Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:3]=1.N1C=CC=CC=1.[C:22]1([CH3:31])[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:29]([NH:28][C:25]3[CH:26]=[CH:27][C:22]([CH3:31])=[CH:23][CH:24]=3)=[O:30])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: Nc1ccc(Oc2cc(Cl)ncn2)cc1
Reactant: Cc1ccc(N=C=O)cc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)Nc2ccc(Oc3cc(Cl)ncn3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(6-Chloro-pyrimidin-4-yloxy)-phenylamine (331 mg, 1.50 mmol) is dissolved in DMF (3 mL) under an argon atmosphere at rt. Pyridine (133.2 μL, 1.65 mmol) is added dropwise followed by dropwise addition of p-tolylisocyanate (221 μL, 1.80 mmol). The reaction Is stirred for 30 min at rt. The solvent is removed in vacuo and the residual crude product is titurated with ethyl acetate/hexanes 9:1 to give the title compound as a white powder: m.p.=217-219° C.; C18H15N4O2Cl: M+=355.1; 1H-NMR (DMSO-d6): 8.78 (s, 1H), 8.61 (s, 1H), 8.59 (s, 1H, HN), 7.52 (d, 2H), 7.37 (d, 2H), 7.17 (d, 2H), 7.05 (d, 2H), 2.21 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH2:17])[C:14](/[N:18]=N/C4C=CC=CC=4)=[C:13]([NH2:26])[N:12]=3)=[N:9][N:8]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[C:5]2=[N:6][CH:7]=1>CN(C=O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH2:17])[C:14]([NH2:18])=[C:13]([NH2:26])[N:12]=3)=[N:9][N:8]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[C:5]2=[N:6][CH:7]=1
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncc(F)cc23)nc(N)c1/N=N/c1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncc(F)cc23)nc(N)c1N
Reaction time: 8 h

Procedure:
In DMF (800 ml), 39.23 g (85.75 mmol) of the compound from Example 10A were introduced and then 4 g of palladium (10% on carbon) were added. The mixture was hydrogenated with stirring overnight under standard hydrogen pressure. The batch was filtered over kieselguhr and the filter product was washed with a little DMF and then with a little methanol, and concentrated to dryness. The residue was admixed with ethyl acetate and stirred vigorously, and the precipitate was filtered off with suction, washed with ethyl acetate and diisopropyl ether and dried under a high vacuum over Sicapent.
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=2)=[CH:16][CH:15]=1.S(Cl)(Cl)=O>C(COC)OC.C(Cl)Cl.CC(N(C)C)=O>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]2[CH:35]=[CH:36][C:37]([C:38]([NH:10][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])=[O:39])=[CH:41][CH:42]=2)=[CH:18][CH:19]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: O=C(NS(=O)(=O)c1ccccc1)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Reaction time: 0.5 h

Procedure:
A solution of 31.4 g. of benzenesulfonamide in 250 ml. of dry dimethylacetamide is added dropwise, with stirring and cooling, to a suspension of 5.5 g. of sodium hydride in 100 ml. of dry dimethylacetamide during 30 minutes at room temperature. Stirring is continued for a further 30 minutes. In the meantime, a mixture of 36.5 g. of 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoic acid in 100 ml. of methylene chloride, 300 ml. of dimethoxyethane, and 40 ml. of thionyl chloride is refluxed for 1 hour and 15 minutes. The solution is evaporated and to the resulting oil residue is added, in one portion, the previously prepared mixture of sodium benzenesulfonamide in dimethylacetamide. The mixture is stirred for 30 minutes, without cooling, and then filtered. The filtrate is poured into 2 l. of water and 250 ml. of saturated sodium chloride solution. The product is collected by filtration and then dissolved in methylene chloride, the mixture is filtered through diatomaceous earth, and brine is added to break the emulsion. The layers are separated, the organic phase is dried and evaporated. The residue is crystallized from toluene to yield 4-[13-(4-chlorophenyl)tridec-12-ynylamino]-N-(phenylsulfonyl)benzamide.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]([CH3:23])[NH:18][C:19](=[O:22])[NH:20][N:21]=2)=[CH:12][CH:11]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]([CH3:23])[NH:18][C:19](=[O:22])[NH:20][N:21]=2)=[CH:14][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC1NC(=O)NN=C1c1ccc(NCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.3 %

Procedure:
Benzaldehyde (0.25 g) was added to a solution of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.48 g) in methanol (45 ml), and the mixture was stirred for 1.5 hours at room temperature. Acetic acid (0.13 ml) was added thereto and then a solution of sodium cyanoborohydride (0.1 g) in methanol (0.7 ml) was added dropwise with stirring. After adding, the reaction mixture was warmed at 50° C. for 2 hours under stirring and evaporated in vacuo. An aqueous solution of sodium bicarbonate was added to the residue and the mixture was triturated to give 6-(4-benzylaminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.68 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:16][CH2:17][CH3:18])[CH2:10][NH:11][NH:12][C:13](=[O:15])C.[CH:19](O)=[O:20]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:16][CH2:17][CH3:18])[CH2:10][N:11]([CH:19]=[O:20])[NH:12][CH:13]=[O:15]
Reactant: CCCC(CNNC(C)=O)c1ccc(Cl)cc1Cl
Reactant: O=CO
Product: CCCC(CN(C=O)NC=O)c1ccc(Cl)cc1Cl

Procedure:
5.0 g (0.017 mol) of 1-[2-(2,4-dichlorophenyl)-pentyl-2-acetylhydrazine in 20 ml of 85% aqueous formic acid are heated for 18 hours at 100° C. Column-chromatography of the residue obtained after concentration by evaporation yields pure 1-[2-(2,4-dichlorophenyl)-pentyl]-1,2-diformylhydrazine:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:40])[NH:19][C@H:20]([C:36]([O:38][CH3:39])=[O:37])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[C:29]=3[CH3:35])=[CH:24][CH:23]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:41][CH2:42][C@H:43]([C:45]4[CH:50]=[CH:49][CH:48]=[C:47]([OH:51])[CH:46]=4)[O:44][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:52]1([CH2:58]O)[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC(C)C)=O)=NC(OCC(C)C)=O>C(Cl)Cl.CCOC(C)=O.CO>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:40])[NH:19][C@H:20]([C:36]([O:38][CH3:39])=[O:37])[CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[C:29]=3[CH3:35])=[CH:26][CH:27]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:41][CH2:42][C@H:43]([C:45]4[CH:50]=[CH:49][CH:48]=[C:47]([O:51][CH2:58][CH:52]5[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]5)[CH:46]=4)[O:44][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCC1CCCCC1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1cccc(O)c1)CO3
Agent: CC(C)COC(=O)N=NC(=O)OCC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1cccc(OCC2CCCCC2)c1)CO3
Temperature: 0 °C
Reaction time: 4 h
Yield: 94.9 %

Procedure:
(3S,8S)-8-{(S)-2-[4-(2,3-Dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethylcarbamoyl}-3-(3-hydroxy-phenyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (25 mg), cyclohexyl methanol (12 mg), triphenyl phosphine (38 mg) were taken in 1 mL of anhydrous DCM and cooled to 0° C. Diisobutyl azodicarboxylate (22 mg) was added and reaction was warmed to room temperature and stirred for 4 hours. After the completion, reaction was loaded onto a silica gel column (1:1 EtOAc:hexanes to 4% MeOH in 1:1 EtOAc:hexanes) gave (3S,8S)-3-(3-cyclohexylmethoxy-phenyl)-8-{(S)-2-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethylcarbamoyl}-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (27 mg). This was taken in 2 mL anhydrous DCM and cooled 0° C., HCl (0.5 mL, 4N in dioxane) was added and stirred at room temperature for 1 hour. All volatiles were evaporated and the residue was precipitated from DCM/hexanes to get (S)-2-{[(3S,8S)-3-(3-cyclohexylmethoxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester dihydrochloride (25 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1.[Cl:22][CH2:23][C:24](NC1SC(C2C=CN=C(NC3C=CC=C([N+]([O-])=O)C=3)N=2)=C(C)N=1)=[O:25]>>[Cl:22][CH2:23][C:24]([NH:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[N:9]=2)=[C:5]([CH3:7])[N:6]=1)=[O:25]
Reactant: Cc1nc(N)sc1-c1ccnc(Nc2ccc(F)cc2)n1
Reactant: Cc1nc(NC(=O)CCl)sc1-c1ccnc(Nc2cccc([N+](=O)[O-])c2)n1
Product: Cc1nc(NC(=O)CCl)sc1-c1ccnc(Nc2ccc(F)cc2)n1

Procedure:
This compound was prepared from [4-(2-amino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl]-(4-fluoro-phenyl)-amine in a manner analogous to that described above for compound [60]. 1H-NMR (DMSO-d6) δ: 2.94 (s, 3H, CH3), 4.75 (s, 2H, CH2), 7.44 (m, 3H, pyrimidinyl-H & Ph-H), 8.09 (m, 2H, Ph-H), 8.28 (s, 1H, NH), 8.80 (d, 1H, J=5.2 Hz, pyrimidinyl-H).
Reaction SMILES: N1CCCC1.[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([N:13]=[C:14]([N:16]3[CH2:21][CH2:20]O[CH2:18][CH2:17]3)[N:15]=2)[CH:12]=1>>[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[N:11]([N:13]=[C:14]([N:16]3[CH2:21][CH2:20][CH2:18][CH2:17]3)[N:15]=2)[CH:12]=1
Reactant: Brc1ccc2nc(N3CCOCC3)nn2c1
Solvent: C1CCNC1
Product: Brc1ccc2nc(N3CCCC3)nn2c1

Procedure:
Using pyrrolidine, this compound was prepared following the same method as for the synthesis of 6-bromo-2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridine Off white solid (1.0 g, 41%). MS: m/z=268 (M+H+).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: OCc1ccc(Br)nc1
Reactant: OB(O)c1ccc(Br)cc1
Product: OCc1ccc(-c2ccc(Br)cc2)nc1

Procedure:
In accordance with Example 11-(1), but using (6-bromopyridin-3-yl)methanol instead of 4-bromobenzyl bromide, and 4-bromophenylboronic acid instead of [3-(hydroxymethyl)phenyl]boronic acid, [6-(4-bromophenyl)pyridin-3-yl]methanol was afforded as a white solid (yield 51%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=1O.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([O:12][C:34]2[C:33]([F:32])=[CH:38][CH:37]=[CH:36][C:35]=2[F:39])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC(O)CC1
Reactant: Oc1c(F)cccc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCC(Oc2c(F)cccc2F)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 33.5 %

Procedure:
4-Hydroxycyclohexanecarboxylic acid ethyl ester (300 mg; 1.7 mmol), triphenylphosphine (1 g; 4.2 mmol) and 2,6-difluorophenol (340 mg; 2.6 mmol) were stirred in anhydrous toluene and chilled to 0° C. under nitrogen flow. Diethyl azodicarboxylate (2 mL; 4.3 mmol) was added to the mixture over 1 minute and warmed to room temperature. Reaction continued for 16 hours. Reaction was quenched with water, and mixture was extracted with 4×5 mL with ethyl acetate. Combined organics were washed with brine and dried over MgSO4. Oily residue was triturated with diethyl ether and solids filtered off. Filtrate was concentrated at reduced pressure and purified via flash chromatography using 5-20% ethyl acetate in hexanes to give 162 mg of title compound. (34% yield).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([C:13]3[N:17]=[C:16]([C:18]4[CH:19]=[CH:20][C:21]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([CH:25]=4)[C:23]#[N:24])[O:15][N:14]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2.[S:30](N)([NH2:33])(=[O:32])=[O:31].CCN(C(C)C)C(C)C>O1CCOCC1>[C:23]([C:22]1[CH:25]=[C:18]([C:16]2[O:15][N:14]=[C:13]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]4[C:9]=3[CH2:10][CH2:11][CH2:12][C@H:3]4[NH:2][S:30]([NH2:33])(=[O:32])=[O:31])[N:17]=2)[CH:19]=[CH:20][C:21]=1[O:26][CH:27]([CH3:29])[CH3:28])#[N:24]
Reactant: NS(N)(=O)=O
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@H]4N)no2)cc1C#N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@H]4NS(N)(=O)=O)no2)cc1C#N
Temperature: 110 °C
Yield: 41.9 %

Procedure:
Prepared using General Procedure 5: To a stirring solution of (R)-5-(3-(5-amino-5,6,7,8-tetrahydronaphthalen-1-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile HCl 3 (50 mg, 0.12 mmol) in dioxane (3 mL) were added sulfamide (58 mg, 0.61 mmol) and DIEA (47.2 μL, 0.37 mmol) and the mixture was heated to 110° C. for 14 h. The solvent was evaporated and the residue was purified by preparative HPLC to provide 22.8 mg (42%) of (R)-N-(5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)sulfamide 26. LCMS-ESI (m/z) calculated for C22H23N5O4S: 453.5; found 454.1 [M+H]+, tR=3.47 min. 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J=2.2 Hz, 1H), 8.33 (dd, J=8.9, 2.2 Hz, 1H), 7.97 (dd, J=7.7, 1.2 Hz, 1H), 7.72 (d, J=7.7 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 4.78 (ddd, J=13.4, 11.7, 5.7 Hz, 2H), 4.59 (d, J=19.8 Hz, 2H), 4.55 (d, J=8.2 Hz, 1H), 3.19 (dt, J=18.0, 5.6 Hz, 1H), 3.02 (dt, J=18.2, 7.2 Hz, 1H), 2.23-2.03 (m, 2H), 1.92 (dt, J=12.4, 6.3 Hz, 2H), 1.48 (d, J=6.1 Hz, 6H).
Reaction SMILES: [CH2:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19]C)=[O:18])=[CH:16][C:3]1=2.C(O)C.[OH-].[Na+].Cl>O>[CH2:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([OH:19])=[O:18])=[CH:16][C:3]1=2
Reactant: C=C1c2ccccc2COc2ccc(C(=O)OC)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=C1c2ccccc2COc2ccc(C(=O)O)cc21
Reaction time: 2 h

Procedure:
Dissolve the residue of Step A above in 40 ml. of ethanol with warming. Cool and add 40 ml. of 20% aqueous sodium hydroxide solution. Allow to stand for 2 hour and strip away the alcohol. Dilute with water and acidify with 5 N hydrochloric acid. Separate the solids by filtration and dry to obtain the title product (yield 850 mg). Purify by recrystallization from ethanol (m.p. 255°-257° C.).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]3[N:12]=[C:13]([NH2:15])[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[N:18]([CH3:20])[CH3:19].[O:21]([CH2:28][C:29](Cl)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]3[N:12]=[C:13]([NH:15][C:29](=[O:30])[CH2:28][O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[N:18]([CH3:20])[CH3:19]
Reactant: CN(C)c1cc(-c2ccc3nc(N)sc3c2)cnc1Cl
Reactant: O=C(Cl)COc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)c1cc(-c2ccc3nc(NC(=O)COc4ccccc4)sc3c2)cnc1Cl

Procedure:
To a mixture of 6-(6-chloro-5-(dimethylamino)pyridin-3-yl)benzo[d]thiazol-2-amine (100 mg, 328 μmol) in pyridine (0.3 mL) and DCM (2 mL) was added 2-phenoxyacetyl chloride (150 μl, 1086 μmol). A clear solution formed. More 2-phenoxyacetyl chloride (150 μl, 1086 μmol) was added until the reaction was complete. The DCM was evaporated and the mixture was diluted with EtOAc (10 mL). The mixture was filtered, washed with EtOAc, H2O (3×5 mL) and dried in air to give a gray powder. MS (ESI, POS. ION) M/Z: calc'd for C22H19ClN4O2S: 438.1. found: 439.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.85 (s, 6H) 4.95 (s, 2H) 6.90-7.08 (m, 3H) 7.33 (t, J=7.78 Hz, 2H) 7.75-7.92 (m, 3H) 8.36 (s, 1H) 8.44 (s, 1H) 12.70 (s, 1H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][N:6]1[NH:10][CH:9]=[C:8]([C:11]2[N:12]([CH3:19])[C:13]([N+:16]([O-:18])=[O:17])=[CH:14][N:15]=2)[O:7]1.N1C=CC=CC=1.C1C=CC=CC=1>O>[C:1]([NH:5][N:6]1[NH:10][CH:9]=[C:8]([C:11]2[N:12]([CH3:19])[C:13]([N+:16]([O-:18])=[O:17])=[CH:14][N:15]=2)[O:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cn1c([N+](=O)[O-])cnc1C1=CNN(N)O1
Solvent: c1ccncc1
Solvent: O
Solvent: c1ccccc1
Product: CC(=O)NN1NC=C(c2ncc([N+](=O)[O-])n2C)O1
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
Four grams of acetyl chloride are slowly added to 3.6 grams (0.017 mole) of 2-(2-amino-5-oxadiazolyl)-1-methyl-5-nitroimidazole suspended in a mixture of 44 ml. of pyridine and 35 ml. of benzene. The addition is completed in 30 minutes, the mixture heated at 60°-70° C. for 10 minutes, and then poured into 500 ml. of ice and water. After the resulting mixture is stirred for 1 1/2hours, the product separates. Recrystallization from 150 ml. of acetone containing some N,N-dimethylformamide affords 2.4 grams (56%) of pale yellow product. A second recrystallization from acetone gives 2.1 g. of product, melting point 224°-225° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.[OH:9][CH2:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC(C)(C)C>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:15]2[CH:16]=[C:11]([CH2:10][OH:9])[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: OCc1cccc(B(O)O)c1
Reactant: Brc1cnc(I)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: OCc1cccc(-c2ncc(Br)cn2)c1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
750 mg (0.65 mmol) of tetrakis(triphenylphosphine)palladium are added to a solution, kept under nitrogen, of 6.11 g (21.5 mmol) of 5-bromo-2-iodopyrimidine, 3.91 g (25.7 mmol) of 3-(hydroxymethyl)benzeneboronic acid and 9.11 g (42.9 mmol) of tripotassium phosphate trihydrate in 120 ml of dioxane and 14 ml of water, and the mixture is stirred at 90° C. for 18 hours. The reaction mixture is cooled to room temperature, tert-butyl methyl ether and water are added, and the mixture is filtered through kieselguhr. The organic phase of the filtrate is separated off, dried over sodium sulfate and evaporated. The residue is chromatographed on a silica-gel column with dichloromethane/methanol as eluent.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:25])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([N+:18]([O-])=O)=[CH:13][C:12]=2[O:21][CH:22]([F:24])[F:23])[CH2:5][CH2:4]1.C1COCC1.[Cl:33][C:34]1[C:47]([N:48]=[C:49]=S)=[C:46]([Cl:51])[CH:45]=[CH:44][C:35]=1[CH2:36][NH:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40].CC(C)N=C=NC(C)C>CC#N.[Pd]>[F:1][C:2]([F:27])([F:26])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:11]2[C:12]([O:21][CH:22]([F:24])[F:23])=[CH:13][C:14]3[NH:18][C:49]([NH:48][C:47]4[C:46]([Cl:51])=[CH:45][CH:44]=[C:35]([CH2:36][NH:37][C:38](=[O:43])[C:39]([CH3:40])([CH3:41])[CH3:42])[C:34]=4[Cl:33])=[N:17][C:15]=3[CH:16]=2)=[O:25])[CH2:5][CH2:4]1
Reactant: Nc1cc(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)c(OC(F)F)cc1[N+](=O)[O-]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Agent: [Pd]
Agent: CC(C)N=C=NC(C)C
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3cc(C(=O)N[C@H]4CC[C@H](C(F)(F)F)CC4)c(OC(F)F)cc3[nH]2)c1Cl
Reaction time: 2 h

Procedure:
A mixture of N-(trans-4-trifluoromethyl-cyclohex-1-yl)-2-(difluoromethoxy)-5-amino-4-nitro-benzoic acid amide (70 mg, 0.176 mmol), Pd/C (15 mg) and 10 mL THF is stirred under a H2-atmosphere (3 bar) for 2 h. The crude mixture is filtered into a flask charged with N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (59 mg, 0.185 mmol) and the filter cake is washed with 40 mL THF. The mixture is stirred for 4 h at rt and overnight at 60° C. Then the reaction mixture is concentrated to −10 mL and stirred for additional 8 h at 60° C. Then it is concentrated i. vac., diluted with MeCN (2.0 mL) and DIC (29 μl, 0.186 mmol) is added and it is stirred for 4 d. Then the mixture is concentrated, diluted with DMF and THF and purified via HPLC.
Reaction SMILES: C([O:3][C:4](=[O:32])/[CH:5]=[C:6](\[CH3:31])/[CH:7]=[CH:8]/[C:9](/[F:30])=[C:10](\[C:13]1[CH:14]=[C:15]([CH:27]([CH3:29])[CH3:28])[CH:16]=[C:17]2[C:22]=1[N:21]([CH2:23][CH3:24])[CH2:20][CH2:19][C:18]2([CH3:26])[CH3:25])/[CH2:11][CH3:12])C.[OH-].[Na+]>>[CH2:23]([N:21]1[C:22]2[C:17](=[CH:16][C:15]([CH:27]([CH3:29])[CH3:28])=[CH:14][C:13]=2/[C:10](/[CH2:11][CH3:12])=[C:9](/[F:30])\[CH:8]=[CH:7]\[C:6](\[CH3:31])=[CH:5]\[C:4]([OH:32])=[O:3])[C:18]([CH3:26])([CH3:25])[CH2:19][CH2:20]1)[CH3:24]
Reactant: CCOC(=O)/C=C(C)/C=C/C(F)=C(/CC)c1cc(C(C)C)cc2c1N(CC)CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Product: CC/C(=C(F)/C=C/C(C)=C/C(=O)O)c1cc(C(C)C)cc2c1N(CC)CCC2(C)C

Procedure:
Following General Procedure I, (2E,4E,6E)-7-(1-ethyl-6-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-8-yl)-6-fluoro-3-methyl-nona-2,4,6-trienoic acid ethyl ester (Compound 25, 630 mg, 14.3 mmol) was hydrolyzed with NaOH to yield the title compound as a yellow solid after purification by column chromatography (silica, first using 100% hexane, followed by 5:95 ethyl acetate:hexane, then 1:1 ethyl acetate:hexane) to yield a yellow oil. The resulting yellow oil was recrystallized from acetonitrile.
Reaction SMILES: [CH2:1]([N:8]([CH3:15])[CH2:9][CH2:10][C:11]([O:13]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][CH2:18][CH2:19][NH2:20]>>[CH2:1]([N:8]([CH3:15])[CH2:9][CH2:10][C:11]([NH:20][CH2:19][CH2:18][O:17][CH3:16])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCN(C)Cc1ccccc1
Reactant: COCCN
Product: COCCNC(=O)CCN(C)Cc1ccccc1
Temperature: 100 °C
Reaction time: 48 h
Yield: 60.7 %

Procedure:
To methyl 3-(benzyl(methyl)amino)propanoate (1.5 g, 7.24 mmol, 1.00 equiv) was added 2-methoxyethanamine (11 g, 146.45 mmol, 20.00 equiv) and the mixture was stirred for 2 days at 100° C. in sealed tube. The resulting mixture was concentrated under vacuum and purified via silica gel chromatography (dichloromethane/methanol 30:1) to afford 1.1 g (61%) of the product as a yellow oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]([S:15]([OH:17])=[O:16])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:18]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28]Br)[CH:23]=1)(=[O:20])[CH3:19].C(=O)(O)[O-].[Na+].CN(C)C=O>O>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:15]([CH2:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:18](=[O:20])[CH3:19])[CH:23]=2)(=[O:17])=[O:16])=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(S(=O)O)c2cccnc12
Reactant: CC(=O)Oc1cccc(CBr)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ccc(S(=O)(=O)Cc2cccc(OC(C)=O)c2)c2cccnc12
Reaction time: 0.5 h

Procedure:
8-Acetamido-5-quinolinesulfinic acid (10 g, 40 mmole), m-(bromomethyl)phenyl acetate (11 g, 44 mmole), excess sodium bicarbonate (5 g) and dry dimethylformamide (50 ml) were mixed and heated on the steam bath for 11/2 hours. The mixture was slowly poured into 800 ml stirred water and the mixture stirred another 30 min. The solid was filtered off, washed with water, and air-dried overnight. Yield 15.8 g (99 percent) of crude but relatively pure product, m.p. 179°-182° C. A sample recrystallized from toluene, melted 180°-182° C.