Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH3:22])[CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:25](N1C=CN=C1)(N1C=CN=C1)=[O:26].[NH:37]([C:41]1[S:42][CH:43]=[C:44]([CH2:46][S:47][CH2:48][CH2:49][NH2:50])[N:45]=1)[C:38]([NH2:40])=[NH:39]>>[F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]([CH2:14][CH2:15][N:16]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:25]([NH:50][CH2:49][CH2:48][S:47][CH2:46][C:44]2[N:45]=[C:41]([NH:37][C:38]([NH2:40])=[NH:39])[S:42][CH:43]=2)=[O:26])[CH3:22])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(CCCCN)CCN(Cc1ccc(F)cc1)c1ccccn1
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Product: CN(CCCCNC(=O)NCCSCc1csc(NC(=N)N)n1)CCN(Cc1ccc(F)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 63, using 0.20 g (0.6 mmol) of N-[2-[N-(4-fluorobenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,4-butanediamine and the equimolar amounts of 1,1'-carbonyldiimidazole and 2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethaneamine as starting materials. Working up by chromatography analogously to Example 63 yields the purified title compound in the form of a viscous oil. MS (+FAB method): m/z (rel. int. [%])=588 ([M+H]+, 2), 109 (100); IR (KBr): 1685 cm-1 (C=O); C27H38FN9OS2 (587.90).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[S:13])[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:3][CH2:2]1.[CH2:14]=O.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>CO>[CH:1]1([NH:4][C:5](=[S:13])[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:14][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:3][CH2:2]1
Reactant: C=O
Reactant: S=C(Cc1ccccn1)NC1CC1
Reactant: C1COCCN1
Solvent: CO
Product: S=C(NC1CC1)C(CN1CCOCC1)c1ccccn1

Procedure:
By the procedure of Example 2, N-cyclopropyl-2-(2-pyridyl)thioacetamide is reacted with formaldehyde and morpholine in methanol to give N-cyclopropyl-3-morpholino-2-(2-pyridyl)thiopropanamide.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH:6]=[C:7]([OH:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:14][C:15]([C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1F)=[O:16].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH:6]=[C:7]([O:13][C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=3[C:15](=[O:16])[CH3:14])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Oc1cnc2c(F)c(F)ccc2c1
Reactant: CC(=O)c1c(F)cccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1c(F)cccc1Oc1cnc2c(F)c(F)ccc2c1
Temperature: 100 °C
Reaction time: 4.5 h
Yield: 40.2 %

Procedure:
After 0.91 g of 7,8-difluoro-3-hydroxyquinoline and 0.94 g of 2,6-difluoroacetophenone were dissolved in 10 ml of dimethylformamide, 0.9 g of potassium carbonate was added. The reaction solution was heated to 100° C. and the mixture was stirred for 4.5 hours. Dilute hydrochloric acid was added to the reaction solution and the solution was separated by ethyl acetate. The organic layer was concentrated and purified by silica gel column chromatography to obtain 0.64 g of 1-[2-(7,8-difluoroquinolin-3-yloxy)-6-fluoro-phenyl]-ethanone (Compound Number 391).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)=[CH:4][CH:3]=1.[CH2:23]=O.C[O-].[Na+].[BH4-].[Na+]>CO.CC(C)=O>[CH3:22][C@H:11]1[CH2:10][N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH3:23])=[CH:3][CH:4]=2)[CH2:14][CH2:13][N:12]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: C[C@H]1CN(Cc2ccc(N)cc2)CCN1C(=O)OC(C)(C)C
Reactant: C=O
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Product: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of D2 (4.14 g, 13.56 mmol) in dry MeOH (80 mL) at 50° C. under an argon atmosphere was added paraformaldehyde (1.22 g, 40.67 mmol) and sodium methoxide (3.65 g, 67.78 mmol). The mixture was stirred for ˜24 h then sodium borohydride (1.54 g, 40.67 mmol) was added portionwise and the reaction stirred at 50° C. overnight. After cooling to room temperature, acetone (10 mL) was added and the solvent removed in vacuo. The residue was partitioned between DCM and water and the organic phase was washed with brine, then dried and concentrated. Column chromatography gave the title compound as a colourless, crystalline solid (3.73 g). δH (CDCl3, 400 MHz) 7.13 (2H, d), 6.57 (2H, d), 4.16 (1H, br.s), 3.78 (1H, m), 3.67 (1H, br.s), 3.42 (1H, d), 3.30 (1H, d), 3.08 (1H, td), 2.83 (3H, s), 2.75 (1H, m), 2.59 (1H, m), 2.06 (1H, dd), 1.94 (1H, m), 1.45 (9H, s), 1.21 (3H, d).
Reaction SMILES: CC(C)[C@H]([NH:6][C@@H:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH2:8][CH3:9])CO.CN.I(O)(=O)(=O)=O>CO.O>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C@H:7]([NH2:6])[CH2:8][CH3:9]
Reactant: CC[C@@H](N[C@H](CO)C(C)C)c1ccccn1
Agent: CN
Agent: [O-][I+3]([O-])([O-])O
Solvent: O
Solvent: CO
Product: CC[C@@H](N)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-3-methyl-2-((R)-1-(pyridin-2-yl)propylamino)butan-1-ol (step 2, crude product) (40.8 mmol) in MeOH (250 ml) was added methylamine (60 ml of a 40% aqueous solution) followed by a solution of periodic acid (37.2 g, 163 mmol) in water (70 ml). The mixture was stirred at RT overnight and the resulting white solid precipitate was filtered off. The filtrate was concentrated in vacuo to remove the MeOH. The residual aqueous layer was then extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with a 0-20% MeOH/DCM gradient affords the title product; [M+H]+ 137.
Reaction SMILES: [CH3:1][C:2]([N+:11]([O-:13])=[O:12])([CH3:10])[CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[CH3:14][I:15]>C(O)C>[I-:15].[CH3:14][N+:4]1([CH2:3][C:2]([CH3:1])([N+:11]([O-:13])=[O:12])[CH3:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CI
Reactant: CC(C)(CN1CCCCC1)[N+](=O)[O-]
Solvent: CCO
Product: CC(C)(C[N+]1(C)CCCCC1)[N+](=O)[O-]
Product: [I-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 54.7 %

Procedure:
1-(2-Methyl-2-nitropropyl)piperidine (10.8 g, 57.9 mmol) was placed into a 48 mL pressure tube. Absolute ethanol (8.5 mL, 6.8 M) and methyl iodide (18.0 mL, 5 equiv, 0.29 mol) was added to the pressure tube. A stir bar was added and the pressure tube sealed. The reaction was left to stir at room temperature for 3 days. A thick yellow suspension had formed. The suspension was filtered and the solid washed with DCM to give a white powdery solid. The mother liquor was concentrated to deep yellow mushy solid. This solid was washed with DCM to give a white powdery solid. The two solids were combined and dried under high vacuum to give a white powder (10.4 g, 60%). 1H NMR (D2O, 400 MHz): δ 1.54-1.64 (m, 1H), 1.72-1.78 (m, 1H), 1.87 (s, 6H), 1.86-2.01 (m, 4H), 3.10 (s, 3 H), 3.42-3.51 (m, 4H), 4.20 (s, 2H). LRMS (ESI+) for C10H21N2O2+ (201.2); Found: 201 (M+).
Reaction SMILES: [CH:1]([P:3](=[O:17])([CH:15]=[CH2:16])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][CH3:14])[CH:5]=1)=[CH2:2].Cl.[CH2:19]([NH2:21])[CH3:20].[OH-].[Na+].C(N)C>C1COCC1>[CH2:19]([N:21]1[CH2:16][CH2:15][P:3](=[O:17])([C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][CH3:14])[CH:5]=2)[CH2:1][CH2:2]1)[CH3:20]
Reactant: CCN
Reactant: C=CP(=O)(C=C)c1ccc([N+](=O)[O-])c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN1CCP(=O)(c2ccc([N+](=O)[O-])c(OC)c2)CC1
Temperature: 105 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
Diethenyl(3-methoxy-4-nitrophenyl)phosphane oxide (0.480 g, 1.94 mmol), ethylamine hydrochloride (0.174 g, 2.12 mmol), and 1 N NaOH (2 mL) were dissolved in 50% aqueous THF (5 mL) and heated to 105° C. under nitrogen. After one hour, another portion of ethylamine was added to the reaction mixture. The reaction mixture was refluxed for an additional 2 h, and then cooled to it. The reaction mixture was partitioned between saturated aqueous NaHCO3 and CH2Cl2. The aqueous phase was washed once with CH2Cl2 and the organic layers were combined. The organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0-10% 7N ammonia in methanol:dichloromethane) to afford the compound (0.267 g, 46% yield).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:20]([CH2:27][CH2:28][CH2:29][CH2:30][Br:31])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1C=CC=CC=1>[Br-:31].[C:14]1([P+:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:30][CH2:29][CH2:28][CH2:27][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: BrCCCCOc1ccccc1
Solvent: c1ccccc1
Product: [Br-]
Product: c1ccc(OCCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 81 %

Procedure:
Triphenylphosphine and 4-phenoxybutyl bromide were refluxed in benzene for 36 hours to yield triphenyl(4-phenoxybutyl)phosphonium bromide in 81% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C:7]2[C:16]([OH:17])=[C:15]([C:18]([OH:20])=[O:19])[C:14]3[C:9](=[C:10](C4C=CC=CC=4)[CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[CH:4][CH:3]=1.[Br:29]C1C=CC=C2C=1NC(=O)C2=O.C(OCC(=O)CC1C=CC(Cl)=CC=1)(=O)C>>[Br:29][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[C:7]([CH2:6][C:5]1[CH:27]=[CH:28][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:16]([OH:17])=[C:15]2[C:18]([OH:20])=[O:19]
Reactant: O=C(O)c1c(O)c(Cc2ccc(Cl)cc2)nc2c(-c3ccccc3)cccc12
Reactant: O=C1Nc2c(Br)cccc2C1=O
Agent: CC(=O)OCC(=O)Cc1ccc(Cl)cc1
Product: O=C(O)c1c(O)c(Cc2ccc(Cl)cc2)nc2c(Br)cccc12
Yield: 23 %

Procedure:
This compound was synthesized by the procedure described above for Compound 2, reacting 7-Bromo-1H-indole-2,3-dione (1.00 g, 4.42 mmol) with intermediate 2 (1.25 g, 5.53 mmol). The crude acid was purified as described above for Compound 3, then recrystallized from acetonitrile to give product as large, bright yellow crystals (Compound 9, 0.398 g, 23% yield): 1H NMR (400 MHz, DMSO-D6) δ 4.35 (s, 2H) 7.35 (m, 4H) 7.46 (dd, J=8.6, 7.6 Hz, 1H) 7.92 (dd, J=7.5, 1.1 Hz, 1H) 8.50 (dd, J=8.6, 1.3 Hz, 1H); HRMS (ESI/FTMS) calcd for C17H12BrClNO3 (MH+) 391.9684, found 391.9689. Anal. Calcd for C17H11BrClNO3: C, 52.00; H, 2.82; N, 3.57. Found: C, 51.72; H, 2.77; N, 3.53.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[N:7]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[CH:6]=1)=[O:4].O[Li].O>O.C1COCC1.CO>[Cl:14][C:10]1[CH:9]=[C:8]2[C:13]([C:5]([C:3]([OH:4])=[O:2])=[CH:6][N:7]2[CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[CH:12][CH:11]=1
Reactant: COC(=O)c1cn(CCN(C)C)c2cc(Cl)ccc12
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CN(C)CCn1cc(C(=O)O)c2ccc(Cl)cc21
Temperature: 40 °C
Reaction time: 8 h

Procedure:
The ester was hydrolyzed in a mixture of H2O/THF/MeOH (ratio 1:1:1) with LiOH.H2O (3 eq.). The reaction mixture was stirred at 40° C. overnight. The acid was extracted several times with EtOAc, and the combined organic phases were dried over Na2SO4. Recrystallisation in Et2O afforded 35 mg (34% overall yield) of the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3]1.Cl.[F:11][CH2:12][CH2:13][NH:14][CH3:15]>>[F:11][CH2:12][CH2:13][N:14]([CH3:15])[C:7]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:9]
Reactant: CNCCF
Reactant: Cn1cc(C(=O)O)cn1
Agent: Cl
Product: CN(CCF)C(=O)c1cnn(C)c1

Procedure:
From 1-methyl-1H-pyrazole-4-carboxylic acid (1.0 g, 7.93 mmol) and 2-fluoro-N-methylethanamine hydrochloride (991 mg, 8.72 mmol). Yellow oil (1.41 g, 92%).
Reaction SMILES: [F:1][S:2]([F:15])([F:14])([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[N+:21]([O-])([OH:23])=[O:22]>>[F:1][S:2]([F:12])([F:13])([F:14])([F:15])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:21]([O-:23])=[O:22])[CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1cccc(S(F)(F)(F)(F)F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc([N+](=O)[O-])cc(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Pentafluorosulfanylbenzoic acid (3.0 g) was dissolved in fuming nitric acid (20 ml) and stirred at RT with exclusion of moisture. Concentrated sulfuric acid (1.5 ml) was then added and the mixture was stirred at 75° C. After stirring at 75° C. for 6 h, it was allowed to stand overnight, then further sulfuric acid (1.5 ml) was added and the mixture was heated at 75° C. for 8 h. After allowing to stand overnight, it was added to ice water and stirred for 2 h. The commencing crystallization was completed overnight in a refrigerator. The precipitate was then filtered off with suction and dried in a high vacuum. 2.7 g of 3-pentafluorosulfanyl-5-nitrobenzoic acid were obtained. It was possible to obtain a further 530 mg from the mother liquor after extracting three times with methylene chloride, drying the combined methylene chloride phases over magnesium sulfate and concentrating the solvent.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[CH2:10][N:9]([C:11](=[O:13])[CH3:12])[CH2:8][C:6]=2[N:7]=1.[CH:20]1([NH:23][C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=[C:29]([F:42])[CH:28]=2)=[O:25])[CH2:22][CH2:21]1>>[C:11]([N:9]1[CH2:10][C:5]2[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:3][C:2]([C:30]3[CH:31]=[CH:32][C:27]([NH:26][C:24]([NH:23][CH:20]4[CH2:22][CH2:21]4)=[O:25])=[CH:28][C:29]=3[F:42])=[N:7][C:6]=2[CH2:8]1)(=[O:13])[CH3:12]
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2F)OC1(C)C
Reactant: CC(=O)N1Cc2nc(Cl)nc(N3CCOCC3)c2C1
Product: CC(=O)N1Cc2nc(-c3ccc(NC(=O)NC4CC4)cc3F)nc(N3CCOCC3)c2C1
Yield: 15 %

Procedure:
Method as described for (S)-1-cyclopropyl-3-(3-fluoro-4-(6-methyl-4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea(example 147) using 1-(2-chloro-4-morpholino-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)ethanone (intermediate 23) and 1-cyclopropyl-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 29). Residue was then purified by prep. HPLC at high pH to afford a cream solid (15% yield).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([F:14])([F:13])[F:12])[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[C:4]2[CH:19]=[CH:20][CH:21]=[CH:22][C:3]1=2.[OH:23][C:24]([CH3:37])([C:28]([NH:30][CH2:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:29])[C:25](O)=[O:26].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[OH:23][C:24]([CH3:37])([C:28]([NH:30][CH2:31][CH2:32][C:33]([F:34])([F:35])[F:36])=[O:29])[C:25]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([F:14])([F:12])[F:13])[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[C:4]2[CH:19]=[CH:20][CH:21]=[CH:22][C:3]1=2)=[O:26]
Reactant: N[C@@H]1C(=O)N(CC(F)(F)F)c2ccccc2-c2ccccc21
Reactant: CC(O)(C(=O)O)C(=O)NCCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)(C(=O)NCCC(F)(F)F)C(=O)N[C@@H]1C(=O)N(CC(F)(F)F)c2ccccc2-c2ccccc21
Reaction time: 8 h
Yield: 65.4 %

Procedure:
A solution of 200 mg (0.65 mmol) (S)-7-amino-5-(2,2,2-trifluoro-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and 150 mg (0.65 mmol) (RS)-2-hydroxy-2-methyl-N-(3,3,3-trifluoro-propyl)-malonamic acid in 7 ml tetrahydrofuran were cooled to 0° C. and 102 mg (0.65 mmol) 1-hydroxy-benzotriazole hydrate, 228 μl (1.31 mmol) diisopropylethylamine and 128 mg (0.65 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride were added. Stirring was continued overnight at room temperature. Removal of the solvent by distillation and chromatography on silicagel with ethylacetate/heptane (gradient 1/4 to 4/1) yielded 220 mg (65%) (R/S)-2-hydroxy-2-methyl-N-[(S)-6-oxo-5-(2,2,2-trifluoro-ethyl)-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-N′-(3,3,3-trifluoro-propyl)-malonamide as a white solid, MS (m/e): 518.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:24][C:25]1[CH:26]=[C:27]([CH:34]=[CH:35][C:36]=1[CH3:37])[C:28]([NH:30][CH:31]1[CH2:33][CH2:32]1)=[O:29].N1C=CC=CC=1>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:24][C:25]2[CH:26]=[C:27]([CH:34]=[CH:35][C:36]=2[CH3:37])[C:28]([NH:30][CH:31]2[CH2:32][CH2:33]2)=[O:29])=[O:15])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
To a solution of 4-benzyloxybenzoic acid (11.0 g, 48 mmol) in DCM (100 mL) at 0° C. was added oxalyl chloride (8.4 mL, 96 mmol) followed by DMF (two drops). The resulting mixture was stirred at room temperature for 2 hours. The mixture was evaporated giving a white solid which was dissolved in DCM (50 mL). The resulting solution was added portionwise to a stirred solution of 3-amino-N-cyclopropyl-4-methylbenzamide (7.61 g, 40 mmol) and pyridine (7.76 mL, 96 mmol) in DCM (100 mL) at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The solid was collected by filtration and washed three times with DCM to give the title compound as a white solid (13.9 g, 87%); NMR Spectrum: (DMSOd6) 0.60 (m, 4H), 2.25 (s, 3H), 2.84 (m, 1H), 5.20 (s, 2H), 7.14 (d, 2H), 7.39 (m, 6H), 7.63 (d, 1H), 7.79 (s, 1H), 7.97 (d, 2H), 8.37 (s, 1H), 9.82 (s, 1H); Mass Spectrum: M+H+ 399.
Reaction SMILES: [C:1]1([S:7]([N@@:10]2[CH2:12][CH:11]2[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[C:31]1([N:37]=[C:38]=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:1]1([S:7]([N:10]2[CH2:12][C@H:11]([C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[CH3:28])[CH2:19][CH2:20]3)=[O:14])[N:37]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:38]2=[O:39])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3C[N@]3S(=O)(=O)c3ccccc3)CC2)c1
Reactant: O=C=Nc1ccccc1
Agent: [I-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)[C@H]3CN(S(=O)(=O)c4ccccc4)C(=O)N3c3ccccc3)CC2)c1

Procedure:
In analogy to example 2, ((R)-1-benzenesulfonyl-aziridin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone was reacted with sodium iodide and phenylisocyanate to give the title compound as a colorless solid. MS: 519.0 ([M+H]+)
Reaction SMILES: [OH2:1].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[C:19](Cl)(Cl)=[O:20].[OH-:23].[Na+]>C1C=CC(Cl)=C(Cl)C=1.C(Cl)Cl.[Cl-].[Na+].O.C(Cl)Cl.O>[CH3:11][C:9]([C:6]1[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=1)([C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=1)[CH3:10].[C:19]([OH:20])([OH:23])=[O:1]
Reactant: O=C(Cl)Cl
Reactant: O
Reactant: [OH-]
Agent: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Clc1ccccc1Cl
Solvent: ClCCl
Product: O=C(O)O

Procedure:
As used herein, the term polymer includes both high molecular weight polymers, for example bisphenol A polycarbonate having a number average molecular weight Mn of 10,000 atomic mass units (amu) or more, and relatively low molecular weight oligomeric materials, for example bisphenol A polycarbonate having a number average molecular weight of about 800 amu. Typically, the polymer-solvent mixture is a product mixture obtained after a polymerization reaction, or polymer derivatization reaction, conducted in a solvent. For example, the polymer-solvent mixture may be the product of the condensation polymerization of bisphenol A dianhydride (BPADA) with m-phenylenediamine in the presence of phthalic anhydride chainstopper in ODCB, or the polymerization of a bisphenol, such as bisphenol A, with phosgene conducted in a solvent such as methylene chloride. In the first instance, a water soluble catalyst is typically employed in the condensation reaction of BPADA with m-phenylenediamine and phthalic anhydride, and this catalyst can removed prior to any polymer isolation step. Thus, the product polyetherimide solution in ODCB is washed with water and the aqueous phase is separated to provide a water washed solution of polyetherimide in ODCB. In such an instance, the water washed solution of polyetherimide in ODCB may serve as the polymer-solvent mixture which is separated into polymeric and solvent components using the method described herein. Similarly, in the preparation of bisphenol A polycarbonate by reaction of bisphenol A with phosgene in a methylene chloride-water mixture in the presence of an inorganic acid acceptor such as sodium hydroxide, the reaction mixture upon completion of the polymerization is a two-phase mixture of polycarbonate in methylene chloride and brine. The brine layer is separated and the methylene chloride layer is washed with acid and pure water. The organic layer is then separated from the water layer to provide a water washed solution of bisphenol A polycarbonate in methylene chloride. Here again, the water washed solution of bisphenol A polycarbonate in methylene chloride may serve as the polymer-solvent mixture which is separated into polymeric and solvent components using the method described herein.
Reaction SMILES: [C:1]1(B(O)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH2:21][N:22]2[CH:26]=[CH:25][N:24]=[C:23]2[CH3:27])[N:18]=[N:19][CH:20]=1>>[ClH:14].[CH3:27][C:23]1[N:22]([CH2:21][C:17]2[N:18]=[N:19][CH:20]=[C:15]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)[CH:16]=2)[CH:26]=[CH:25][N:24]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Product: Cc1nccn1Cc1cc(-c2ccc3ccccc3c2)cnn1
Product: Cl

Procedure:
The title compound, MS: m/e=301.3 (M+H+), was prepared from naphtylboronic acid and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [CH:1]1([N:7]2[C:12](=O)[NH:11][C:10]([O:14][CH3:15])=[N:9][S:8]2(=[O:17])=[O:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)(Cl)[Cl:19]>P(Cl)(Cl)(Cl)=O>[Cl:19][C:12]1[N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[S:8](=[O:17])(=[O:16])[N:9]=[C:10]([O:14][CH3:15])[N:11]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COC1=NS(=O)(=O)N(C2CCCCC2)C(=O)N1
Solvent: O=P(Cl)(Cl)Cl
Product: COC1=NS(=O)(=O)N(C2CCCCC2)C(Cl)=N1

Procedure:
A mixture of the thiatriazinone from Step 2. above (77.3 g) and phosphorus pentachloride (92.4 g) in phosphorus oxychloride (230 ml) is refluxed overnight. The reaction mixture is evaporated at 50° C. yielding an oil (92.3 g) which is used without further purification in the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[F:18][C:19]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][C:22]([NH2:23])=[C:21]([O:29][CH3:30])[CH:20]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)CCC>[Cl:17][C:5]1[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[N:7][C:2]([NH:23][C:22]2[CH:24]=[C:25]([N+:26]([O-:28])=[O:27])[C:19]([F:18])=[CH:20][C:21]=2[O:29][CH3:30])=[N:3][CH:4]=1
Reactant: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCCC(C)O
Product: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Temperature: 125 °C

Procedure:
A mixture of 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (Intermediate 11, 391 mg, 1.48 mmol), 4-fluoro-2-methoxy-5-nitroaniline (Intermediate 23, 289 mg, 1.55 mmol) and p-toluenesulfonic acid monohydrate (310 mg, 1.63 mmol) in 2-pentanol (25 mL) was heated at 125° C. for 18 h. The mixture was cooled and used in the next step without further purification; m/z: ES+ MH+ 414.12.