Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[NH2:43][C:44]1[S:45][CH:46]=[C:47]([C:49]([CH3:52])([CH3:51])[CH3:50])[N:48]=1>C(Cl)(Cl)Cl.O>[C:49]([C:47]1[N:48]=[C:44]([NH:43][C:35]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([O:9][C:10]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]=[CH:12][CH:11]=3)=[CH:8][C:2]=2[Cl:1])=[O:41])[S:45][CH:46]=1)([CH3:52])([CH3:51])[CH3:50]
Reactant: CC(C)(C)c1csc(N)n1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4nc(C(C)(C)C)cs4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.1 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (30 mg) was dissolved in chloroform (3 ml) to prepare a solution. Triethylamine (0.3 ml) and a solution of triphosgene (27 mg) in chloroform (0.2 ml) were then added thereto, and the mixture was stirred at room temperature for 30 min. Next, a solution of 2-amino-4-t-butylthiazole (64 mg) in chloroform (0.6 ml) was added thereto, and the mixture was further stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The extract was washed with saturated brine and was dried over anhydrous sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give 14 mg of the title compound.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=O)[CH2:10][C:9](=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+:19].[C:20]([CH2:23][C:24](=O)[CH3:25])(=O)[CH3:21]>C(O)C>[CH3:21][C:20]1[CH:23]=[C:24]([CH3:25])[C:10]2[C:9](=[O:14])[CH2:8][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][C:11]=2[N:19]=1
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Reactant: CC(=O)CC(C)=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: Cc1cc(C)c2c(n1)CC(c1ccccc1)CC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.5 %

Procedure:
To a mixture of 5-phenylcyclohexane-1,3-dione (2.0 g) and ammonium acetate (0.90 g) in ethanol (30 ml) was added acetylacetone (1.1 g), and the mixture was stirred at room temperature for 1 hour and refluxed for 21 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with sodium hydrogen carbonate solution, water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and insoluble materials were filtered off. The filtrate was concentrated, and the residue was purified with silica gel column chromatography (EtOAc/hexane). The resulting crystals were recrystallized from diisopropylether and hexane to give colorless crystals of 2,4-dimethyl-7-phenyl-5,6,7,8-tetrahydroquinolin-5-one (0.6 g).
Reaction SMILES: [CH:1]12[O:7][CH:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2]2.C(O)C.[N-:16]=[N+:17]=[N-:18].[Na+]>O>[N:16]([C@@H:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2][C@H:1]1[OH:7])=[N+:17]=[N-:18].[N:16]([C@H:1]1[C@H:6]([OH:7])[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:2]1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)N1CCC2OC2C1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)N1CC[C@@H](N=[N+]=[N-])[C@H](O)C1
Product: CCOC(=O)N1CC[C@@H](O)[C@H](N=[N+]=[N-])C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %
Yield: 15 %

Procedure:
To a stirred emulsion of 53.8 parts of ethyl 7-oxa-3-azabicyclo-[4.1,0]heptane-3-carboxylate, 17.6 parts of ethanol and 195 parts of water were added portionwise, during a 15 minutes-period, 28.6 parts of sodium azide while cooling in an ice bath. The mixture was warmed slowly to room temperature and stirring was continued overnight at room temperature. The aqueous phase was separated and extracted twice with dichloromethane. The combined organic phases were washed with a small amount of water, dried, filtered and evaporated, yielding 56.3 parts (82%) of a mixture of 80% of ethyl trans- 4-azido-3-hydroxy-1-piperidinecarboxylate (interm. 3) and 15% of ethyl trans-3-azido-4-hydroxy-1-piperidinecarboxylate.
Reaction SMILES: Br[C:2]1[C:3]([CH3:9])=[N:4][N:5]([CH3:8])[C:6]=1[Cl:7].[Cl:10][C:11]1[C:16]([F:17])=[CH:15][CH:14]=[C:13]([O:18][CH3:19])[C:12]=1[C@H:20]([C:22]1[C:30]2[C:25](=[N:26][CH:27]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:29]=2)[NH:24][CH:23]=1)[CH3:21].C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[Cl:7][C:6]1[N:5]([CH3:8])[N:4]=[C:3]([CH3:9])[C:2]=1[C:28]1[CH:29]=[C:30]2[C:22]([C@@H:20]([C:12]3[C:13]([O:18][CH3:19])=[CH:14][CH:15]=[C:16]([F:17])[C:11]=3[Cl:10])[CH3:21])=[CH:23][NH:24][C:25]2=[N:26][CH:27]=1
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Cc1nn(C)c(Cl)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3c(C)nn(C)c3Cl)cc12
Temperature: 100 °C

Procedure:
A solution of 4-bromo-5-chloro-1,3-dimethyl-1H-pyrazole (0.0219 g, 0.104 mmol), 3-[(S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)-ethyl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (0.030 g, 0.070 mmol), potassium carbonate (0.0289 g, 0.209 mmol) and Pd(PPh3)4 (8.04 mg, 0.00697 mmol) in previously degassed 4:1 dioxane:water (1.50 mL) was evacuated and charged with N2 (2×) and heated under microwave conditions [Biotage, 100° C., 30 min, high absorption]. This was further purified by Gilson HPLC resulting in the title compound as white solid. 1H NMR (400 MHz, CD3OD): δ=1.82 (d, J=7.3 Hz, 3H), 2.13 (s, 3H), 3.66 (br. s., 3H), 3.84 (s, 3H), 5.12 (q, J=7.2 Hz, 1H), 6.91 (dd, J=4.2, 9.0 Hz, 1H), 7.09 (dd, J=8.8, 8.8 Hz, 1H), 7.39 (d, J=1.3 Hz, 1H), 7.45 (s, 2H). MS (ES+): m/z 433.03, 435.01 (76/24) [MH+]. HPLC: tR=4.25 min (polar—5 min, ZQ3).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=O)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[O-]CC.[Na+].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][N:27]=[C:28](Br)[C:29]([F:32])([F:31])[F:30])=[CH:22][CH:21]=1>C(O)C>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:28]([C:29]([F:30])([F:31])[F:32])=[N:27]2)=[CH:22][CH:21]=1
Reactant: CCOC(=O)CC(=O)c1ccco1
Reactant: COc1ccc(NN=C(Br)C(F)(F)F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(C(F)(F)F)nn(-c2ccc(OC)cc2)c1-c1ccco1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.3 %

Procedure:
To a solution of ethyl 3-(2-furyl)-3-ketopropionate (2.45 g, 13.4 mmol) in 20 mL of absolute ethanol was added sodium ethoxide (4.6 mL of a 21% weight solution in ethanol, 12.2 mmol) followed by 2, 2, 2-trifluoroacetoyl bromide -N-(4-methoxyphenyl)hydrazone (1.82 g, 6.1 mmol). This mixture was stirred at ambient temperature for 4 h. The volatiles were removed in vacuo and the residue was dissolved in ethyl acetate, washed with water and brine, dried (MgSO4) and concentrated. The residue was purified by recrystallization from hexane/ethyl acetate to afford 1.4 g (61%) of the title compound. LRMS (ES+): 381.2 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:8]2[CH:9]=[N:10][C:11]([NH:13][C:14]([NH:16][C@@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])=[O:15])=[CH:12][C:7]=2[N:6](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:5]=1)[CH3:2].CCN(C(C)C)C(C)C.[C:53](Cl)(=[O:55])[CH3:54].C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[CH2:1]([N:3]([C:4]1[C:8]2[CH:9]=[N:10][C:11]([NH:13][C:14]([NH:16][C@@H:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH3:18])=[O:15])=[CH:12][C:7]=2[NH:6][N:5]=1)[C:53](=[O:55])[CH3:54])[CH3:2]
Reactant: CCNc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Reactant: CC(=O)Cl
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(C(C)=O)c1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(R)-1-(3-(Ethylamino)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (Example 2, Step 2; 680 mg, 1.198 mmol) was dissolved in DCM (20 mL), charged with DIEA (0.42 mL, 2.396 mmol), and cooled to 0° C. Acetyl chloride (0.095 mL, 1.318 mmol) was added drop-wise and the reaction was warmed to room temperature and stirred for 1 h. The reaction was charged with TFA (2.3 mL, 30.0 mmol) and triethylsilane (0.20 mL, 1.198 mmol) and stirred for 1 h at room temperature. The solvents were removed in vacuo and the residue was treated with DCM (3 mL) and triethylamine (1 mL) and stirred for 15 min. The residue was purified by flash chromatography (2-10% MeOH/DCM w/NH3) to afford (R)—N-ethyl-N-(6-(3-(1-phenylethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-3-yl)acetamide. MS ESI calc'd. for C19H22N6O2 [M+1]+ 366. found 366.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[CH3:9][C:10]([CH3:15])([CH2:13]O)[CH2:11][OH:12]>C1(C)C=CC=CC=1>[CH3:9][C:10]1([CH3:15])[CH2:11][O:12][C:3]2([CH2:4][CH2:5][CH2:6][C:1](=[O:8])[CH2:2]2)[O:7][CH2:13]1
Reactant: O=C1CCCC(=O)C1
Reactant: CC(C)(CO)CO
Solvent: Cc1ccccc1
Product: CC1(C)COC2(CCCC(=O)C2)OC1

Procedure:
125 g (630 mmole) 3,3-dimethyl-1,5-dioxa-spiro[5,5] undecan-8-one, which was obtained by the azeotropic acetylation of cyclohexane-1,3-dione with 2,2-dimethylpropane-1,3-diol in toluene as a solvent using p-toluenesulphonic acid as a catalyst, and 59 g (630 mmole) dimethylammonium methylene chloride were stirred at room temperature in 400 ml of dry acetonitrile. After adding 1 ml acetyl chloride the mixture was stirred for a further 3 hours at room temperature, whereupon a clear colourless solution was obtained. 800 ml of dry ether were then added drop-wise to the reaction mixture, whereupon the hydrochloride crystallised out. 158 g of (18) were obtained (98% theoretical).
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1N)[C@H:13]1[NH:23][C@H:12]1[CH2:11]3.Cl.CCCCCC.[OH-:32].[Na+]>CCOCC>[CH3:1][C:2]1[C:3](=[O:32])[C:4](=[O:5])[C:6]2[C@@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C@@:14]3([O:21][CH3:22])[C@H:13]4[NH:23][C@H:12]4[CH2:11][N:10]3[C:7]=2[C:8]=1[OH:9]
Reactant: [OH-]
Reactant: CO[C@@]12[C@H](COC(N)=O)C3=C(C(=O)C(C)=C(N)C3=O)N1C[C@@H]1N[C@@H]12
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Product: CO[C@@]12[C@H](COC(N)=O)C3=C(C(O)=C(C)C(=O)C3=O)N1C[C@@H]1N[C@@H]12
Temperature: 25 °C
Reaction time: 30 h
Yield: 63 %

Procedure:
Mitomycin C (2.2 g, 6.6 mmoles) was dissolved in 140 ml 0.1 N methanolic NaOH (50%) and the reaction mixture was stirred at room temperature for 30 hours. The solution was then adjusted to ca. pH 4.0 with lN HCl and extracted with ethyl (4×500 ml). The combined ethyl acetate extracts were dried (Na2SO4) and evaporated under reduced pressure at about 30° C. to 35° C. to obtain a solid residue, which upon dissolving in ether and treating with excess hexane afforded a purple precipitate. The precipitate was collected and air dried to afford the title compound as a fine purple powder (1.4 g, 63%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.IC1C=CC(I)=CC=1.FC1C=CC=CN=1.[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31]>>[CH3:29][Si:30]([C:33]#[C:34][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1)([CH3:32])[CH3:31]
Reactant: C#C[Si](C)(C)C
Reactant: Ic1ccc(-c2ccccn2)cc1
Agent: Fc1ccccn1
Agent: Ic1ccc(I)cc1
Product: C[Si](C)(C)C#Cc1ccc(-c2ccccn2)cc1
Yield: 89 %

Procedure:
The strategy for a sample convergent synthesis of a highly branched first generation organometallic dendrimer of the invention is shown in FIGS. 1 and 2. Taking FIG. 1 as an example, 2-(4-iodophenyl)pyridine (1) was prepared in a 40% yield by reaction of the mono-lithiated 1,4-diiodobenzene with 2-fluoropyridine. Trimethylsilylacetylene was then coupled with (1) under Sonogashira conditions to afford 2-(4-trimethylsilylethynylphenyl)pyridine (2) in an 89% yield. The acetylene was easily deprotected with either tetra-n-butylammonium fluoride in tetrahydrofuran or by treatment with aqueous potassium hydroxide in a methanol/dichloromethane mixture. Both methods gave 2-(4-acetylenylphenyl)pyridine (3) in an isolated yield of 80%. The dendronised ligand (5) was then formed by reaction of 3 with 2,3,4,5-tetraphenylcyclopentadienone (4). The reaction was heated at 220° C. for two to three hours using diphenyl ether as the solvent after which (5) was isolated in a 93% yield. The complexation of (5) to form the fac-tris(2-phenylpyridyl)iridium (III) cored dendrimer utilised the standard two step procedure. In the first step 2.5 equivalents of (5) was reacted with iridium trichloride trihydrate in aqueous 2-ethoxyethanol heated at reflux to give a mixture of the bis-iridium bis-chloro dimer and unreacted ligand. This mixture was then reacted with an excess of (5) in the presence of silver trifluoromethylsulfonate in diglyme at 130° C. to give, after purification, the desired dendrimer (6) in a 63% yield for the two steps. Gel permeation chromatography (GPC) showed that the dendrimer was mono-disperse and the facial nature of the dendrimer was confirmed by 1H NMR by comparison with spectra reported for other dendrimers with fac-tris(2-phenylpyridyl)iridium (III) cores.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.F[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1.[C:25](=O)([O-])[O-:26].[K+].[K+]>CN(C=O)C.O>[CH3:25][O:26][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(F)c1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(Oc2ccnc3[nH]c(=O)c4ccccc4c23)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 9.7 %

Procedure:
1-Chloro-5H-benzo[c][1,8]naphthyridin-6-one (30 mg, 0.13 mmol), 3-fluorophenol (44 mg, 0.39 mmol), and potassium carbonate (90 mg, 0.65 mmol) were suspended in DMF (2 mL), and stirred overnight at 100° C. The reaction mixture was diluted with H2O, and extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated. The crude product was purified via Biotage eluting with a gradient of 25 to 75% EtOAc in hexanes to provide 126 (4 mg, 10% yield) as a solid. LC-MS (M+H=307, obsd.=307). 1H NMR (400 MHz, d6-DMSO): δ 12.17 (s, 1H), 9.00 (d, 1H), 8.43 (dd, 1H), 8.33 (d, 1H), 7.88 (dt, 1H), 7.71 (t, 1H), 7.58 (t, 1H), 7.36 (dt, 1H), 7.20 (m, 2H), 6.64 (d, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[C:15](=[O:18])([O-])[O-].[K+].[K+].[CH2:21]=[O:22]>O>[OH:22][CH2:21][C:7]1([CH2:15][OH:18])[C:2](=[O:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6]1
Reactant: O=C([O-])[O-]
Reactant: C=O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=O)C(CO)(CO)C1
Temperature: 40 °C
Yield: 267.4 %

Procedure:
To tert-butyl 4-oxopiperidine-1-carboxylate (1.00 g, 5.02 mmol), water (2.0 mL) and potassium carbonate (10.4 mg, 0.0750 mmol) were added at room temperature and thereafter the mixture was heated to 40° C., followed by adding formaldehyde (36% aqueous solution) (0.795 mg, 9.54 mmol) and stirring the resultant mixture for 2 hours. After completion of the reaction, the reaction solution was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) to obtain the title compound (52.0 mg, yield 4%).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:30])[C@:4]1([OH:29])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C:18](=[CH:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[O:24][CH2:25][C:26](=[O:28])[CH3:27].[Cl-:31].[Li+].ClN1C(=O)CCC1=O.[ClH:41]>C(O)(=O)C.O1CCCC1.O>[Cl:31][C@:18]12[C@@H:19]([Cl:41])[CH2:20][C@@:21]3([CH3:22])[C@@H:7]([CH2:6][C@@H:5]([O:24][CH2:25][C:26](=[O:28])[CH3:27])[C@:4]3([OH:29])[C:3](=[O:30])[CH2:2][Cl:1])[C@@H:8]1[CH2:9][CH2:10][C:11]1[C@:16]2([CH3:17])[CH:15]=[CH:14][C:13](=[O:23])[CH:12]=1
Reactant: Cl
Reactant: [Cl-]
Reactant: CC(=O)CO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@@]1(O)C(=O)CCl
Agent: O=C1CCC(=O)N1Cl
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)CO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(Cl)[C@@H](Cl)C[C@]2(C)[C@@]1(O)C(=O)CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 21-chloro-17-hydroxy-16α-(2-oxopropoxy)pregna-1,4,9(11)-triene-3,20-dione (4mmoles) and 7.2 g of lithium chloride in 72 ml of glacial acetic acid is stirred at 0°-5°C and 592 mg of N-chlorosuccinimide is added. A solution of 180 mg of dry hydrogen chloride in 2.9 ml of tetrahydrofuran is added and the resulting mixture stirred at room temperature for 2 hours, poured into 400 ml of cold water, and extracted with chloroform. The chloroform solution is washed with water, dried, and evaporated to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[N:16]O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[NH4+]>CCO.[Ni]>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(C=NO)c1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)COc1cccc(CN)c1
Reaction time: 4 h

Procedure:
To a solution of (3-(hydroxyimino-methyl)-phenoxy)-acetic acid tert-butyl ester prepared of Preparation 20, Step B (2.25 g, 5.96 mmol) in EtOH (10 mL) was added Raney Nickel (about 1 g, washed with water followed by EtOH) in 100 mL EtOH. Additional EtOH (90 mL) was required for the transfer. Ammonium hydroxide (10 mL) was added and the mixture was shaken under 45 psi for H2 for 4 hours. The catalyst was removed via filtration through Celite® and the solution was concentrated to a clear oil. Purification via flash chromatography on silica gel (96.5/3.5/0.1 to 9/1/0.1 CH2Cl2/MeOH/NH4OH) afforded the title compound as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.23 (m, 1H), 6.92 (m, 2H), 6.72 (d, 1H), 4.50 (s, 2H), 3.82 (s, 2H), 1.96 (m, 2H), 1.46 (s, 9H); MS 238 (M+1).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[C:5](O)[C:6]2[CH2:12][CH2:11][N:10]([C:13]3[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=3)[CH2:9][CH2:8][C:7]=2[N:23]=1.C(OC(C1C(=O)CCN([C:38]2[C:43]([C:44]([F:47])([F:46])[F:45])=[CH:42][CH:41]=[CH:40][N:39]=2)CC1)=O)C.[CH3:48]C[O-].[Na+].NC(N)=S>CCO>[CH3:1][S:2][C:3]1[N:4]=[C:5]([NH:39][C:40]2[CH:41]=[CH:42][C:43]([C:44]([F:45])([F:46])[F:47])=[CH:38][CH:48]=2)[C:6]2[CH2:12][CH2:11][N:10]([C:13]3[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=3)[CH2:9][CH2:8][C:7]=2[N:23]=1
Reactant: CSc1nc(O)c2c(n1)CCN(c1ncccc1C(F)(F)F)CC2
Reactant: CC[O-]
Reactant: CCOC(=O)C1CCN(c2ncccc2C(F)(F)F)CCC1=O
Agent: NC(N)=S
Agent: [Na+]
Solvent: CCO
Product: CSc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
2-Methylsulfanyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ol. To solution of 5-oxo-1-(3-trifluoromethyl-pyridin-2-yl)-azepane-4-carboxylic acid ethyl ester (3.0 g, 9.09 mmol) in EtOH (40 mL) was added NaOEt (1.97 g, 29.1 mmol) and thiourea (1.1 g, 13.6 mmol). The mixture was heated at reflux for 12 h. The mixture was cooled, treated with Mel (0.74 mL, 11.8 mmol) drop-wise, and stirred at rt for 1 h. Thee mixture was concentrated and the residue was dissolved in water and acidified to pH=7 with HOAc (a precipitate formed). The solid was filtered to give the title compound (3.3 g, >99%), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[CH:10]=[C:9]([NH2:12])[S:8][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>C1COCC1.CN(C1C=CN=CC=1)C>[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:12][C:9]2[S:8][C:7]3[C:6]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=3[CH:10]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc(-c2ccccc2)c2sc(N)cc12
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(-c2ccccc2)c2sc(NC(=O)c3ccc(F)cc3)cc12
Temperature: 20 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
A solution of (4-methoxy-7-phenyl-benzo[b]thiophen-2-yl)-amine (100 mg, 392 mmol) in THF (5 ml) with triethylamine (0.049 ml, 0.9 eq.) and DMAP (5 mg, 0.1 eq) was stirred together at 0° C. under an argon atmosphere. To this was slowly added 4-fluorobenzoyl chloride (0.038 ml, 314 mmol, 0.8 eq.) and the mixture stirred to 20° C. over 2 h. The mixture was then evaporated to dryness and chromatographed over silica gel eluting with a gradient of heptane/EtOAc (6:1 to 2:1). The product fractions were pooled and evaporated to afford the title compound (74 mg, 50% yield) as a yellow solid MS: m/e=378.3 (M+H+).
Reaction SMILES: [Br:1][C:2]1[N:3]([CH3:23])[N:4]=[C:5]2[C:10](=[O:11])[NH:9][C:8]([C:12]3[C:13]([O:20][CH2:21][CH3:22])=[N:14][CH:15]=[C:16]([C:18]#[CH:19])[CH:17]=3)=[N:7][C:6]=12.[OH:24]S(O)(=O)=O>CC(C)=O>[C:18]([C:16]1[CH:17]=[C:12]([C:8]2[NH:9][C:10](=[O:11])[C:5]3[C:6](=[C:2]([Br:1])[N:3]([CH3:23])[N:4]=3)[N:7]=2)[C:13]([O:20][CH2:21][CH3:22])=[N:14][CH:15]=1)(=[O:24])[CH3:19]
Reactant: C#Cc1cnc(OCC)c(-c2nc3c(Br)n(C)nc3c(=O)[nH]2)c1
Reactant: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CCOc1ncc(C(C)=O)cc1-c1nc2c(Br)n(C)nc2c(=O)[nH]1
Reaction time: 14 h

Procedure:
A mixture of 3-bromo-5-(2-ethoxy-5-ethynyl-3-pyridinyl)-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (Example 57) (750 mg, 2 mmol), 1N H2SO4 (2 mL) and HgSO4 (50 mg, 0.17 mmol) in acetone (25 mL) was stirred at reflux for 10 h then at room temperature for 14 h. Further H2SO4 (5 mL of 1 N) was added and refluxing was continued for a further 4 h. The mixture was cooled and the solvent evaporated and the residue partitioned between dichloromethane and water. After basifying with solid sodium bicarbonate a white precipitate formed which was filtered off before separating the phases. The organic layer was dried (MgSO4), concentrated and combined with the solid previously filtered to give the title compound as a poorly soluble solid.
Reaction SMILES: [S:1]([OH:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].C.C1C(Br)=C(Br)[NH:15]C=1C(O)=O.N([O-])=O.[Na+]>O>[OH-:2].[S:1]([C:3]1[CH:4]=[CH:5][C:6]([N+:9]#[N:15])=[CH:7][CH:8]=1)([OH:11])(=[O:10])=[O:2]
Reactant: O=C(O)c1cc(Br)c(Br)[nH]1
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Agent: C
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: N#[N+]c1ccc(S(=O)(=O)O)cc1
Product: [OH-]
Reaction time: 0.01 h

Procedure:
A pin pelletizer was charged with 42.4 g of sulfanilic acid and with 200 g of a carbon black having a CTAB surface area of 350 m2 /g and a DBPA of 120 ml/100 g. After mixing for 30 seconds, a solution of 17.4 g NaNO2 in 150 g of boiling water was added and the mixture was pelletized for 45 seconds. 4-Sulfobenzenediazonium hydroxide inner salt is formed, which reacts with the carbon black. The product, which was then at 35° C. was dried in an oven at 120° C. The product had a 325 mesh residue of 0.2%, compared to 97% for the unreacted carbon black. The product has attached p-C6H4SO3- groups.