Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[S:12][C:13]([S:16][C:17]#N)=[CH:14][N:15]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].SC[C@H]([C@@H](CS)O)O.ClC1[CH:33]=[CH:32][N:31]=[C:30]([C:34]([O:36][CH3:37])=[O:35])[C:29]=1[F:38].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CO.O.CN(C=O)C>[F:38][C:29]1[C:30]([C:34]([O:36][CH3:37])=[O:35])=[N:31][CH:32]=[CH:33][C:17]=1[S:16][C:13]1[S:12][C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=2)=[N:15][CH:14]=1
Reactant: N#CSc1cnc(Nc2ccc([N+](=O)[O-])cn2)s1
Reactant: COC(=O)c1nccc(Cl)c1F
Agent: O=P([O-])([O-])[O-]
Agent: O[C@H](CS)[C@H](O)CS
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nccc(Sc2cnc(Nc3ccc([N+](=O)[O-])cn3)s2)c1F
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a stirring suspension of N-(5-nitropyridin-2-yl)-5-thiocyanatothiazol-2-amine (2.00 g, 7.16 mmol) in MeOH (72 mL) was added dithiothreitol (2.22 g, 14.39 mmol). After 5 minutes, methyl 4-chloro-3-fluoropicolinate (1.51 g, 7.97 mmol), K3PO4 (1.98 g, 9.33 mmol) and DMF (72 mL) were sequentially added. After 2 hours, the reaction was poured into an ice/water (˜1.4 L) mixture with stirring for 90 minutes, diluted to ˜3.5 L with water, allowed to sit overnight. The solid was collected by filtration, washed with water and allowed to air dry overnight. The product was obtained (2.384 g, 82%) as a solid: 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.68 (1H, s), 9.19 (1H, d, J=2.78 Hz), 8.53 (1H, dd, J=9.35, 2.78 Hz), 8.32 (1H, d, J=5.05 Hz), 7.96 (1H, s), 7.23 (1H, d, J=9.35 Hz), 7.15 (1H, t, J=5.43 Hz), 3.89 (3H, s); LC/MS (M+H)+: 408. HPLC ret. time (Condition B): 1.78 min.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:26]2[CH:31]=[CH:30][C:29]([O:32]C)=[CH:28][CH:27]=2)=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12]C)[CH:6]=2>C(Cl)(Cl)Cl.CO>[OH:12][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([CH3:1])[C:3]([C:26]3[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=3)=[C:4]2[O:14][C:15]2[CH:16]=[CH:17][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[CH:19][CH:20]=2)=[CH:9][CH:8]=1
Reactant: COc1ccc(-c2c(C)cc3ccc(OC)cc3c2Oc2ccc(/C=C/C(=O)O)cc2)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1cc2ccc(O)cc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1ccc(O)cc1

Procedure:
Synthesized in a manner similar to Example 46 (Step 8) using (2E)-3-[4-({3-methyl-7-(methyloxy)-2-[4-(methyloxy)phenyl]-1-naphthalenyl}oxy)phenyl]-2-propenoic acid (266). 1H NMR (CD3OD, 400 MHz) δ 7.71 (d, J=8.6 Hz, 1H), 7.58 (s, 1H), 7.49 (d, J=15.5 Hz, 1H), 7.34 (d, J=8.4 Hz, 2H), 7.04 (dd, J=8.7, 2.0 Hz, 1H), 7.00 (s, 1H), 6.94 (d, J=8.5 Hz, 2H), 6.68 (d, J=8.4 Hz, 2H), 6.58 (d, J=8.4 Hz, 2H), 6.27 (d, J=15.2 Hz, 1H), 2.19 (s, 3H). TLC (90:10; CHCl3/MeOH): Rf=0.19.
Reaction SMILES: [CH2:1]([S:3]([NH:6][CH2:7][CH2:8][C:9]([O:11]C)=O)(=[O:5])=[O:4])[CH3:2].[Cl:13][C:14]1[CH:32]=[CH:31][C:17]2[O:18][C:19]3[CH:30]=[CH:29][CH:28]=[CH:27][C:20]=3[CH2:21][N:22]([C:23]([NH:25][NH2:26])=[O:24])[C:16]=2[CH:15]=1>>[CH2:1]([S:3]([NH:6][CH2:7][CH2:8][C:9]([NH:26][NH:25][C:23]([N:22]1[CH2:21][C:20]2[CH:27]=[CH:28][CH:29]=[CH:30][C:19]=2[O:18][C:17]2[CH:31]=[CH:32][C:14]([Cl:13])=[CH:15][C:16]1=2)=[O:24])=[O:11])(=[O:4])=[O:5])[CH3:2]
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: CCS(=O)(=O)NCCC(=O)OC
Product: CCS(=O)(=O)NCCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-[(ethylsulfonyl)amino]-1-oxopropyl]hydrazide (22) was prepared from N-(ethylsulfonyl)-β-alanine, methyl ester (21), prepared as described above in Example 21, and 8-chlorodibenz[b,f][1,4]-oxazepine-10(11H)-carboxylic acid, hydrazide (1), prepared as described above in Example 1, in the manner described in Example 18 above on a 2.0 mmol scale to yield 0.25 g (28%) of product.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:29](OC)=[O:30])=[C:11]2[C:15]=1[N:14]=[C:13]1[N:16]([C:20]3[C:25]([CH3:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=3[Cl:28])[CH2:17][CH2:18][CH2:19][N:12]21.O1[CH2:37][CH2:36][CH2:35]C1>>[Cl:6][C:7]1[C:15]2[N:14]=[C:13]3[N:16]([C:20]4[C:25]([CH3:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=4[Cl:28])[CH2:17][CH2:18][CH2:19][N:12]3[C:11]=2[C:10]([C:29]([CH:35]2[CH2:36][CH2:37]2)([CH:1]2[CH2:3][CH2:2]2)[OH:30])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(C)cc(Cl)cc1Cl
Reactant: C1CCOC1
Reactant: Br[Mg]C1CC1
Product: Cc1cc(Cl)cc(Cl)c1N1CCCn2c1nc1c(Cl)ccc(C(O)(C3CC3)C3CC3)c12
Temperature: 60 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Cyclopropylmagnesium bromide (1.0 M solution in tetrahydrofuran, 2.4 mL, 2.4 mmol) was added to a stirred solution of methyl 9-chloro-1-(2,4-dichloro-6-methylphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (200 mg, 0.471 mmol) in tetrahydrofuran (3.0 mL), and the mixture was stirred at 60° C. for 8 hr. The reaction was quenched by aqueous saturated ammonium chloride, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 8-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (179 mg, 0.375 mmol, 80%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9](Cl)([Cl:11])=[O:10].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C1(C)C=CC=CC=1>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:9]([Cl:11])=[O:10]
Reactant: O=C(Cl)Cl
Reactant: CNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CN(C(=O)Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
A vigorously stirred solution of 10.7 g (0.1 mole) of N-methylaniline in 100 ml of acetonitrile was added dropwise under a nitrogen atmosphere to a cold mixture of 155 ml (0.3 mole) of a 1.93M solution of phosgene in toluene and 83.0 g (0.6 mole) of anhydrous potassium carbonate in 200 ml of acetonitrile. After the final addition, the mixture was stirred at ambient temperature for 16 h, filtered, and the filtrate concentrated under reduced pressure. The residue was recrystallized from benzene/petroleum ether (60°-110° C.) to yield 15.9 g (94%) of white solid, mp 85°-86° C.
Reaction SMILES: N[C@H:2]([C:8]([OH:10])=O)CCC(=O)O.[NH2:11][CH2:12][C:13]([OH:15])=[O:14].[NH2:16][C@H](C(O)=O)[C@@H](C)O>>[NH2:11][C@H:12]([C:13]([OH:15])=[O:14])[CH2:2][C:8](=[O:10])[NH2:16]
Reactant: C[C@@H](O)[C@H](N)C(=O)O
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: NCC(=O)O
Product: NC(=O)C[C@H](N)C(=O)O

Procedure:
1.1 (1), Glu:2.0 (2), Ser:2.3 (2), Gly:4.4 (4), Thr:1.0 (1),
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[C:4]([C:8]([OH:10])=O)=[N:3]1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][CH:44]=1)[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([N:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[CH:32]=1>CN(C)C=O.CN(C)C(=O)C>[CH:39]1([C:37]([NH:36][C:34]2[N:35]=[C:30]3[CH:29]=[CH:28][C:27]([O:26][C:25]4[CH:24]=[C:23]([NH:22][C:8]([C:4]5[C:5]([CH3:7])=[CH:6][N:2]([CH3:1])[N:3]=5)=[O:10])[CH:44]=[CH:43][CH:42]=4)=[CH:32][N:31]3[N:33]=2)=[O:38])[CH2:40][CH2:41]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: Cc1cn(C)nc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1cn(C)nc1C(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Yield: 68.9 %

Procedure:
In the same manner as in Example 18-4 and using 1,4-dimethyl-1H-pyrazole-3-carboxylic acid (127 mg, 0.904 mmol), tetrahydrofuran (8 mL), oxalyl chloride (86.7 μL, 0.994 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (60.0 mg, 0.194 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (3 mL) as starting materials, the title compound (57.7 mg, 69%) was obtained as a white solid.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([S:9][C:10]2[C:15]([Cl:16])=[CH:14][N+:13]([O-:17])=[CH:12][C:11]=2[Cl:18])=[C:6]([N+:19]([O-:21])=[O:20])[CH:5]=1)([OH:3])=O.[CH3:22][N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1>>[Cl:18][C:11]1[CH:12]=[N+:13]([O-:17])[CH:14]=[C:15]([Cl:16])[C:10]=1[S:9][C:7]1[S:8][C:4]([C:1](=[O:3])[NH:29][CH:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)=[CH:5][C:6]=1[N+:19]([O-:21])=[O:20]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)c[n+]([O-])cc2Cl)s1
Reactant: CN1CCC(N)CC1
Product: CN1CCC(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)c[n+]([O-])cc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for example 70 from 4-((5-carboxy-3-nitrothiophen-2-yl)thio)-3,5-dichloropyridine N-oxide (200 mg, 0.54 mmol) from above and 1-methylpiperidin-4-amine (64.0 mg, 0.65 mmol). The title compound was obtained as a solid (70.0 mg, 28% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, m), 8.67 (1H, m), 8.51 (1H, s), 3.65 (1H, m), 2.85 (2H, m), 2.50 (3H, s), 2.24 (2H, m), 1.77 (2H, m), 1.57 (2H, m). MS m/z: 463.08, 465.08 [M+H]+.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][SH:3].[CH3:8][N:9]([CH3:22])[CH:10]=[N:11][C:12]1[S:13][C:14]([CH:20]=O)=[C:15](Cl)[C:16]=1[C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C)C=O>[CH3:22][N:9]([CH3:8])[CH:10]=[N:11][C:12]1[S:13][C:14]2[CH:20]=[C:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])[S:3][C:15]=2[C:16]=1[C:17]#[N:18]
Reactant: CCOC(=O)CS
Reactant: CN(C)C=Nc1sc(C=O)c(Cl)c1C#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2sc(N=CN(C)C)c(C#N)c2s1
Temperature: 50 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
120 parts of ethyl thioglycolate were added to a mixture of 241.5 parts of N,N-dimethyl-N'-(4-chloro-3-cyano-5-formylthien-2-yl)formamidine, 138 parts of potassium carbonate and 1,400 parts of N,N-dimethylformamide. After the slightly exothermic reaction had died down, the reaction mixture was stirred at 50° C. for 2 hours. 1,000 parts of ice, 1,000 parts of water and 150 parts of concentrated hydrochloric acid were then added. The precipitate was filtered off with suction, washed with water and dried. This gave 284 parts (93% of theory) of N,N-dimethyl-N'-(3-cyano-5-ethoxycarbonylthieno[3,2-b]thien-2-yl)formamidine.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:4]=1I)[CH3:2].[CH3:14][N:15]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:34]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[C:23]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:34])[N:15]([CH3:14])[CH:24]=1)[CH3:2]
Reactant: CCc1ccc(S(C)(=O)=O)cc1I
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2ccccc2c1=O
Product: CCc1ccc(S(C)(=O)=O)cc1-c1cn(C)c(=O)c2ccccc12

Procedure:
The title compound of Example 312, step 3 was reacted with the title compound of Example 89, step 1 in a manner similar to Example 312, step 4 to give the title compound. 1H NMR (400 MHz, CDCl3): δ 1.10 (3H, t, J=8.0 Hz), 2.51-2.56 (2H, m), 3.10 (3H, s), 3.67 (3H, s), 6.97-7.02 (2H, m), 7.52-7.59 (3H, m), 7.80 (1H, s), 7.97 (1H, d, J=8.0 Hz), 8.54 (1H, d, J=8.0 Hz). LCMS: 342 (M+1)+
Reaction SMILES: [OH-:1].[Na+].[C:3]1(=[O:10])[NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>>[NH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:10])=[O:1]
Reactant: O=C1CCCCCN1
Reactant: [OH-]
Agent: [Na+]
Product: NCCCCCC(=O)O

Procedure:
The removal of water takes place in the presence of a total of less than 20 mmol of sodium hydroxide, in aqueous solution, per kg of caprolactam. The aqueous sodium hydroxide solution for this is added to the caprolactam prior to the evaporators. The aqueous sodium hydroxide solution is to react with caprolactam to give the Na-salt of 6-aminocaproic acid. This salt, according to DD-A-202870, has the same purification effect as sodium hydroxide, but, in contrast to sodium hydroxide, does not cause any caprolactam oligomerization.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@@:11]([OH:19])([CH2:16][CH:17]=[CH2:18])[CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O>C(Cl)Cl>[CH2:16]([C@:11]1([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12][C:13](=[O:15])[O:19]1)[CH:17]=[CH2:18]
Reactant: C=CC[C@@](O)(CC(=O)O)C(=O)OCc1ccccc1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC[C@]1(C(=O)OCc2ccccc2)CC(=O)O1
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
A solution of hydroxyacid 81 (1.02 g, 3.86 mmol, 1.00 equiv) and triethylamine (519 μL, 17.37 mmol, 4.50 equiv) in CH2Cl2 (77 mL) was added via syringe pump over 4 h to a solution of 2,4,6-trichlorobenzoyl chloride (904 μL, 5.79 mmol, 1.50 equiv) and N,N-dimethylaminopyridine (DMAP) (519 mg, 4.25 mmol, 1.10 equiv) in CH2Cl2 (39 mL). The solution was then allowed to stir for 30 minutes after complete addition after which it was quenched with H2O (100 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (2×100 mL). The organic phases were combined, dried over MgSO4, and the solvent was removed via rotary evaporation to yield a black oil which was purified by silica gel column chromatography (CH2Cl2) to yield 82 (639 mg, 67%) as a yellow oil. Rf=0.52 (CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.38 (m, 5H, aryl H), 5.76 (m, 1H, vinyl H), 5.26 (s, 2H, PhCH2), 5.22 (m, 2H, vinyl H), 3.65 (d, 1H, J=16.5 Hz, C(O)CH2), 3.42 (d, 1H, J=16.5 Hz, C(O)CH2), 2.89 (dd, 1H, J=14.6, 6.8 Hz, CHCH2), 2.80 (dd, 1H, J=14.6, 6.8 Hz, CHCH2); 13C NMR (125 MHz, CDCl3) δ 169.03, 165.61, 134.75, 129.10, 128.95, 128.89, 128.59, 121.82, 75.65, 68.17, 45.86, 39.06; IR (neat film) 3034 (w), 1843 (s), 1741 (s), 1644 (w), 1456 (m) cm−1; LRMS (ESI) calcd. for C14H14O4Na (M+Na+) 269.1, observed 269.1.
Reaction SMILES: [C:1]1([OH:8])(O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:12]1[N:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([N:28]([CH3:30])[CH3:29])=[C:24]([CH3:31])[CH:23]=2)[CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[N:17]2>CC(N(C)C)=O.ClCCl>[OH:8][C@H:1]1[CH2:2][CH2:3][C@H:4]([C:12]2[N:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([N:28]([CH3:30])[CH3:29])=[C:24]([CH3:31])[CH:23]=3)[CH:19]=[C:18]3[C:13]=2[CH:14]=[CH:15][CH:16]=[N:17]3)[CH2:5][CH2:6]1
Reactant: OC1(O)CCCCC1
Reactant: Cc1cc(-c2cc3ncccc3c(Cl)n2)ccc1N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2cc3ncccc3c([C@H]3CC[C@H](O)CC3)n2)ccc1N(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
200 mg (1.7 mmol) cyclohexanediol was placed in 1.5 ml dimethylacetamide and 47 mg (1.17 mmol) sodium hydride (60%) were added and the mixture was stirred for 15 min at ambient temperature. Then 100 mg (0.31 mmol) 6.1 was added and the mixture was stirred for 2 h at 70° C. The reaction mixture was diluted with dichloromethane and extracted 1× with water. The organic phase was dried with MgSO4 and evaporated down. The residue was purified by chromatography (RP-HPLC-MS). The corresponding fractions were freeze-dried.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:23][C:24]1[C:32]2[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([NH2:39])[CH:34]=3)=[N:30][C:29]([CH3:40])=[N:28][C:27]=2[S:26][C:25]=1[C:41](O)=[S:42].CCN(C(C)C)C(C)C.[C:53]([NH2:57])([CH3:56])([CH3:55])[CH3:54]>C(Cl)Cl.CN(C=O)C.C(Cl)Cl>[C:53]([NH:57][C:41]([C:25]1[S:26][C:27]2[N:28]=[C:29]([CH3:40])[N:30]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([NH2:39])[CH:34]=3)[C:32]=2[C:24]=1[NH2:23])=[S:42])([CH3:56])([CH3:55])[CH3:54]
Reactant: CC(C)(C)N
Reactant: Cc1nc(-c2cccc(N)c2)c2c(N)c(C(O)=S)sc2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(-c2cccc(N)c2)c2c(N)c(C(=S)NC(C)(C)C)sc2n1
Reaction time: 3 h

Procedure:
TBTU (16.1 g) was added to a solution of 5-amino-4-(3-aminophenyl)-2-methylthio-thieno[2,3-d]pyrimidine-6-carboxylic acid (example 1(f), 14.0 g), DIPEA (17.4 ml) and tert-butylamine (7.3 g) in DCM/DMF (1/1, v/v, 250 ml). After 3 h at room temperature, the mixture was diluted with DCM (50 ml), washed with sat. aq. NaHCO3 (3×100 ml), 0.1 N aq. HCl (100 ml) and water (100 ml). The organic layer was concentrated under reduced pressure. The crude product was purified by crystallisation from warm abs.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:63][O:64][C:65](=[O:78])[C:66]1[CH:71]=[CH:70][C:69]([NH2:72])=[C:68]([O:73][CH2:74][CH2:75][CH2:76][CH3:77])[CH:67]=1>>[CH3:63][O:64][C:65](=[O:78])[C:66]1[CH:71]=[CH:70][C:69]([NH:72][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:37])([CH3:35])[CH3:36])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[C:68]([O:73][CH2:74][CH2:75][CH2:76][CH3:77])[CH:67]=1
Reactant: CCCCOc1cc(C(=O)OC)ccc1N
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1cc(C(=O)OC)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.4 g, 0.69 mmol), was reacted with diisopropylethylamine (0.46 g, 3.6 mmol), diphenylphosphinic chloride (0.34 g, 1.4 mmol), then reacted with 4-amino-3-butoxy-benzoic acid methyl ester (0.24 g, 1.1 mmol) prepared in Example 149 to give rac-3-butoxy-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-benzoic acid methyl ester as a light brown solid (Yield, 0.14 g, 30%).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:30])[C:4](=[O:29])[C:5]([C:20]2[CH:21]=[C:22]([CH:27]=[O:28])[N:23]([CH2:25][CH3:26])[CH:24]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[C:14]([F:19])=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:8]=2)[N:6]=1.[BH4-].[Na+].[CH2:33](O)C>>[NH2:1][C:2]1[N:3]([CH3:30])[C:4](=[O:29])[C:5]([C:20]2[CH:21]=[C:22]([CH2:27][O:28][CH3:33])[N:23]([CH2:25][CH3:26])[CH:24]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[C:14]([F:19])=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:8]=2)[N:6]=1
Reactant: CCO
Reactant: CCn1cc(C2(c3cccc(-c4cccnc4F)c3)N=C(N)N(C)C2=O)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Product: CCn1cc(C2(c3cccc(-c4cccnc4F)c3)N=C(N)N(C)C2=O)cc1COC
Reaction time: 8 h

Procedure:
A solution of 4-{2-amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}-1-ethyl-1H-pyrrole-2-carbaldehyde in dry ethanol was treated with 2 equivalents of sodium borohydride at 0° C., allowed to come to room temperature, quenched with water and evaporated to dryness under reduced pressure. The resultant residue is dispersed in water and extracted with ethyl acetate. The extracts are combined, dried over MgSO4 and concentrated in vacuo. The resultant residue was dissolved in 0.5M methanolic HCl, stirred overnight and evaporated to dryness under reduced pressure. This residue was dissolved in chloroform, washed with dilute sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo. The resultant residue was purified using flash chromatography and was crystallized from ethylacetate/hexane to give the title compound as a solid, mp 154-157° C., identfied by NMR and mass spectral analyses.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[C:13]([CH3:14])=[C:12]([C:15](=O)[NH2:16])[N:11]([CH3:18])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCOCC1>[F:1][C:2]1[C:3]([C:9]2[C:13]([CH3:14])=[C:12]([C:15]#[N:16])[N:11]([CH3:18])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1c(-c2ncc(Cl)cc2F)nn(C)c1C(N)=O
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Product: Cc1c(-c2ncc(Cl)cc2F)nn(C)c1C#N
Temperature: 22 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
1.82 g of 3-(3-fluoro-5-chloro-2-pyridyl)-4-methyl-5-carbamoyl-1-methyl-[1H]-pyrazole (Example H44) are suspended in 20 ml of dioxane. First 1.65 ml of pyridine and then 1.44 ml of trifluoroacetic anhydride are added, while cooling in an ice-bath. 5 minutes later, the cooling bath is removed and the mixture is stirred at 22° C. for 1 hour. The brown-red solution is diluted with diethyl ether and washed with one molar hydrochloric acid and then with brine. After drying over sodium sulfate and filtering, the filtrate is concentrated directly together with twice the amount of silica gel. After application of this silica gel to a flash column, the column is eluted with n-hexane/ethyl acetate 4/1. 1.60 g of the desired title compound are obtained as a beige solid of melting point 144-146° C.
Reaction SMILES: Cl.[N:2]1([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10][N:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.S(C1C=CC(C)=CC=1)(O[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:24]=1[N+:30]([O-:32])=[O:31])(=O)=O>>[CH3:29][C:25]1[C:24]([N+:30]([O-:32])=[O:31])=[C:23]([CH2:22][CH2:21][N:5]2[CH2:6][CH2:7][N:2]([C:8]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[S:10][N:9]=3)[CH2:3][CH2:4]2)[CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: Cc1ccc(S(=O)(=O)OCCc2cccc(C)c2[N+](=O)[O-])cc1
Agent: Cl
Product: Cc1cccc(CCN2CCN(c3nsc4ccccc34)CC2)c1[N+](=O)[O-]
Yield: 11 %

Procedure:
3-{4-[2-(3-Methyl-2-nitro-phenyl)-ethyl]-piperazin-1-yl}-1,2-benzisothiazole was prepared according to the general method as outlined in Preparation 2 starting with 3-piperazin-1-yl-benzoisothiazole hydrochloride (1.71 g, 6.7 mmol) and 3-methyl-2-nitrophenethyl tosylate (1.8 g, 5.37 mmol). The product was isolated via column chromatography to afford 290 mg of brown oil. Yield 11%; MS (APCI): 383 [M+H]+.
Reaction SMILES: [C:1]1([Li])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:15]([SiH:18]([Cl:20])Cl)[CH:16]=[CH2:17].[CH2:21](OCC)C>>[CH2:15]([SiH:18]([Cl:20])[CH2:21][C:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1)[CH:16]=[CH2:17]
Reactant: [Li]c1cccc2c1Cc1ccccc1-2
Reactant: CCOCC
Reactant: C=CC[SiH](Cl)Cl
Product: C=CC[SiH](Cl)Cc1cccc2c1Cc1ccccc1-2
Temperature: 25 °C

Procedure:
8.6 g (50 mmol) of compound II were dissolved in 250 ml of diethyl ether. At room temperature and with stirring, 11.1 g (72 mmol) of allyldichlorosilane (compound III) were added to this mixture, which was then stirred at room temperature for a further 3 h. The solvent was subsequently completely removed under reduced pressure and the residue was taken up in 200 ml of petroleum ether. The lithium chloride was centrifuged off, the supernatant was concentrated to a volume of about 20 ml and the reaction product was crystallized at −78° C. The yield was 8.59 g (60.4%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][S:6][C:7]1[S:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1>S(=O)(=O)(O)O>[CH3:5][S:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([N+:1]([O-:4])=[O:2])[CH:13]=[CH:12][C:10]=2[N:11]=1
Reactant: CSc1nc2ccccc2s1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CSc1nc2ccc([N+](=O)[O-])cc2s1
Temperature: 5 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
See FIG. 4A. Fuming nitric acid (1.93 g) was added dropwise to a solution of 2-(methylthio)benzothiazole (5 g) in concentrated sulfuric acid (16.8 g) cooled in an ice bath. After stirring at 5° C. for 3 h the solution was poured onto ice and filtered to provide a yellow solid (5.7 g, 25 mmol, 91%).