4 and 31.5) as a gum.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(OC(=O)C)(=O)C.S(=O)(=O)(O)O.[C:17]([CH2:19][N:20]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[O:23][CH2:22][C:21]1=[O:30])#[N:18].[OH-].[Na+]>O>[C:17]([CH2:19][N:20]1[C:25]2[CH:26]=[C:27]([N+:1]([O-:4])=[O:2])[CH:28]=[CH:29][C:24]=2[O:23][CH2:22][C:21]1=[O:30])#[N:18]
Reactant: N#CCN1C(=O)COc2ccccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: N#CCN1C(=O)COc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Fuming (α 1.52) nitric acid (1.3 ml) is added dropwise to 0° C. to acetic anhydride (11.3 g), and thereafter a catalytic amount of concentrated sulfuric acid is added. To the solution is added portionwise at 0° C. 4-cyanomethyl-2H-1,4-benzoxazin-3(4H)-one (1.88 g). The mixture is stirred at 0° C. for 20 minutes, treated dropwise with a cold solution which is made by dissolving sodium hydroxide (10 g) in water (87.5 ml) and cooled to 0° C., stirred at 0° C. for 30 minutes to finish the reaction, and extracted with methyl isobutyl kotone. The extract is washed with water, dried, and evaporated. The resultant solid is recrystallized from ethanol to obtain an end product 4-cyanomethyl-6-nitro-2H-1,4-benzoxazin-3(4H)-one (1.3 g). mp. 173° C.
Reaction SMILES: [NH2:1][C:2](=[O:15])[CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.F[B-](F)(F)F.[CH3:21][O+](C)C.Cl>C(Cl)Cl>[CH2:7]([O:6][C:5]([NH:4][CH2:3][C:2](=[NH:1])[O:15][CH3:21])=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[O+](C)C
Reactant: NC(=O)CNC(=O)OCc1ccccc1
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC(=N)CNC(=O)OCc1ccccc1
Reaction time: 24 h

Procedure:
To a solution of benzyl (2-amino-2-oxoethyl)carbamate (8.5 g, 40.8 mmol) in CH2Cl2 (204 mL) was added trimethyloxonium tetrafluoroborate (6.0 g, 40.8 mmol) in one portion. The resulting mixture was stirred for 24 h, then acidified to pH˜3 with 1N ethereal HCl. The resulting mixture was concentrated under reduced pressure to yield methyl 2-(((benzyloxy)carbonyl)amino)acetimidate. A solution of methyl 2-(((benzyloxy)carbonyl)amino)acetimidate (9.3 g, 36 mmol), 4-(benzyloxy)benzothiohydrazide (8.0 g, 24 mmol) and diisopropylethylamine (4.2 mL, 24 mmol) in methanol (480 mL) was refluxed for 12 h. The resulting mixture was cooled to room temperature, at which point benzyl ((5-(4-(benzyloxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)carbamate precipitated and was collected (MS m/z=432 MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13][CH2:12]1)[C:5](O)=[O:6].S(Cl)([Cl:21])=O>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13][CH2:12]1)[C:5]([Cl:21])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(C(=O)O)ccc1N1CCCN(C)CC1
Product: Cc1cc(C(=O)Cl)ccc1N1CCCN(C)CC1

Procedure:
Prepared analogously to Example 29a from 3-methyl-4-(4-N-methyl-[1,4]diazepan-1-yl)-benzoic acid and thionyl chloride.
Reaction SMILES: Cl[CH:2]([C:4]1[N:13]([CH3:14])[C:12]2[C:11](=[O:15])[N:9]([CH3:10])[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[N:5]=1)[CH3:3].[C:18]([O-:26])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1.[K+]>CN(C)C=O>[C:18]([O:26][CH:2]([C:4]1[N:13]([CH3:14])[C:12]2[C:11](=[O:15])[N:9]([CH3:10])[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[N:5]=1)[CH3:3])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][CH:20]=1
Reactant: CC(Cl)c1nc2c(c(=O)n(C)c(=O)n2C)n1C
Reactant: O=C([O-])c1cccnc1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(OC(=O)c1cccnc1)c1nc2c(c(=O)n(C)c(=O)n2C)n1C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
2.57 g of 8-α-chloroethylcaffeine are dissolved in 25 ml of anhydrous dimethylformamide, to which 2.98 g of dry potassium nicotinate are added. The mixture is heated under shaking at 100° C for 1 hour, then filtered off and the filtrate evaporated under reduced pressure. The residue, after washing with water, gives 3.1 g of slightly crude product which is purified by crystallization from 95% ethanol : m.p. (EtOH) 160° C. The monohydrochloride melts at 200°-210° C.
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C:14]2[N:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:16]=[C:17]3[C:22]=2[CH:21]=[CH:20][CH:19]=[CH:18]3)=[O:12])=[C:6]([CH3:35])[CH:5]=1.[OH-].[Li+]>C1COCC1.CO>[CH:29]1([N:13]([C:14]2[N:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:16]=[C:17]3[C:22]=2[CH:21]=[CH:20][CH:19]=[CH:18]3)[C:11](=[O:12])[NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:36])=[O:2])=[CH:5][C:6]=2[CH3:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: COC(=O)c1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccccc2)C2CCCCC2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)ccc1NC(=O)N(c1c2ccccc2nn1-c1ccccc1)C1CCCCC1

Procedure:
In analogy to the procedure described in example 2.2, 4-[3-cyclohexyl-3-(2-phenyl-2H-indazol-3-yl)-ureido]-3-methyl-benzoic acid methyl ester was treated with 1 N aqueous lithium hydroxide solution in THF/MeOH 1/1 for 14 h at ambient temperature to give the title compound as off-white solid. MS: m/e=469.4 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([CH2:11][CH:12]=[CH:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH2:6][CH2:7][CH2:8][C:9]#[N:10])=[O:4].N>CO.[Rh]>[NH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([CH2:11][CH2:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)C(CC=Cc1cccnc1)CCCC#N
Agent: [Rh]
Agent: N
Solvent: CO
Product: COC(=O)C(CCCCN)CCCc1cccnc1
Reaction time: 6 h

Procedure:
A mixture of 8.7 g of 5-methoxycarbonyl-8-(3-pyridyl)-oct-7-enenitrile and 4.35 g of 5% rhodium on alumina in 87 ml of methanol saturated with ammonia (7.4N) is hydrogenated at room temperature for about 6 h. Additional catalyst is added if required. The reaction mixture is then worked up to yield methyl 6-amino-2-[3-(3-pyridyl)propyl]-hexanoate.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([CH:19]=[O:20])=[N:10]2.CO>C1COCC1>[OH:20][CH2:19][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[C:14]([O:15][CH3:16])[C:5]=2[O:4][CH3:3])[N:10]=1
Reactant: COc1cc2nc(C=O)ccc2c(OC)c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc2nc(CO)ccc2c(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (418 mg) and 5,6,7-trimethoxyquinoline-2-carboaldehyde (2.14 g) were successively added to a mixed solvent of methanol (30 mL) and THF (30 mL) under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was then extracted with ethyl acetate. The resultant organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After concentrating the organic layer under reduced pressure, the residue was purified by column chromatography on silica gel (chloroform:methanol=30:1) to obtain the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:11](=[O:29])[NH:12][C:13](=[O:28])[C:14]=2[C:15]2[C:23]3[C:18](=[CH:19][C:20]([N+:24]([O-:26])=[O:25])=[CH:21][CH:22]=3)[N:17]([CH3:27])[CH:16]=2)=[CH:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:40](Cl)(=[O:42])[CH3:41]>C1COCC1>[C:40]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:11](=[O:29])[NH:12][C:13](=[O:28])[C:14]=2[C:15]2[C:23]3[C:18](=[CH:19][C:20]([N+:24]([O-:26])=[O:25])=[CH:21][CH:22]=3)[N:17]([CH3:27])[CH:16]=2)=[CH:2]1)(=[O:42])[CH3:41]
Reactant: CC(=O)Cl
Reactant: Cn1cc(C2=C(c3c[nH]c4ccccc34)C(=O)NC2=O)c2ccc([N+](=O)[O-])cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)n1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)NC2=O)c2ccccc21
Yield: 65 %

Procedure:
A solution of 3-(l H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-pyrrole-2,5-dione (51 mg, 0.13 mmol), prepared as described in U.S. Ser. No. 09/268,887, in THF (20 ml) and cooled to −70° C. To this solution was added lithium bis(trimethylsilyl)amide (0.5 mmol, 0.5 ml, 3.8 eq, 1.0 M in THF, followed by excess acetyl chloride (0.1 ml). The resulting solution was stirred until the temperature reached −45° C. The reaction was evaporated and purified by silica gel chromatography to give 33 mg of 3-(1-acetyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-pyrrole-2,5-dione. (Yield 65 %).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[CH3:12][Mg]Br>C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([CH3:12])([OH:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC(=O)Cc1ccc(Br)cc1
Reactant: C[Mg]Br
Solvent: CCOCC
Product: CC(C)(O)Cc1ccc(Br)cc1
Temperature: 25 °C
Yield: 84 %

Procedure:
A solution of 4-bromophenylacteone (6.85 g, 32 mmol) in diethyl-ether (100 ml) was cooled to 0° C. and treated with methylmagnesium bromide (23.5 ml of a 3M solution in diethyl-ether, 70 mmol). The reaction mixture was allowed to warm gradually to room temperature. After 2 hours the reaction was quenched by addition of saturated aqueous ammonium chloride (200 ml). The organic phase was separated and washed with saturated sodium chloride (100 ml), dried (sodium sulfate) and reduced in vacuo. Purification by flash column chromatography on silica gel eluting with pentane:dichloromethane (60:40 changing to 0:100, by volume) gave the title compound as a colourless oil (6.23 g, 84%).