Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[C:10](Cl)=[CH:9][C:8]([Cl:12])=[N:7][CH:6]=1)[CH3:2].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[C:10]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][C:8]([Cl:12])=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Reactant: Nc1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(Cl)cc1Nc1ccccc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
4,6-Dichloronicotinic acid ethyl ester 16 (500 mg, 2.27 mmol) is dissolved in anhydrous dioxane (10 mL) and aniline (0.66 mL, 7.72 mmol) is added. The reaction is stirred at 100° C. overnight. The solvent is removed in vacuo and the crude product is purified using flash chromatography (hexane:ethyl acetate=10:1) to give 6-chloro-4-phenylamino-nicotinic acid ethyl ester 17. 1H NMR (400 MHz, CDCl3) δ 9.77 (s, 1H), 8.70 (s, 1H), 7.33-7.37 (m, 2H), 7.15-7.21 (m, 3H), 6.80 (s, 1H), 4.31 (q, 2H), 1.34 (t, 3H).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([OH:20])=[C:15]([Cl:21])[CH:14]=1>>[Cl:19][C:17]1[CH:18]=[C:13]([NH2:12])[CH:14]=[C:15]([Cl:21])[C:16]=1[O:20][C:2]1[S:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Clc1ccc2nc(Cl)sc2c1
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Product: Nc1cc(Cl)c(Oc2nc3ccc(Cl)cc3s2)c(Cl)c1

Procedure:
3,5-Dichloro-4-(6-chloro-benzothiazol-2-yloxy)-phenylamine was synthesized (65%) from 2,6-dichlorobenzotiazole (259) and 4-amino-2,6-dichlorophenol (Aldrich) in a similar manner as described in Example 417. 1H NMR (400 MHz, DMSO-d6) δ 8.10 (d, J=2.2 Hz, 1H), 7.78 (d, J=8.7 Hz, 1H), 7.47 (dd, J=8.7, 2.2 Hz, 1H), 6.73 (s, 2H), 5.88 (s, 2H). MS (EI): m/z 345 (M+H).
Reaction SMILES: [Br:1][C:2]1[N:6]([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=O)[C:5]([C:18]([O:20]C)=O)=[CH:4][CH:3]=1.[CH2:22]([NH2:25])[CH2:23][NH2:24]>O1CCOCC1>[Br:1][C:2]1[N:6]2[CH2:7][C:8]3([C:10]4[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=4)[NH:25][CH2:22][CH2:23][N:24]3[C:18](=[O:20])[C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Br)n1CC(=O)c1ccc(OC)cc1
Reactant: NCCN
Solvent: C1COCCO1
Product: COc1ccc(C23Cn4c(Br)ccc4C(=O)N2CCN3)cc1
Yield: 52.5 %

Procedure:
To a solution of methyl 5-bromo-1-[2-(4-methoxyphenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylate (250 mg, 0.71 mmol) in 1,4-dioxane (50 mL) was added ethane-1,2-diamine (1.0 mL, 15 mmol). The solution was heated at reflux one week. During that time a batch of ethane-1,2-diamine (1.5 mL, 22 mmol) was added. The mixture was concentrated in vacuo to give a oil that was partitioned between water (30 mL) and CH2Cl2 (30 mL). The aqueous layer was further extracted with CH2Cl2 (2×30 mL). The organic layers were dried (MgSO4), filtered and concentrated in vacuo to give a oil that was purified by flash chromatography (Biotage SP4, 12 g cartridge, gradient 0-10% methanol in CH2Cl2) to give 8-bromo-10a-(4-methoxyphenyl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one as a pale yellow solid (135 mg, yield 52%). ESI-MI m/z calculated [M+H]+ 364.0.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:21]([OH:25])[C:22](O)=[O:23])=[O:18])[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([N:40]([C:49]([CH3:52])([CH3:51])[CH3:50])[C:41](=[O:48])[C@@H:42]1[CH2:46][C@@H:45]([Cl:47])[CH2:44][NH:43]1)=O)(C)(C)C>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C@H:21]([OH:25])[C:22]([N:43]1[CH2:44][C@H:45]([Cl:47])[CH2:46][C@H:42]1[C:41]([NH:40][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:48])=[O:23])=[O:18])[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)[C@@H]1C[C@@H](Cl)CN1)C(C)(C)C
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H](Cl)CN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Yield: 24 %

Procedure:
Following a procedure similar to that described in Example 1, but using 146 mg (0.33 mmol) of (2S,3S)-3-(N2 -benzyloxycarbonyl-L-asparaginyl)amino-2-hydroxy-4-phenylbutyric acid and 100 mg (0.33 mmol) of (4R)-N-t-butoxycarbonyl-4-chloro-N-t-butyl-L-prolinamide, 50 mg of the title compound were obtained as a colorless powder, melting at 103°-107° C.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[CH:14]([NH:18]C1C(=O)NC=CC=1)[C:15]([NH2:17])=[O:16].N>>[NH2:18][CH:14]([C:8]1[C:9]([Cl:13])=[CH:10][CH:11]=[CH:12][C:7]=1[Cl:6])[C:15]([NH2:17])=[O:16]
Reactant: NC(=O)C(Nc1ccc[nH]c1=O)c1c(Cl)cccc1Cl
Agent: N
Agent: O=S(=O)(O)O
Product: NC(=O)C(N)c1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a stirred and cooled mount of 450 g of concentrated sulfuric acid there were added 23 g of intermediate (2). Stirring was continued overnight at room temperature. The reaction mixture was poured into 2000 g of ice-water and the whole was basified with ammonia. The product was extracted with trichloromethane and the extract was dried, filtered and evaporated. The residue was crystallized from 240 g of 2-propanol at -20° C. The product was filtered off, washed with 2-propanol and petroleumether and dried, yielding 13.5 g of (±)-α-amino-2,6-dichlorobenzeneacetamide; mp. 166.3° C. (interm. 3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[CH:10][N:11]([CH3:26])[C:12]=2[C:13]2[S:25][C:16]3[N:17]=[CH:18][N:19]=[C:20](S(C)(=O)=O)[C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.C[N:28]1C(C2SC3N=CN=C(S(C)(=O)=O)C=3C=2)=C(C2C=CC=CC=2)N=C1>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[CH:10][N:11]([CH3:26])[C:12]=2[C:13]2[S:25][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH2:28])[C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cnc(-c2ccccc2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Reactant: Cn1cnc(-c2cccc(Br)c2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Product: Cn1cnc(-c2cccc(Br)c2)c1-c1cc2c(N)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Example 8 but using 6-[4-(3-Bromophenyl)-1-methyl-1H-imidazol-5-yl]-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (Intermediate 59) in place of 6-(1-methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (intermediate 17). Solid (357 mg, 58%);
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[C:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:30]2[O:34][N:33]=[C:32]([CH3:35])[N:31]=2)=[C:26]([CH:29]=1)[CH:27]=O.OOS([O-])=O.[K+]>CN(C=O)C.O>[C:15]([N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:19]=[C:27]1[C:26]1[CH:29]=[C:22]([O:21][CH3:20])[CH:23]=[CH:24][C:25]=1[C:30]1[O:34][N:33]=[C:32]([CH3:35])[N:31]=1)([CH3:16])([CH3:18])[CH3:17]
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Reactant: COc1ccc(-c2nc(C)no2)c(C=O)c1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2nc(C)no2)c(-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 9.1 %

Procedure:
To a mixture of 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (155 mg, 0.60 mmol) and 5-methoxy-2-(3-methyl-1,2,4-oxadiazol-5-yl)-benzaldehyde (155 mg, 0.60 mmol) in DMF (10.0 mL) is added Oxone (155 mg, 0.71 mmol) in H2O (2.0 mL). The reaction mixture is stirred at room temperature for 1.5 hours and then quenched with saturated sodium thiosulfate aq. (25 mL). The quenched reaction mixture is extracted with EtOAc (25 mL×2) and the combined organic layers are washed with H2O (50 mL×2), dried with Na2SO4 and filtered. The filtrate is concentrated under reduced pressure and the residue is purified by silica gel flash column chromatography with 5% MeOH in CH2Cl2 as the eluent to afford the title compound (25 mg, 9%) as a white solid. LCMS (ESMS): m/z 456.20 (M++1)
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](Cl)=[O:26])[CH:4]=[N:3]1.Cl.[CH3:29][NH:30][CH2:31][C:32]([O:34][CH3:35])=[O:33]>>[CH3:35][O:34][C:32](=[O:33])[CH2:31][N:30]([CH3:29])[C:25]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7](=[O:24])[NH:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:17]=[C:11]2[CH:10]=1)=[O:26]
Reactant: CNCC(=O)OC
Reactant: Cn1ncc(C(=O)Cl)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Agent: Cl
Product: COC(=O)CN(C)C(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1

Procedure:
This compound was prepared in the same manner as described in example 92 starting from 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carbonyl chloride (Example 92, step a) (263 mg, 691 μmol) and methyl 2-(methylamino)acetate hydrochloride (482 mg, 3.45 mmol). Additional TEA (349 mg, 481 μl) was added to the reaction mixture. The final product was isolated as white solid (146 mg, 46%); MS: m/z=448.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH2:31][CH3:32])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C([Sn](CCCC)(CCCC)/[CH:60]=[CH:61]\[O:62][CH2:63][CH3:64])CCC.C(N(CC)CC)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C)C=O>[CH2:63]([O:62]/[CH:61]=[CH:60]\[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH2:31][CH3:32])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1)[CH3:64]
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(Br)ccn34)c12
Reactant: CCCC[Sn](/C=C\OCC)(CCCC)CCCC
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCO/C=C\c1ccn2c(C(=O)Nc3cccc4c3c(CC)nn4Cc3cccc(C)n3)cnc2c1
Temperature: 100 °C
Reaction time: 10 h
Yield: 75.9 %

Procedure:
A round bottom flask was charged with 7-Bromo-N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (330 mg, 0.674 mmol), trio-tolylphosphine (41 mg, 0.135 mmol), tris(dibenzylideneacetone)dipalladium (62 mg, 0.067 mmol) To the flask were added 10 mL of anhydrous dimethylformamide, followed by (Z)-tributyl(2-ethoxyvinyl)stannane (0.34 ml, 1.01 mmol), and triethylamine (0.11 mL, 0.81 mmol). The reaction mixture was degassed under nitrogen, and stirred at 100° C. for 10 hours. The reaction mixture was cooled, diluted with water, and extracted thoroughly with DCM and EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate, and concentrated. The crude product was subjected to preparative thin-layer chromatography on silica with 5% MeOH-DCM as eluent to afford 246 mg of product as a yellow, foamy solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15](=O)/[CH:16]=[CH:17]/[N:18](C)C)=[N:9]2)=[CH:4][CH:3]=1.[Cl:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([NH:33]N)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([N:33]2[C:15]([C:10]3[C:11](=[O:14])[CH:12]=[CH:13][N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[N:9]=3)=[CH:16][CH:17]=[N:18]2)=[CH:25][CH:24]=1
Reactant: NNc1ccc(Cl)c2ccccc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(Cl)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(Cl)cc2)nc1-c1ccnn1-c1ccc(Cl)c2ccccc12

Procedure:
The product was obtained starting from 1-(4-Chloro-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-24) and (4-chloro-naphthalen-1-yl)-hydrazine according to the method described for example 1. MS: M=433.1 (M+H)+
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:10]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9](=[O:22])[N:8]([CH:23]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:24]([O:26]C(C)(C)C)=[O:25])[C:7]=2[CH:37]=1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:10]([S:11]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)(=[O:13])=[O:12])[C:9](=[O:22])[N:8]([CH:23]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:24]([OH:26])=[O:25])[C:7]=2[CH:37]=1)#[N:2]
Reactant: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)OC(C)(C)C)c3ccccc3)c3cc(C#N)ccc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)O)c3ccccc3)c3cc(C#N)ccc32)cc1
Temperature: 25 °C

Procedure:
1.75 g (3.37 mmol) of tert-butyl [6-cyano-3-(4-methoxybenzenesulfonyl)-2-oxo-2,3-dihydrobenzimidazol-1-yl]phenylacetate (XIIc) were dissolved in dichloromethane (20 ml) and, while stirring at room temperature, trifluoroacetic acid (10 ml) was added. The reaction solution was stirred for 2 h and then the solvent and excess trifluoroacetic acid were removed in vacuo. The residue was taken up again in toluene, concentrated in vacuo and then dried in vacuo. Yield: 1.49 g (96%) of white solid
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH2:13]([CH:31]([C:50]([CH:52]([CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78]/[CH:79]=[CH:80]\[CH2:81]/[CH:82]=[CH:83]\[CH2:84][CH2:85][CH2:86][CH2:87][CH3:88])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60]/[CH:61]=[CH:62]\[CH2:63]/[CH:64]=[CH:65]\[CH2:66][CH2:67][CH2:68][CH2:69]C)=[O:51])CCCCCCCC/C=C\C/C=C\CCCCC)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29]C.[Li].C1C[O:93]CC1>>[CH2:53]([CH:52]([CH:71]([OH:93])[CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78]/[CH:79]=[CH:80]\[CH2:81]/[CH:82]=[CH:83]\[CH2:84][CH2:85][CH2:86][CH2:87][CH3:88])[C:50](=[O:51])[CH2:31][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59]/[CH:60]=[CH:61]\[CH2:62]/[CH:63]=[CH:64]\[CH2:65][CH2:66][CH2:67][CH2:68][CH3:69]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(CCCCCCCC/C=C\C/C=C\CCCCC)C(=O)C(CCCCCCCC/C=C\C/C=C\CCCCC)CCCCCCCC/C=C\C/C=C\CCCCC
Reactant: C1CCOC1
Agent: [Li]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: CCCCC/C=C\C/C=C\CCCCCCCCC(=O)C(CCCCCCC/C=C\C/C=C\CCCCC)C(O)CCCCCCC/C=C\C/C=C\CCCCC
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 62 %

Procedure:
To a cooled (−40° C.) solution of N,N,-di-isopropylamine (462 μL, 3.27 mmol) in THF (9 mL) was added nBuLi (1.45 mL, 3.63 mmol as a 2.5M solution in hexanes). After stirring (40 min) the solution was cooled (−78° C.) and treated with di-linoleylmethylketone (1.50 g, 2.85 mmol, neat) dropwise. After stirring (40 min) the newly generated lithium enoloate was added to a cold (−78° C.) solution of linoleyl aldehyde (804 mg, 3.04 mmol) in THF (4 mL). After stirring (1 h, −78° C.) the mixture was quenched by the addition of sat. aq. NH4Cl, then extracted with EtOAc, dried (Na2SO4), filtered and concentrated. The crude material was subjected to chromatography (0.5%→1% EtOAc-hexanes) to yield (6Z,9Z,29Z,32Z)-20-((8Z,11Z)-heptadeca-8,11-dien-1-yl)-21-hydroxyoctatriaconta-6,9,29,32-tetraen-19-one (10) (1.50 g, 62%) as a colorless oil. Rf 0.27 (5% EtOAc-hexanes), FW 791.39, C55H98O2.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([CH2:15]Br)[CH:12]=[CH:11][C:10]=1[S:17]([CH3:20])(=[O:19])=[O:18])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][NH2:22]>C1COCC1>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([CH2:15][NH:22][CH3:21])[CH:12]=[CH:11][C:10]=1[S:17]([CH3:20])(=[O:19])=[O:18])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)c1cc(CBr)ccc1S(C)(=O)=O
Reactant: CN
Solvent: C1CCOC1
Product: CNCc1ccc(S(C)(=O)=O)c(S(=O)(=O)NC(C)(C)C)c1
Reaction time: 2.5 h
Yield: 73.7 %

Procedure:
At 0° C., 51 g of N-tert-butyl-5-bromomethyl-2-methanesulfonylbenzenesulfonamide (55% by weight A 28.05 g=0.669 mol) dissolved in 250 ml of THF are added to a solution of 59.5 ml (0.69 mol) of a 40% strength aqueous methylamine solution in 150 ml of THF. Stirring is continued at 0-5° C. for 2-3 h. For work-up, the solution is completely concentrated, the residue is taken up in plenty of 2N HCl and extracted with diethyl ether (2×200 ml). The acidic aqueous phase is adjusted to pH 9 with 4N NaOH and extracted with ethyl acetate (3×200 ml). The combined ethyl acetate extracts are washed with water, dried over Na2SO4 and evaporated in vacuo. 17 g (73.7%) of N-tert-butyl-5-methylaminomethyl-2-methanesulfonylbenzenesulfonamide of melting point 76-78° C. are obtained as residue.
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][C:14]2[N:15]=[N+:16]([O-:24])[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.O.C(Cl)[Cl:29]>>[OH:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][C:14]2[N:15]=[N+:16]([O-:24])[C:17]3[CH:23]=[C:22]([Cl:29])[CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:11][CH:10]=1
Reactant: [O-][n+]1nc(Oc2ccc(OCc3ccccc3)cc2)nc2ccccc21
Reactant: ClCCl
Solvent: O
Product: [O-][n+]1nc(Oc2ccc(O)cc2)nc2ccc(Cl)cc21
Reaction time: 0.67 h

Procedure:
A solution of 0.05 mole borontribromide in 100 cc methylene chloride is added, dropwise, to a well stirred cold (-62°) solution of 3-(4-benzyloxyphenoxy)-1,2,4-benzotriazine-1-oxide (0.05 mole) in 400 cc methylene chloride. When the addition is complete, the temperature of the reaction is allowed to rise slowly to room temperature. The reaction mixture is then poured into 1 liter of water and an additional 500 cc of methylene chloride is added. The mixture is stirred vigorously for 40 minutes and the insoluble solid is filtered.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([CH2:11][NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH:10]=1)=[O:5])[CH3:2].C(N(CC)C(C)C)(C)C.[C:29](Cl)(=[O:31])[CH3:30]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([CH2:11][N:12]([C:29](=[O:31])[CH3:30])[C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(CNc2ccc(Cl)cc2)c[nH]1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cc(CN(C(C)=O)c2ccc(Cl)cc2)c[nH]1
Temperature: 0 °C
Yield: 81.8 %

Procedure:
4-[(4-chlorophenylamino)-methyl]-1H-pyrrole-2-carboxylic acid ethyl ester (187) (0.2868 g, 1.03 mmol) was weighed out into a 10 mL flask. A stir bar and septum were added, and the flask was purged with nitrogen. The amine was dissolved in methylene chloride (2.6 mL, 0.4 M) and then the flask was cooled to 0° C. N,N-diisopropyl ethyl amine (0.1971 mL, 1.13 mmol) was added, then acetyl chloride (0.0805 mL, 1.13 mmol) was added slowly by syringe to the stirring 0° C. solution. The reaction was then allowed to warm to room temperature. When the reaction was judged complete by HPLC (90 min) the reaction was diluted with methylene chloride and quenched with water. The organic phase was removed, washed with brine, dried with Na2SO4, filtered and concentrated en vacuo. The crude product was purified by silica gel chromatography (Combiflash column, 2:1 Hexanes:Ethyl acetate) to obtain pure 4-[(acetyl-(4-chlorophenyl)-amino)-methyl]-1H-pyrrole-2-carboxylic acid ethyl ester (189, 0.2701 g, 82%) as a sticky white solid. 1H (CD3OD, 400 MHz): δ 11.25 (1H, broad s), 7.35 (2H, d, J=8.4 Hz), 7.05 (2H, d, J=8.4 Hz), 6.76 (1H, s), 6.69 (1H, s), 4.68 (2H, s), 4.22 (2H, q, J=7.1 Hz), 1.81 (3H, s), 1.29 (3H, t, J=7.1 Hz) ppm. 13C (CD3OD, 100 MHz): δ 172.17, 162.50, 142.39, 134.87, 130.94, 130.70, 124.46 & 124.30, 123.94, 121.91 & 121.88, 116.64, 61.13, 46.43, 22.70, 14.75 ppm. DEPT (CD3OD, 100 MHz): CH3 carbons: 22.70, 14.75; CH2 carbons: 61.13, 46.43; CH carbons: 130.94, 130.70, 124.46 & 124.30, 116.64 ppm. HPLC: 9.247 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19]Br>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: Nc1ccc(Br)cc1C(F)(F)F
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Product: FC(F)(F)c1cc(Br)ccc1N1CCCC1
Yield: 17.3 %

Procedure:
In a manner similar to that of Example 18a, by reacting 40 g of 4-bromo-2-trifluoromethylphenylamine (0.167 mol) with 16.6 g of sodium hydride (0.42 mol) and 49.7 mL of 1,4-dibromobutane (0.42 mol), 8.5 g of 1-(4-bromo-2-trifluoromethylphenyl)pyrrolidine (yield=17%) are obtained in the form of a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:19])[NH:7][N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([N:7]1[C:6](=[O:19])[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:8]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)n[nH]c1=O
Reactant: BrCc1ccccc1
Product: COC(=O)c1cc(-c2ccc(OC)cc2)nn(Cc2ccccc2)c1=O
Yield: 96.9 %

Procedure:
Using 4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and benzyl bromide as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 96.9%.
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:13][C:14]([CH3:20])([CH3:19])[CH2:15][C:16](Cl)=[O:17]>>[CH3:13][C:14]([CH3:20])([CH3:19])[CH2:15][C:16]([N:1]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:17]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: C1COCCOCCOCCN1
Product: CC(C)(C)CC(=O)N1CCOCCOCCOCC1

Procedure:
Analogously to Example 14 from 1-aza-4,7,10-trioxacyclododecane and 3,3-dimethylbutyryl chloride.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:40][CH:41]([CH3:43])[CH3:42])[C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:22][N:21]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:20]1)=[O:17].[CH2:44](N(CC)CC)C.CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:44][O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:40][CH:41]([CH3:43])[CH3:42])[C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:22][N:21]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])[CH2:20]1)=[O:17]
Reactant: CCN(CC)CC
Reactant: CC(C)CN(C(=O)c1nc2ccccc2n1CCCCCO)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (3S,5R)-3-[{[1-(5-hydroxypentyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (150 mg) and triethylamine (70 μl) in tetrahydrofuran (5 ml) was added methanesulfonyl chloride (725 μl) at 0° C., and the mixture was stirred at room temperature for 2 hr. Aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in methanol (5 ml), 28% sodium methoxide-methanol solution (482 mg) was added at room temperature and the mixture was stirred at 60° C. for 3 days. The reaction mixture was diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (123 mg).