Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[O:100])[CH2:3][NH:4][C:5](=[O:99])[C@@H:6]([NH:13][C:14](=[O:98])[C@@H:15]([N:17]([CH3:97])[C:18]([C@H:20]([CH2:86][C:87]([O:89]CC1C=CC=CC=1)=[O:88])[NH:21][C:22](=[O:85])[C@H:23]([CH2:78][C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1)[NH:24][C:25](=[O:77])[C@H:26]([CH:74]([CH3:76])[CH3:75])[NH:27][C:28](=[O:73])[C@H:29]([CH3:72])[NH:30][C:31](=[O:71])[C@H:32]([CH2:67][CH:68]([CH3:70])[CH3:69])[NH:33][C:34](=[O:66])[CH2:35][NH:36][C:37](=[O:65])[C@H:38]([CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[N:39]([CH3:57])[C:40](=[O:56])[C@H:41]([CH3:55])[NH:42][C:43](=[O:54])[C@H:44]([CH3:53])[NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:19])[CH3:16])[CH2:7][O:8][C:9]([CH3:12])([CH3:11])[CH3:10].C(OCC)(=O)C.[H][H]>CO.O[Pd].[C]>[NH2:1][C:2](=[O:100])[CH2:3][NH:4][C:5](=[O:99])[C@@H:6]([NH:13][C:14](=[O:98])[C@@H:15]([N:17]([CH3:97])[C:18]([C@H:20]([CH2:86][C:87]([OH:89])=[O:88])[NH:21][C:22](=[O:85])[C@H:23]([CH2:78][C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1)[NH:24][C:25](=[O:77])[C@H:26]([CH:74]([CH3:76])[CH3:75])[NH:27][C:28](=[O:73])[C@H:29]([CH3:72])[NH:30][C:31](=[O:71])[C@H:32]([CH2:67][CH:68]([CH3:69])[CH3:70])[NH:33][C:34](=[O:66])[CH2:35][NH:36][C:37](=[O:65])[C@H:38]([CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[N:39]([CH3:57])[C:40](=[O:56])[C@H:41]([CH3:55])[NH:42][C:43](=[O:54])[C@H:44]([CH3:53])[NH:45][C:46](=[O:52])[O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:19])[CH3:16])[CH2:7][O:8][C:9]([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N(C)[C@@H](C)C(=O)N[C@@H](COC(C)(C)C)C(=O)NCC(N)=O)C(C)C
Reactant: [H][H]
Agent: O[Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(=O)O)C(=O)N(C)[C@@H](C)C(=O)N[C@@H](COC(C)(C)C)C(=O)NCC(N)=O)C(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 88 %

Procedure:
Hydroxypalladium/carbon (250 mg, 50% wet w/w) was added to a solution of benzyl (6S,9S,12S,18S,21S,24S,27S,30S)-30-(((S)-1-(((S)-1-((2-amino-2-oxoethyl)amino)-3-(tert-butoxy)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamoyl)-12,27-dibenzyl-18-isobutyl-24-isopropyl-2,2,6,9,11,21-hexamethyl-4,7,10,13,16,19,22,25,28-nonaoxo-3-oxa-5,8,11,14,17,20,23,26,29-nonaazadotriacontan-32-oate synthesized according to a conventional method (Compound SP-502, Boc-Ala-Ala-MePhe-Gly-Leu-Ala-Val-Phe-Asp(OBn)-MeAla-Ser(tBu)-Gly-NH2) (749 mg, 0.536 mmol) in methanol (5 ml)-ethyl acetate (5 ml) under a nitrogen atmosphere, the atmosphere was replaced with hydrogen, and the mixture was then stirred at room temperature for 3.5 hours. The reaction solution was then filtered through celite, and the filtrate was concentrated under reduced pressure to afford the title compound (SP-501) (620 mg, 88%).
Reaction SMILES: B.O1CCCC1.CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1.[CH2:28]([O:35][C:36]1[CH:37]=[CH:38][C:39]([C:47](=[O:50])[CH2:48][Cl:49])=[C:40]2[C:45]=1[NH:44][C:43](=[O:46])[CH:42]=[CH:41]2)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1>[CH2:28]([O:35][C:36]1[CH:37]=[CH:38][C:39]([C@@H:47]([OH:50])[CH2:48][Cl:49])=[C:40]2[C:45]=1[NH:44][C:43](=[O:46])[CH:42]=[CH:41]2)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(CCl)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: C1CCOC1
Product: O=c1ccc2c([C@@H](O)CCl)ccc(OCc3ccccc3)c2[nH]1
Temperature: 5 °C
Reaction time: 0.08 h

Procedure:
Borane-tetrahydrofuran complex (1M in tetrahydrofuran, 1 ml, 1 mMol) was added dropwise to a solution of (R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo [1,2-c][1,3,2]oxazaborole (0.1 equiv, 30 mg, 0.1 mMol) in tetrahydrofuran (6 ml) at ambient temperature under an argon atmosphere. After 5 minutes, 8-benzyloxy-5-chloroacetylcarbostyril (328 mg, 1 mMol) was added and the reaction mixture was stirred for a further 15 minutes. The reaction mixture was cooled to 5° C. and quenched by the dropwise addition of methanol (2 ml). The quenched reaction mixture was stirred for 15 minutes at 5° C. and for 30 minutes at ambient temperature. The solvent was evaporated and the residue was purified by chromatography on silica gel eluting with 10% methanol in ethyl acetate to afford the title compound as a pale yellow solid; m.p. 148°-149° C.; [α]D25 -9.0° (c=1, methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([N:12]([CH2:14][C:15]1[O:19][CH:18]=[C:17]([C:20](O)=[O:21])[CH:16]=1)[CH3:13])(=[O:11])=[O:10].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:35]1[CH2:39][CH2:38][N:37]=[C:36]1[C:40]1[CH:45]=[CH:44][C:43]([CH2:46][CH2:47][NH:48][CH3:49])=[CH:42][CH:41]=1.Cl>ClCCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([N:12]([CH2:14][C:15]1[O:19][CH:18]=[C:17]([C:20]([N:48]([CH2:47][CH2:46][C:43]2[CH:42]=[CH:41][C:40]([C:36]3[NH:37][CH2:38][CH2:39][N:35]=3)=[CH:45][CH:44]=2)[CH3:49])=[O:21])[CH:16]=1)[CH3:13])(=[O:10])=[O:11]
Reactant: CN(Cc1cc(C(=O)O)co1)S(=O)(=O)c1ccc(Cl)cc1Cl
Reactant: CNCCc1ccc(C2=NCCN2)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: CN(CCc1ccc(C2=NCCN2)cc1)C(=O)c1coc(CN(C)S(=O)(=O)c2ccc(Cl)cc2Cl)c1
Reaction time: 2 h

Procedure:
5-({[(2,4-dichlorophenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (34 mg, 0.08 mmol) was dissolved in DCE (1 mL) and CDI (26 mg, 0.16 mmol) was added. The reaction was stirred for 2 h. The activated acid solution in DCE was added to a vial containing 2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methylethanamine.HCl (43 mg, 0.16 mmol) and TEA (0.022 mL, 0.16 mmol). The reaction was stirred at ambient temperature for 18 h, then partitioned between saturated aqueous NaHCO3 (1 mL) and DCE (3×1 mL)). The organic layer was dried over MgSO4 and solvents were removed in vacuo. A portion of the crude product was purified by prep method A.
Reaction SMILES: Cl[CH:2]([C:15](=O)[CH3:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH:32][C:33]([NH2:35])=[S:34])[CH:23]=[CH:24][C:25]=1[N:26]1[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]1>C(O)C>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][C:2]2[S:34][C:33]([NH:32][C:22]3[CH:23]=[CH:24][C:25]([N:26]4[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]4)=[C:20]([O:19][CH3:18])[CH:21]=3)=[N:35][C:15]=2[CH3:16])=[CH:5][C:6]=1[C:11]([F:14])([F:13])[F:12]
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: CC(=O)C(Cl)Cc1ccc(Cl)c(C(F)(F)F)c1
Solvent: CCO
Product: COc1cc(Nc2nc(C)c(Cc3ccc(Cl)c(C(F)(F)F)c3)s2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 1 step e) from crude 2-chloro-1-(4-chloro-3-trifluoromethyl-phenyl)-butan-3-one and 53 mg (0.2 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea in ethanol (1 ml). The crude product was purified on silica gel with methylene chloride/methanol 9/1 yielding 87 mg (88%) of the title compound as a brown solid. MS ISP (m/e): 493.2/495.2 (100/35) (M+H)+. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.63 (s, 1H), 7.51 (s, 1H), 7.43 (d, 1H), 7.30 (d, 1H), 7.23 (s, 1H), 7.15 (d, 1H), 6.90 (d, 1H), 6.85 (s, 1H), 4.00 (s, 2H), 3.82 (s, 3H), 2.31 (s, 6H).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]([CH2:8][C:9]1[C:10]2[CH2:11][C:12]3[N:17]4[CH:18]=[C:19]([C:21]([O:23]CC)=[O:22])[N:20]=[C:16]4[C:15](=[O:26])[NH:14][C:13]=3[C:27]=2[CH:28]=[CH:29][CH:30]=1)=[O:7])(=[O:4])=[O:3].[OH-].[Na+].O1CCOCC1>O>[CH3:1][S:2]([NH:5][C:6]([CH2:8][C:9]1[C:10]2[CH2:11][C:12]3[N:17]4[CH:18]=[C:19]([C:21]([OH:23])=[O:22])[N:20]=[C:16]4[C:15](=[O:26])[NH:14][C:13]=3[C:27]=2[CH:28]=[CH:29][CH:30]=1)=[O:7])(=[O:3])=[O:4]
Reactant: CCOC(=O)c1cn2c3c([nH]c(=O)c2n1)-c1cccc(CC(=O)NS(C)(=O)=O)c1C3
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)NC(=O)Cc1cccc2c1Cc1c-2[nH]c(=O)c2nc(C(=O)O)cn12
Reaction time: 20 h

Procedure:
The 9-methylsulphonamidocarbonylmethyl-4-oxo-4,5-dihydro-10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-2-carboxylic acid can be obtained in the following manner: 4.4 ml of 1 N aqueous sodium hydroxide are added dropwise to a solution of 0.48 g of ethyl 9-methylsulphonamidocarbonylmethyl-4-oxo-4,5-dihydro-10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-2-carboxylate, 45 ml of dioxane and 1.3 ml of distilled water. The reaction medium is kept stirring for 20 hours, filtered on sintered glass and the solid thus obtained is washed with twice 20 ml of dioxane, air-dried and then under reduced pressure at 60° C. 0.46 g of 9-methylsulphonamidocarbonylmethyl-4-oxo-4,5-dihydro-10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-2-carboxylic acid is thus obtained as disodium salt in the form of a pink solid melting above 260° C. (Analysis: C17H12N4O6S1Na2, 6.21 H2O, 0.49 C4H8O2, % calculated C: 45.75, H: 2.71, N: 12.55, S: 7.18; % found C: 45.7, H: 2.3, N: 12.5, S: 7.2).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)=[O:4].C(O)=O.C(N(CC)CC)C>C(OCC)(=O)C>[Cl:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4]
Reactant: O=C(CCl)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O=CO
Product: OC(CCl)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.6 %

Procedure:
2-Chloro-3′-chloroacetophenone (94.5 mg; 0.5 mmol) and a formic acid/triethylamine azeotropic mixture (0.1 ml) were added to a solution of chloro(pentamrethylcyclopentadienyl)iridium (III) (1R,2R)-N-(p-toluenesulfonyl)-1,2-diaminocyclohexane (3.5 mg, 0.0005 mmol, s/c=100) in ethyl acetate (0.5 ml), followed by stirring at room temperature for 16 hours. After completion of the reaction, the reaction mixture was purified by silica gel column chromatography to give a desired compound, (+)-2-chloro-1-(3′-chlorophenyl)ethanol (88.5 mg; yield: 92.7%; optical purity: 91.0%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=O.CC(C)([O-])C.[K+].O>C1COCC1>[CH:11]1[CH:12]=[CH:13][CH:14]=[C:9]2[C:10]=1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:6]1[CH2:5][CH2:4][CH2:3][CH2:2][N:8]12
Reactant: CCOC(=O)Cc1ccccc1NC(=O)CCCCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c2n(c3ccccc13)CCCC2
Yield: 19 %

Procedure:
A solution of ethyl 2-(5-chlorovalerylamino)phenylacetate (8.10 g, 0.027 mole) in dry THF (50 ml) was added to a stirred suspension of potassium t-butoxide (7.62 g, 0.068 mole) in dry THF (200 ml) at room temperature under nitrogen. After 1 h the purple solution produced was treated with water (10 ml) and concentrated in vacuo. The residue was shaken with ethyl acetate (200 ml) and sat.ammonium chloride solution (150 ml), then the organic layer separated, dried (Na2SO4) and concentrated in vacuo to afford an orange oil. This was chromatographed on silica gel eluting with ether to afford the title compound as a yellow solid (1.25 g, 20%).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:17][C:18]#[CH:19])[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])(=[O:7])=[O:6].[N+:20](=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N-:21].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCCC1>C1C=CC=CC=1>[N+:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[S:5]([N:4]1[CH2:3][CH2:2][N:21]2[N:20]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:19]=[C:18]2[CH2:17]1)(=[O:7])=[O:6])([O-:16])=[O:15]
Reactant: C#CCN(CCCl)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2n(n1)CCN(S(=O)(=O)c1ccccc1[N+](=O)[O-])C2
Temperature: 25 °C

Procedure:
A solution of N-(2-chloroethyl)-2-nitro-N-(prop-2-yn-1-yl)benzenesulfonamide (0.51 g, 1.69 mmol and ethyl diazoacetate (0.266 mL, 2.532 mmol) in benzene (2 mL) was heated in a microwave reactor at 140° C. for 1 hour. Upon cooling to room temperature, cesium carbonate (0.637 g, 1.95 mmol) along with tetrahydrofuran (1 mL) was added. The vial was again sealed and heated at 140° C. for 30 minutes in the microwave reactor. Upon cooling to room temperature, the solvents were then evaporated in vacuo and the residue obtained was partitioned between water (10 mL) and EtOAc (15 mL). The aqueous layer was washed with additional EtOAc (15 mL), the combined organic layers were dried over anhydrous MgSO4, concentrated and purified via silica chromatography (20-90% EtOAc/hexane) to afford Intermediate 16 as a semi solid (0.235 g, 37%). LC-MS: (FA) ES+381; 1H NMR (400 MHz, CDCl3) δ 8.07 (dd, J=7.5, 1.7 Hz, 1H), 7.79-7.67 (m, 3H), 6.63 (s, 1H), 4.64 (s, 2H), 4.41-4.31 (m, 4H), 3.92-3.89 (m, 2H), 1.37 (t, J=7.1 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Br:10])[CH:3]=1.[Li]CCCC.CCCCCC.[CH3:22][C:23]([CH3:25])=[O:24]>C1COCC1>[Br:10][C:4]1[CH:3]=[C:2]([C:23]([OH:24])([CH3:25])[CH3:22])[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1
Reactant: CC(C)=O
Reactant: COc1cc(Br)cc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(Br)cc(C(C)(C)O)c1
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1,3-dibromo-5-methoxy-benzene (20.7 g, 78 mmol) in dry THF (100 mL) was added under nitrogen a 1.6 M solution of nBuLi in hexane (48.7 mL, 78 mmol) at such a rate that the reaction temperature did not rise above −50° C. After the addition the mixture was cooled to −70° C. and acetone (6.86 mL, 78 mmol) was added over a 5 min period. After 2 min the reaction was quenched with saturated NH4Cl solution and stirred for 10 min. The mixture was diluted with water and extracted with TBME. The organic layer was dried with MgSO4, filtered and evaporated. Chromatographic purification over silica gel (hexane-EtOAc 95:5 to 85:15) provided impure 2-(3-bromo-5-methoxy-phenyl)-propan-2-ol as a yellow oil: TLC (hexane-AcOEt 6:1) Rf=0.22; HPLC RtH1=2.35 min; ESIMS [M−OH]−=227,229; 1H NMR (400 MHz, CDCl3): δ 7.27 (t, 1H), 7.02 (dd, 1H), 6.97 (dd, 1H), 3.83 (s, 3H), 1.59 (s, 6H). This material was treated with (±) camphor sulfonic acid (70 mg) in refluxing hexane with the azeotropical removal of water. After 1 h the cooled reaction mixture is diluted with TBME, washed with 5% aq. NaHCO3, dried with MgSO4, filtered and evaporated. Chromatographic purification over silica gel (hexane-toluene 0-10%) gave impure 1-bromo-3-iso-propenyl-5-methoxy-benzene as a slightly yellow oil: 1H NMR (400 MHz, CDCl3): δ 7.27 (t, 1H), 7.07 (s, 1H), 6.99 (s, 1H), 5.48 (s, 1H), 5.16 (s, 1H), 3.75 (s, 3H), 2.07 (s, 3H). This material was stirred in the presence of Ra—Ni catalyst (5 g) in EtOH (15 mL) under a hydrogen atmosphere for 18 h. The mixture was filtered over a bed of Celite and evaporated to obtain a yellow oil that contained still some starting material. It was taken up in CH2Cl2 (10 mL) and treated with meta-chlorperbenzoic acid (250 mg). The mixture was washed with sodium sulfite solution, followed by water and evaporated. Chromatography over silica gel (hexane-CH2Cl2 100:1 to 9:1) gave the title compound as a colorless oil: TLC (hexane-EtOAc 9:1) Rf=0.50; HPLC RtH1=3.79 min; 1H NMR (400 MHz, CDCl3): δ 6.97 (t, 1H), 6.86 (t, 1H), 6.69 (t, 1H), 3.78 (s, 3H), 2.84 (heptet, 1H), 1.22 (d, 6H).
Reaction SMILES: F[C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].CN1CCN(C)C1=[O:22]>O>[F:11][C:10]1[C:9]([F:12])=[CH:8][CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]=1[OH:22]
Reactant: O=C(O)c1ccc(F)c(F)c1F
Reactant: CN1CCN(C)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(F)c(F)c1O
Temperature: 150 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
1.76 g (0.01 mole) of 2,3,4-trifluorobenzoic acid, 1.62 g (0.04 mole) of powdery 99% sodium hydroxide and 20 ml of 1,3-dimethyl-2-imidazolidinone were fed into a 100-ml four-necked flask provided with a thermometer, a stirrer and a reflux condenser. The mixture was stirred at 150° C. for 2 hours to give rise to a reaction. After the completion of the reaction, part of 1,3-dimethyl-2-imidazolidinone was recovered. The resulting reaction mixture was diluted with 500 ml of water and then subjected to precipitation with a 10% aqueous hydrochloric acid solution. The resulting material was cooled in an ice bath. The resulting crystals were collected by filtration, washed with water, and dried to obtain 1.66 g of 3,4-difluorosalicylic acid. The isolated yield was 95.1% relative to the 2,3,4-trifluorobenzoic acid used.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:5]=2[S:4](=[O:14])(=[O:13])[N:3]=1.[CH2:15]([NH:17][CH3:18])[CH3:16]>>[Cl:12][C:9]1[CH:10]=[CH:11][C:5]2[S:4](=[O:14])(=[O:13])[N:3]=[C:2]([N:17]([CH2:15][CH3:16])[CH3:18])[NH:7][C:6]=2[CH:8]=1
Reactant: CCNC
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)ccc21
Product: CCN(C)C1=NS(=O)(=O)c2ccc(Cl)cc2N1

Procedure:
Starting from 3,6-dichloro-4H-1,2,4-benzothiadiazine 1,1-dioxide (500 mg; 1.99 mmol) and N-ethyl-N-methylamine (500 mg; 8.47 mmol) and with the use of same procedure as in example 21 200 mg (36.7%) of the title compound was prepared; m.p. >220° C.; 1H-NMR (DMSO-d6) ppm; 10.35 (s, 1H, NH), 7.65 (d, 1H, H-8), 7.58 (dd, 1H, H-5), 7.3 (d, 1H, H-7), 3.5 (q, 2H, CH2), 3.11 (s, 3H, CH3), 1.14 (t, 3H, CH3). Analysis: C10H12ClN3O2S requires C, 43.88; H, 4.42; N, 15.35; (found C, 43.78; H, 4.51; N, 15.24).
Reaction SMILES: [CH3:1][C:2]([CH3:46])([CH3:45])[CH2:3][O:4][C:5](=[O:44])[N:6]=[C:7]([NH2:43])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:15]([C:29]2[N:33]=[C:32]([O:34][CH2:35]Cl)[N:31]([C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:30]=2)[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH2:25][CH2:26][OH:27])[C:17]=2[F:28])=[CH:10][CH:9]=1.C(=O)([O-])O.[K+].[I-].[Na+].[CH:54]1([C:60]([OH:62])=[O:61])[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]1.[Cl-].[NH4+]>CN(C=O)C>[NH2:43][C:7](=[N:6][C:5]([O:4][CH2:3][C:2]([CH3:46])([CH3:45])[CH3:1])=[O:44])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:15]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH2:25][CH2:26][OH:27])[C:17]=2[F:28])[C:29]2[N:33]=[C:32]([O:34][CH2:35][O:62][C:60]([CH:54]3[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]3)=[O:61])[N:31]([C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:30]=2)=[CH:10][CH:9]=1
Reactant: O=C(O)C1CCCCC1
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(N)=NC(=O)OCC(C)(C)C)cc2)c2nc(OCCl)n(-c3ncccn3)n2)c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(N)=NC(=O)OCC(C)(C)C)cc2)c2nc(OCOC(=O)C3CCCCC3)n(-c3ncccn3)n2)c1
Temperature: 45 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To a mixture of [1-amino-1-[4-({(5-chloromethoxy-1-pyrimidin-2-yl-1H-[1,2,4]triazol-3-yl)-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]methyl}amino)phenyl]methylidene]carbamic acid 2,2-dimethylpropyl ester (Example 2b, 120 mg), potassium hydrogen carbonate (131 mg), and DMF (16 mL), sodium iodide (140 mg) and cyclohexanecarboxylic acid (163 mg) were added, and the resulting mixture was stirred at 45° C. overnight. After cooling the reaction mixture to room temperature, ice and saturated aqueous ammonium chloride solution were added thereto, and the resulting mixture was extracted three times with a mixture of THF and ethyl acetate. The organic layer was collected, washed with saturated aqueous ammonium chloride solution, and dried over anhydrous magnesium sulfate. The resulting mixture was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by NAM silica gel column chromatography (mixed solvent of methanol-ethyl acetate) to obtain the captioned compound (123 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[NH:4][C:5]1[C:14]2[CH:13]=[C:12]3[O:15][CH2:16][CH2:17][NH:18][C:11]3=[CH:10][C:9]=2[N:8]=[CH:7][C:6]=1[C:19]#[N:20].[Cl:26][CH2:27][CH2:28][CH2:29][CH:30]=O.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O.O1CCCC1.FC(F)(F)C(O)=O>[Cl:26][CH2:27][CH2:28][CH2:29][CH2:30][N:18]1[C:11]2[C:12](=[CH:13][C:14]3[C:5]([NH:4][C:3]4[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:2]=4[Cl:1])=[C:6]([C:19]#[N:20])[CH:7]=[N:8][C:9]=3[CH:10]=2)[O:15][CH2:16][CH2:17]1
Reactant: O=CCCCCl
Reactant: N#Cc1cnc2cc3c(cc2c1Nc1ccc(Cl)cc1Cl)OCCN3
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: N#Cc1cnc2cc3c(cc2c1Nc1ccc(Cl)cc1Cl)OCCN3CCCCCl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.9 %

Procedure:
An amount of 100 mg (0.27 mmol) of 9-(2,4-dichloroanilino)-3,4-dihydro-2H-[1,4]oxazino[2,3-g]quinoline-8-carbonitrile, was stirred in N,N-dimethylformamide (2 mL), and to this was added a solution of 4-chloro-butyraldehyde (719 mg, 6.8 mmol) in tetrahydrofuran (2 mL) and trifluoroacetic acid (1.4 mL). The reaction mixture was stirred at room temperature, and to this was added sodium borohydride (128 mg, 3.4 mmol) portionwise, in 1.5 hours. The mixture was stirred for 16 hours, basified with saturated sodium bicarbonate solution, and extracted with ethyl acetate. After separation of the layers, the organic layer was washed with saturated brine solution, dried over sodium sulfate and evaporated to an oil. Purification was done by flash chromatography (10% acetone in dichloromethane) to give a yellow solid (66 mg, 53% yield), m.p 56-57° C.; 1H NMR (DMSO-d6) δ 9.92 (bs, 1H), 8.59 (s, 1H), 7.81 (d, 2H), 7.51 (m, 2H), 6.98 (s, 1H), 4.30 (t, 2H), 3.70 (t, 2H), 3.57 (t, 2H), 3.51 (t, 2H), 1.80 (m, 4H); HRMS (EI) m/z 461.06917 (M+1). Analysis for C22H19Cl3N4O.0.7CH3CO2C2H5.3.9H2O Found: C, 49.81; H, 3.78; N, 9.65. Calcd: C, 50.12; H, 5.46; N, 9.43.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[S:13]1[CH:17]=[CH:16][C:15]2[C:18]([C:22]([OH:24])=[O:23])=[CH:19][CH:20]=[CH:21][C:14]1=2.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C>C1COCC1>[C:22]([C:18]1[C:15]2[CH:16]=[C:17]([B:25]([OH:30])[OH:26])[S:13][C:14]=2[CH:21]=[CH:20][CH:19]=1)([OH:24])=[O:23]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: O=C(O)c1cccc2sccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1cccc2sc(B(O)O)cc12
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A solution of n-BuLi (2.5M in hexane, 1.69 mol, 676 mL) is added slowly at −78° C. to a solution of diisopropylamine (1.69 mol, 236 mL) in 2 L of anhydrous THF. The mixture is stirred for 30 min. A solution of benzo[b]thiophene-4-carboxylic acid (0.8 mol, 143 g) in 2 L of anhydrous THF is added slowly and the mixture is allowed to reach 0° C. The reaction is cooled to −30° C. and the triisopropyl borate (2 mol, 463 mL) is added slowly. The cooling bath is removed and the mixture is allowed to reach room temperature. The reaction is quenched with 1.3 L of concentrated HCl and 1 L of water. The mixture is stirred overnight. The organic solvent is removed under reduced pressure. The precipitate is collected by filtration, washed with water, and dried under vacuum to yield the title compound (170.5 g, 96%). ES/MS m/e 221 (M−1).
Reaction SMILES: [I:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][C:19]([CH3:22])(C)[CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:26]1(O)[CH2:31]CCC[CH2:27]1>CCO.CCO.CCO.CCO.[Ti].[F-].[K+]>[I:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH:19]3[CH2:20][CH2:31][CH2:26][CH2:27][CH2:22]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c(I)cccc1-2
Reactant: OC1CCCCC1
Agent: [Ti]
Agent: [F-]
Agent: [K+]
Solvent: CCO
Product: O=C(OC1CCCCC1)c1ncn2c1[C@@H]1CCN1C(=O)c1c(I)cccc1-2

Procedure:
12 g (26.6 mmol) of tert.butyl (S)-12,12a-dihydro-8-iodo-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate, 70 ml (660 mmol) of cyclohexanol and 2 g (8 mmol) of tetraethyl orthotitanate are stirred at 120° overnight, the solution is evaporated to dryness and the residue is taken up in chloroform. The solution obtained is stirred for 0.5 hour with 120 ml of a saturated potassium fluoride solution, the resulting emulsion is filtered through siliceous earth, the organic phase is separated, washed with water, dried over magnesium sulphate and evaporated. By crystallization from ethyl acetate and hexane there is obtained cyclohexyl (S)-12,12a-dihydro-8-iodo-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate of melting point 124°-125°.