Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]([OH:7])=O)[CH3:3].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[C:37]1([C:43]2[CH:48]=[C:47]([CH:49]3[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]3)[CH:46]=[CH:45][C:44]=2[NH:55][C:56]([C:58]2[NH:59][CH:60]=[C:61]([C:63]#[N:64])[CH:62]=2)=[O:57])[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]=1>C(Cl)Cl>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[C:37]1([C:43]2[CH:48]=[C:47]([CH:49]3[CH2:50][CH2:51][N:52]([C:5](=[O:7])[CH2:4][N:2]([CH3:3])[CH3:1])[CH2:53][CH2:54]3)[CH:46]=[CH:45][C:44]=2[NH:55][C:56]([C:58]2[NH:59][CH:60]=[C:61]([C:63]#[N:64])[CH:62]=2)=[O:57])[CH2:42][CH2:41][CH2:40][CH2:39][CH:38]=1
Reactant: CN(C)CC(=O)O
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CC(=O)N1CCC(c2ccc(NC(=O)c3cc(C#N)c[nH]3)c(C3=CCCCC3)c2)CC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 99.6 %

Procedure:
A suspension of 9.10 mg (0.0881 mmol) dimethylamino-acetic acid in 5 mL CH2Cl2 was treated with 21.7 mg (0.0852 mmol) BOP—Cl and 32.8 μL (0.235 mmol) triethylamine at RT for 50 min. This mixture was added to a suspension of 22.0 mg (0.0588 mmol) 4-cyano-1H-pyrrole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acid salt (as prepared in the previous step) in 5 mL CH2Cl2. The mixture stirred at RT for 23 h, was diluted with CH2Cl2 (15 mL), and washed with saturated aqueous NaHCO3 (1×10 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Purification of the residue by RP-HPLC (C18) with 20-80% CH3CN in 0.1% TFA/H2O over 30 min to afford 33.6 mg (83%) of the title compound as a white solid: 1H-NMR (CD3OD; 400 MHz): δ 7.54 (d, 1H, J=1.6 Hz), 7.41 (d, 1H, J=8.0 Hz), 7.14 (dd, 1H, J=8.4 Hz, J=2.0 Hz), 7.12-7.08 (m, 1H), 7.07 (d, 1H, J=2.0 Hz), 5.70-5.65 (m, 1H), 4.67-4.59 (m, 1H), 4.26 (q, 2H, J=16.4 Hz), 3.78-3.70 (m, 1H), 3.26-3.17 (m, 1H), 2.97-2.89 (m, 6H), 2.88-2.75 (m, 2H), 2.25-2.18 (m, 2H), 2.15-2.07 (m, 2H), 1.94-1.85 (m, 2H), 1.76-1.54 (m, 6H). Mass spectrum (ESI, m/z): Calcd. for C27H33N5O2, 460.3 (M+H), found 460.3.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([O:30][CH3:31])=[CH:12][CH:13]=[C:14]2[C:19]=1[NH:18][C:17](=[O:20])[CH:16]=[C:15]2[NH:21][C:22]1[C:27]([Cl:28])=[CH:26][N:25]=[CH:24][C:23]=1[Cl:29].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:29][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([Cl:28])[C:22]=1[NH:21][C:15]1[C:14]2[C:19](=[C:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][N:2]([CH3:3])[CH3:1])[C:11]([O:30][CH3:31])=[CH:12][CH:13]=2)[NH:18][C:17](=[O:20])[CH:16]=1
Reactant: CNC
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCN(C)C
Reaction time: 2.5 h

Procedure:
A solution of dimethylamine (1.5 mL, 2M THF, 3 mmol) was added to a solution of 8-(4-bromobutoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (146 mg, 0.3 mmol) and DMSO (3 mL). After 2.5 h, the reaction was poured into 10% K2CO3 (30 mL) and extracted with dichloromethane (40 mL×2). The combined extracts were dried, filtered, concentrated, and purified by silical gel chromatography (1:0→4:1; dichlormethane:methanol w/1% conc. NH4OH solution) and then reverse-phase HPLC (1:9→1:1; acetonitrile:water) to give 4-(3,5-dichloropyridin-4-ylamino)-8-(4-(dimethylamino)butoxy)-7-methoxyquinolin-2(1H)-one: 1H NMR (400 MHz, DMSO-d6): δ 10.29 (s, 1H), 8.81 (s, 1H), 8.75 (s, 2H), 7.87 (d, 1H), 7.04 (d, 1H), 4.77 (s, 1H), 3.99 (t, 2H), 3.90 (s, 3H), 2.27 (t, 2H), 2.13 (s, 6H), 1.73 (m, 2H), 1.54 (m, 2H); MS (ESI): 451.0.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=3)[CH2:19][S:20][C:21]3[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=3)[C:24]([OH:26])=[O:25])=[O:15])=[C:9]([C:33]3[CH:38]=[C:37]([C:39](=[O:52])[NH:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:51])([F:50])[F:49])[CH:43]=4)[CH:36]=[CH:35][N:34]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1COCC1.[OH2:58].OOS([O-])=O.[K+].C[OH:66]>C(OCC)(=O)C.[Pd]>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=3)[CH2:19][S:20]([C:21]3[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=3)[C:24]([OH:26])=[O:25])(=[O:66])=[O:58])=[O:15])=[C:9]([C:33]3[CH:38]=[C:37]([C:39](=[O:52])[NH:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:51])([F:49])[F:50])[CH:43]=4)[CH:36]=[CH:35][N:34]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc(SCc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)c1
Reactant: O
Reactant: CO
Agent: [Pd]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(S(=O)(=O)Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)c1
Reaction time: 2 h

Procedure:
A solution of 25 mg of 3-((3-((4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)benzyl)thio)benzoic acid 8.25 in 2 mL of a 2:1:1 mixture of THF, methanol, and water was treated with 110 mg of Oxone®. The mixture was stirred for 2 h and then it was diluted with ethyl acetate. The organic phase was washed with water, which caused a precipitate to form. The precipitate was redissolved by adding methanol. The organic phase was separated and filtered. Evaporation of the solvent gave a white solid. This solid was dissolved in methanol and treated with 5 mg of 5% Pd/C. The mixture was stirred under a hydrogen atmosphere for 15 minutes, and then it was filtered. The solvent was evaporated and the residue was purified by reverse phase HPLC, eluting with 0.05% TFA in a water/acetonitrile gradient. The process yielded 8.6 mg of product. MS (ES, m/z) 757 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH2:25]([C:27]1[CH:31]=[C:30]([C:32](O)=[O:33])[N:29]([CH3:35])[N:28]=1)[CH3:26].S(Cl)(Cl)=O>CN(C)C=O.CN(C)C(=O)C>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([F:24])=[C:2]([NH:1][C:32]([C:30]5[N:29]([CH3:35])[N:28]=[C:27]([CH2:25][CH3:26])[CH:31]=5)=[O:33])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: CCc1cc(C(=O)O)n(C)n1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: CCc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2F)n(C)n1
Yield: 55.2 %

Procedure:
Using N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (327 mg, 1.0 mmol), 3-ethyl-1-methyl-1H-pyrazole-5-carboxylic acid (170 mg, 1.1 mmol) tetrahydrofuran (2.0 mL), N,N-dimethylformamide (1 drop), thionyl chloride (0.08 mL, 1.1 mmol) and N,N-dimethylacetamide (6.0 mL), and by a reaction in the same manner as in Example 203, the title compound (256 mg, 55%) was obtained as colorless crystals. melting point 236° C.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([O:21][C:22]2[C:27](=[O:28])[N:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4[C:37]([C:42]#[N:43])=[CH:38][CH:39]=[CH:40][CH:41]=4)=[CH:32][CH:31]=3)[C:25]([CH2:44][CH2:45][CH3:46])=[N:24][C:23]=2[CH2:47][CH3:48])[CH:15]=1>C(OCC)(=O)C>[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([O:21][C:22]2[C:27](=[O:28])[N:26]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[C:42]4[NH:3][C:4](=[O:7])[O:5][N:43]=4)=[CH:32][CH:31]=3)[C:25]([CH2:44][CH2:45][CH3:46])=[N:24][C:23]=2[CH2:47][CH3:48])[CH:15]=1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1nc(CC)c(Oc2cc(C)cc(C)n2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)c(Oc2cc(C)cc(C)n2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
A mixture of hydroxylammonium chloride (0.29 g), sodium hydrogen carbonate (0.42 g) and dimethyl sulfoxide (6 mL) was stirred at 40° C. for 30 min, 4′-{[5-[(4,6-dimethylpyridin-2-yl)oxy]-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.24 g) was added, and the mixture was stirred at 90° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (8 mL). N,N′-carbonyldiimidazole (0.12 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.16 g, 60%).
Reaction SMILES: [CH3:1][C@:2]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][NH:3]1.[CH2:10]=O.[H][H]>[Pd].O.CO>[CH3:10][N:3]1[CH2:4][CH2:5][CH2:6][C@:2]1([CH3:1])[C:7]([OH:9])=[O:8]
Reactant: C[C@]1(C(=O)O)CCCN1
Reactant: C=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CN1CCC[C@]1(C)C(=O)O

Procedure:
To a parr flask containing 2-methyl-D-proline (432 mg, 3.34 mmol, 1.0 eq.), Formaldehyde 37 wt. % in water (1.0 mL, 37 mM, 11 eq.), 3.5 mL of methanol and 1 mL of water, Palladium 10 wt. % on Carbon (108 mg, 0.304 mmol, 0.304 eq.) was added. The flask was placed on a parr shaker and allowed to shake under 30 psi of hydrogen for ˜48 hours. Hydrogen was removed and reaction was washed through a pad of celite, which was subsequently washed with methanol. The organics where concentrated in vacuo and then azeotroped with toluene affording #152 (517 mg, 100%) as a solid. 1H NMR (400 MHz, methanol-d4): δ [3.61-3.56 (m, 1H), 3.07-2.96 (m, 1H), 2.68 (br s, 3H), 2.34-2.22 (m, 1H), 2.01-1.88 (m, 1H), 1.87-1.73 (m, 1H), 1.40 (br s, 3H)].
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH:19]=[N:20][OH:21])[C:3]=1[S:22]([CH3:24])=[O:23].[OH:25]O.O>CO.C(O)(=O)C>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH:19]=[N:20][OH:21])[C:3]=1[S:22]([CH3:24])(=[O:25])=[O:23]
Reactant: OO
Reactant: CS(=O)c1c(C=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)(=O)c1c(C=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 20 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
A mixture of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-mehtylsulfinyl-1H-pyrazole-3-carboxaldehyde oxime (1.38 g), 30% hydrogen peroxide (1.38 ml) sodium tungstate dihydrate (0.17 g) in methanol/acetic acid was stirred at 20° C. overnight, then at 50° C. for 4 hours, and again at 20° C. overnight. Water was added and the solid filtered, water-washed and dried to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfonyl-1H-pyrazole-3-carboxaldehyde oxime (0.93 g) m.p.209.5-211° C. (decomposition). Compound 16.
Reaction SMILES: [CH3:1][C:2]([OH:8])([CH2:4][CH:5]([OH:7])[CH3:6])[CH3:3].[H-].[Na+].F[C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20]>C1COCC1>[F:18][C:16]1[CH:15]=[CH:14][C:13]([N+:19]([O-:21])=[O:20])=[C:12]([CH:17]=1)[O:7][CH:5]([CH3:6])[CH2:4][C:2]([CH3:3])([OH:8])[CH3:1]
Reactant: CC(O)CC(C)(C)O
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(CC(C)(C)O)Oc1cc(F)ccc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
2-Methylpentane-2,4-diol (2.8 ml) was dissolved in THF (20.0 ml) and NaH (60% in mineral oil; 1 g) was added. At room temperature 2,4-difluoronitrobenzene was added and the reaction mixture was stirred overnight. Then the reaction was quenched with water and concentrated in vacuo. The residue was dissolved in dichloromethane, washed with water and concentrated in vacuo.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]([OH:8])[CH2:6][N:5]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:23])[CH2:4]1.[N:24]1[C:29]2[O:30][CH2:31][CH2:32][O:33][C:28]=2[CH:27]=[C:26]([CH:34]=O)[N:25]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)[Cl:57]>CO>[ClH:57].[N:24]1[C:29]2[O:30][CH2:31][CH2:32][O:33][C:28]=2[CH:27]=[C:26]([CH2:34][NH:1][CH2:2][C@@H:3]2[C@H:7]([OH:8])[CH2:6][N:5]([CH2:9][CH2:10][N:11]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=4)[CH:14]=[CH:13][C:12]3=[O:23])[CH2:4]2)[N:25]=1
Reactant: O=Cc1cc2c(nn1)OCCO2
Reactant: COc1ccc2ccc(=O)n(CCN3C[C@H](CN)[C@H](O)C3)c2c1
Reactant: ClCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2ccc(=O)n(CCN3C[C@H](CNCc4cc5c(nn4)OCCO5)[C@H](O)C3)c2c1
Product: Cl
Reaction time: 18 h
Yield: 20 %

Procedure:
1-{2-[(3S,4S)-3-(Aminomethyl)-4-hydroxy-1-pyrrolidinyl]ethyl}-7-(methyloxy)-2(1H)-quinolinone (118 mg, 0.372 mmol) and 6,7-dihydro[1,4]dioxino[2,3-c]pyridazine-3-carbaldehyde (68 mg, 0.409 mmol) were combined in anhydrous DCM (5 ml) and anhydrous MeOH (1 ml) with a spatula of solid sodium carbonate. The reaction mixture was stirred under nitrogen for 18 h then sodium triacetoxyborohydride (247 mg, 1.12 mmol) was added and stirred for 1 h. The reaction mixture was concentrated and purified to obtain the free base of the title compound as a pale oil (35 mg, 20%) after column:chromatography (90:10:1: DCM:MeOH:NH4OH).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]2[N:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:3]=1[C:4]([NH:6][C:7]([NH:28][C:25]1[CH:26]=[N:27][C:22]([S:21][C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)=[CH:23][CH:24]=1)=[O:8])=[O:5]
Reactant: Nc1ccc(Sc2ccc(Cl)cc2)nc1
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Solvent: CCOC(C)=O
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1ccc(Sc2ccc(Cl)cc2)nc1
Reaction time: 4 h

Procedure:
2,6-Dichlorobenzoyl isocyanate (2.16 grams; 0.01 mole) and 6-(4-chlorophenylthio)-3-aminopyridine (2.37 grams; 0.01 mole) were mixed in dry ethyl acetate and stirred for 4 hours. The ethyl acetate was removed in vacuo. TLC showed a 3-spot mixture. The reaction mixture was then poured over a silica column with ethyl acetate, and the major spot collected. It was crystallized from ethyl acetate-hexanes, yield 1.5 g., m.p. 160°-162° C.
Reaction SMILES: [C:1]([O:9][C:10]1[C:18]([O:19][CH3:20])=[CH:17][C:13]([C:14]([OH:16])=O)=[C:12]([N+:21]([O-:23])=[O:22])[CH:11]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[C:30]([O:32][CH3:33])=[O:31].C(Cl)CCl.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH2:1]([O:9][C:10]1[C:18]([O:19][CH3:20])=[CH:17][C:13]([C:14]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]2[C:30]([O:32][CH3:33])=[O:31])=[O:16])=[C:12]([N+:21]([O-:23])=[O:22])[CH:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OC(=O)c1ccccc1
Reactant: COC(=O)[C@H]1CCCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: ClCCCl
Product: COC(=O)[C@H]1CCCCN1C(=O)c1cc(OC)c(OCc2ccccc2)cc1[N+](=O)[O-]
Yield: 73.7 %

Procedure:
4-(benzoyloxy)-5-methoxy-2-nitrobenzoic acid (1.70 g, 5.61 mmol), (R)-methyl piperidine-2-carboxylate (1.05 g, 5.84 mmol), EDC (3.90 g, 20.31 mmol) and DIPEA (1.0 ml, 5.75 mmol) was stirred in 20 ml of DMA over night. The mixture was evaporated, diluted with DCM, washed with washed 1M NaH2PO4/NaCl (conc) and 0.1 M NaHCO3/NaCl (conc) separately. The organic solvent layer was separated and dried over MgSO4, filtered, concentrated and purified on SiO2 chromatography eluted with EtAc/DCM (1:15) to afford 1.772 g (74%) of the title product. 1H NMR (CDCl3) 7.69 (s, 1H), 7.40-7.38 (m, 2H), 7.35-7.27 (m, 3H), 6.76 (d, 1H), 5.15 (s, 2H), 3.91 (s, 3H), 3.83 (s, 1H), 3.73 (s, 3H), 3.18 (m, 2H), 1.70 (m 2H), 1.47 (m, 4H); 13C NMR 171.89, 171.33, 155.10, 154.78, 148.32, 135.59, 129.05, 128.74, 127.80, 109.66, 109.58, 109.41, 71.63, 56.92, 52.70, 52.19, 45.70, 39.92, 27.29, 26.35, 21.63; MS m/z+ 451.2 (M+Na).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[N:16]1([C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35](O)=[O:36])=[CH:30][C:29]=2[O:38][CH3:39])=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[N:16]1([C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][C:35]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C@H:8]([CH3:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=3)=[O:36])=[CH:30][C:29]=2[O:38][CH3:39])=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1
Reactant: CCOC(=O)C[C@@H](C)c1ccc(N)cc1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)N1CCc2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C[C@@H](C)c1ccc(NC(=O)Cc2ccc(NC(=O)N3CCc4ccccc43)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
A solution of ethyl (R) 3-(4-aminophenyl)butyrate (790 mg), 4-[(2,3-dihydro-indole-1-carbonyl)-amino]-3-methoxy-phenyl-acetic acid (1.24 g, Reference Example 5) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.45 g) in dimethylformamide (20 mL) was treated in one portion with diisopropylethylamine (1.4 mL). The resulting mixture was stirred at room temperature for 2 hours then poured into water (100 mL) and then extracted three times with ethyl acetate (50 mL). The combined extracts were washed with hydrochloric acid (0.5M), then with sodium hydrogen carbonate solution, then dried and then evaporated. The residue was triturated with a mixture of ethyl acetate and petrol to give the title compound (1.7 g) as a pink/orange powder. HPLC: RT=18.9 minutes (86% by ELS).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[C:6]([NH:8][C:9](=[S:29])[NH:10][C:11]1[S:21][C:14]2[CH2:15][O:16][C:17]([CH3:20])([CH3:19])[CH2:18][C:13]=2[C:12]=1[C:22]([O:24]C(C)(C)C)=[O:23])=[O:7]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[C:6]([NH:8][C:9](=[S:29])[NH:10][C:11]1[S:21][C:14]2[CH2:15][O:16][C:17]([CH3:20])([CH3:19])[CH2:18][C:13]=2[C:12]=1[C:22]([OH:24])=[O:23])=[O:7]
Reactant: COc1cccc(C(=O)NC(=S)Nc2sc3c(c2C(=O)OC(C)(C)C)CC(C)(C)OC3)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(C(=O)NC(=S)Nc2sc3c(c2C(=O)O)CC(C)(C)OC3)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
A solution of 40% v/v TFA/DCM (20 mL) was added to tert-butyl 2-(3-(3-methoxybenzoyl)thioureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (0.32 g, 0.67 mmol) and the mixture was stirred at room temperature for 1 h. The volatiles were removed at 30° C. and the material was purified by reverse-phase chromatography (10-100% MeCN/water). 2-(3-(3-Methoxybenzoyl)thioureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylic acid (0.114 g, 0.26 mmol, 39% yield) was isolated as a pale, yellow solid. 1H NMR (500 MHz, DMSO) δ 14.84 (s, 1H), 13.39 (s, 1H), 11.78 (s, 1H), 7.58-7.54 (m, 1H), 7.54-7.51 (m, 1H), 7.45 (apparent t, J=7.9 Hz, 1H), 7.22 (apparent ddd, J=8.3, 2.6, 0.9 Hz, 1H), 4.66 (s, 2H), 3.85 (s, 3H), 2.74 (s, 2H), 1.23 (s, 6H). 13C NMR (126 MHz, DMSO) δ 174.24, 166.41, 165.25, 158.88, 146.70, 133.23, 129.51, 128.99, 123.98, 120.94, 119.29, 116.40, 113.19, 70.04, 58.71, 55.33, 37.16, 26.08. LCMS retention time: 3.199 min; LCMS purity at 214 nm=97%. HRMS m/z calculated for C19H21N2O5S2 [M++1]: 421.0886. found 421.0889. Melting point 199.3° C., decomposition.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([C:10]([F:13])([F:12])[F:11])=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:22])=[CH:17][C:16]=1[O:29][CH2:30][CH2:31][F:32].FC(F)(F)C(O)=O>COCCO>[F:32][CH2:31][CH2:30][O:29][C:16]1[CH:17]=[C:18]([C:21]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[O:22])[CH:19]=[CH:20][C:15]=1[NH:14][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([C:10]([F:13])([F:12])[F:11])=[CH:4][N:3]=1
Reactant: Nc1ccc(C(=O)N2CCOCC2)cc1OCCF
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Solvent: COCCO
Solvent: O=C(O)C(F)(F)F
Product: CNc1nc(Nc2ccc(C(=O)N3CCOCC3)cc2OCCF)ncc1C(F)(F)F
Temperature: 95 °C
Reaction time: 6 h
Yield: 29.3 %

Procedure:
A mixture of 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (0.10 g, 0.47 mmol), (4-amino-3-(2-fluoroethoxy)phenyl)(morpholino)methanone (0.13 g, 0.47 mmol), trifluoroacetic acid (0.07 mL, 0.9 mmol) in 2-methoxyethanol (2.5 mL) was stirred at 95° C. for 6 hours. The reaction was the concentrated. The crude product was purified by reverse phase HPLC to give the title compound (61 mg, 29%). Additional compounds made using the above procedure are shown in Table 6 below.
Reaction SMILES: CO[CH:3](OC)[C:4](=[N:7][OH:8])[C:5]#[N:6].[OH:11][CH2:12][CH2:13][NH:14][NH2:15].[ClH:16]>CO>[ClH:16].[NH2:6][C:5]1[N:14]([CH2:13][CH2:12][OH:11])[N:15]=[CH:3][C:4]=1[N:7]=[O:8]
Reactant: COC(OC)C(C#N)=NO
Reactant: NNCCO
Agent: Cl
Solvent: CO
Product: Nc1c(N=O)cnn1CCO
Temperature: 67 °C
Yield: 94 %

Procedure:
To a flask having an inner volume of 25 ml and equipped with a stirring device, a thermometer and a reflux condenser were charged 1.47 g (10.0 mmol) of 3,3-dimethoxy-2-hydroxyiminopropionitrile with a purity of 98.1% by weight synthesized in the same manner as in Example 1, 0.84 g (10.5 mmol) of 2-hydroxyethylhydrazine with a purity of 95% by weight, 10 ml of methanol and 1.5 ml (18.0 mmol) of conc. hydrochloric acid, and the mixture was reacted under reflux (67° C.) for 1.5 hours. After completion of the reaction, when the reaction mixture was analyzed by high performance liquid chromatography (absolute calibration curve method), it was found that 1.81 g of 5-amino-1-(2-hydroxyethyl)-4-nitrosopyrazole hydrochloride (Reaction yield: 93.8%) had been formed.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:10]2[CH:9]=[C:8]([C:11]([CH3:24])=[CH:12][C:13]3[CH:23]=[CH:22][C:16]([C:17]([O:19]CC)=[O:18])=[CH:15][CH:14]=3)[S:7][C:6]=2[C:5]([CH3:26])([CH3:25])[CH2:4][CH2:3]1.[OH-].[K+].S(=O)(=O)(O)O>C(O)C.O>[CH3:1][C:2]1([CH3:27])[C:10]2[CH:9]=[C:8](/[C:11](/[CH3:24])=[CH:12]/[C:13]3[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:22][CH:23]=3)[S:7][C:6]=2[C:5]([CH3:26])([CH3:25])[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C=C(C)c2cc3c(s2)C(C)(C)CCC3(C)C)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C/C(=C\c1ccc(C(=O)O)cc1)c1cc2c(s1)C(C)(C)CCC2(C)C
Temperature: 50 °C
Reaction time: 3 h
Yield: 86.3 %

Procedure:
3.0 g of ethyl p-[2-(4,5,6,7-tetrahydro-4,4,7,7-tetramethylbenzo[b]thien-2-yl)propenyl]benzoate are dissolved in 100 ml of ethanol and the solution is treated with a solution of 3.9 g of potassium hydroxide in 20 ml of water. After stirring at 50° C. for 3 hours, the mixture is cooled, poured into ice-water and acidified with 2N sulphuric acid. The mixture is extracted with ethyl acetate, the organic phase is washed with water, dried over sodium sulphate and evaporated. After recrystallization of the residue from ethyl acetate, there are obtained 2.4 g of p-[(E)-2-(4,5,6,7-tetrahydro-4,4,7,7-tetramethylbenzo[b]thien-2-yl)propenyl]benzoic acid in the form of pale yellowish crystals, m.p. 236°-238° C.