Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[O:12][CH2:13][CH:14]1[CH2:16][CH2:15]1)[CH3:2].Cl[C:18]1[N:23]=[N:22][C:21]([C:24]([NH2:26])=[O:25])=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C.CN(C=O)C>O>[Cl:11][C:9]1[CH:8]=[CH:7][C:6]([O:12][CH2:13][CH:14]2[CH2:15][CH2:16]2)=[C:5]([CH:10]=1)[CH2:4][N:3]([C:18]1[N:23]=[N:22][C:21]([C:24]([NH2:26])=[O:25])=[CH:20][CH:19]=1)[CH2:1][CH3:2]
Reactant: NC(=O)c1ccc(Cl)nn1
Reactant: CCNCc1cc(Cl)ccc1OCC1CC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(Cc1cc(Cl)ccc1OCC1CC1)c1ccc(C(N)=O)nn1
Yield: 57.2 %

Procedure:
A mixture of N-ethyl-5-chloro-2-(cyclopropylmethoxy)benzylamine (reference example 20) (4.4 g, 18.4 mmol), 6-chloropyridazine-3-carboxamide (3.0 g 19 mmol), di-isopropylethylamine (5.0 ml, 29 mmol) and DMF (25 ml) was stirred at reflux for 16 hours. The mixture was cooled and diluted with water (50 ml), the gum was allowed to settle out and the supernatant liquor decanted. The gum was dissolved in dichloromethane and stirred while adding 2N hydrochloric acid (50 ml). A precipitate formed after 10 minutes. The solid was filtered off and washed with dichloromethane (10 ml) and ether (20 ml) to give a buff solid (3.8 g, 61%) m.p. 177-8° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH2:11][C:12](=O)[CH3:13])[N:4]=1.Cl.[CH2:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24]N)[CH3:17]>[Cl-].[Zn+2].[Cl-].C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]2[C:20]3[C:19](=[C:18]([CH2:16][CH3:17])[CH:23]=[CH:22][CH:21]=3)[NH:24][C:12]=2[CH3:13])[N:4]=1
Reactant: CCc1ccccc1NN
Reactant: COc1cc(OC)nc(CC(C)=O)n1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: CCc1cccc2c(-c3nc(OC)cc(OC)n3)c(C)[nH]c12
Temperature: 25 °C
Yield: 81.3 %

Procedure:
Into a reactor were fed 2.4 g (12.2 m moles) of 1-(4,6-dimethoxypyrimidine-2-yl)-2-propanone, 1.7 g (9.98 m moles) of 2-ethylphenylhydrazine hydrochloride, 1.4 g (10.2 m moles) of zinc chloride and 10 ml of toluene, followed by refluxing for 2 hours with heating. After the completion of the reaction, the reaction mixture was cooled to room temperature. Thereto were added water and ethyl acetate and phase separation was made. The ethyl acetate layer was concentrated. The concentrate was subjected to silica gel column chromatography separation (developing solvent: n-hexane/ethyl acetate) to obtain 2.38 g (8.01 m moles) of 3-(4,6-dimethoxypyrimidine-2-yl)-2-methyl-7-ethylindole. Yield: 80.3% Melting point: 90.3 to 94.8° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([C:7](=[O:9])[CH3:8])[CH2:2]1.C(N(CC)CC)C.[C:17](Cl)(=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(Cl)Cl>[C:7]([CH:3]1[O:4][CH2:5][CH2:6][N:1]([C:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:26])[CH2:2]1)(=[O:9])[CH3:8]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(=O)C1CNCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)C1CN(C(=O)OCc2ccccc2)CCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.3 %

Procedure:
To a solution of 1-(morpholin-2-yl)ethanone (3.9 g, 30.0 mmol) in DCM (60 mL) was added triethylamine (1.0 g, 10 mmol) to adjust pH 9. Then benzyl carbonochloridate (5.6 g, 33.0 mmol) and triethylamine (3.0 g, 30.0 mmol) were added and the mixture was stirred at room temperature for 16 hr. The reaction solution was added H2O (20 mL) and extracted by DCM (100 mL*3). The organic layer was concentrated and purified by column chromatography on silica gel (eluted: petroleum ether/ethyl acetate=20/1-15/1-10/1) to give benzyl 2-acetylmorpholine-4-carboxylate (5.0 g, 63%).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.[C:14]([NH:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(NC(C)C)(C)C.[I-].[Na+]>CN(C)C=O.O>[C:4]1([CH2:3][CH2:2][N:26]2[CH2:27][CH2:28][CH:23]([NH:22][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:24][CH2:25]2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: BrCCc1cccc2ccccc12
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(C)NC(C)C
Product: O=C(NC1CCN(CCc2cccc3ccccc23)CC1)c1ccccc1
Temperature: 70 °C
Yield: 65.6 %

Procedure:
1-(2-Bromoethyl)naphthalene (3.0 g.) was added to a solution of 4-benzamidopiperidine (3.0 g.), di-isopropylamine (4 ml.) and a trace of sodium iodide in dimethylformamide (10 ml.). The mixture was heated at 70° C. overnight, then poured into water and extracted with methylene chloride. The washed and dried extracts were evaporated and the residue was recrystallised from benzene to give the title compound (3.0 g.), m.p. 160°-162° C. (Found: C, 80.5; H, 7.4; N, 7.5 C24H26N2O requires C, 80.4; H, 7.3; N, 7.8%).
Reaction SMILES: [C:1]1([C:13]2[C:14](=[O:30])[N:15]([CH3:29])[C:16](=[O:28])[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH3:27])[CH:19]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[H][H].C1(C)C=CC=CC=1>CO.C(OC(=O)C)C.[Pd]>[C:1]1([C@H:13]2[C@@H:17]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH3:27])[CH:19]=3)[C:16](=[O:28])[N:15]([CH3:29])[C:14]2=[O:30])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: CN1C(=O)C(c2cn(C)c3ccccc23)=C(c2cn3c4c(cccc24)CCC3)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN1C(=O)[C@H](c2cn(C)c3ccccc23)[C@H](c2cn3c4c(cccc24)CCC3)C1=O
Yield: 56.7 %

Procedure:
To a solution of 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1-methylindol-3-yl)-1-methylpyrrole-2,5-dione (93 mg) in methanol (5 ml) and ethylacetate (5 ml) was added 10% Pd—C (50 mg) and the mixture stirred at room temperature under 1 atmosphere of hydrogen for 48 hours. Toluene (50 ml) was added and the mixture again stirred at room temperature under 1 atmosphere of hydrogen for 2 hours. The mixture was then filtered through a pad of celite and evaporated to dryness to yield a residue. The residue was purified using silica gel chromatography eluting with 35-40% ethylacetate in hexanes to give (±)-cis-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1-methylindol-3-yl)-1-methylpyrrolidine-2,5-dione as a pale yellow solid (53 mg). 1H NMR (CDCl3) 400 MHz δ: 7.23 (s, 1H), 7.05-7.07 (m, 2H), 7.01 (d, 1H, J=7.2 Hz), 6.92-6.97 (m, 1H), 6.85 (t, 1H, J=7.2 Hz), 6.74 (d, 1H, J=6.8 Hz), 6.64 (d, 2H, J=6.4 Hz), 4.78 (m, 2H), 3.75-3.84 (m, 2H), 3.45 (s, 3H), 3.27 (s, 3H), 2.79 (t, 2H, J=5.6 Hz), 1.98 (m, 2H).
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:44])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][C:27]([N:29]2[CH2:33][CH2:32][CH2:31][C@@H:30]2[C:34]([O:36]CC2C=CC=CC=2)=[O:35])=[O:28])[N:20]=1)=[O:10])C1C=CC=CC=1>C(O)C.[Pd]>[C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:44])[CH2:17][CH2:18][C:19]1[N:20]=[C:21]([CH2:25][CH2:26][C:27]([N:29]2[CH2:33][CH2:32][CH2:31][C@@H:30]2[C:34]([OH:36])=[O:35])=[O:28])[CH:22]=[CH:23][CH:24]=1)([OH:10])=[O:8]
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)CCc1cccc(CCC(=O)N2CCC[C@@H]2C(=O)OCc2ccccc2)n1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)[C@H]1CCCN1C(=O)CCc1cccc(CCC(=O)N2CCC[C@@H]2C(=O)O)n1
Yield: 90.9 %

Procedure:
0.17 g (0.29 mmol) (R)-1-[3-[6-[3-[(R)-2-benzyloxycarbonyl-pyrrolidin-1-yl]-3-oxo-propyl]-pyridin-2-yl]-propionyl]-pyrrolidine-2-carboxylic acid benzyl ester in 100 ml ethanol were hydrogenated in the presence of 35 mg 5% Pd on carbon. Filtration and evaporation of the solvent yielded 0.11 g (92%) (R)-1-[3-[6-[3-[(R)-2-carboxy-pyrrolidin-1-yl]-3-oxo-propyl]-pyridin-2-yl]propionyl]-pyrrolidine-2-carboxylic acid as colorless oil. MS-ISP: 418 (M+H)+.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([F:30])[C:14]([F:29])=[C:15]([C@:17]2([CH3:28])[CH2:22][C@@H:21]([C:23]([F:26])([F:25])[F:24])[O:20][C:19]([NH2:27])=[N:18]2)[CH:16]=1>>[F:29][C:14]1[C:13]([F:30])=[CH:12][C:11]([NH:10][C:2]2[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:16][C:15]=1[C@:17]1([CH3:28])[CH2:22][C@@H:21]([C:23]([F:24])([F:25])[F:26])[O:20][C:19]([NH2:27])=[N:18]1
Reactant: COc1cccnc1Br
Reactant: C[C@@]1(c2cc(N)cc(F)c2F)C[C@@H](C(F)(F)F)OC(N)=N1
Product: COc1cccnc1Nc1cc(F)c(F)c([C@]2(C)C[C@@H](C(F)(F)F)OC(N)=N2)c1

Procedure:
The title compound was synthesized by procedures and steps analogous to those described in Method B, Example 8 above, but using 2-bromo-3-methoxypyridine and (4S,6S)-4-(5-amino-2,3-difluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine in step 2. MS m/z=417 [M+H]+. Calculated for C18H17F5N4O2: 416.3.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O-:12])([O-])=[O:10].[K+].[K+].CN([CH:18]=[O:19])C>CCOCC>[OH:19][C:18]1[CH:5]=[CH:4][C:3]([C:9]([O:12][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])=[C:2]([CH3:7])[CH:1]=1
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Reactant: BrCc1ccccc1
Agent: [K+]
Solvent: CCOCC
Product: Cc1cc(O)ccc1C(=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
9.5 gm (63 mmol) of material prepared as described in Step A above was dissolved in DMF (100 ml) and benzyl bromide (8.4 ml, 69.3 mmol) was added followed by powdered K2CO3 (13 gm, 94 mmol). This mixture was stirred at 60° C. for 2 hr and then was cooled, diluted with Et2O and poured onto ice chilled aq. HCl. The layers were separated and the aqueous layer was extracted twice more with Et2O. The pooled organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to dryness. This crude product was purified by flash chromatography (silica gel, using 10%-30% EtOAc in hexane as eluant) to give the title compound as an oil which upon trituration with hexane and cooling gave 8.5 gm of a white solid.
Reaction SMILES: C(N(CC)CC)C.[OH:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19].[C:20]([O:24][C:25](=[O:46])[NH:26][CH2:27][CH2:28][CH2:29][N:30]1[C:42]2[C:41]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[N:35]=[C:34]([NH2:43])[C:33]=2[N:32]=[C:31]1[CH2:44]Cl)([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C.O>[NH2:43][C:34]1[C:33]2[N:32]=[C:31]([CH2:44][O:8][N:9]3[C:10](=[O:19])[C:11]4[C:12](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:14])[N:30]([CH2:29][CH2:28][CH2:27][NH:26][C:25](=[O:46])[O:24][C:20]([CH3:21])([CH3:23])[CH3:22])[C:42]=2[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[N:35]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)NCCCn1c(CCl)nc2c(N)nc3ccccc3c21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCn1c(CON2C(=O)c3ccccc3C2=O)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 74.8 %

Procedure:
Triethylamine (4.6 mL, 33.1 mmol) was added to a solution of N-hydroxyphthalimide (2.16 g, 13.2 mmol) in DMF (10 mL). A solution of tert-butyl[3-(4-amino-2-chloromethyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]carbamate (4.3 g, 11.0 mmol) in DMF (20 ml) was added. The reaction was stirred at ambient temperature for 3.5 hours and then diluted with water (100 mL). The resulting precipitate was isolated by filtration, washed with water, and then dried in a vacuum oven at 60° C. over the weekend to provide 4.25 g of tert-butyl (3-{4-amino-2-[(1,3-dioxo-1,3-dihydroisoindol-2-yl)oxymethyl]-1H-imidazo[4,5-c]quinolin-1-yl}propyl)carbamate as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.S(OC)(O[CH3:34])(=O)=O>C(O)C>[CH3:34][NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: COS(=O)(=O)OC
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Solvent: CCO
Product: CNc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
A solution of [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone (100 mg) and dimethyl sulfate (150 mg) in ethanol was stirred at r.t. for 4 hrs. The solution was concentrated and purified by semi-HPLC to give [4-(3-methylamino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone as a gum.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:13][CH:12]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].[C:22](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:13][CH:12]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)CCc1ccc(Sc2ccc([N+](=O)[O-])cn2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)CCc1ccc(Sc2ccc([N+](=O)[O-])cn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-[4-(5-nitropyridin-2-ylsulfanyl)phenyl]propionic acid (86.0 g, 0.283 mmol) in DMF (1 mL) were added potassium carbonate (59.0 mg, 0.424 mmol) and methyl iodide (0.0260 mL, 0.424 mmol), and the resulting solution was stirred for 1 hour at room temperature. Water was added to the reaction mixture, and then cooled with ice. The precipitated solid matter was collected by filtration, to thereby yield 76.9 mg of the title compound.
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][C:7]([F:34])=[C:8]2[C:12]([C:13](=[O:33])[C:14]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:25]=[N:24][N:23]=4)[CH2:18][CH2:17]3)=[O:15])=[CH:11][NH:10][C:9]=12)(=O)[CH3:2].Cl.[NH2:36][OH:37]>CCO>[F:34][C:7]1[CH:6]=[N:5][C:4](/[C:1](=[N:36]/[OH:37])/[CH3:2])=[C:9]2[NH:10][CH:11]=[C:12]([C:13](=[O:33])[C:14]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:25]=[N:24][N:23]=4)[CH2:18][CH2:17]3)=[O:15])[C:8]=12
Reactant: NO
Reactant: CC(=O)c1ncc(F)c2c(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c[nH]c12
Agent: Cl
Solvent: CCO
Product: C/C(=N\O)c1ncc(F)c2c(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccc4)CC3)c[nH]c12
Temperature: 25 °C

Procedure:
To a suspension of 1-(7-acetyl-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (0.05 g, 0.11 mmol) in EtOH (10 mL) was added hydroxylamine hydrochloride (0.04 g, 0.58 mmol). The mixture was heated to reflux for 1 h, and was then cooled to rt, and concentrated in vacuo. The residue was diluted with MeOH, and the solids that formed were collected and washed with water. The title compound was isolated as an off-white solid (0.027 g). LCMS: m/e 478.5 (M+H)+, ret time 1.53 min (method 1). 1H NMR (500 MHz, DMSO-D6) δ ppm 11.95 (s, 1 H) 11.61 (s, 1 H) 8.34 (d, J=1.83 Hz, 1 H) 8.30 (d, J=3.36 Hz, 1 H) 7.56-7.71 (m, 5 H) 3.68-3.72 (m, 2 H) 3.43-3.48 (m, 2 H) 3.30-3.34 (m, 2 H) 3.13-3.17 (m, 2 H) 2.35 (s, 3 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](OS(C(F)(F)F)(=O)=O)=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[N:8][C:9]2[C:14]([C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][C:12]([Cl:24])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2ccc(Cl)cc2c1Cc1ccccc1Cl
Reactant: C1CCNC1
Product: CCOC(=O)c1c(N2CCCC2)nc2ccc(Cl)cc2c1Cc1ccccc1Cl

Procedure:
This compound was prepared in analogy to example 29 step D from 6-chloro-4-(2-chloro-benzyl)-2-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid ethyl ester (prepared as described in example 29 step C, 100 mg, 0.2 mmol) and pyrrolidine (0.032 ml, 0.39 mmol). Pale yellow solid (60 mg, 71%). LC-MS (ESI): 429 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][N:32]3C(OC(C)(C)C)=O)=[O:30])[CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][NH:32]3)=[O:30])[CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)N1CCCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCN(C(=O)C2CCCCN2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-[1-(tert-Butoxycarbonyl)piperidine-2-carbonyl]-piperidine-3-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (27) (1.35 g; 2.29 mmol) is dissolved in methylene chloride (40 mL) at ambient temperature. Trifluoroacetic acid (20 mL) is added in a slow stream, and the solution is stirred for 4 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (200 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken and the layers separated. The water layer is extracted with methylene chloride (3×50 mL). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product as a solid foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:14](=[O:17])(=[O:16])[NH2:15])[C:5]2[O:10][S:9](=[O:12])(=[O:11])[CH:8]=[CH:7][C:6]=2[CH:13]=1.[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([N:28](C2C=CC=CC=2)[C:29](=O)[O-:30])[N:21]=1.N12CCCN=C1CCCCC2.Cl>C(#N)C.O>[Br:1][C:2]1[CH:3]=[C:4]([S:14]([NH:15][C:29]([NH:28][C:22]2[N:21]=[C:20]([O:19][CH3:18])[CH:25]=[C:24]([O:26][CH3:27])[N:23]=2)=[O:30])(=[O:17])=[O:16])[C:5]2[O:10][S:9](=[O:12])(=[O:11])[CH:8]=[CH:7][C:6]=2[CH:13]=1
Reactant: NS(=O)(=O)c1cc(Br)cc2c1OS(=O)(=O)C=C2
Reactant: COc1cc(OC)nc(N(C(=O)[O-])c2ccccc2)n1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: O
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2cc(Br)cc3c2OS(=O)(=O)C=C3)n1
Reaction time: 2 h
Yield: 65.3 %

Procedure:
0.3 g of 6-bromo-8-sulfamoyl-2,2-dioxo-1,2-benzoxathiine are dissolved in 10 ml of acetonitrile. To this solution are added 0.25 g of N-(4,6-dimethoxypyrimidin-2-yl)phenylcarbamate and 0.15 g of 1,8-diazabicyclo[5.4.0]undec-7-ene and the mixture is stirred for 2 hours at 20°-25° C. The mixture is then acidified with 5% hydrochloric acid and diluted with water. The precipitated oil is extracted with ethyl acetate and the combined organic phases are washed with water, dried and concentrated. The oily residue is crystallised from ether, affording 0.3 g of N-(6-bromo-2,2-dioxo-1,2-benzoxathiin-8-ylsulfonyl)-N'-(4,6-dimethoxypyrimidin-2-yl)urea of m.p. 204°-209° C. (decompos.).
Reaction SMILES: [Li+].[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]([Cl:24])=[C:19]([CH:23]=2)C([O-])=O)[CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].C1(P([N:39]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.O.C(OCC)(=O)C.O>CN(C)C=O>[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]([Cl:24])=[C:19]([NH2:39])[CH:23]=2)[CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)c(C(=O)[O-])c2)CC1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)c(N)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-(4-tert-butoxycarbonyl-piperazin-1-yl)-2-chloro-benzoic acid lithium salt (2.1 g) in N,N-dimethylformamide (50 ml) was added diphenyl phosphorylazide (1.4 ml) and reaction mixture stirred at ambient temperature for 1 hour. Water (30 ml) was added and the reaction mixture heated to 60° C. for 2 hours. After cooling to room temperature, the reaction was poured into ethyl acetate/water, the organic layer separated, washed with water, aqueous NaHCO3 and brine. The organic layer was dried (MgSO4) and concentrated. Purification of the residue by silica gel chromatography (eluting ethyl acetate/iso-hexane (1:3 to 1:1) gave the subtitle product (1.5 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH2:13][C:14](=[CH:17]N2CCOCC2)[C:15]#[N:16])[C:6]2[CH:7]=[CH:8][CH2:9][O:10][C:5]=2[C:4]=1[O:24][CH3:25].Cl.NC1C=CC=CC=1.Cl.[NH2:35][C:36]([NH2:38])=[NH:37].C[O-].[Na+]>>[NH2:37][C:36]1[N:38]=[C:15]([NH2:16])[C:14]([CH2:13][C:11]2[C:6]3[CH:7]=[CH:8][CH2:9][O:10][C:5]=3[C:4]([O:24][CH3:25])=[C:3]([O:2][CH3:1])[CH:12]=2)=[CH:17][N:35]=1
Reactant: N=C(N)N
Reactant: COc1cc(CC(C#N)=CN2CCOCC2)c2c(c1OC)OCC=C2
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Nc1ccccc1
Product: COc1cc(Cc2cnc(N)nc2N)c2c(c1OC)OCC=C2
Yield: 42.7 %

Procedure:
2-(7,8-Dimethoxy-2H-1-benzopyran-5-ylmethyl)-3-morpholino acrylonitrile (562 g, 1.64 mol) and aniline hydrochloride (234 g, 1.80 mol) were refluxed in SD3A (2.4 L) for one hour. The reaction was cooled, and guanidine hydrochloride (313 g, 3.28 mol) and sodium methoxide (275 g, 5.08 mol) were added. After continued reflux, the product crystallized from the cooled reaction mixture. Filtration followed by water wash (2 L) gave 2,4-diamino-5-(7,8-dimethoxy-2H-1-benzopyran-5-ylmethyl)pyrimidine (220 g, 42.7%). Crystallization from ethanol-water gave title compound, mp 235°-238°, identical to the product of Example 1C.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.C[O:8][C:9]([C:11]1[CH:12]=[C:13]([CH3:35])[C:14]2[O:20][C:19]3[C:21]([Cl:31])=[CH:22][C:23]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[CH:24][C:18]=3[CH2:17][S:16](=[O:33])(=[O:32])[C:15]=2[CH:34]=1)=[O:10]>ClCCl.N1C=CC=CC=1>[Cl:31][C:21]1[C:19]2[O:20][C:14]3[C:13]([CH3:35])=[CH:12][C:11]([C:9]([OH:10])=[O:8])=[CH:34][C:15]=3[S:16](=[O:32])(=[O:33])[CH2:17][C:18]=2[CH:24]=[C:23]([N:25]2[CH2:26][CH2:27][N:28]([C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[CH2:29][CH2:30]2)[CH:22]=1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCNCC3)cc(Cl)c1O2
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N3CCN(C(=O)C4CC4)CC3)cc1CS2(=O)=O
Reaction time: 0.75 h

Procedure:
A solution of cyclopropyl carbonyl chloride (0.22 mL, 2.4 mmol) in dichloromethane (2 mL) was added to a suspension of Example 104k (0.35 g, 0.8 mmol) in pyridine (3 mL)/dichloromethane (1 mL) at 10° C. The reaction mixture was stirred for 45 min, concentrated, treated with chilled water and dilute HCl to pH 6. The precipitated solid was filtered and dried to obtain the title compound. Yield: 0.372 g, (91.5%); 1H NMR (DMSO-d6): δ 0.76 (m, 4H, 2CH2); 2.06 (m, 1H, CH); 2.68 (s, 3H, CH3); 3.24 (s, 2H, CH2); 3.32 (s, 2H, CH2); 3.64 (S, 2H, CH2); 3.84 (s, 2H, CH2); 5.15 (s, 2H, CH2); 7.12 (d, 1H, Ar); 7.2 (d, 1H, Ar); 8.1 (s, 1H, Ar); 8.2 (s, 1H, Ar); 8.38 (s, 1H, OH). MS: m/e (ES+) 532 (M+1).