Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH2:31])=[CH:25][CH:24]=1)([O-:22])=[O:21]>>[N+:20]([C:23]1[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][NH:31][C:17]([C:15]2[CH:16]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:12]=[N:13][CH:14]=2)=[O:19])=[CH:27][CH:28]=1)([O-:22])=[O:21]
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)NCCc3ccc([N+](=O)[O-])cc3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 2-(4-nitro-phenyl)-ethyl-amine to afford the title compound. MS: m/e=407 (M+H). 1H NMR (δ ppm): 11.72 (s, 1H); 8.87 (d, 1H, J=2.1 Hz); 8.78 (t, 1H, J=5.4 Hz); 8.68 (d, 1H, 2.1 Hz); 8.17 (d, 2H, J=8.6 Hz); 8.05 (t, 1H, J=2.1 Hz); 7.55 (d, 2H, J=8.6 Hz); 7.27 (s, 1H); 3.58 (m, 2H); 3.02 (t, 2H, J=7.1 Hz); 2.43 (q, 2H, J=7.4 Hz); 2.17 (s, 3H); 1.11 (t, 3H, J=7.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH:9][C:10](=O)[CH2:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[CH:17][CH:16]=[CH:15]3)=[CH:4][CH:3]=1>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[N:9][N:8]=2)[N:7]=1
Reactant: O=C(Cc1ccc2ncccc2c1)NNc1ccc(Cl)nn1
Solvent: CC(=O)O
Product: Clc1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Yield: 53 %

Procedure:
A solution of N′-(6-chloropyridazin-3-yl)-2-(quinolin-6-yl)acetohydrazide (8 g crude, 25.5 mmol) in 250 mL acetic acid was heated at 50° C. for 5 hours. After the reaction was completed, the solvent was evaporated and the crude was dissolved in EtOAc and filtered. The solid was mainly the impurity dicyclohexyl urea and the product dissolved in EtOAc. Solvent was evaporated and resulted the title compound as a yellow solid (4 g, 53%). 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.82 (d, 1H), 8.33 (d, 1H), 8.25 (d, 1H), 8.0 (d, 1H), 7.93 (s, 1H), 7.83 (d, 1H), 7.53 (m, 1H), 7.42 (d, 1H), 4.79 (s, 2H). LCMS (method A): [MH]+=296.0, tR=1.88 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[CH2:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH3:18]>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:17][CH3:18])=[CH:20][CH:21]=1)(=[O:27])=[O:26])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Product: CCc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-chloro-phenyl)-phenyl-methanone and 102 mg of 4-ethyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.13 (t, 3H, J=8.0 Hz), 2.53 (q, 2H, J-15.3 Hz, 7.6 Hz), 7.07 (d, 2H, J=8.4 Hz), 7.32 (d, 1H, J=2.8 Hz), 7.34-7.42 (m, 4H), 7.48 (dd, 1H, J=8.8 Hz, 2.4 Hz), 7.56 (m, 3H), 7.76 (d, 1H, J=8.8 Hz), 9.75 (s, 1H). MS: m/z 400.8 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH2:24][CH3:25])=[C:6]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:13][C:11]=3[N:12]=2)[CH:7]=1.[CH:26]1[C:31]([C:32]([OH:34])=[O:33])=[CH:30][C:29]2[C:35]([O:37][C:38](=O)[C:28]=2[CH:27]=1)=[O:36]>>[CH2:24]([O:23][C:5]1[CH:4]=[CH:3][C:2]([N:1]2[C:35](=[O:36])[C:29]3[C:28](=[CH:27][CH:26]=[C:31]([C:32]([OH:34])=[O:33])[CH:30]=3)[C:38]2=[O:37])=[CH:7][C:6]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][C:11]=2[N:12]=1)[CH3:25]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: CCOc1ccc(N)cc1-c1nc2cc(-c3ccccc3)ccc2o1
Product: CCOc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3ccccc3)ccc2o1

Procedure:
Prepared by the method of Example 1b), from 2-(5-amino-2-ethoxyphenyl)-5-phenylbenzoxazole (157 mg, 0.44 mmol) and 1,2,4-benzenetricarboxylic anhydride (84 mg, 0.44 mmol) the title compound was obtained (133 mg, 60%). 1H NMR (DMSO) δ 8.50(dd, 1H), 8.40(s, 1H), 8.25(d, 1H), 8.17(m, 2H), 7.93(d, 1H), 7.80(m, 4H), 7.50(m, 4H), 4.41(q, 2H), 1.52(t, 3H). MS 505 m/z (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)([OH:27])=[O:26]>>[CH2:1]([NH:8][C:9](=[O:10])[NH:11][C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([C:25]([OH:27])=[O:26])[CH:33]=2)=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)NCc1ccccc1
Product: Cc1noc(-c2ccc(-c3cccc(C(=O)O)c3)cc2)c1NC(=O)NCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 1-benzyl-3-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-urea and 3-carboxyphenylboronic acid.
Reaction SMILES: Cl.Cl.[CH3:3][Si:4]([CH3:31])([CH3:30])[CH2:5][CH2:6][O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C:23]4([CH2:27][C:28]#[N:29])[CH2:26][NH:25][CH2:24]4)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1.[OH:32][CH2:33][C:34]1[N:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[N:37]=[C:36]([O:44][CH:45]2[CH2:50][CH2:49][C:48](=O)[CH2:47][CH2:46]2)[CH:35]=1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[OH:32][CH2:33][C:34]1[N:39]=[C:38]([C:40]([F:43])([F:41])[F:42])[N:37]=[C:36]([O:44][C@@H:45]2[CH2:50][CH2:49][C@H:48]([N:25]3[CH2:24][C:23]([CH2:27][C:28]#[N:29])([N:21]4[CH:22]=[C:18]([C:17]5[C:12]6[CH:11]=[CH:10][N:9]([CH2:8][O:7][CH2:6][CH2:5][Si:4]([CH3:30])([CH3:3])[CH3:31])[C:13]=6[N:14]=[CH:15][N:16]=5)[CH:19]=[N:20]4)[CH2:26]3)[CH2:47][CH2:46]2)[CH:35]=1
Reactant: O=C1CCC(Oc2cc(CO)nc(C(F)(F)F)n2)CC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN([C@H]5CC[C@@H](Oc6cc(CO)nc(C(F)(F)F)n6)CC5)C4)c3)ncnc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
{3-[4-(7-{[2-(Trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (1.20 g, 2.49 mmol) (from WO 2009114512) and 4-{[6-(hydroxymethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexanone (0.900 g, 3.10 mmol) in dry 1,2-dichloroethane (30.00 mL, 380.8 mmol) were stirred for 5 minutes, and sodium triacetoxyborohydride (1.87 g, 8.82 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours, at which time LCMS analysis showed mainly the two diastereomeric products. The reaction was quenched with water, neutralized with NaHCO3 and extracted with ethyl acetate. The mixture was purified by preparative-HPLC/MS (C18 column eluting with a gradient of ACN/H2O containing 0.15% NH4OH). Fractions containing the second peak were combined and stripped down to give {1-(cis-4-{[6-(hydroxymethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile. 1H NMR (500 MHz, CDCl3) δ: 8.90 (s, 1H), 8.47 (s, 1H), 8.37 (s, 1H), 7.46 (d, 1H), 6.98 (s, 1H), 6.86 (d, 1H), 5.73 (s, 2H), 5.41 (m, 1H), 4.80 (s, 2H), 3.82 (d, 2H), 3.67 (d, 2H) 3.59 (m, 2H), 3.46 (s, 2H), 3.15 (m, 1H), 2.42 (m, 2H), 2.11 (m, 2H), 1.70-1.90 (m, 6H), 0.96 (m, 2H), −0.4 (s, 9H). MS (ES): 683 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19](Cl)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:29][CH2:30][CH2:31][N:32]([CH3:38])[S:33]([CH2:36][CH3:37])(=[O:35])=[O:34].C(OCC)(=O)C>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19]([O:29][CH2:30][CH2:31][N:32]([S:33]([CH2:36][CH3:37])(=[O:35])=[O:34])[CH3:38])[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2c(Cl)ncnc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: CCS(=O)(=O)N(C)CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCS(=O)(=O)N(C)CCOc1ncnc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1-c1ccc(C)cc1
Temperature: 25 °C
Yield: 34.2 %

Procedure:
100 mg 4-tert.-butyl-N-[6-chloro-5-(p-tolyl)-4-pyrimidinyl]-benzene sulfonamide was dissolved in 5 ml dry THF. 162 mg of potassium-tert.-butylate and 200 mg of N-(2-hydroxyethyl)-N-methyl-ethanesulfonamide was added and the mixture was heated to reflux for 8 h then cooled to room temperature. Ethyl acetate was added and the precipitated side product was filtered off. The filtrate was concentrated in vacuo. The crude product was purified by column chromatography (silica gel; ethyl acetate) to give 45 mg of 4-tert.-butyl-N-{6-[2-(ethanesulfonyl-methyl-amino)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-benzenesulfonamide. LC-MS: tR=5.58 min, [M−1]−=545.54.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27](O)=[O:28])[CH:22]=[CH:23][C:24]=1[Cl:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:27](=[O:28])[CH2:26][C:21]2[CH:22]=[CH:23][C:24]([Cl:25])=[C:19]([Cl:18])[CH:20]=2)[CH2:7]1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: O=C(Cc1ccc(Cl)c(Cl)c1)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 16.2 %

Procedure:
Example 15 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.055 g) and (3,4-dichlorophenyl)acetic acid (0.041 g) to give the title compound (0.015 g).
Reaction SMILES: [C:1]([N:18]1[CH2:21][CH:20]([C:22](O)=[O:23])[CH2:19]1)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[C:46]([O:50][C:51]([N:53]1[CH2:58][CH2:57][C:56](=[C:59]([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[C:60]([NH:62][NH2:63])=[O:61])[CH2:55][CH2:54]1)=[O:52])([CH3:49])([CH3:48])[CH3:47]>C(Cl)Cl.O>[C:46]([O:50][C:51]([N:53]1[CH2:54][CH2:55][C:56](=[C:59]([C:64]2[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=2)[C:60]([NH:62][NH:63][C:22]([CH:20]2[CH2:21][N:18]([C:1]([O:3][CH2:4][CH:5]3[C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:12]4[C:17]3=[CH:16][CH:15]=[CH:14][CH:13]=4)=[O:2])[CH2:19]2)=[O:23])=[O:61])[CH2:57][CH2:58]1)=[O:52])([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)OC(=O)N1CCC(=C(C(=O)NN)c2ccccc2)CC1
Reactant: O=C(O)C1CN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(=C(C(=O)NNC(=O)C2CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)c2ccccc2)CC1
Reaction time: 0.17 h
Yield: 101.6 %

Procedure:
To a solution of Fmoc-azetidine-3-carboxylic acid (0.495 g, 1.53 mmol) in CH2Cl2 (10 mL) was added HOBt (0.290 g, 2.14 mmol) and EDCI (0.411 g, 2.14 mmol), and the mixture was allowed to stir for 10 min. To this solution was added 4-(1-phenyl-1-hydrazinocarbonyl-methylene)piperidine-1-carboxylic acid tert-butyl ester (0.507 g, 1.53 mmol), the mixture was stirred for 1 h and then it was diluted with H2O and the layers separated. The aqueous phase was extracted with CH2Cl2 (×3) and the combined organic layers were washed (H2O, brine), dried (Na2SO4) and evaporated to give the title compound (0.99 g, 100%) which was of sufficient purity to be used as such in the following step:
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:10]([OH:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].CN(C)C=O.[H-].[Na+]>C(O)(=O)C>[CH2:10]([O:28][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Reactant: O=C(O)c1ccc(Br)o1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCCCCCCC/C=C\CCCCCCCCOc1ccc(C(=O)O)o1
Temperature: 25 °C

Procedure:
A mixture of 30.0 g (0.157 mole) of 5-bromofuroic acid, 43.7 g (0.157 mole) of oleylalcohol and 500 ml of dried dimethylformamide is flushed with nitrogen and stirred at room temperature after which 7.55 g (0.314 mole) of sodium hydride is added. The mixture is stirred at room temperature for an hour then heated to reflux. The mixture is refluxed for 92 hours after which the mixture is poured into an ice-water mixture, acidified with acetic acid and extracted with ether. The ether layer is washed with water and salt water, dried over sodium sulfate, filtered and evaporated replacing the ether with hexane. Upon cooling a solid is formed which is recrystallized from methanol to give 5-(cis-9-octadecenyloxy)-2-furoic acid, M.P. 93°-96° C.
Reaction SMILES: C=O.[Cl:3][C:4]1[C:5]([F:34])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:32][CH3:33])=[C:18]([O:21][C@H:22]4[CH2:27][CH2:26][NH:25][C@H:24]([C:28]([NH:30][CH3:31])=[O:29])[CH2:23]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O.C(Cl)Cl>[Cl:3][C:4]1[C:5]([F:34])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:32][CH3:33])=[C:18]([O:21][C@H:22]4[CH2:27][CH2:26][N:25]([CH3:35])[C@H:24]([C:28]([NH:30][CH3:31])=[O:29])[CH2:23]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CNC(=O)[C@@H]1C[C@@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CNC(=O)[C@@H]1C[C@@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1C
Yield: 64.7 %

Procedure:
Molecular sieves (5 g) followed by aqueous formaldehyde (10 ml) were added to a stirred solution of (2S,4S)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-methylpiperidine-2-carboxamide (3.0 g, 6.52 mmol) in DCM-AcOH (100:10 ml) at room temperature. The reaction mixture was stirred for 1-2 minutes before solid sodium triacetoxyborohydride (2.77 g, 13.1 mmol) was added portionwise over 5 minutes. The reaction was essentially complete after all the sodium triacetoxyborohydride reducing agent had been added. DCM was added (100 ml) and the reaction was carefully neutralised with saturated aqueous NaHCO3(aq). The organic extract was washed with brine, dried (MgSO4) and concentrated to a yellow foam. The residue was purified by flash chromatography (silica gel, DCM-NH3/MeOH 2%) to give the title product as a white solid (2 g, 65%): 1H NMR Spectrum: (DMSO d6) 1.85-1.96 (m, 3H), 2.07 (m, 1H), 2.15 (s, 3H), 2.45-2.50 (m, 1H), 2.59 (d, 3H), 2.71 (m, 1H), 2.84 (m, 1H), 3.96 (s, 3H), 4.81 (m, 1H), 7.23 (s, 1H), 7.28 (t, 1H), 7.47-7.53 (m, 2H), 7.81 (s, 2H), 8.37 (s, 1H), 9.59 (s, 1H); Mass Spectrum: (M+H)+ 474.1.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:4]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH:3]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][SH:36])=[CH:31][CH:30]=1.CCN(C(C)C)C(C)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].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][S:36][C:2]2[N:7]=[N:6][C:5]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)=[C:4]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH:3]=2)=[CH:31][CH:30]=1
Reactant: SCc1ccc(Cl)cc1
Reactant: COc1ccc(COc2cc(Cl)nnc2OCc2ccc(OC)cc2)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(COc2cc(SCc3ccc(Cl)cc3)nnc2OCc2ccc(OC)cc2)cc1
Yield: 100 %

Procedure:
A mixture of 6-chloro-3,4-bis[(4-methoxybenzyl)oxy]pyridazine (Intermediate 7; 550 mg, 1.42 mmol), (4-chlorophenyl)methanethiol (248 mg, 1.56 mmol), Pd2(DBA)3 (52.1 mg, 0.057 mmol), XANTPHOS (65.8 mg, 0.114 mmol) and Hunig's base (ethyl diisopropylamine; 404 mg, 3.13 mmol) was subjected to microwave irradiation at 120° C. for 1 hour. The resulting mixture was poured into water and extracted into ethyl acetate before the combined organics were washed with brine and then dried (magnesium sulphate). The resulting solution was evaporated in vacuo and purified by silica chromatography (eluting with 0-40% dichlormethane in petrol) to yield 6-[(4-chlorobenzyl)sulfanyl]-3,4-bis[(4-methoxybenzyl)oxy]pyridazine (201 mg, 1.42 mmol, 28% yield).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[N:20]=[C:21]=[O:22]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=1[Cl:12])=[O:22]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C=Nc1cccc(Cl)c1Cl
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1cccc(Cl)c1Cl
Yield: 73.1 %

Procedure:
The urea was prepared from 2-hydroxy 4-nitro aniline(308 mg, 2 mmol) and 2,3-dichloro phenyl isocyanate(2 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.5 g, 73%). EI-MS m/z 342(M+H)+
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([N+:11]([O-])=O)[C:8]([O:14][CH3:15])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[CH:16][C:17]#[N:18].C(N(CC)CC)C>C(OCC)(=O)C.[C].[Pd]>[NH2:11][C:9]1[C:8]([O:14][CH3:15])=[C:7]2[C:3]([CH2:4][CH2:5][C:6]2=[CH:16][C:17]#[N:18])=[CH:2][CH:10]=1
Reactant: COc1c([N+](=O)[O-])cc(Br)c2c1C(=CC#N)CC2
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1c(N)ccc2c1C(=CC#N)CC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
(4-Bromo-7-methoxy-6-nitro-2,3-dihydro-1H-inden-1-ylidene)acetonitrile (47.0 mg, 0.152 mmol) and triethylamine (22.3 μL, 0.160 mmol) were dissolved in ethyl acetate (1.5 mL), a 10% palladium-carbon powder (10 mg) was added, and the mixture was stirred at room temperature for 1.5 hr under a hydrogen atmosphere. The catalyst was filtered off using celite, and the filtrate was concentrated under reduced pressure to give the title compound (30.4 mg, yield 100%).
Reaction SMILES: [OH:1][NH:2][C:3](=[O:23])[CH:4]([OH:22])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7].C1COCC1.NO>CO>[OH:1][NH:2][C:3](=[O:23])[C@@H:4]([OH:22])[CH2:5][S:6]([C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:13][CH:14]=1)(=[O:7])=[O:8]
Reactant: O=C(NO)C(O)CS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Agent: NO
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NO)[C@@H](O)CS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
Part F: To a solution of the sulfone of part E (3.9 g, 11.6 mmol) in methanol (20 mL) and THF (20 mL) was added 50% aqueous hydroxylamine (14 mL). The solution was stirred for 18 hours at ambient temperature. The solution was concentrated in vacuo and recrystallization (acetone/H2O) provided (R)-N,2-dihydroxy-3-[(4-phenoxyphenyl)sulfonyl]propanamide as a white solid (2.6 g, 67%). HPLC purity: 99%. HRMS calculated for C15H15NO6S: 338.0698, found: 338.0673.
Reaction SMILES: [CH2:1]([C:8]1(S(C2C=CC(C)=CC=2)(=O)=O)[CH:12]([C:13]2[N:14]=[N:15][N:16]([CH2:24][C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=3)[C:17]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)O[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:49].CO>C1(C)C(C)=CC=CC=1>[CH2:1]([C:8]1[NH:9][CH:10]=[N:49][C:12]=1[C:13]1[N:14]=[N:15][N:16]([CH2:24][C:25]2[CH:26]=[C:27]([C:35]([F:38])([F:36])[F:37])[CH:28]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:30]=2)[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: Cc1ccc(S(=O)(=O)C2(Cc3ccccc3)N=COC2c2nnn(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2-c2ccccc2)cc1
Solvent: Cc1ccccc1C
Solvent: CO
Product: FC(F)(F)c1cc(Cn2nnc(-c3nc[nH]c3Cc3ccccc3)c2-c2ccccc2)cc(C(F)(F)F)c1
Temperature: 136 °C
Reaction time: 18 h

Procedure:
Combine 4-[4-benzyl-4-(toluene-4-sulfonyl)-4,5-dihydro-oxazol-5-yl]-1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole (0.084 mmol), 1.0 mL of xylene, and 7N solution of ammonia in methanol (48.0 μL, 0.337 mmol). Heat in a sealed pyrex tube to 136° C. After 18 hours, cool to RT, and concentrate the mixture to 1.0 mL and apply to a 2 mm chromatotron plate with CH2Cl2 and elute with a EtOAc/hexanes gradient to provide the title compound. Exact Mass 527.2: mass spectrum (IS): m/z=529.1 (M+1), 527.1 (M−1); 1H NMR (250 MHz, CDCl3) 7.84 (s, 1H), 7.67 (s, 1H), 7.65-7.05 (m, 13H), 5.60 (s, 2H), 4.28 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[C:11]1([SH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)(O)[O-].[Na+]>CC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[N:5]=[C:6]([S:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1
Reactant: COc1nc(Cl)nc(Cl)n1
Reactant: Sc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1nc(Cl)nc(Sc2ccccc2)n1
Reaction time: 2 h

Procedure:
The 2,4-dichloro-6-methoxy-s-triazine obtained according to Example A-3 is suspended, with partial solution, in 1000 parts by volume of acetone, 110 parts of thiophenol and 90 parts of sodium bicarbonate are added, and the reaction is carried out at about 20° C. After about 2 hours, the synthesis mixture is evaporated. The compound 2-chloro-4-methoxy-6-phenylthio-s-triazine is obtained as a powder containing electrolyte salt. It serves as a monochloro-triazine starting compound for the synthesis of dyestuffs according to the invention.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C@@H:8]2[C@H:11]([NH:12]C(=O)OCC3C=CC=CC=3)[C:10](=[O:23])[NH:9]2)[N:5]=[CH:4][N:3]=1>CO.[Pd]>[NH2:12][C@H:11]1[C@@H:8]([CH2:7][N:6]2[C:2]([CH3:1])=[N:3][CH:4]=[N:5]2)[NH:9][C:10]1=[O:23]
Reactant: Cc1ncnn1C[C@H]1NC(=O)[C@H]1NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Cc1ncnn1C[C@H]1NC(=O)[C@H]1N
Reaction time: 2 h

Procedure:
A slurry of benzyl ((2R,3S)-2-((5-methyl-1H-1,2,4-triazol-1-yl)methyl)-4-oxoazetidin-3-yl)carbamate (240 mg, 0.76 mmol) and Pd on C (10%, 100 mg) in MeOH (20 mL) was evacuated and backfilled with H2 (3×), bringing the final pressure to 35 psi. After 2 h of stirring the mixture was filtered over celite, washing with MeOH and the filtrate was concentrated in vacuo. The crude residue was used as such in the following step.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH:29]([C:31](=[O:38])[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[NH2:30]>>[N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]3[O:38][C:31]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[N:29][N:30]=3)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: CCOC(=O)CC(=O)NN
Product: CCOC(=O)Cc1nnc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)o1

Procedure:
100 mg (0.249 mmol) of the compound from Example 44A and 40 mg (0.273 mmol) of ethyl 3-hydrazinyl-3-oxopropanoate were reacted according to the General Method 4. Yield: 9 mg (6% of theory).