Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH2:2][CH3:3].[CH3:4][O:5][C:6](=[O:17])[C:7]1[CH:12]=[C:11]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:9][C:8]=1[OH:16].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:4][O:5][C:6](=[O:17])[C:7]1[CH:12]=[C:11]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:9][C:8]=1[O:16][CH2:2][CH3:3]
Reactant: CCI
Reactant: COC(=O)c1cc(C(C)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOc1ccc(C(C)=O)cc1C(=O)OC
Yield: 43.5 %

Procedure:
Iodoethane (16.4 g, 0.105 mol) was added to a stirred mixture of 5-acetyl-2-hydroxybenzoic acid methyl ester (10 g, 51.5 mol) and anhydrous potassium carbonate (14.4 g, 0.104 mol) in 2-butanone (200 ml) and the resulting mixture heated under reflux for 3 days. The solvent was removed by evaporation under vacuum and the residue partitioned between water (100 ml) and ethyl acetate (100 ml). The aqueous phase was removed and extracted with further ethyl acetate (4×100 ml). The organic solutions were combined, dried (Na2SO4) and evaporated under vacuum. The residue was chromatographed on silica gel (130 g), using a methanol in dichloromethane elution gradient (0-1% methanol), to give the title compound as colourless crystals (10.15 g, 89%) m.p. 50°-55° C. Found C,64.88; H,6.38. C12H14O4 requires C,64.85; H,6.35%.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][OH:43])[CH2:37][CH2:36]1>>[F:23][C:22]1[CH:21]=[C:20]([CH3:24])[CH:19]=[C:18]([F:25])[C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]2[CH2:36][CH2:37][N:38]([CH2:41][CH2:42][OH:43])[CH2:39][CH2:40]2)=[O:29])[S:14][N:13]=1
Reactant: NCCCCN1CCN(CCO)CC1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCN3CCN(CCO)CC3)c2C(N)=O)c(F)c1

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 2-[4-(4-amino-butyl)-piperazin-1-yl]-ethanol by the procedure analogous to Example 1. MS (APCl, m/z): 527 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[N:25]([C:26]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6](=[O:45])[N:5]([CH2:46][CH2:47][CH3:48])[C:4](=[O:49])[CH:3]=1.[Cl:50]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:50][C:3]1[C:4](=[O:49])[N:5]([CH2:46][CH2:47][CH3:48])[C:6](=[O:45])[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[N:25]([C:26]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCn1c(=O)cc(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Solvent: ClC(Cl)Cl
Product: CCCn1c(=O)c(Cl)c(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Yield: 34.9 %

Procedure:
A mixture of 6-chloro-3-propyl-1-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (0.6 g) and N-chlorosuccinimide (0.14 g) in chloroform (10 ml) was heated under reflux for 18 hours. The reaction mixture concentrated to dryness and the resulting residue was purified by column chromatography on silica gel to give colorless amorphous powders (0.22 g, 35%).
Reaction SMILES: [ClH:1].[C:2]1([N:8]([CH2:32][C:33]([O:35]CC)=[O:34])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][O:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>>[ClH:1].[C:2]1([N:8]([CH2:32][C:33]([OH:35])=[O:34])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][O:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH2:28])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN(C(=O)c1ccc2c(c1)nc(COc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(COc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CC(=O)O)c3ccccc3)ccc21
Yield: 58 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[(4-amidinophenyl)oxymethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(ethoxycarbonylmethyl)amide hydrochloride and sodium hydroxide solution. Yield: 58% of theory, C25H23N5O4 (457.5); EKA mass spectrum: (M+H)+=458; (M+Na)+=480; (M+2Na)++=251.6.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:10]([NH:12][C@H:13]2[CH2:21][CH2:20][CH2:19][C@H:18]([O:22][CH2:23][CH2:24][CH3:25])[C@@H:17]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C@H:16]([CH3:31])[O:15][C:14]2=[O:32])=[O:11])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([O-])([O-])=O.[K+].[K+].[C:39]([O:42][CH2:43]Br)(=[O:41])[CH3:40]>CC(C)=O.C(Cl)Cl>[C:39]([O:42][CH2:43][O:1][C:2]1[C:3]([C:10](=[O:11])[NH:12][C@H:13]2[CH2:21][CH2:20][CH2:19][C@H:18]([O:22][CH2:23][CH2:24][CH3:25])[C@@H:17]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C@H:16]([CH3:31])[O:15][C:14]2=[O:32])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9])(=[O:41])[CH3:40]
Reactant: CCCO[C@H]1CCC[C@H](NC(=O)c2nccc(OC)c2O)C(=O)O[C@@H](C)[C@@H]1CCC(C)C
Reactant: CC(=O)OCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCCO[C@H]1CCC[C@H](NC(=O)c2nccc(OC)c2OCOC(C)=O)C(=O)O[C@@H](C)[C@@H]1CCC(C)C
Temperature: 50 °C
Reaction time: 6 h
Yield: 77.3 %

Procedure:
To a solution of 3-hydroxy-N-((3S,7S,8S,9S)-8-isopentyl-9-methyl-2-oxo-7-propoxyoxonan-3-yl)-4-methoxypicolinamide (125 mg, 0.277 mmol) and K2CO3 (77 mg, 0.555 mmol) in acetone (2.77 mL) was added bromomethyl acetate (54.4 μL, 0.555 mmol). The reaction was sealed, heated to 50° C., stirred at this temperature for 6 h, and then cooled to room temperature. The mixture was diluted with DCM (4 mL) and treated with Celite® (3 scoopula tip-fulls). The solvent was removed under reduced pressure and the resulting adsorbed material was directly loaded onto a column and purified using flash column chromatography (24 g SiO2, 0→100% EtOAc/hexanes) to afford the title compound (112 mg, 0.214 mmol, 77%) as a sticky, slightly yellow oil: IR (thin film): 3378, 2954, 2872, 1740, 1677, 1504, 1202 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J=8.1 Hz, 1H), 8.28 (d, J=5.4 Hz, 1H), 6.95 (d, J=5.4 Hz, 1H), 5.74 (s, 2H), 4.74 (dq, J=10.1, 6.3 Hz, 1H), 4.61 (app dt, J=10.7, 7.6 Hz, 1H), 3.91 (s, 3H), 3.52 (app dt, J=8.9, 6.4 Hz, 1H), 3.31-3.22 (m, 1H), 3.15 (app dt, J=8.9, 6.6 Hz, 1H), 2.45-2.33 (m, 1H), 2.21-2.09 (m, 1H), 2.07 (s, 3H), 1.98-1.86 (m, 1H), 1.85-1.70 (m, 1H), 1.67-1.28 (m, 10H), 1.24-1.03 (m, 2H), 0.97-0.84 (m, 10H); HRMS-ESI m/z [M+Na]1 calcd for: C27H42N2NaO8, 545.2833; found, 545.2853.
Reaction SMILES: CN(C)CCCN=C=NCC.[CH3:12][O:13][CH2:14][CH2:15][NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][C:18]=1[N+:29]([O-])=O.[N:32]([C:35]1[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=1)=[C:33]=S>O1CCCC1.C(OCC)(=O)C>[CH3:12][O:13][CH2:14][CH2:15][N:16]1[C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][C:18]=2[N:29]=[C:33]1[NH:32][C:35]1[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=1
Reactant: COC(=O)c1ccc(N=C=S)cc1
Reactant: COCCNc1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCn1c(Nc2ccc(C(=O)OC)cc2)nc2cc(-c3ccccc3)ccc21
Yield: 55.6 %

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide (EDC, 200 mg, 1.44 mg) is added to a solution of N-(2-methoxyethyl)-3-nitrobiphenyl-4-amine (119 mg, 0.48 mmol) and methyl 4-isothiocyanatobenzoate (83 mg, 0.43 mmol) in tetrahydrofuran. The reaction may reflux for an appropriate time period, such as 2 hours and cooled. The mixture may be diluted with ethyl acetate, filtered and concentrated. The residue may be purified by any appropriate method including Biotage column chromatography to give methyl 4-(1-(2-methoxyethyl)-5-phenyl-1H-benzo[d]imidazol-2-ylamino)benzoate (96 mg)
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:26])([F:25])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:15]2=[O:24])=[CH:10][CH:9]=1.[CH3:27][C:28]1[S:29][CH:30]=[C:31]([C:33](Cl)=[O:34])[N:32]=1.Cl>>[CH3:27][C:28]1[S:29][CH:30]=[C:31]([C:33]([N:21]2[CH2:20][CH2:19][C:16]3([C:15](=[O:24])[N:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][C:6]([F:5])([F:25])[F:26])=[CH:9][CH:10]=4)[CH2:18][CH2:17]3)[CH2:23][CH2:22]2)=[O:34])[N:32]=1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: Cc1nc(C(=O)Cl)cs1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1nc(C(=O)N2CCC3(CC2)CCN(c2ccc(OC(F)(F)F)cc2)C3=O)cs1

Procedure:
The title compound was prepared in analogy to example 7 step A from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (described in example 180 step C) and 2-methyl-thiazole-4-carbonyl chloride; hydrochloride. Off-white solid. MS (ESI): 440.2 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]1([CH:8]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[CH:16][CH:15]=2)[CH:9]=[C:10]([F:13])[CH2:11][OH:12])[CH2:7][CH2:6]1.C1C=CC=CC=1>N1C=CC=CC=1>[C:1]([O:12][CH2:11][C:10]([F:13])=[CH:9][CH:8]([CH:5]1[CH2:6][CH2:7]1)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[CH:16][CH:15]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOc1ccc(C(C=C(F)CO)C2CC2)cc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCOc1ccc(C(C=C(F)COC(C)=O)C2CC2)cc1
Yield: 99 %

Procedure:
The method of Example 11 was repeated using acetyl chloride (1.2 ml), 4-cyclopropyl-4-(4-ethoxyphenyl)-2-fluorobut-2-enol (Example 7) (0.65 g), benzene (34 ml) and pyridine (0.24 ml) to yield the title compound (0.75 g, 99%).
Reaction SMILES: [F:1][C:2]([F:29])([C:7]1[CH:8]=[CH:9][C:10]2[O:15][C:14]([CH2:18][F:19])([CH2:16][F:17])[C@@H:13](O)[C@H:12]([N:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]3=[O:27])[C:11]=2[CH:28]=1)[C:3]([F:6])([F:5])[F:4].CS(Cl)(=O)=O.C(N(CC)CC)C>O1CCCC1>[F:29][C:2]([F:1])([C:7]1[CH:8]=[CH:9][C:10]2[O:15][C:14]([CH2:18][F:19])([CH2:16][F:17])[CH:13]=[C:12]([N:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]3=[O:27])[C:11]=2[CH:28]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: O=c1ccccn1[C@@H]1c2cc(C(F)(F)C(F)(F)F)ccc2OC(CF)(CF)[C@H]1O
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=c1ccccn1C1=CC(CF)(CF)Oc2ccc(C(F)(F)C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
A mixture of 0.15 g of trans-6-pentafluoroethyl-2,2-bisfluoromethyl-3,4-dihydro-4-(1,2-dihydro-2-oxo-1-pyridyl)-2H-1-benzopyran-3-ol, 0.07 g of methanesulfonyl chloride, 0.08 g of triethylamine and 10 ml of tetrahydrofuran was stirred at room temperature for 8 hours and the solvent was distilled off. Water was added thereto and the mixture was extracted with methylene chloride. After the organic layer was washed with water and dried, the solvent was distilled off. The resultant residue was dissolved in 4 ml of tetrahydrofuran and 0.06 g of sodium hydrate (60%) was added thereto with stirring under ice-cooling. The mixture was then stirred at room temperature for 66 hours. Ice water was added thereto and the mixture was extracted with methylene chloride. After the organic layer was washed with water and dried, the solvent was distilled off. The resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 0.09 g of 6-pentafluoroethyl-2,2-bisfluoromethyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-2H-1-benzopyran represented by the following formula having a melting point of 137°-138° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:13][CH:14]=2)[C@H:9]([NH:20]C(OCC2C=CC=CC=2)=O)[CH2:8][C@@H:7]1[CH2:31][CH3:32])=[O:5])[CH3:2]>C1CCCCC=1.C(O)C.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:17])([F:18])[F:19])=[CH:13][CH:14]=2)[C@H:9]([NH2:20])[CH2:8][C@@H:7]1[CH2:31][CH3:32])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(C(F)(F)F)cc2[C@H](NC(=O)OCc2ccccc2)C[C@@H]1CC
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CCOC(=O)N1c2ccc(C(F)(F)F)cc2[C@H](N)C[C@@H]1CC
Yield: 69.6 %

Procedure:
A solution of cis-4-benzyloxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 7C) (18.0 g, 40 mmol) in 150 mL each of cyclohexene and ethanol was treated with 10% palladium on carbon (10.0 g, 50% water by weight). After heating at reflux for 1 h, the cooled mixture was filtered through Celite® and concentrated in vacuo to afford the crude product, which was purified by silica gel chromatography using 25-50% ethyl acetate/hexanes as eluent to afford 8.8 g of the title product. 1H NMR (CDCl3) δ 0.83 (t, 3H), 1.25 (m, 4H), 1.45 (m, 1H), 1.6 (m, 1H), 2.49 (m, 1H), 3.81 (m, 1H), 4.2 (m, 2H), 4.4 (m, 1H), 7.47 (m, 2H), 7.69 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)=[O:14])[C:9]([OH:11])=O.[CH3:23][N:24]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1)[CH3:25]>>[CH3:25][N:24]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:34]=[CH:35][C:36]([NH:39][C:9](=[O:11])[CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[O:14])=[CH:37][CH:38]=1)[CH3:23]
Reactant: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)O
Reactant: CN(C)Cc1ccccc1-c1ccc(N)cc1
Product: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)Nc1ccc(-c2ccccc2CN(C)C)cc1

Procedure:
The titled compound was prepared analogously as describe in EXAMPLE 55, using 2-(2-methylphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetic acid and 4-(2-dimethylaminomethyl-phenyl)phenylamine MS 527.7 and 529.6 (M+H, Cl pattern).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][OH:7].[F:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=1)[CH2:12][NH:13][C:14]([NH:16][C:17]1[S:21][N:20]=[C:19]([CH2:22]Cl)[N:18]=1)=[O:15].ClCCl>C1COCC1>[F:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=1)[CH2:12][NH:13][C:14]([NH:16][C:17]1[S:21][N:20]=[C:19]([CH2:22][O:7][CH2:6][CH2:5][O:4][CH3:3])[N:18]=1)=[O:15]
Reactant: COCCO
Reactant: O=C(NCc1cccc(F)c1)Nc1nc(CCl)ns1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COCCOCc1nsc(NC(=O)NCc2cccc(F)c2)n1
Temperature: 0 °C

Procedure:
Sodium hydride (4 eq, 2.66 mmol, 0.13 g of a 50 wt-% suspension in oil) was suspended in THF (2 mL) and cooled to 0° C. 2-methoxy ethanol (3 eq, 1.99 mmol, 0.15 g) and 15-crown-5-ether (1 drop) were added. 1-(3-Fluorobenzyl)-3-(3-(chloromethyl)-1,2,4-thiadiazol-5-yl)urea (Intermediate XXV) was added and the mixture was stirred over night with temperature allowed to rise to room temperature. Dichloromethane (50 mL) was added. The mixture was washed with water (2×10 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude material (0.2 g of an oil) was further purified by preparative HPLC to give 0.101 g. 1H-NMR (300 MHz, CD3OD): δ 7.34 (m, 1H), 7.14 (d, 1H), 7.07 (d, 1H), 6.99 (m, 1H), 4.58 (s, 2H), 4.45 (s, 2H), 3.70 (t, 2H), 3.56 (t, 2H), 3.30 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([O:9][CH2:10]C)([O:6][CH2:7]C)[CH3:5])C.[Cl:12]Cl>C(O)C>[Cl:12][CH2:5][C:4]([O:9][CH3:10])([O:6][CH3:7])[O:3][CH3:1]
Reactant: CCOC(C)(OCC)OCC
Reactant: ClCl
Solvent: CCO
Product: COC(CCl)(OC)OC
Reaction time: 4 h
Yield: 90.9 %

Procedure:
A 1000 ml flask equipped with a stirrer and gas inlet tube was initially charged at 10° C. with a mixture of 648 g (4 mol) of 1,1,1-triethoxyethane and 70 g (approx. 11% by weight) of ethanol. Within 4 hours, 260 g (3.70 mol) of chlorine were introduced into the flask in gaseous form, and the internal temperature of the flask did not rise above 15° C. Once the entire amount of chlorine had been introduced into the flask, the mixture was worked-up by distillation. A distillation apparatus having approx. 5 theoretical plates was used to remove low boilers such as methanol and methyl acetate in the first stages at a reflux ratio of 5:1. In the main fraction, 520 g of 2-chloro-1,1,1 trimethoxyethane in a purity of >99.0% were obtained at a reflux ratio of 2:1. This amount of product corresponds to a yield of approx. 67%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:14][C:6]([C:7]([O:9]CCOC)=[O:8])=[C:5]([N+:21]([O-:23])=[O:22])[CH:4]=1.[OH-].[Na+]>CCO.O>[CH3:1][O:2][C:3]1[C:15]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:14][C:6]([C:7]([OH:9])=[O:8])=[C:5]([N+:21]([O-:23])=[O:22])[CH:4]=1
Reactant: COCCOC(=O)c1cc(OCCOC)c(OC)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COCCOc1cc(C(=O)O)c([N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2-methoxyethyl 4-methoxy-5-(2-methoxyethoxy)-2-nitrobenzoate (5.0 g, 15.2 mmol) in EtOH (40 mL) was added 2N NaOH (40 mL, 76.0 mmol, 5 eq.). The mixture was stirred at RT for 12 h. The mixture was diluted with water (100 mL) and washed with CH2Cl2 (1×100 mL). The aqueous layer was acidified to pH=1 using 1N HCl (A solid began to precipitate, this was dissolved by the addition of EtOAc). The aqueous mixture was extracted with EtOAc (2×200 mL). The combined organics were washed with brine (1×100 mL), dried (Na2SO4), filtered and concentrated in vacuo to give 4-methoxy-5-(2-methoxyethoxy)-2-nitrobenzoic acid as an off white solid (3.55 g, 12.4 mmol, 86%). HPLC retention time 4.94 mins.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[CH2:5].[C:6]1(=[O:16])[NH:10][C:9](=[O:11])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12.[K]>CN(C=O)C.CCOCC>[CH2:2]([N:10]1[C:6](=[O:16])[C:7]2[C:8](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9]1=[O:11])[CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=CCCN1C(=O)c2ccccc2C1=O
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 4-bromo-1-butene (8-3, 20 g, 148 mmol) in DMF (150 mL) was added potassium phthalimide (8-4, 25 g, 133 mmol) and the mixture stirred for 18 hours at 70° C. After cooling to RT, the mixture was diluted with ether, washed with water and brine, dried over MgSO4, and concentrated to give 8-5 as a white solid.
Reaction SMILES: [Cl:1]/[C:2](/[C:12]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[O:13])=[C:3](\Cl)/[C:4]([O:6][CH2:7][CH:8]([CH3:10])[CH3:9])=[O:5].C([O-])(=O)C.[NH4+:23]>CN(C)C=O>[NH2:23]/[C:3](/[C:4]([O:6][CH2:7][CH:8]([CH3:10])[CH3:9])=[O:5])=[C:2](\[Cl:1])/[C:12]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[O:13]
Reactant: CC(C)COC(=O)/C(Cl)=C(/Cl)C(=O)OCC(C)C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CC(C)COC(=O)/C(N)=C(/Cl)C(=O)OCC(C)C
Yield: 80.3 %

Procedure:
29.7 g (0.1 mol) of diisobutyl dichloromaleate, 19.27 g (0.25 mol) of ammonium acetate and 40 ml of dimethylformamide were reacted under the same conditions as described in Example 1. A reddish oil was obtained which crystallized on trituration. After the crystal slurry had been washed with hexane, 22.3 g (80%) of diisobutyl aminochloromaleate were obtained as cubic crystals (m.p. 80° C.-81° C.).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[N+:16]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Fe]>[CH2:1]([NH:8][C:9]1[C:10]([NH2:16])=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(NCc2ccccc2)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Product: Cc1ccc(NCc2ccccc2)c(N)c1
Temperature: 40 °C

Procedure:
To a solution of benzyl-(4-methyl-2-nitro-phenyl)-amine (300 mg, 1.24 mmol) in 5 mL acetic acid, was added iron (300 mg, 1.24 mmol). The reaction mixture was heated to 40° C. under argon for 2 h. The mixture was cooled to ambient temperature and filtered through celite and the filtrate was concentrated. The resulting solid was dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO3, dried over MgSO4, filtered and the filtrate was concentrated in vacuo to yield crude product that was used in step 3.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[C:8]([C:10]3[CH:32]=[CH:31][C:13]4[C:14]5[N:18]([CH2:19][CH2:20][O:21][C:12]=4[CH:11]=3)[CH:17]=[C:16]([C:22]3[N:23]([CH:28]([CH3:30])[CH3:29])[N:24]=[C:25]([CH3:27])[N:26]=3)[N:15]=5)[CH:7]=[N:6]2)[CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:66](O)(=[O:70])[C@H:67]([CH3:69])[OH:68]>>[OH:68][C@@H:67]([CH3:69])[C:66]([N:1]1[CH2:2][CH:3]([N:5]2[CH:9]=[C:8]([C:10]3[CH:32]=[CH:31][C:13]4[C:14]5[N:18]([CH:17]=[C:16]([C:22]6[N:23]([CH:28]([CH3:30])[CH3:29])[N:24]=[C:25]([CH3:27])[N:26]=6)[N:15]=5)[CH2:19][CH2:20][O:21][C:12]=4[CH:11]=3)[CH:7]=[N:6]2)[CH2:4]1)=[O:70]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C5CNC5)c4)cc2OCC3)n(C(C)C)n1
Reactant: C[C@H](O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C5CN(C(=O)[C@H](C)O)C5)c4)cc2OCC3)n(C(C)C)n1

Procedure:
8-(1-Azetidin-3-yl-1H-pyrazol-4-yl)-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene was coupled with DIPEA, HATU, and L-lactic acid to give 228. MS (ESI+) 503.2. 1H NMR (400 MHz, DMSO) δ 8.45 (d, J=1.7, 1H), 8.37 (d, J=8.4, 1H), 8.12 (s, 1H), 7.89 (s, 1H), 7.42 (dd, J=8.4, 1.7, 1H), 7.32 (d, J=1.7, 1H), 5.92-5.74 (m, 1H), 5.34-5.25 (m, 1H), 5.21 (t, J=5.5, 1H), 4.84-4.66 (m, 1H), 4.60-4.53 (m, 1H), 4.52 (s, 4H), 4.40-4.31 (m, 1H), 4.26-4.09 (m, 2H), 2.25 (s, 3H), 1.47 (d, J=6.6, 6H), 1.22 (d, J=6.7, 3H)
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:14]=1[OH:15])[CH2:8][CH:9]1[CH2:11][O:10]1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][C:21]1([CH3:28])[NH:25][C:24](=[O:26])[NH:23][C:22]1=[O:27]>[Cl-].[Li+]>[OH:10][CH:9]([CH2:8][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:14]([OH:15])=[C:13]([C:16]([CH3:19])([CH3:17])[CH3:18])[CH:12]=1)[CH2:11][N:23]1[C:22](=[O:27])[C:21]([CH3:28])([CH3:20])[NH:25][C:24]1=[O:26]
Reactant: CC(C)(C)c1cc(CC2CO2)cc(C(C)(C)C)c1O
Reactant: CC1(C)NC(=O)NC1=O
Agent: [Cl-]
Agent: [Li+]
Product: CC1(C)NC(=O)N(CC(O)Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Reaction time: 1 h
Yield: 79.4 %

Procedure:
25 mg of lithium chloride are added to 5.25 g (0.02 mol) of 3,5-di-tert.-butyl-4-hydroxybenzyl-oxirane and 2.56 g (0.02 mol) of 5,5-dimethylhydantoin and the mixture is kept at a melt at 220°-230° C for 60 minutes whilst stirring in a nitrogen atmosphere. After cooling, a glassy residue is obtained, which when recrystallised from toluene/isopropanol gives 6.2 g (78% of theory) of 3-[2-hydroxy-3-(3,5-di-tert.-butyl-4-hydroxyphenyl)-propyl]-5,5-dimethylhydantoin of melting point 175°-76° C in the form of colourless crystals.
Reaction SMILES: [N:1]1([C:6]2[CH:18]=[CH:17][C:9]3[O:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][O:16][C:8]=3[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C[Al](C)C.[CH3:23][S:24]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](OC)=[O:36])=[CH:30][CH:29]=1)(=[O:26])=[O:25]>>[N:1]1([C:6]2[CH:18]=[CH:17][C:9]3[O:10][CH2:11][CH2:12][N:13]([C:35](=[O:36])[CH2:34][C:31]4[CH:30]=[CH:29][C:28]([NH:27][S:24]([CH3:23])(=[O:25])=[O:26])=[CH:33][CH:32]=4)[CH2:14][CH2:15][O:16][C:8]=3[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1cn(-c2ccc3c(c2)OCCNCCO3)cn1
Reactant: COC(=O)Cc1ccc(NS(C)(=O)=O)cc1
Agent: C[Al](C)C
Product: CS(=O)(=O)Nc1ccc(CC(=O)N2CCOc3ccc(-n4ccnc4)cc3OCC2)cc1

Procedure:
In a manner similar to preparation 7, react 9-(1H-imidazol-1-yl)-3,4,5,6-tetrahydro-2H-1,7,4-benzodioxazonine, trimethylaluminum, and 4-[(methylsulfonyl)amino]benzeneacetic acid, methyl ester to obtain the title compound.