Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([NH2:20])=[N:18][CH:19]=3)=[C:7]2[N:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:4]=1.[NH4+].[OH-].Cl.O.[C:37](OC(=O)C)(=[O:39])[CH3:38]>C1COCC1>[F:32][C:2]([F:1])([F:31])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:37](=[O:39])[CH3:38])=[N:18][CH:19]=3)=[C:7]2[N:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][CH:22]=2)[CH:4]=1
Reactant: Nc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1
Temperature: 120 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A mixture of 5-[7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-3-ylethynyl]-pyridin-2-ylamine (example 55) (2.00 g, 4.47 mmol) in acetic anhydride (15 mL) was stirred at 120° C. for 1 h. Cooled to 60° C., concentrated in vacuum to dryness (water bath temperature 60° C.) and dried in HV to give an orange solid (2.465 g, 113%, mixture of mono- and diacetylated compound). Suspended in THF (30 mL) at 23° C., added NH4OH (25%, 13.3M, 1.0 mL, 13.4 mmol) and stirred at 23° C. for 1.5 h resulting in a clear red solution, adjusted pH with 1N HCl until pH 1, added H2O (total volume 200 mL), filtered the precipitate off, washed with H2O and dried in HV, followed by trituration with ether and drying in HV to give the title compound as an orange solid (2.130 g, 97%). MS [ISN] 488.1 [(M−H)−]; mp 266° C.
Reaction SMILES: C(OC(=O)[CH2:5][C:6]([CH:8]=[CH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1)=O)C.[CH2:21]([O:23][C:24](=[O:33])[CH:25]=[C:26]([N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[NH2:27])[CH3:22]>C(O)C>[CH2:21]([O:23][C:24]([C:25]1[CH:9]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)[CH:8]([C:24]([O:23][CH2:21][CH3:22])=[O:33])[C:6]([CH3:5])=[N:27][C:26]=1[N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:33])[CH3:22]
Reactant: CCOC(=O)CC(=O)C=Cc1cccc2ccccc12
Reactant: CCOC(=O)C=C(N)N1CCCC1
Solvent: CCO
Product: CCOC(=O)C1=C(N2CCCC2)N=C(C)C(C(=O)OCC)C1c1cccc2ccccc12
Yield: 52 %

Procedure:
Boiling a solution of 13.4 g of naphth-1-ylmethylideneacetoacetic acid ethyl ester and 9.2 g of 3-pyrrolidino-3-aminoacrylic acid ethyl ester in 100 ml of ethanol for 2 hours yields 2-pyrrolidino-6-methyl-4-naphth-1-yl-4,5-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 121° C. (ethanol).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:22]1[CH:23]=[CH:24][C:25]([O:29][CH3:30])=[C:26]([NH2:28])[CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:22]1[CH:23]=[CH:24][C:25]([O:29][CH3:30])=[C:26]([NH:28][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([OH:1])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=2)[CH:27]=1
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: COc1ccc(-c2cc3ccccc3[nH]2)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(-c2cc3ccccc3[nH]2)cc1NCc1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.4 %

Procedure:
4-Hydroxy-3-nitrobenzaldehyde (0.334 g, 2.0 mmol) was added to a stirred mixture of 5-(1H-indol-2-yl)-2-methoxy-phenylamine (0.476 g, 2.0 mmol) in methylene chloride (125 mL), followed by acetic acid (0.2 g). The resulting mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.46 g, 2.2 mmol) was added in one portion, and the resulting homogeneous solution was stirred at room temperature for 3 days. Saturoted aqueous sodium bicarbonate solution (100 mL) was added and the mixture was stirred for 2 hours. The mixture was shaken, the organic layer was separated and dried over Na2SO4. The solvent was evaporated to give a brown gum. Recrystallization from methanol gave the product (307 mg), mp 165-166° C.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[C:5]2[CH:17]=[CH:18][N:19]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:4]=2[C:3]1=[O:30].Br[C:32]1[CH:39]=[CH:38][C:35]([NH:36][CH3:37])=[C:34]([N+:40]([O-:42])=[O:41])[C:33]=1[O:43][CH2:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>>[CH:45]1([CH2:44][O:43][C:33]2[C:34]([N+:40]([O-:42])=[O:41])=[C:35]([NH:36][CH3:37])[CH:38]=[CH:39][C:32]=2[C:6]2[C:5]3[CH:17]=[CH:18][N:19]([S:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[C:4]=3[C:3](=[O:30])[N:2]([CH3:1])[CH:7]=2)[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)cn(C)c(=O)c32)cc1
Reactant: CNc1ccc(Br)c(OCC2CCCCC2)c1[N+](=O)[O-]
Product: CNc1ccc(-c2cn(C)c(=O)c3c2ccn3S(=O)(=O)c2ccc(C)cc2)c(OCC2CCCCC2)c1[N+](=O)[O-]

Procedure:
This compound was synthesized according to the procedure of Example 10, Step 5, using 6-methyl-1-[(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one and 4-bromo-3-(cyclohexylmethoxy)-N-methyl-2-nitroaniline as the starting materials. LCMS calculated for C29H33N4O6S (M+H)+: m/z=565.2. found: 565.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:11]=[C:12]([C:16]([N:18]=[S@:19]([CH2:27][C:28](OCC)=[O:29])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:20])=[O:17])[CH:13]=[N:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:33]([CH2:35][NH2:36])[OH:34]>>[OH:34][CH2:33][CH2:35][NH:36][C:28](=[O:29])[CH2:27][S:19](=[O:20])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[N:18][C:16](=[O:17])[C:12]1[CH:11]=[C:10]([C:9]#[C:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=2)[CH:15]=[N:14][CH:13]=1
Reactant: CCOC(=O)C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Reactant: NCCO
Product: O=C(CS(=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1)NCCO
Yield: 80 %

Procedure:
In a manner similar to that described for Example 471, (S)-Ethyl [N-({5-[(3-hydroxyphenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate (75 mg, 0.17 mmol) and ethanolamine (0.05 mL, 0.84 mmol) were reacted to give the title compound as colorless oil (63 mg, 81%)
Reaction SMILES: CO.[Si:3]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[C:19][CH:20]1[C:29]2[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=2)[S:23][CH2:22][C:21]1([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)[CH3:32])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]>[Pd].C(OCC)(=O)C>[Si:3]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]1[C:29]2[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=2)[S:23][CH2:22][C:21]1([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)[CH3:32])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])[CH3:5]
Reactant: COc1ccc(C2(C)CSc3cc(OC)ccc3C2C#CCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(C2(C)CSc3cc(OC)ccc3C2CCCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Reaction time: 48 h
Yield: 80 %

Procedure:
Methanol (60 ml) and 10% Pd/C (500 mg) were added to 4-[9-(t-butyl-dimethylsilyloxy)-1-nonynyl]-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman (560 mg, 1.01 mmol) obtained in Example 28, and the mixture was stirred for 2 days under hydrogen gas (normal pressure). Ethyl acetate was added to the reaction solution which was then filtered, washed several times with ethyl acetate and concentrated under reduced pressure to remove the organic solvent. To the residue were added methanol (60 ml) and 10% Pd/C (300 mg), and the reaction mixture was stirred for 8 hours at 5 atomsphere under hydrogen gas. Ethyl acetate was added again to the reaction solution which was then filtered and concentrated under reduced pressure to obtain 450 mg (yield: 80%) of the title compound as an oil. The resulting compound was used in the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:7](=[O:8])[CH:6]=[CH:5][CH2:4][CH2:3]1.[OH:16][C:17]([CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]1[C@@H:31]2[C@@H:26]([NH:27][C:28]([NH:30]2)=[O:29])[CH2:25][S:24]1)=O.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[C:17]([NH:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:7](=[O:8])[CH:6]=[CH:5][CH2:4][CH2:3]1)(=[O:16])[CH2:19][CH2:20][CH2:21][CH2:22][C@H:23]1[C@@H:31]2[C@@H:26]([NH:27][C:28]([NH:30]2)=[O:29])[CH2:25][S:24]1
Reactant: NC1(c2ccccc2Cl)CCC=CC1=O
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: O=C(CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)NC1(c2ccccc2Cl)CCC=CC1=O
Yield: 31.7 %

Procedure:
A solution of 6-amino-6-(2-chlorophenyl)-2-cyclohexen-1-one (50 mg, 0.23 mmol), (+)-biotin (56 mg, 0.23 mmol), hydroxybenzotriazole (31 mg, 0.23 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (66 mg, 0.35 mmol) in dimethylformamide (1 ml) was stirred at room temperature for 42 h. The reaction was partitioned between water and ethyl acetate, the organic phase was washed with water, brine, dried (Na2SO4), and the solvent removed by evaporation. Flash chromatography on silica gel eluted with 17:3 ethyl acetate/hexane afforded 6-biotinoylamino-6-(2-chlorophenyl)-2-cyclohexen-1-one (32.7 mg, 32%).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:15]=[C:14]([NH2:16])[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[N:26]=[C:27]=[O:28]>C(OCC)(=O)C>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[NH:26][C:27]([NH:16][C:14]1[CH:15]=[C:10]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:17])[CH3:1])[CH:4]=2)[N:11]=[CH:12][N:13]=1)=[O:28]
Reactant: CN(C)c1cccc(Nc2cc(N)ncn2)c1
Reactant: O=C=Nc1c(Cl)cccc1Cl
Solvent: CCOC(C)=O
Product: CN(C)c1cccc(Nc2cc(NC(=O)Nc3c(Cl)cccc3Cl)ncn2)c1

Procedure:
The title compound is prepared analogously as described in Example 105B from N-(3-dimethylamino-phenyl)-pyrimidine-4,6-diamine and 2,6-dichlorophenyl isocyanate using ethyl acetate instead of CH2Cl2 for the work-up procedure.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH:21]=[CH:20][C:19]3[C:11]2=[N:12][CH:13]=[C:14]2[C:18]=3[N:17]([C:22]3([CH3:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:16]=[N:15]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[N:36]1[CH:41]=[CH:40][CH:39]=[C:38]([S:42](Cl)(=[O:44])=[O:43])[CH:37]=1>C(Cl)Cl>[C:1]1([S:7]([N:10]2[CH:21]=[CH:20][C:19]3[C:11]2=[N:12][CH:13]=[C:14]2[C:18]=3[N:17]([C:22]3([CH3:28])[CH2:27][CH2:26][N:25]([S:42]([C:38]4[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=4)(=[O:44])=[O:43])[CH2:24][CH2:23]3)[N:16]=[N:15]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC1(n2nnc3cnc4c(ccn4S(=O)(=O)c4ccccc4)c32)CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(n2nnc3cnc4c(ccn4S(=O)(=O)c4ccccc4)c32)CCN(S(=O)(=O)c2cccnc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.8 %

Procedure:
A mixture of 6-benzenesulfonyl-1-(4-methyl-piperidine-4-yl)1,6-dihydro-1,2,3,5,6-pentaaza-as-indacene (60.0 mg, 0.15 mmol) was dissolved in DCM, triethylamine (28.0 μL, 0.20 mmol) was added followed by pyridine-3-sulfonyl chloride (32.0 mg, 0.18 mmol) and the reaction stirred at room temperature for 16 hr. The reaction mixture was diluted with DCM, washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated under vacuum to afford 74 mg (91%) of 6-benzenesulfonyl-1-[4-methyl-1-(pyridine-3-sulfonyl)-piperidin-4-yl]-1,6-dihydro-1,2,3,5,6-pentaaza-as-indacene. LCMS (Method H, ESI): RT=3.52 min, m+H=538.3; 1H NMR (400 MHz, DMSO): δ 9.21 (s, 1H), 8.84 (m, 2H), 8.19 (m, 3H), 8.10 (m, 1H), 7.74 (d, 1H), 7.62 (m, 3H), 7.31 (d, 1H), 3.45 (d, 2H), 2.82-2.67 (m, 4H), 2.33 (m, 2H), 1.69 (s, 3H).
Reaction SMILES: C([O:5][C:6](=[O:45])[C@H:7]([CH2:33][CH2:34][CH2:35][CH2:36][NH:37]C(OC(C)(C)C)=O)[NH:8][C:9](=[O:32])[CH:10]([CH2:27][S:28][C:29](=[O:31])[CH3:30])[CH2:11][CH2:12][CH2:13][NH:14]C(OCC1C=CC(OC)=CC=1)=O)(C)(C)C.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]>>[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49].[C:29]([S:28][CH2:27][CH:10]([CH2:11][CH2:12][CH2:13][NH2:14])[C:9]([NH:8][C@H:7]([C:6]([OH:45])=[O:5])[CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])=[O:32])(=[O:31])[CH3:30]
Reactant: COc1ccc(COC(=O)NCCCC(CSC(C)=O)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)SCC(CCCN)C(=O)N[C@@H](CCCCN)C(=O)O

Procedure:
A solution of Nα -[2-acetylthiomethyl-5-(p-methoxybenzyloxycarbonylamino)pentanoyl]-Nε -tert-butyloxycarbonyl-L-lysine tert-butyl ester (1 g) in trifluoroacetic acid (5 ml) is stored at room temperature for one hour and then concentrated to dryness in vacuo to yield Nα -(2-acetylthiomethyl-5-aminopentanoyl)-L-lysine trifluoroacetate.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH:9]=O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[CH2:21][CH2:22][C:23]#[N:24].CC([O-])(C)C.[K+]>>[CH3:20][O:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH3:11])[C:14]=1[CH2:21][C:22]1[C:23]([NH2:24])=[N:2][C:3]2[C:4]([CH:9]=1)=[CH:5][N:6]=[CH:7][CH:8]=2
Reactant: Nc1ccncc1C=O
Reactant: COc1cccc(OC)c1CCC#N
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: COc1cccc(OC)c1Cc1cc2cnccc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 4-amino-3-pyridine carboxaldehyde hydrochloride and 3-(2,6-dimethoxyphenyl)propionitrile. One equivalent of potassium tert-butylate was additionally used.
Reaction SMILES: [NH2:1]N.[N:3]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]C2C=CC=C3C(NC(=O)C=23)=O)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1>CO>[N:3]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:1])[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1
Reactant: NN
Reactant: O=C1NC(=O)c2c(CCCCCCCN3CCOCC3)cccc21
Solvent: CO
Product: NCCCCCCCN1CCOCC1

Procedure:
Hydrazine (aqueous solution at 35% by wt.) (0.15 ml; 1.6 mmoles) was added to 7-morpholinylheptylphthalimide (264 mg; 0.8 mmoles) in methanol (5 ml) and the resulting solution was refluxed. Reaction times and process as per Example 1.
Reaction SMILES: [C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:24]1([NH2:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)(Cl)Cl>[C:24]1([NH:30][C:8](=[O:9])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1ccccc1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)N(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
Diphenylcarbamic chloride (23 g, 0.1 mol, Aldrich Chemical Co., Milwaukee, Wis., U.S.A.) was added to a solution of 10.1 g of triethylamine and 9.3 g (0.1 mol) of benzeneamine in 150 ml of chloroform. The resulting solution was heated under reflux overnight. The solution was cooled to room temperature and washed three times with 100-ml portions of brine solution, dried over anhydrous magnesium sulfate, and evaporated to give an off-white solid which was triturated with diethyl ether to give triphenylurea as a white solid, mp 136°-138° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH3:13])[C:10](=[O:14])[O:9][CH2:8][CH2:7][C:6]=2[CH:15]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:35])=[CH:19][N:18]=1>>[Cl:35][C:20]1[C:21]([NH:23][C:24]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[N:22][C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH2:12][CH3:13])[C:10](=[O:14])[O:9][CH2:8][CH2:7][C:6]=3[CH:15]=2)=[N:18][CH:19]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)OCCc2cc(N)ccc21
Product: CCN1C(=O)OCCc2cc(Nc3ncc(Cl)c(Nc4c(F)cccc4C(=O)NC)n3)ccc21

Procedure:
Following a procedure analogous to Example 1742a, 2-amino-5-ethyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide were converted to 2-[5-chloro-2-(5-ethyl-6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide. HCl salt: 1H NMR (400 MHz, CD3OD) δ 8.04 (s, 1H), 7.41-7.30 (m, 3H), 7.12 (d, 1H), 7.04 (s, 2H), 4.27 (t, 2H), 3.66 (q, 2H), 2.68 (t, 2H), 2.66 (s, 3H), 0.98 (t, 3H); MS (m/e) 485 (M+1).
Reaction SMILES: N[C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.[ClH:16].N([O-])=O.[Na+].[OH-].[Na+]>O>[Cl:16][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2
Reactant: Cl
Reactant: Nc1c(C(F)(F)F)ccc2ccncc12
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: FC(F)(F)c1ccc2ccncc2c1Cl
Reaction time: 8 h

Procedure:
8-Amino-7-trifluoromethylisoquinoline (0.7 g.) in 2 ml. of concentrated hydrochloric acid and 10 ml. of water is diazotized at 0° C. with 0.25 g. of sodium nitrite in 5 ml. of water. The resulting solution is added to a solution of 2 g. of cuprous chloride in 20 ml. of concentrated hydrochloric acid previously warmed to 70° C. After standing overnight, the reaction mixture is basified with 10% aqueous sodium hydroxide solution and extracted with ether. The ether extracts are washed with water, dried over sodium sulfate and evaporated to give 8-chloro-7-trifluoromethylisoquinoline as the residue. This isoquinoline is converted to the hydrochloride and recrystallized from ethanol and ether.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][O:20][C:21]4[CH:25]=[CH:24][O:23][N:22]=4)[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:4]1.C(=O)(O)[O-].[Na+].[C:33](OC(=O)C)(=[O:35])[CH3:34]>ClCCl>[C:33]([NH:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][O:20][C:21]4[CH:25]=[CH:24][O:23][N:22]=4)[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:4]1)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@H]1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)C1
Reaction time: 18 h
Yield: 62.1 %

Procedure:
3-(4-((3S)-3-Amino-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)-oxazolidin-2-one hydrochloride salt (170 mg, 0.43 mmol) was stirred in a mixture of saturated sodium bicarbonate solution (5 ml) and dichloromethane (5 ml) in an ice-bath. Acetic anhydride (2 mmol) was added dropwise, and the mixture stirred 18 hours, allowing the temperature to rise to ambient. Dichloromethane (10 ml) was added, and the mixture filtered through phase separating paper, the organic layer evaporated, and crystallised from ethanol to give the desired product (108 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[CH3:16][N:17]([CH3:23])[CH:18]1[CH2:22][CH2:21][NH:20][CH2:19]1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:10][C:11]1[CH:6]=[N:5][C:4]([N:20]2[CH2:21][CH2:22][CH:18]([N:17]([CH3:23])[CH3:16])[CH2:19]2)=[CH:3][CH:2]=1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: CN(C)C1CCNC1
Product: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCC(N(C)C)C2)nc1
Yield: 185 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (250 mg, 1.0 mmol) was reacted with N,N-dimethylpyrrolidin-3-amine (260 mg, 1.2 mmol) to afford the desired product (380 mg, 89%) as an orange solid: 1H NMR (300 MHz, CDCl3) δ 11.35 (s, 1H), 9.00 (s, 1H), 8.10 (d, J=8.7 Hz, 1H), 8.02 (dd, J=2.7, 0.7 Hz, 1H), 7.47 (d, J=8.7 Hz, 1H), 7.30 (dd, J=8.9, 2.7 Hz, 1H), 6.35 (d, J=8.9 Hz, 1H), 3.88-3.77 (m, 1H), 3.62-3.72 (m, 1H), 3.49-3.37 (m, 1H), 3.33-3.22 (m, 1H), 2.94-2.76 (m, 1H), 2.68 (s, 3H), 2.34 (s, 6H), 2.34-2.18 (m, 1H), 2.06-1.89 (m, 1H); ESI MS m/z 411 [M+H]+
Reaction SMILES: C(OC([NH:11][C@:12]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][C:16](=[O:18])[NH:15][C:13]1=[O:14])=O)C1C=CC=CC=1.O.[H][H]>C(O)C.[Pd]>[NH2:11][C@:12]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][C:16](=[O:18])[NH:15][C:13]1=[O:14]
Reactant: [H][H]
Reactant: CCOC(=O)[C@@]1(NC(=O)OCc2ccccc2)CC(=O)NC1=O
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CCOC(=O)[C@@]1(N)CC(=O)NC1=O
Temperature: 35 °C
Reaction time: 33 h
Yield: 86.7 %

Procedure:
(2R)-2-Benzyloxycarbonylamino-2-ethoxycarbonylsuccinimide (24.4 g, 76.2 mmol) in ethanol (73.2 ml) was heated at 60° C. to be dissolved and 5% Pd—C (2.71 g) and water (2.17 g) were added at 30-40° C. of inner temperature. After the atmosphere was substituted with nitrogen gas, hydrogen gas was introduced and the mixture was stirred at 30-40° C. for about 33 hours. When completion of the reaction was confirmed by HPLC, the reaction solution was filtered, the insoluble materials were washed with sprayed ethanol (20 ml×2) and the filtrate was concentrated. The resulting crystals were recrystallized from ethanol (24.4 ml) and the precipitated crystals were filtered, washed with sprayed ethanol (15 ml) and dried in vacuo at room temperature to give (2R)-2-amino-2-ethoxycarbonylsuccinimide (12.3 g). Yield 86.7%, HPLC 99.7%, Optical purity 100% e.e.
Reaction SMILES: CCCP(=O)=O.[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=O)=[C:10]([N:17]2[C:24](=[O:25])[C:23]3[CH:22]=[CH:21][N:20]([CH:26]([CH3:28])[CH3:27])[C:19]=3[CH:18]2[C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[CH:9]=1.CCN(CC)CC>CCOC(C)=O>[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]#[N:14])=[C:10]([N:17]2[C:24](=[O:25])[C:23]3[CH:22]=[CH:21][N:20]([CH:26]([CH3:28])[CH3:27])[C:19]=3[CH:18]2[C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[CH:9]=1
Reactant: CC(C)n1ccc2c1C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C(N)=O)C2=O
Agent: CCCP(=O)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)n1ccc2c1C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C#N)C2=O
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A solution of propylphosphonic anhydride (T3P/PPA) (50% in EtOAc) (7.13 mmol) was added dropwise to a solution of 4-chloro-2-[6-(4-chloro-phenyl)-1-isopropyl-4-oxo-4,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-5-yl]benzamide (Step AB2) (3.10 mmol) and Et3N (3.41 mmol) in EtOAc (25 mL) at 45° C. After 23 h, the reaction mixture was cooled to rt and partitioned between EtOAc and H2O. The organice phase was successively washed with a saturated aqueous solution of NaHCO3, water and brine, dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a white solid. tR: 4.97 min (HPLC 1); ESI-MS: tR=1.19 min, [M+H]+ 410/412/414 (LC-MS 1); TLC: Rf=0.16 (1:3 EtOAc/heptanes).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([N+:16]([O-])=O)[CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:15])([F:14])[F:13])(=[O:4])=[O:3].[H][H]>CO.[Pd]>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:13])([F:14])[F:15])[NH2:16])(=[O:4])=[O:3]
Reactant: [H][H]
Reactant: CS(=O)(=O)c1cc([N+](=O)[O-])ccc1OC(F)(F)F
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)c1cc(N)ccc1OC(F)(F)F
Yield: 91.3 %

Procedure:
3-Methylsulfonyl-4-trifluoromethoxynitrobenzene (17.5 g) was dissolved in methanol (400 mL) followed by addition of palladium on carbon (10%, 50% water, 3.2 g). The reaction mixture was hydrogenated for 17 hours at 1 atm of hydrogen, filtered and concentrated in vacuo to give 14.3 g of 3-methylsulfonyl-4-trifluoromethoxyaniline.