Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:6]=1)[CH2:3][OH:4].[C:18]1([CH:24]2[CH2:26][CH:25]2[C:27](O)=[O:28])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:2]([NH:1][C:27]([CH:25]2[CH2:26][CH:24]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:28])[CH2:3][OH:4])=[CH:6][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=C(O)C1CC1c1ccccc1
Reactant: N[C@@H](CO)c1ccc(F)c(N2CCOCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC(CO)c1ccc(F)c(N2CCOCC2)c1)C1CC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
A mixture of (R)-2-amino-2-(4-fluoro-3-morpholin-4-yl-phenyl)-ethanol (0.1 mmol), 2-phenyl-cyclopropanecarboxylic acid (0.1 mmol), EDAC.HCl (0.2 mmol), DMAP (0.1 mmol), triethylamine (0.4 mmol) in dichloromethane (2 mL) was stirred at room temperature overnight. The reaction mixture was purified by flash chromatography with 3% methanol in ethyl acetate to give the desired product (27 mg) as a solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.[CH2:7]([O:9][C:10](=[O:27])[C:11]1[CH:19]=[C:18]([C:20](=[O:26])[N:21]([CH3:25])[CH2:22][CH2:23][CH3:24])[CH:17]=[C:13]([C:14](O)=[O:15])[CH:12]=1)[CH3:8].ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C>ClCCl>[CH2:7]([O:9][C:10](=[O:27])[C:11]1[CH:12]=[C:13]([C:14]([N:3]2[CH2:4][CH2:5][CH2:6][CH:2]2[CH3:1])=[O:15])[CH:17]=[C:18]([C:20]([N:21]([CH3:25])[CH2:22][CH2:23][CH3:24])=[O:26])[CH:19]=1)[CH3:8]
Reactant: CCCN(C)C(=O)c1cc(C(=O)O)cc(C(=O)OCC)c1
Reactant: CC1CCCN1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(C(=O)OCC)cc(C(=O)N2CCCC2C)c1
Temperature: 25 °C
Yield: 27.7 %

Procedure:
Add 2-methyl pyrrolidine (204 mg, 2.4 mmol) to a solution of 5-(methyl-propylcarbamoyl)-isophthalic acid monoethyl ester (640 mg, 2.18 mmol) in dichloromethane (8 mL) followed by 1-hydroxybenzotriazole (20 mg, 0.15 mmol) and diisopropyl carbodiimide (375 μL, 2.4 mmol). Stir the solution at room temperature over the weekend. Add ethyl acetate (25 mL) and wash with saturated aqueous ammonium chloride (2×10 mL), saturated aqueous sodium bicarbonate (10 mL), saturated aqueous sodium chloride (10 mL), dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with 50:50 ethyl acetate:hexanes) to give the title compound as an oil (218 mg, 28%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.N1C=CC=CC=1.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[S:21]([NH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1)(=[O:23])=[O:22]
Reactant: Nc1nccs1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1nccs1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a slurry of 2-aminothiazole (15.08 g, 0.1506 mol) in methylene chloride (100 mL) and pyridine (24 mL, 0.30 mol) was added dropwise over 20 minutes a solution of 2,4-difluorobenzenesulfonyl chloride (10 mL, 0.07 mol) in 10 mL of methylene chloride. After stirring at room temperature for 48 hours the reaction was concentrated and purified by flash column chromatography eluting with hexane/ethyl acetate. LCMS Rt=1.21 minutes
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:8][CH2:9][C:10]2([CH2:13][C:14]#[N:15])[CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:16][O:17][C:18]([C:20]1[S:29][C:23]2[N:24]=[C:25](Cl)[N:26]=[CH:27][C:22]=2[C:21]=1[CH3:30])=[O:19]>>[C:14]([CH2:13][C:10]1([CH2:9][O:8][C:3]2[C:2]([NH:1][C:27]3[C:22]4[C:21]([CH3:30])=[C:20]([C:18]([O:17][CH3:16])=[O:19])[S:29][C:23]=4[N:24]=[CH:25][N:26]=3)=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:12][CH2:11]1)#[N:15]
Reactant: COC(=O)c1sc2nc(Cl)ncc2c1C
Reactant: N#CCC1(COc2ncccc2N)CC1
Product: COC(=O)c1sc2ncnc(Nc3cccnc3OCC3(CC#N)CC3)c2c1C

Procedure:
Prepared analogously to example 32.1 using 2-(1-((3-aminopyridin-2-yloxy)methyl)cyclopropyl)acetonitrile (264 mg) and chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (152 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:15][CH2:16][CH2:17][CH3:18])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.Cl.Cl.[CH3:21][N:22]([CH2:24][CH:25]([OH:35])[CH2:26][O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)[CH3:23].CO.N>C(O)CCC>[CH3:23][N:22]([CH2:24][CH:25]([OH:35])[CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([NH:32][C:2]2[N:7]=[C:6]([N:8]([CH2:15][CH2:16][CH2:17][CH3:18])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:33][CH:34]=1)[CH3:21]
Reactant: CCCCN(c1ccccc1)c1ccnc(Cl)n1
Reactant: CN(C)CC(O)COc1ccc(N)cc1
Agent: Cl
Agent: N
Solvent: CCCCO
Solvent: CO
Product: CCCCN(c1ccccc1)c1ccnc(Nc2ccc(OCC(O)CN(C)C)cc2)n1
Temperature: 95 °C
Yield: 15.2 %

Procedure:
2-Chloro-4-(N-(n-butyl)anilino)pyrimidine (570 mg, 2.18 mmol) was dissolved in n-butanol (4 ml) and 4-[3-(N,N-dimethyl)amino-2-hydroxypropoxy]aniline dihydrochloride (Reference Example D-1; 554 mg, 1.97 mmol) was added. The resulting suspension was treated with methanol until all the solid dissolved. The reaction mixture was heated at 95° C. for 12 hours and allowed to cool to ambient temperature. The reaction mixture was then basified to pH 9–10 using methanolic ammonia and then evaporated onto silica (5 ml). The residue was purified by column chromatography eluting with methanol (15%):DCM:aqueous ammonia (1%). The resulting gum was re-evaporated from EtOAc twice to give the title product as a foam (130 mg).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:4]([O:28][CH3:29])[CH:3]=1.[H-].[Na+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CN(C)C=O>[CH3:27][O:26][C:20]1[CH:19]=[C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:10]([N:9]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:5]3[CH:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[CH:3][C:4]=3[O:28][CH3:29])=[O:11])[CH2:13][CH2:14]2)[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=1
Reactant: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc(C)c(C)cc3OC)CC2)c1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(C(=O)N1CCN(c2cc(OC)cc(OC)c2)CC1)c1cc(C)c(C)cc1OC
Temperature: 25 °C
Yield: 79 %

Procedure:
1-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine(0.2 g, 0.5 mmol) was dissolved in dimethylformamide(15 ml), sodium hydride(18.5 mg, 0.5 mmol) was added thereto, and the resulting mixture was stirred at room temperature. Then, ethyl bromoacetate(83.5 mg, 0.5 mmol) was added thereto and the resulting mixture was stirred for 3 hours, concentrated under the reduced pressure to remove the used solvent and purified by column chromatography(ethylacetate:hexane=1:2) to obtain the titled compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29]1[N:30]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:32][C:33]=1[CH3:34]>CN(C=O)C>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:28][C:29]2[N:30]=[C:31]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:32][C:33]=2[CH3:34])[CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CCCN1C(=O)Cc1cccc(O)c1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1CCCN1C(=O)Cc1cccc(OCc2nc(-c3ccccc3)oc2C)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the title A compound, (R)-1-[2-(3-hydroxy-phenyl)-acetyl]-pyrrolidine-2-carboxylic acid ethyl ester (1.0 g, 3.61 mmol) in 10 mL DMF is added potassium carbonate (0.60 g, 4.33 mmol) followed by 4-chloromethyl-5-methyl-2-phenyl-oxazole (0.75 g, 3.61 mmol). The mixture is stirred for 24 h at RT, and partitioned between ethyl acetate and water. The organic layer is separated and washed with brine, dried over anhydrous sodium sulfate, concentrated and purified by flash chromatography (silica gel) eluting with hexane:ethyl acetate (3:7) to give (R)-1-{2-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-acetyl}-pyrrolidine-2-carboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C@@:8]2([F:24])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[N:10]([CH2:21]Cl)[C:9]2=[O:23])[CH:7]=1.C(#N)C.[C:30]([OH:34])(=[O:33])[CH2:31][OH:32].C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C@@:8]2([F:24])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[N:10]([CH2:21][O:34][C:30](=[O:33])[CH2:31][OH:32])[C:9]2=[O:23])[CH:7]=1
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(CCl)c2cc(C(F)(F)F)ccc21
Reactant: O=C(O)CO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CC#N
Product: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(COC(=O)CO)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 36 h
Yield: 57.5 %

Procedure:
To a 10 mL flask containing (S)-3-(5-chloro-2-methoxy-phenyl)-1-chloromethyl-3-fluoro-6-trifluoromethyl-1,3-dihydro-indol-2-one ((S)-V) (0.200 g, 0.489 mmol) was added 3 mL anhydrous acetonitrile, glycolic acid (0.045 g, 0.588 mmol) and cesium carbonate (0.079 g, 0.245 mmol). The reaction was stirred for 36 hours at room temperature, then the organic layer was diluted with 5 mL diethyl ether and the organic solution was decanted away from the solid cesium chloride. The solvent was evaporated in vacuo and the resulting white foam was purified by flash chromatography (silica gel 4:1 hexanes:acetone) producing the title compound (0.126 g, 58%) as a white powder. 1H NMR (CDCl3 400 MHz): δ=7.79 (s, 1H), 7.38-7.33 (m, 3H), 7.26 (d, 1H, J=7 Hz), 6.75 (d, 1H, J=7 Hz), 5.99 (d, 1H, J=12 Hz), 5.91 (d, 1H, J=12 Hz), 4.26 (s, 2H), 3.49 (s, 3H).
Reaction SMILES: [N:1]1([S:6](Cl)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][C:11]1[CH:12]=[C:13]([C:18]2[CH:19]=[CH:20][C:21]3[N:22]=[CH:23][N:24]=[C:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:26]=3[N:27]=2)[CH:14]=[C:15]([F:17])[CH:16]=1>N1C=CC=CC=1>[F:17][C:15]1[CH:14]=[C:13]([C:18]2[CH:19]=[CH:20][C:21]3[N:22]=[CH:23][N:24]=[C:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[C:26]=3[N:27]=2)[CH:12]=[C:11]([NH:10][S:6]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:8])=[O:7])[CH:16]=1
Reactant: O=S(=O)(Cl)N1CCCC1
Reactant: CC(C)(C)OC(=O)Nc1ncnc2ccc(-c3cc(N)cc(F)c3)nc12
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1ncnc2ccc(-c3cc(F)cc(NS(=O)(=O)N4CCCC4)c3)nc12
Temperature: 60 °C
Reaction time: 4 h
Yield: 60.9 %

Procedure:
Pyrrolidine-1-sulfonyl chloride (CAS 1689-02-7) (56 mg, 0.92 mmol) was added to a solution of tert-butyl 6-(3-amino-5-fluorophenyl)pyrido[3,2-d]pyrimidin-4-ylcarbamate (33-A) (300 mg, 0.84 mmol) in pyridine at ice bath. After the reaction mixture was stirred at 60° C. for 4 h, it was partitioned between water and EtOAc and purified by prep-TLC (PE:EtOAc=2:1) to give title product (250 mg, 61%).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:15][OH:16])[CH:5]=[CH:4][C:3]1=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:43]1[CH:53]=[CH:52][C:46]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:45][CH:44]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(OCC)C>[CH3:1][C:2]1([CH3:22])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:15][O:16][C:43]3[CH:53]=[CH:52][C:46]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:45][CH:44]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCCCCC(CO)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCC(COc1ccc(C(=O)OCC)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 99.2 %

Procedure:
400 mg of (RS)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-heptanol dissolved in 25 ml of THF absolute were treated with 382 mg of triphenylphosphine, 242 mg of ethyl 4-hydroxybenzoate and 0.24 ml of diethyl azodicarboxylate. The reaction mixture was heated to reflux for 6 hours. The mixture was diluted with 1 portion of 50 ml of diethylether and washed with 2 portions of 25 ml of water and 1 portion of 50 ml of a saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4 and concentrated in vacuo. The resulting yellow oil was purified by flash chromatography (SiO2, 3% ethyl acetate/hexanes), giving 591 mg of (RS)-ethyl 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-heptyloxy]-benzoate as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[CH3:9])=[CH:4][CH:3]=1.[SH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N+:13]=1[O-:18].[Na]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N+:13]=2[O-:18])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(Cl)c1ccc(Cl)cc1
Reactant: [O-][n+]1ccccc1S
Agent: [Na]
Product: CC(Sc1cccc[n+]1[O-])c1ccc(Cl)cc1
Yield: 78 %

Procedure:
The intermediate 2(-1-[4-chlorophenyl]ethylthio)pyridine N-oxide was prepared from 1-(4-chlorophenyl)ethylchloride and 2-mercaptopyridine N-oxide, sodium salt by the procedure described in Example 2. Melting point 106° - 108°C. Structure confirmed by IR and NMR.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[Cl:8].O>CN(C=O)C.[Cu]I>[Cl:8][C:7]1[CH:6]=[C:5]([CH3:9])[N:4]=[C:3]2[CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:1][C:2]=12
Reactant: Cc1cc(Cl)c(N)c(C#Cc2ccccc2)n1
Agent: [Cu]I
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Cl)c2[nH]c(-c3ccccc3)cc2n1
Temperature: 110 °C
Yield: 48.5 %

Procedure:
3-Amino-4-chloro-6-methyl-2-(2-phenyl ethynyl)pyridine (1.24 g, 5.1 mmol) was dissolved in anhydrous DMF (90 mL), CuI (150 mg, 0.8 mmol) was added and the mixture was heated at 110° C. for 18 h. The cooled mixture was poured into H2O (125 mL) and extracted with EtOAc (2×100 mL). The combined extracts were washed with H2O and brine, dried over MgSO4 and filtered through a plug of silica using CHCl3. The crude product was triturated with 20:1 hexanes:EtOAc, filtered, and dried under high vacuum to afford 600 mg (48%) of 7-chloro-5-methyl-2-phenyl pyrrolo-[3,2-b]pyridine. 1H NMR (DMSO-d6; 500 MHz): δ 2.40 (s, 3), 7.05 (s, 1), 7.16 (s,1), 7.38 (t, 1, J=5.2), 7.49 (m, 2), 8.02 (d, 2, J=7.2). MS m/z: 243 (M+H). This intermediate chloride (273 mg, 1.1 mmol) was taken up in 4:1 o-xylene/piperidine (10 mL) and heated to 140° C. in a Teflon-capped pressure tube for 7 d. The mixture was cooled to room temperature, diluted with H2O (125 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with H2O and brine, dried over MgSO4 filtered, and concentrated in vacuo. Chromatography on silica gel eluting with 10:1 CHCl3:MeOH afforded 244 mg (75%, 36% overall) of the title compound as a pale yellow solid. The product's 1H-NMR was identical to that obtained using Method A.
Reaction SMILES: [Br:1][C:2]1[C:15](=[O:16])[N:14]([CH:17]([CH3:19])[CH3:18])[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1.[CH3:20][NH2:21]>O1CCOCC1>[Br:1][C:2]1[C:15](=[O:16])[N:14]([CH:17]([CH3:19])[CH3:18])[C:5]2[N:6]=[C:7]([NH:21][CH3:20])[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1
Reactant: Cc1nc(S(C)=O)nc2c1cc(Br)c(=O)n2C(C)C
Reactant: CN
Solvent: C1COCCO1
Product: CNc1nc(C)c2cc(Br)c(=O)n(C(C)C)c2n1
Temperature: 110 °C
Yield: 100 %

Procedure:
To a stirred solution of 6-bromo-8-isopropyl-4-methyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one (175 mg, 0.508 mmol) in 1,4-dioxane (2.5 mL) was added methyl amine (0.80 mL, 2.0 M in THF, 1.6 mmol). The mixture was sealed and heated at 110° C. microwave for 15 min. The solvent was evaporated and the crude product was washed with EtOAc/Hexane to give the title compound (158 mg, 76%).
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([O:20][CH3:21])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:21][O:20][C:13]1[CH:12]=[C:11]([N:3]2[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]2)[CH:16]=[CH:15][C:14]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C1CCNCC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 20 h
Yield: 61.9 %

Procedure:
To a solution of 4-piperidone hydrochloride monohydrate (10.0 g, 0.065 mol) in DMF (80 mL) are added 4-Fluoro-2-methoxy-1-nitro-benzene (10.0 g, 0.058 mol) and potassium carbonate (20.2 g), and the mixture is stirred at 70° C. for 20 h. After a filtration, the filtrate is poured into H2O (ca. 300 mL), and the resulting precipitates are collected by a filtration followed by washing with H2O for several times to give title compound (8.98 g) in 61% yield. Orange solid. 1H-NMR (400 MHz, CDCl3, δ): 2.65-2.62 (4H, m), 3.81-3.78 (4H, m), 3.98 (3H, s), 6.34 (1H, d), 6.45 (1H, dd), 8.05 (1H, d).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]=O.[BH4-].[Na+]>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([NH:1][CH2:23][C:19]3[O:18][CH:22]=[CH:21][CH:20]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccco1
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: CCO
Product: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1NCc1ccco1
Yield: 38 %

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide (100 mg) was suspended in EtOH (4 mL) and 2-Furaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain product as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr. Resulting imine (100 mg) was suspended in 5 mL MeOH and sodium borohydride (10 eq.) was added. HPLC confirmed reaction was complete (absence of imine). After completion (1 hr), precipitate was filtered to obtain D96 as a light yellow powder. Product was washed with deionized water to remove excess sodium borohydride. Product was allowed to dry under vacuum for 18 hrs. 40 mg (38% yield) of final product was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:45])=[C:4]([S:9]([N:12]([CH2:21][C:22]2[CH:23]=[C:24]([CH:34]=[C:35]([O:37][C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH:36]=2)[CH2:25][NH:26]C(=O)OC(C)(C)C)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:26][CH2:25][C:24]1[CH:23]=[C:22]([CH:36]=[C:35]([O:37][C:38]2[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=2)[CH:34]=1)[CH2:21][N:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)[S:9]([C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[OH:45])(=[O:11])=[O:10]
Reactant: CC(C)(C)OC(=O)NCc1cc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc(Oc2ccc(F)cc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1cc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc(Oc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.3 %

Procedure:
To a solution of tert-butyl 3-((3,5-dichloro-N-(4-fluorobenzyl)-2-hydroxyphenylsulfonamido)methyl)-5-(4-fluorophenoxy)benzylcarbamate (0.65 g, 0.96 mmol) in CH2Cl2 (8 mL) was added TFA (1.10 mL, 14.4 mmol). The reaction mixture was stirred at rt. for 3 h. The reaction mixture was concentrated and to the residue was added saturated NaHCO3 solution and ethyl acetate. The organic layer was washed with brine twice, dried over MgSO4, and concentrated in vacuo to give white solid (0.53 g, 96%). 1H NMR (CD3OD): δ 7.49 (d, J=2.8 Hz, 1H), 7.35 (d, J=2.8 Hz, 1H), 7.21-7.09 (m, 4H), 6.99-6.90 (m, 5H), 6.85 (s, 1H), 6.64 (s, 1H), 4.48 (s, 2H), 4.40 (s, 2H), 3.93 (s, 2H); MS (ESI): (M+H)+=579.0.
Reaction SMILES: N1(C2C=C[C:10]([NH:13][C:14]([C:16]3[NH:17][C:18]4[C:23](C(=O)C=3)=CC(OC)=CC=4Br)=O)=CC=2)CCOCC1.CN.[N:32]1([C:38]2[CH:43]=[CH:42][C:41]([NH:44][C:45]([C:47]3[CH:56]=[C:55]([NH:57][CH3:58])[C:54]4[C:49](=[C:50](Br)[CH:51]=[C:52]([O:59][CH3:60])[CH:53]=4)[N:48]=3)=[O:46])=[CH:40][CH:39]=2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[N:32]1([C:38]2[CH:43]=[CH:42][C:41]([NH:44][C:45]([C:47]3[CH:56]=[C:55]([NH:57][CH3:58])[C:54]4[C:49](=[C:50]([N:17]5[CH2:16][CH2:14][N:13]([CH3:10])[CH2:23][CH2:18]5)[CH:51]=[C:52]([O:59][CH3:60])[CH:53]=4)[N:48]=3)=[O:46])=[CH:40][CH:39]=2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: COc1cc(Br)c2[nH]c(C(=O)Nc3ccc(N4CCOCC4)cc3)cc(=O)c2c1
Reactant: CNc1cc(C(=O)Nc2ccc(N3CCOCC3)cc2)nc2c(Br)cc(OC)cc12
Agent: CN
Product: CNc1cc(C(=O)Nc2ccc(N3CCOCC3)cc2)nc2c(N3CCN(C)CC3)cc(OC)cc12

Procedure:
The title compound was prepared from 8-bromo-6-methoxy-4-oxo-1,4-dihydro-quinoline-2-carboxylic acid (Reference Example 27b) according to the procedure described for Example 98 using N-methyl amine to prepare 8-bromo-4-methylamino-6-methoxy-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide. A glassy orange solid was obtained. Mass Spec.: calc. for [C27H34N6O3+H]+ Theor. m/z=491; Obs.=491.5.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH:21]1([N:27]=[C:28]=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>O1CCCC1>[CH:21]1([NH:27][C:28]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[N:4]([CH3:19])[C:3]2=[O:20])=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C=NC1CCCCC1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Solvent: C1CCOC1
Product: CN1C(=O)C(NC(=O)NC2CCCCC2)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and cyclohexylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p 287°-288° C.
Reaction SMILES: [C:1]([C:5]([NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:9]=1Cl)=[S:6])([CH3:4])([CH3:3])[CH3:2].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.O>CS(C)=O>[C:1]([C:5]1[S:6][C:9]2[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[C:12]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)=[CH:13][C:8]=2[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)C(=S)Nc1cc(Cl)c([N+](=O)[O-])cc1Cl
Solvent: O
Solvent: CS(C)=O
Product: CN1CCN(c2cc3nc(C(C)(C)C)sc3cc2[N+](=O)[O-])CC1

Procedure:
A solution of 171 g of N-t-butylthiocarbonyl-2,5-dichloro-4-nitroaniline, described in Example 1, and 605 ml of N-methylpiperazine in 1700 ml of dimethylsulphoxide is heated at 140° for 8 hours, cooled and poured into water. The solid is filtered, washed with water and cold isopropanol to yield 2-tert-butyl-5-[4-methylpiperazin-1-yl]-6-nitrobenzothiazole, melting at 132°-135°.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][NH:6]1)=[O:4].[C:20](OC(C)(C)C)(=[O:25])[CH2:21][C:22]([CH3:24])=[O:23]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:11])=[O:12])[CH2:7][N:6]1[C:20](=[O:25])[CH2:21][C:22](=[O:23])[CH3:24])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)CC(C)=O

Procedure:
In analogy to the procedure described in example 192f, (2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with tert-butyl acetoacetate to give the title compound as yellow solid.