Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]([CH:10]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[C:19]3[C:20]([F:28])=[CH:21][N:22]=[CH:23][C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:11]1)C)=O)(C)(C)C.FC1C2C(S([Cl:43])(=O)=O)=CC=CC=2C=NC=1.C(OC(N(C1CCNC1)C)=O)(C)(C)C.BrC1C2C(S(Cl)(=O)=O)=CC=CC=2C=NC=1.C(OC(N([C@H]1CCNC1)C)=O)(C)(C)C>>[F:28][C:20]1[C:19]2[C:18]([S:15]([N:12]3[CH2:13][CH2:14][CH:10]([NH:8][CH3:6])[CH2:11]3)(=[O:16])=[O:17])=[CH:27][CH:26]=[CH:25][C:24]=2[CH:23]=[N:22][CH:21]=1.[ClH:43]
Reactant: O=S(=O)(Cl)c1cccc2cncc(F)c12
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(S(=O)(=O)c2cccc3cncc(F)c23)C1
Agent: CN(C(=O)OC(C)(C)C)C1CCNC1
Agent: CN(C(=O)OC(C)(C)C)[C@H]1CCNC1
Agent: O=S(=O)(Cl)c1cccc2cncc(Br)c12
Product: CNC1CCN(S(=O)(=O)c2cccc3cncc(F)c23)C1
Product: Cl

Procedure:
3-[N-(tert-Butoxycarbonyl)-N-methylamino]-1-(4-fluoro-5-isoquinolinesulfonyl)pyrrolidine (Intermediate 22) can be prepared by using 4-fluoro-5-isoquinolinesulfonyl chloride and 3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine in the method of Example 1-3, Step A instead of 4-bromo-5-isoquinolinesulfonyl chloride and (S)-3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine, respectively, and then used in the method of Example 1-3, Step B in a similar manner to obtain the title compound as hydrochloride.
Reaction SMILES: Br[CH2:2][C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[CH2:5][O:6][Si:7]([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([O-:37])=[O:36])=[CH:31][CH:30]=1.[Na+]>C(O)CC>[C:20]([Si:7]([O:6][CH2:5][C:4]1[CH:24]=[CH:25][CH:26]=[CH:27][C:3]=1[CH2:2][S:35]([C:32]1[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=1)(=[O:37])=[O:36])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:21])([CH3:23])[CH3:22]
Reactant: O=S([O-])c1ccc(Cl)cc1
Reactant: CC(C)(C)[Si](OCc1ccccc1CBr)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CCCO
Product: CC(C)(C)[Si](OCc1ccccc1CS(=O)(=O)c1ccc(Cl)cc1)(c1ccccc1)c1ccccc1
Temperature: 90 °C
Reaction time: 14 h

Procedure:
In propanol (20 ml) was dissolved (2-bromo methylbenzyloxy)-t-butyldiphenylsilane (3.10 g, 7.05 mmol), followed by the addition of sodium 4-chlorobenzenesulfinate (1.80 g, 9.06 mmol). At 90° C., the resulting mixture was stirred for 14 hours. After the reaction mixture was allowed to cool down, the residue obtained by concentrating the reaction mixture under reduced pressure was added with ethyl acetate. The resulting mixture was washed with water, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, whereby the title compound (3.90 g, quant.) was obtained as a white solid.
Reaction SMILES: N(OS(=O)(=O)O)=O.N[C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH2:17][CH:16]([NH:19][CH3:20])[CH:15]=[CH:14][C:13]=2[CH:21]=1.[CH3:22][OH:23]>C(O)(=O)C>[CH3:22][O:23][C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH2:17][CH:16]([NH:19][CH3:20])[CH:15]=[CH:14][C:13]=2[CH:21]=1
Reactant: CO
Reactant: CNC1C=Cc2cc(N)ccc2CC1
Agent: O=NOS(=O)(=O)O
Solvent: CC(=O)O
Product: CNC1C=Cc2cc(OC)ccc2CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.1 g of nitrosyl sulfuric acid were added over 10 minutes at 20° C. to a mixture of 6 g of 2-amino-7-methylamino-6,7-dihydro [5H] benzocycloheptene in 60 ml of acetic acid and the mixture was stirred 2 hours at room temperature. The resulting brown solution was poured into 300 ml of methanol and the mixture was refluxed for 45 minutes and was evaporated to dryness under reduced pressure. The residue was added to 150 ml of water and the neutral fraction was removed by extraction twice with 100 ml of ether. The mixture was alkalinized at 10° C. by addition of sodium hydroxide and was extracted with methylene chloride. The organic phase was washed with water, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure to obtain 3.7 g of raw product. The latter was chromatographed over silica gel and was eluted with a 7-2-1 chloroform-methanol-triethylamine mixture to obtain a homogenous fraction of 3.4 g of 2-methoxy-7-methylamino-6,7-dihydro [5H] benzocycloheptene in the form of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[NH:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F:20][C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1>N1C=CC=CC=1>[F:20][C:21]1[CH:22]=[C:23]([S:27]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[C:5]3[NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1
Reactant: Nc1ccc2[nH]nc(NC(=O)c3ccccc3)c2c1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: c1ccncc1
Product: O=C(Nc1n[nH]c2ccc(NS(=O)(=O)c3cccc(F)c3)cc12)c1ccccc1
Yield: 82 %

Procedure:
N-[5-(3-Fluorobenzenesulfonylamino)-1H-indazol-3-yl]benzamide can be obtained as described in Example 2 from 0.45 g of N-(5-amino-1H-indazol-3-yl)benzamide, 10 ml of pyridine and 0.35 g of 3-fluorobenzenesulfonyl chloride. 0.6 g of N-[5-(3-fluorobenzenesulfonylamino)-1H-indazol-3-yl]-benzamide is thus obtained in the form of a white solid melting at 225° C. (analysis C20H15FN4O3S, % calculated C, 58.53; H, 3.68; F, 4.63; N, 13.65; O, 11.69; S, 7.81. % found C, 58.38; H, 3.42; N, 13.56; S, 7.44).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([CH3:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[CH3:20][NH:21][CH2:22][CH2:23][CH3:24]>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:21]([CH3:20])[CH2:22][CH2:23][CH3:24])[C:11]([CH3:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCNC
Reactant: Cc1cc([N+](=O)[O-])c(NC(=O)OC(C)(C)C)cc1Cl
Solvent: CS(C)=O
Product: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C

Procedure:
The title compound was prepared from (5-chloro-4-methyl-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example B8) (3.5 g, 12.2 mmol) and N-methylpropylamine (6.5 ml, 61.0 mmol) in DMSO (35 mL) at 55° C. according to the general procedure C. Obtained as a yellow oil (3.89 g, 98%).
Reaction SMILES: C(NCC)C.[CH2:6]([O:8][C:9](=[O:37])[CH:10]([CH2:14][C:15]1[CH:16]=[N:17][C:18]([N:22]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:19][C:20]=1[CH3:21])[C:11](O)=O)[CH3:7].C=O.C(OCC)(=O)C>C(Cl)Cl>[CH2:6]([O:8][C:9](=[O:37])[C:10]([CH2:14][C:15]1[CH:16]=[N:17][C:18]([N:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:30]([O:32][C:33]([CH3:36])([CH3:34])[CH3:35])=[O:31])=[CH:19][C:20]=1[CH3:21])=[CH2:11])[CH3:7]
Reactant: CCOC(=O)C(Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1C)C(=O)O
Agent: C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCNCC
Product: C=C(Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1C)C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.6 %

Procedure:
Diethylamine (0.26 g, 2.67 mmol) was added a mixture of 2-(6-[N,N-bis(tert-butoxycarbonyl)amino]-4-methyl-pyridin-3-ylmethyl)-malonic acid monoethyl ester (1.0 g, 2.2 mmol) and 37% aq. solution of formaldehyde (0.24 g, 3.00 mmol) in methylene chloride (2 mL) at 0° C. The mixture was stirred for 16 h at room temperature and ethyl acetate was added. The organic layer was washed with water and 5% NaHCO3 and dried. Concentration under reduced pressure followed by flash chromatography (toluene/ethyl acetate, 3:1→1:1) gave 2-(6-[N,N-bis(tert-butoxycarbonyl)amino]-4-methyl-pyridin-3-ylmethyl)-acrylic acid ethyl ester (0.81 g, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:14])[CH:11]=NO)[CH:5]=[CH:6][C:7]=1[F:8].[OH:15]S(O)(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:11](=[O:15])[C:10](=[O:14])[NH:9]2)=[CH:6][C:7]=1[F:8].[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]2[C:3]=1[C:11](=[O:15])[C:10](=[O:14])[NH:9]2
Reactant: O=C(C=NO)Nc1ccc(F)c(Cl)c1
Reactant: O=S(=O)(O)O
Product: O=C1Nc2cc(Cl)c(F)cc2C1=O
Product: O=C1Nc2ccc(F)c(Cl)c2C1=O
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
To concentrated H2SO4 (100 ml) at 65° C. was added N-(3-chloro-4-fluorophenyl)-2-(hydroxyimino)ethanamide (19.45 g, 90 mmol) portionwise. The mixture was heated at 90° C. for 1.5 h. The mixture was cooled to room temperature, poured onto ice, and stirred for 10 min. The solid was collected by filtration, washed with water, and air dried to afford 6-chloro-5-fluoro-1H-indole-2,3-dione and 4-chloro-5-fluoro-1H-indole-2,3-dione as a mixture of regioisomers (15.5 g, 86% yield). This material was used without further purification.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][C@H:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]2[CH2:18][O:19][C@@H:5]1[O:6]2)=[N+]=[N-].[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1>[CH2:11]([O:10][C@@H:8]1[C@H:7]2[CH2:18][O:19][C@H:5]([O:6]2)[C@H:4]([N:1]2[C:23](=[O:24])[C:22]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]3[C:20]2=[O:25])[CH2:9]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: [N-]=[N+]=N[C@@H]1C[C@H](OCc2ccccc2)[C@H]2CO[C@@H]1O2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [C-]#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CO
Product: O=C1c2ccccc2C(=O)N1[C@@H]1C[C@H](OCc2ccccc2)[C@H]2CO[C@@H]1O2
Reaction time: 360 h
Yield: 14.3 %

Procedure:
1,6-Anhydro-2-azido-4-O-benzyl-2,3-dideoxy-β-D-ribo-hexoyranose (see Example 13) (1.0 g), phthalic anhydride (0.74 g), triphenylphosphine (1.21 g) and tetrabutylammonium cyanide (0.1 g) were heated under reflux in a nitrogen atmosphere in benzene (50 ml) for 40 h. Methanol (10 ml) was then added and the solution was allowed to stand at room temperature for 15 days. The solution was then evaporated and the residue was chromatographed on silica gel to yield the title compound as a crystaline solid (0.2 g, 14%) from amongst a variety of products (t.l.c.evidence). Recrystallised from ethanol it had m.p. 135°-136° C., [α]D -28.4°; 13C-nmr data: 100.4 (C-1), 51.1 (C-2), 25.0 (C-3), 76.5 and 75.7 (C-4 and C-5), 67.4 (C-6), 70.4 (PhCH2O), 167.7 (C=0), 156.0 and 131.8 (q-aromatic), 134.0, 128.3, 127.6, 127.5 and 123.3 (aromatic).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][S:10]1(=[O:19])=[O:18].[Br:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Br:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[S:10]1(=[O:18])=[O:19]
Reactant: O=S1(=O)Nc2ccccc2N1c1ccc(F)cc1F
Reactant: BrCCOCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=S1(=O)N(CCOCCBr)c2ccccc2N1c1ccc(F)cc1F
Yield: 54.4 %

Procedure:
In an analogous manner to general procedure IV, 1-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (2.07 g, 7.3 mmol) was treated with 1-bromo-2-(2-bromoethoxy)ethane (3.2 mL, 25.7 mmol) and cesium carbonate (2.4 g, 7.3 mmol) to give 1-[2-(2-bromoethoxy)ethyl]-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (1.72 g, 53%) as a white amorphous solid. MS (ES) m/z 368.7 [M+H—SO2]+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]=[CH:10][C:9]3[CH:12]=[N:13][N:14]([C:15]4[N:20]=[C:19]([N:21]5[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]5)[CH:18]=[CH:17][CH:16]=4)[C:8]=3[CH:7]=2)[CH:3]=[N:2]1.Br[CH2:36][C:37]#[N:38]>>[N:21]1([C:19]2[N:20]=[C:15]([N:14]3[C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][N:2]([CH2:36][C:37]#[N:38])[CH:3]=5)[N:11]=[CH:10][C:9]=4[CH:12]=[N:13]3)[CH:16]=[CH:17][CH:18]=2)[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: N#CCBr
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccc(-n3ncc4cnc(-c5cn[nH]c5)cc43)n2)CC1
Product: N#CCn1cc(-c2cc3c(cn2)cnn3-c2cccc(N3CCCNCC3)n2)cn1
Yield: 18.5 %

Procedure:
Following the procedures as described in Example 61 and starting with tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate and 2-bromoacetonitrile, 155 was obtained as a white solid (25 mg, 18.5%) over two steps. 1H NMR (500 MHz, CDCl3) δ (ppm) 9.064-9.065 (d, J=0.5 Hz, 1H), 8.75 (s, 1H), 8.25 (s, 1H), 8.19 (s, 1H), 8.05 (s, 1H), 7.61-7.64 (t, J=16.5 Hz, 1H), 7.28 (s, 1H), 6.43-6.45 (d, J=8.5 Hz, 1H), 5.15 (s, 2H), 3.88-3.92 (m, 4H), 3.17-3.19 (t, J=11 Hz, 2H), 2.92-2.94 (t, J=11 Hz, 2H), 2.02-2.05 (t, J=12 Hz, 2H); MS (ESI) m/z: 400 [M+H]+.
Reaction SMILES: O[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[CH:3]=1.S([O:18][CH3:19])(OC)(=O)=O.[C:20](=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH3:20][O:12][C:6]1[CH:7]=[CH:8][C:9]2[C:4](=[CH:3][C:2]([O:18][CH3:19])=[CH:11][CH:10]=2)[CH:5]=1
Reactant: COS(=O)(=O)OC
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc2ccc(O)cc2c1
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc2ccc(OC)cc2c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Methylation of 2,7-dihydroxynaphthalene (10 g:62.43 mmol) is carried out in acetone (100 ml) in the presence of dimethyl sulphate (12.06 ml:127 mmol:2.03 eq.) and dry potassium carbon-ate (42.3 g:306 mmol:4.9 eq.). The temperature of the reaction medium is 56° C. for 6 hours and then 40° C. for 12 hours. Hydrolysis (7.4 ml of water) requires 2 hours of stirring at ambient temperature. After filtering off the salts over Celite and concentrating the remaining filtrate, extraction with dichloromethane yields an organic phase, which, after evaporation, has the appearance of a beige solid. The latter is rendered colourless using active carbon and then recrystallised from a PE/CH2Cl2 mixture.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17](C=CC3C=NC=CC=3)[CH:16]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:29]CCl.[F:32][C:33]([F:46])([F:45])[S:34]([O:37]S(C(F)(F)F)(=O)=O)(=[O:36])=[O:35]>>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:37][S:34]([C:33]([F:46])([F:45])[F:32])(=[O:35])=[O:36])=[C:17]([Cl:29])[CH:16]=2)[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: ClCCl
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(C=Cc3cccnc3)c2)C1
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cc2ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To the solution of 1.80 g (5.5 mmol) (R)-2-(3-chloro-4-hydroxy-benzyl)-morpholine-4-carboxylic acid tert-butyl ester (example 7, intermediate (a)) in 25 mL dichloromethane 1.53 mL (11.0 mmol) triethylamine were added. After cooling down to 0° C. 1.0 mL (6.0 mmol) trifluoromethanesulfonic anhydride were added and the cooling bath was removed. After 1 h stirring at room temperature the reaction mixture was extracted with 10% aqueous sodium bicarbonate solution and brine and the organic layer was dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography on silica gel using n-hexane:ethyl acetate (2:1 v/v) as eluant to give the compound in form of a light yellow oil (98%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=O)=O)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:23].[CH3:24][C:25]1[C:30]([OH:31])=[C:29]([CH:32]=O)[C:28]([CH2:34][OH:35])=[CH:27][N:26]=1.Cl.[OH-].[NH4+:38]>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:23]=[C:32]([C:29]3[C:28]([CH2:34][OH:35])=[CH:27][N:26]=[C:25]([CH3:24])[C:30]=3[OH:31])[NH:38][C:10]=2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C(C(=O)c1ccc(F)cc1)c1ccc(F)cc1
Reactant: [NH4+]
Reactant: Cc1ncc(CO)c(C=O)c1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1ncc(CO)c(-c2nc(-c3ccc(F)cc3)c(-c3ccc(F)cc3)[nH]2)c1O
Temperature: 100 °C

Procedure:
4,4′-Difluorobenzil (2.46 g, 10 mmol), ammonium acetate (11.5 g, 150 mmol) were dissolved in DMSO (60 mL) and heated to 100° C. Pyridoxal hydrochloride (6.1 g, 30 mmol) in DMSO (50 mL) was added drop wise over a period of 40 min. The reaction mixture was cooled to it and poured into icewater (300 mL) and aq. ammonium hydroxide solution (50 mL). The precipitate was filtered off, washed with water (100 mL), dissolved in ethyl acetate (150 mL) and extracted with water (2×50 mL). The organic layer was dried over MgSO4 (10 g) and evaporated to dryness. The residue was purified by flash chromatography on silica gel eluting with toluene/acetone 7/3. Fractions containing product were evaporated to a volume of 50 mL and cooled to 0° C. The precipitate was filtered off and dried to give (250 mg) the title compound as a yellow solid.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:12][C:13]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:14]=1[C:15](O)=[O:16]>>[CH3:12][C:13]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:14]=1[C:15]([NH:11][C@@H:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:16]
Reactant: Cc1cc(C)c(C(=O)O)c(C)c1
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Product: Cc1cc(C)c(C(=O)N[C@@H]2CCC[C@@H]2N2CCCC2)c(C)c1

Procedure:
The title compound, white solid, MS: m/e=301.2 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2,4,6-trimethylbenzoic acid.
Reaction SMILES: [CH:1]1([C:5](O)=O)[CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.N1C=CC=CC=1.[CH3:26][NH:27][C:28](=[S:31])[NH:29][NH2:30]>CN(C)C=O>[CH3:26][N:27]1[C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[N:30][N:29]=[C:28]1[SH:31]
Reactant: CNC(=S)NN
Reactant: O=C(O)C1CCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1c(S)nnc1C1CCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.6 %

Procedure:
5 g of cyclobutyl carboxylic acid (49.9 mmol) were dissolved in 50 ml of dimethylformamide. Within 10 min. 12.15 g of 1,1′-carbonyldiimidazol (74.91 mmol) were added in portions. After stirring for 1 h at room temperature 23 ml of pyridin were added followed by the addition of 10.5 g of 4-methyl-3-thiosemicarbazide (99.88 mmol). The solution was stirred at room temperature for 72 h and then poured into 600 ml of ice water. Stirring was continued for 30 min. before the aqueous layer was extracted three times with 50 ml dichloromethane and three times with 50 ml ethyl acetate each. The combined organic layers were dried over magnesium sulfate, filtered, and the solvent was evaporated, thereby yielding 5.2 g of the crude title product which was used without further purification.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@:19]3([C:23](O)=[O:24])[CH2:21][C@@H:20]3[CH3:22])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[NH2:39][C:40]1[S:41][C:42]([CH3:55])=[C:43]([CH3:54])[C:44]=1[C:45]([C:47]1[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=1)=[O:46]>CN(C=O)C.C(Cl)Cl>[Cl:53][C:50]1[CH:51]=[CH:52][C:47]([C:45]([C:44]2[C:43]([CH3:54])=[C:42]([CH3:55])[S:41][C:40]=2[NH:39][C:23]([C@@:19]2([NH:18][C:16](=[O:17])[O:15][CH2:14][CH:12]3[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[C:5]4[C:13]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[CH2:21][C@@H:20]2[CH3:22])=[O:24])=[O:46])=[CH:48][CH:49]=1
Reactant: Cc1sc(N)c(C(=O)c2ccc(Cl)cc2)c1C
Reactant: C[C@H]1C[C@]1(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1sc(NC(=O)[C@@]2(NC(=O)OCC3c4ccccc4-c4ccccc43)C[C@@H]2C)c(C(=O)c2ccc(Cl)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.1 %

Procedure:
A round bottomed flask was charged with (1R,2S)-1-(((9H-fluoren-9-yl)methoxy)carbonylamino)-2-methylcyclopropanecarboxylic acid (408 mg, 1.209 mmol) and a stir bar. DCM (25 mL, 0.05 M) was added, followed by one drop of DMF and oxalyl chloride (97 μl, 1.109 mmol). Stirred at room temperature 1 h. A solution of triethylamine (562 μl, 4.03 mmol) and (2-amino-4,5-dimethylthiophen-3-yl)(4-chlorophenyl)methanone (268 mg, 1.008 mmol) in DCM (10 mL, 0.1 M) was added dropwise, and the solution stirred at room temperature overnight before being concentrated with celite and purified by flash chromatography to give (9H-fluoren-9-yl)methyl (1R,2S)-1-(3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-ylcarbamoyl)-2-methylcyclopropylcarbamate as a yellow amorphous solid (225 mg) LRMS (M+H)+: 586 m/z.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[O:8][C@:9]3([CH3:49])[O:12][CH:13]=[CH:14][C@H:15]([O:47][CH3:48])[C@@H:16]([CH3:46])[C@@H:17]([O:42][C:43]([CH3:45])=[O:44])[C@H:18]([CH3:41])[C@H:19]([OH:40])[C@H:20]([CH3:39])[C@@H:21]([OH:38])[C@@H:22]([CH3:37])[CH:23]=[CH:24][CH:25]=[C:26]([CH3:36])[C:27](NC4C(=O)[C:4](=[C:5]([C:32](=O)C=4)[C:6]=2[C:10]3=[O:11])[C:3]=1[OH:50])=[O:28].Cl.CO[C:54](=[O:59])[C@H:55]([CH2:57][SH:58])[NH2:56].[CH2:60]([N:62](CC)CC)C>CO>[CH3:37][CH:22]1[CH:21]([OH:38])[CH:20]([CH3:39])[CH:19]([OH:40])[CH:18]([CH3:41])[CH:17]([O:42][C:43]([CH3:45])=[O:44])[CH:16]([CH3:46])[CH:15]([O:47][CH3:48])[CH:14]=[CH:13][O:12][C:9]2([CH3:49])[C:10](=[O:11])[C:6]3=[C:7]([O:8]2)[C:2]([CH3:1])=[C:3]([OH:50])[C:4]2=[C:5]3[C:32]3[N:62]=[CH:60][S:58][C:57]=3[C:55](=[C:54]2[OH:59])[NH:56][C:27](=[O:28])[C:26]([CH3:36])=[CH:25][CH:24]=[CH:23]1
Reactant: COC(=O)[C@@H](N)CS
Reactant: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C=C(NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O
Reactant: CCN(CC)CC
Agent: COC1/C=C\OC2(C)Oc3c(C)c(O)c4c(O)c(c5scnc5c4c3C2=O)NC(=O)/C(C)=C/C=C/C(C)C(O)C(C)C(O)C(C)C(OC(C)=O)C1C
Agent: CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)C=C(NC(=O)/C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)C4=O
Agent: Cl
Solvent: CO
Product: COC1C=COC2(C)Oc3c(C)c(O)c4c(O)c(c5scnc5c4c3C2=O)NC(=O)C(C)=CC=CC(C)C(O)C(C)C(O)C(C)C(OC(C)=O)C1C
Reaction time: 15 h

Procedure:
To a solution of 7 g of rifamycin S in 200 ml of methanol a mixture was added containing 1.8 g of the hydrochloride of cysteine methyl ester and 1.53 g of triethylamine. The mixture was refluxed for 20 minutes and then 20 ml of a buffer pH 4.6 containing 2.2 g of dichlorodicyano-p-quinone was added. The mixture was allowed to stand at room temperature for 15 hours and then was treated as described in Example 1 to obtain the rifamycin P. Yield 2.8 g of the title product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][N:7]=1.C(N(CC)CC)C.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[F:20][C:19]1[CH:18]=[CH:17][C:4]([CH2:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[NH:8][N:7]=2)=[CH:3][C:2]=1[N:1]=[C:29]=[O:31]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C=Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
To a suspension of 4-(3-amino-4-fluoro-benzyl)-2H-phthalazin-1-one (1)(4.0 g, 14.8 mmol) in anhydrous DCM (1.6 L) and triethylamine (4.62 mL, 40.86 mmol), was added a dropwise preformed solution of triphosgene (2.75 g, 9.28 mmol) in anhydrous DCM (327 mL) and stirred for 70 minutes and room temperature. The reaction mixture was then concentrated to dryness in vacuo yielding a grey solid. Single peak in LC-MS analysis, (yield taken to be quantitative) no purification performed. m/z (LC-MS, ESP), RT=4.49 mins, (M+MeOH) 328.0.