Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH:6]2[CH2:7][CH2:8][C@@:3]1([CH2:10][S:11]([N:14]1[CH2:19][CH2:18][C:17]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20]3)[CH2:16][CH2:15]1)(=[O:13])=[O:12])[C:4](=O)[CH2:5]2.Cl.[NH2:30][OH:31].O>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:28])[CH:6]2[CH2:7][CH2:8][C@@:3]1([CH2:10][S:11]([N:14]1[CH2:19][CH2:18][C:17]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20]3)[CH2:16][CH2:15]1)(=[O:13])=[O:12])[C:4](=[N:30][OH:31])[CH2:5]2
Reactant: CC1(C)C2CC[C@@]1(CS(=O)(=O)N1CCC3(C=Cc4ccccc43)CC1)C(=O)C2
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC1(C)C2CC[C@@]1(CS(=O)(=O)N1CCC3(C=Cc4ccccc43)CC1)C(=NO)C2
Reaction time: 2 h
Yield: 90.1 %

Procedure:
(1S)-1'-(((7,7-dimethyl-2-oxobicyclo(2.2.1) hept-1-yl)methyl)sulfonyl)spiro(1H-indene-1,4'-piperidine) (30 g, 0.075 mole) in pyridine (500 mL) was heated in an oil bath to 70° C. (internal). Hydroxylamine hydrochloride (30 g) was added in three portions over ca. 20 minutes. After 2 hours, an additional 10 g of hydroxylamine hydrochloride was added (over 10 minutes). At 30, 40, and 50 minutes additional elapsed time, further 3 g lots of hydroxylamine hydrochloride were added. After another 30 minutes, the mixture was poured into water (2 L) and extracted 3 times with ethyl acetate (300 mL portions). The organic layers were combined, washed with 1N HCl (600 mL total), dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. EtOH (abs; ca. 250 mL) was added to the resulting thick syrup and the solution allowed to stand at ambient temperature overnight. The mixture was filtered and the filtrate boiled down to ca. 80 mL. After standing, the mixture was again filtered and boiled down to ca. 20 mL. After a third filtration, the filtered solids were combined to give (1S)-1'-(((7,7-dimethyl-2-oximinobicyclo(2.2.1)hept-1-yl)-methyl) sulfonyl)spiro(1H-indene-1,4'-piperidine) (28 g).
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[S:3]1.[OH-:11].[Na+].[CH4:13]>C(O)CO>[CH3:13][N:6]([C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[SH:3])[C:2]([NH2:1])=[O:11]
Reactant: C
Reactant: N=c1[nH]c2ccccc2s1
Reactant: [OH-]
Agent: [Na+]
Solvent: OCCO
Product: CN(C(N)=O)c1ccccc1S
Temperature: 80 °C
Reaction time: 6 h
Yield: 90.9 %

Procedure:
A mixture of 164 parts of 2-iminobenzothiazoline, 150 parts of sodium hydroxide and 300 parts of ethyleneglycol is stirred for 6 hours at 130°-140° C., subsequently cooled to 80° C., and introduced with agitation into 3000 parts of icewater. After further agitation for 30 minutes, 5 parts of active charcoal are added, the solution is stirred for a further 15 minutes and then filtered. The pH of the filtrate is adjusted to 5-6 by means of 10% aqueous hydrochloric acid, and the precipitated N-methyl-N-(2-mercaptophenyl)-urea is isolated by filtration. The moist product is immediately introduced into 700 parts of a 10% aqueous hydrochloric acid and heated for 15 minutes with agitation at 90° C. The precipitating 3-methyl-2(3H)-benzothiazolone of the formula ##STR4## is isolated by filtration after cooling the acidic batch, washed with water and dried. 150 Parts of an analytically pure product are obtained; this corresponds to a yield of 90.9% of theory, relative to 2-iminobenzothiazoline, melting point 73°-75° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5](I)=[CH:4][N:3]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14]>C(#N)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:17]#[C:16][Si:13]([CH3:15])([CH3:14])[CH3:12])=[CH:4][N:3]=1
Reactant: Cc1c(I)cnc(N)c1C#N
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Product: Cc1c(C#C[Si](C)(C)C)cnc(N)c1C#N

Procedure:
In another variation in the method to the 2,4-diamino-5,6-disubstituted-5-deazapteridines described above, 2-amino-3-cyano-5-iodo-4-methylpyridine is reacted with trimethylsilylacetylene in the presence of copper(I) iodide and bis(triphenylphosphine)palladium(II) chloride under basic conditions in acetonitrile, affording 2-amino-3-cyano-4-methyl-5-(trimethylsilylethynyl)pyridine. The 5-(trimethylsilylethynyl)pyridine is in turn treated with potassium carbonate in methanol, yielding the corresponding 2-amino-3-cyano-4-methyl-5-ethynylpyridine. The 5-ethynylpyridine is then reacted with an appropriately substituted halide, for example, 4-trifluoromethyl-phenyl iodide, again in the presence of copper(I)iodide and bis(triphenylphosphine)palladium(II) chloride under basic conditions in acetonitrile, yielding a 2-amino-3-cyano-4-methyl-5-(substituted-ethynyl)pyridine, for example, 2-amino-3-cyano-4-methyl-5-[(4-trifluoromethylphenyl)ethynyl]-pyridine. The so-prepared pyridine is then cyclized and hydrohalogenated with chloroformamidine hydrochloride in diglyme, affording the corresponding 2,4-diamino-5-methyl-6-[1-chloro-2-substituted-ethenyl]-5-deazapteridine, for example, 2,4-diamino-5-methyl-6-[1-chloro-2-(4-trifluoromethylphenyl)ethenyl]-5-deazapteridine. Cyclizations with an appropriately substituted 2-amino-3-cyanopyridine and chloroformamidine hydrochloride in diglyme are taught by N. V. Harris et al (J. Med. Chem. 1990, 33, 434-444). Example 10 provides a detailed description of how this reaction is conducted.
Reaction SMILES: C[O:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:17][CH2:18][CH2:19][N:20]=2)=[CH:12][CH:11]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:10]1[CH:11]=[CH:12][C:13]([N:20]2[CH2:19][CH2:18][N:17]=[CH:16]2)=[CH:14][CH:15]=1.[OH:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:10]1[CH:11]=[CH:12][C:13]([C:16]2[NH:20][CH2:19][CH2:18][N:17]=2)=[CH:14][CH:15]=1
Reactant: COc1c(N)cccc1-c1ccc(C2=NCCN2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1cccc(-c2ccc(C3=NCCN3)cc2)c1O
Product: Nc1cccc(-c2ccc(N3C=NCC3)cc2)c1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 173.3 %

Procedure:
2-(2′-Methoxy-3′-amino-biphenyl-4-yl)-4,5-dihydro-1H-imidazol 32c (1.1 g, 4.1 mmol) was dissolved in 50 mL of dichloromethane at room temperature, followed by addition of a solution of boron tribromide in dichloromethane (1 N, 16.5 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction was monitored by TLC until the disappearance of the starting materials and then quenched with methanol. The mixture was concentrated under reduced pressure. The residue was dissolved in 10 mL of ethyl acetate and stirred for 30 minutes. The mixture was filtered and the filter cake was washed with ethyl acetate (5 mL×2) and dried to obtained the title compound 2-(2′-hydroxy-3′-amino-biphenyl-4-yl)-4,5-dihydro-1H-imidazol 32d (900 mg, 89.6%) as a grey solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[CH2:8][CH:7]1[C:11](O)=O.C(N(CC)CC)C.[N+](=C)=[N-].[N+](=CC(C1N(CC2C=CC(OC)=CC=2OC)[C:37](=[O:50])C1)=O)=[N-].[O:51]1CCCC1>C(OCC)C>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[CH2:8][CH:7]1[CH2:11][C:37]([OH:50])=[O:51]
Reactant: COc1ccc(CN2C(=O)CC2C(=O)O)c(OC)c1
Reactant: COc1ccc(CN2C(=O)CC2C(=O)C=[N+]=[N-])c(OC)c1
Reactant: C1CCOC1
Agent: C=[N+]=[N-]
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COc1ccc(CN2C(=O)CC2CC(=O)O)c(OC)c1
Temperature: -15 °C

Procedure:
13.2 g (50 millimoles) of 1-(2,4-dimethoxy-benzyl)-4-oxo-2-azetidine-carboxylic acid prepared according to the preceding paragraph are dissolved in 150 ml of anhydrous tetrahydrofurane and to the solution first 7.3 ml (52.5 millimole) of triethylamine and thereafter under stirring and ice-cooling 5.0 ml (52.5 millimoles) of ethylchloroformiate are added. The mixture is cooled to -15° C., stirred at this temperature for 20 minutes and the precipitated triethylamine salt is filtered off under argon. To the filtrate a solution of 22.5 g (150 millimole) diazomethane and 230 ml of cold diethyl ether is added. The solution is stirred, allowed to warm to ambient temperature and after 2 hours the mixture is evaporated to dryness. The residue is dissolved in 20 ml of benzene and subjected to column chromatography (adsorbent: 150 g of Kieselgel G, diameter 0.063-0.2000 mm; eluant: benzene-acetone 7:2). On rubbing with ether a crystalline product is obtained. Yield: 10.5 g (73%) of 4-diazoacetyl-1-(2,4-dimethoxy-benzyl)-2-azetidinone, m.p.: 90°-91° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[N:14]=[C:15]([C:24]([CH3:28])([CH3:27])[CH2:25][NH2:26])[NH:16][C:17]=1[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH:7]=[CH:6]2.[C:29]([N:33]=[C:34]=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([NH:33][C:34]([NH:26][CH2:25][C:24]([C:15]1[NH:16][C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:13]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=2)[N:14]=1)([CH3:28])[CH3:27])=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: COc1ccc2cc(-c3nc(C(C)(C)CN)[nH]c3-c3ccncc3)ccc2c1
Reactant: CC(C)(C)N=C=O
Product: COc1ccc2cc(-c3nc(C(C)(C)CNC(=O)NC(C)(C)C)[nH]c3-c3ccncc3)ccc2c1
Yield: 39 %

Procedure:
The title compound (10 mg, 39%) was prepared starting from the product of Example 2 and tert-butyl isocyanate using the method described in Example 10; MS(ES) m/e 472 [M+H]+.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[CH:26]=[C:25]([C:27]#[C:28][Si](C)(C)C)[C:23](=[O:24])[NH:22][C:20]1=[O:21])(=O)C.[Na]>CO>[C:27]([C:25]1[C:23](=[O:24])[NH:22][C:20](=[O:21])[N:19]([CH:26]=1)[C@@H:6]1[O:7][C@H:8]([CH2:14][OH:15])[C@@H:9]([OH:10])[C@H:5]1[OH:4])#[CH:28]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C#C[Si](C)(C)C)c(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Na]
Solvent: CO
Product: C#Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of stage b) (9.5 g, 24 mmol) was dissolved in methanol (200 mL) and diluted with a solution containing sodium (0.8 g) and methanol (100 mL). The reaction was stirred at room temperature for 2 hours and was then neutralized using Dowex 5OW-X8 (H+ form) resin. The resin was removed by filtering and washed with methanol. The filtrate was concentrated in vacuo to give 4.85 g of a beige solid. The compound was purified on a Waters Prep 500 reverse phase C18 column which was eluted with H2O/MeOH 85:15 (v:v) to give 1.2 g of the title product (white solid). Impure fractions were re-chromatographed. An additional 1.94 g of product were obtained.
Reaction SMILES: [Li]CCCC.C(OC([N:13]1[C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:16]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[N:15]=[CH:14]1)OCC)C.C(OC([N:38]1[C:42](C2C=CC(F)=CC=2)=[C:41](C2C=CN=CC=2)[N:40]=[CH:39]1)OCC)C.[F:56][C:57]1[N:62]=[C:61]([F:63])[C:60]([F:64])=[C:59](F)[C:58]=1[F:66]>C1COCC1>[F:30][C:27]1[CH:26]=[CH:25][C:24]([C:16]2[N:15]=[C:14]([C:59]3[C:58]([F:66])=[C:57]([F:56])[N:62]=[C:61]([F:63])[C:60]=3[F:64])[NH:13][C:17]=2[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:29][CH:28]=1.[NH:38]1[CH:42]=[CH:41][N:40]=[CH:39]1
Reactant: CCOC(OCC)n1cnc(-c2ccncc2)c1-c1ccc(F)cc1
Reactant: CCOC(OCC)n1cnc(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: Fc1nc(F)c(F)c(F)c1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Fc1ccc(-c2nc(-c3c(F)c(F)nc(F)c3F)[nH]c2-c2ccncc2)cc1
Product: c1c[nH]cn1
Temperature: -55 °C
Reaction time: 0.08 h

Procedure:
1.6 M nBuLi (66 ml; 45 mmol) is added at −45° C. to a ˜1:1 mixture of 1-(1,1-diethoxymethyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole and 1-(1,1-diethoxymethyl)-5-(4-fluorophenyl)-4-(4-pyridinyl)imidazole (15 g; 43 mmol) in THF (210 ml). After 15 min. at −45° C. the reaction mixture is cooled to −55° C. and pentafluoropyridine (5.1 ml; 47 mmol) is rapidly introduced. The cooling bath is removed, the reaction mixture allowed to warm to −15° C. and poured on water (1 l), which is then acidified with 2N HCl (100 ml). After stirring for 5 min. the mixture is combined with a saturated solution of Na2CO3 and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness rendering the title compound as brownish crystals (16.3 g). Chromatography (SiO2; acetone/hexanes 1:1) yields the title compound together with some unreacted and unprotected imidazole starting material, which could be removed by washing with acetone yielding the title compound (8.7 g; 52.4%).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2OC(=O)[S:9][N:8]=2)[CH:2]=1.[C:14]([C:20]([O:22][CH3:23])=[O:21])#[C:15][C:16]([O:18][CH3:19])=[O:17]>ClC1C=CC=CC=1>[C:1]1([CH3:13])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([C:20]([O:22][CH3:23])=[O:21])[S:9][N:8]=2)[CH:2]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: Cc1cccc(-c2nsc(=O)o2)c1
Solvent: Clc1ccccc1
Product: COC(=O)c1snc(-c2cccc(C)c2)c1C(=O)OC
Yield: 52.2 %

Procedure:
5-m-Tolyl-1,3,4-oxathiazol-2-one (19.32 g, 0.1 mol) and dimethyl acetylenedicarboxylate (28.42 g, 0.2 mol) were heated at reflux in 60 ml of chlorobenzene as given above. After the initial crystallization from cold methanol, three recrystallization from diethyl ether/petroleum ether gave 15.18 g (0.0522 mol, 52.2%) of white solid, m.p. 53°-54.5°.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][Cl:10])=[CH:5][CH:4]=1.[CH3:11][CH:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH3:13].C(N(CC)CC)C.Cl>CCOCC.C1COCC1>[ClH:1].[CH3:13][CH:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:22][CH2:23][N:24]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][Cl:10])=[CH:5][CH:4]=2)[CH2:25][CH2:26]1)[CH3:11]
Reactant: ClCc1ccc(CCl)cc1
Reactant: CC(C)Oc1ccccc1N1CCNCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)Oc1ccccc1N1CCN(Cc2ccc(CCl)cc2)CC1

Procedure:
A solution of α,α'-dichoro-p-xylene(30.40 g, 0.174 mol), N-[2-(1-methylethoxy)phenyl]piperazine (12.70 g, 0.058 mol), triethylamine (6.08 g, 0.06 mol), and THF (200 mL) was refluxed for 4 h. Ether (100 mL) and 1N HCl (100 mL) were added producing a white suspension which was filtered to give 4-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]benzyl chloride hydrochloride.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:10]([C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1)#[N:11].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:10]([C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[O:18][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])#[N:11]
Reactant: N#Cc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cccc(C#N)c1
Yield: 99 %

Procedure:
tert-Butyl bromoacetate (9.01 g, 46 mmol) was dropwise added to a mixture of 3-cyanophenol (5.0 g, 42 mmol), potassium carbonate (13.82 g, 100 mmol) and DMF (40 ml) while stirring. After stirring for 8 hours, the mixture was poured onto ice water followed by extraction with ethyl ether. The extract was washed with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure. The residue was applied to column chromatography using silica gel (200 g) and eluted with hexane-ethyl acetate (3:1, v/v) to give the title compound (9.70 g, 99%) as an oily substance.
Reaction SMILES: C([O:8][C:9]1[CH:29]=[CH:28][C:12]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[ClH:30]>CCO>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:20][CH2:21]2)=[CH:28][CH:29]=1.[ClH:30]
Reactant: c1ccc(COc2ccc(OCCN3CCN(c4ccccc4)CC3)cc2)cc1
Agent: Cl
Solvent: CCO
Product: Oc1ccc(OCCN2CCN(c3ccccc3)CC2)cc1

Procedure:
35.75 g of 1-[2-(4-benzyloxyphenoxy)ethyl]-4-phenylpiperazine was added rapidly with stirring to 75 ml concentrated HCl and the mixture was heated on a steam bath for 15 minutes. During this time starting material dissolved and then a white crystalline solid began to form and eventually the reaction mixtue almost solidified. The reaction was cooled to ~5° and then was diluted with 100 ml EtOH. The solids were filtered off and were washed in EtOH and ether to give 1-[2-(4-hydroxyphenoxy) ethyl]-4phenylpiperazine as its monohydrochloride. The salt was dissolved in 150 ml hot MeOH and 50 ml H2O and was then treated with 25 ml triethylamine. Water was then added to the refluxing mixture just to the cloud point whereupon the product began to crystallize from solution. The mixture was chilled and the solids were collected by filtration to give the end product, mp 142°-143°.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:23]([F:26])([F:25])[F:24])=[CH:5][C:4]=2[N:3]=1.[NH2:27][CH2:28][CH2:29][CH2:30][OH:31]>O1CCOCC1.C(OCC)(=O)C>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:14]2[C:10]3[C:9]4[CH:8]=[CH:7][C:6]([C:23]([F:26])([F:25])[F:24])=[CH:5][C:4]=4[N:3]=[C:2]([NH:27][CH2:28][CH2:29][CH2:30][OH:31])[C:11]=3[N:12]=[CH:13]2)=[CH:16][CH:17]=1
Reactant: COc1ccc(-n2cnc3c(Cl)nc4cc(C(F)(F)F)ccc4c32)cc1
Reactant: NCCCO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(-n2cnc3c(NCCCO)nc4cc(C(F)(F)F)ccc4c32)cc1
Reaction time: 19 h
Yield: 85.4 %

Procedure:
To a solution of 4-chloro-1-(4-methoxy-phenyl)-7-trifluoromethyl-1H-imidazo[4,5-c]quinoline (153 mg; 0.41 mmol; 1 eq) in anhydrous 1,4-dioxane (18 mL), 3-aminopropanol (77 μL; 1.0 mmol; 2.5 eq) is added. The resulting solution is heated to reflux and allowed to stir for 19 hours after which period the reaction is still not complete on TLC. Thus, additional 3-aminopropanol (523 μL; 6.9 mmol; 17 eq) is added and the stirring is continued under reflux for 4 hours. The crude mixture is diluted with ethyl acetate (40 mL) and washed three times with a 1M aqueous solution of NaOH (3×40 mL). Aqueous layers are combined and re-extracted with ethyl acetate (75 mL). All organic layers are combined, dried over sodium sulfate and concentrated. The crude residue is purified on silica gel (cyclohexane/ethyl acetate 2:8) to afford the title compound as an off-white powder (145 mg; 0.35 mmol; 85%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[C:13]([CH3:16])=[CH:14][S:15][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].CC(O)=O.C1C(=O)N([Br:28])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[C:13]([CH3:16])=[C:14]([Br:28])[S:15][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)N1CCc2scc(C)c2CC1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)N1CCc2sc(Br)c(C)c2CC1
Reaction time: 0.5 h
Yield: 52.7 %

Procedure:
The product of step (g) (337 mg, 1.4 mmol) was dissolve in 10 mL of 1:1 CHCl3:HOAc and treated with NBS (301 mg, 1.7 mmol). After stirring for ½ hour, the reaction was diluted with DCM and washed with water (50 mL) and 1M NaOH (2×50 mL). The crude product was purified by silica gel chromatography to give 235 mg of the sub-title compound.
Reaction SMILES: [Cr:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Na+:6].[Na+].[S:8](=[O:12])(=[O:11])([OH:10])[OH:9].S(=O)(=O)(O)[O-].[Na+]>>[S:8]([O-:12])([O-:11])(=[O:10])=[O:9].[Na+:6].[Na+:6].[O-:2][Cr:1]([O:5][Cr:1]([O-:4])(=[O:3])=[O:2])(=[O:4])=[O:3].[Na+:6].[Na+:6]
Reactant: O=[Cr](=O)([O-])[O-]
Reactant: O=S(=O)(O)O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Product: O=S(=O)([O-])[O-]
Product: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]

Procedure:
In the drawing, a solution of sodium chromate (Na2CrO4) in line 1 is added to acidifier 2. When sulfuric acid from line 3 and sodium bisulfate from line 4 are added, sodium sulfate and sodium bichromate (Na2Cr2O7) are produced. The solution of sodium bichromate passes through line 5 to evaporator 6 where water is evaporated, resulting in the precipitation of the sodium sulfate. The water is removed through line 7 and the slurry passes through line 8 to separator 9 where the solution of 69 to 92 wt % sodium bichromate is removed through line 10. The solid sodium sulfate is sent through line 11 to dissolver 12 where water is added from line 13 forming a solution of sodium sulfate, typically containing about 200 to about 1000 ppm Cr(VI), as well as a trace amount of Cr(III). The sodium sulfate solution is sent through line 14 to reduction tank 15 where sulfuric acid is added from line 16 and sulfur dioxide (or any suitable reducing agent) from line 17, reducing the Cr(VI) to Cr(III). The solution then passes through line 18 to precipitation tank 19 where sodium hydroxide is added from line 20, resulting in the formation of chromium hydroxide (Cr(OH)3), which precipitates. The resulting slurry passes through line 21 to separator 22 and the precipitated chromium hydroxide is removed through line 23. The remaining solution of sodium sulfate, which typically contains less than 100 ppm of Cr(III), is passed through line 24 to evaporator 25. Water is evaporated through line 26 resulting in the precipitation of the sodium sulfate. The slurry of sodium sulfate is sent through line 27 to separator 28 which removes the precipitated sodium sulfate through line 29. All of the Cr(III) entering through line 24 enters the sodium sulfate product through line 29. Periodically, the mother liquor in separator 28 is recycled through line 30 to either dissolver 12 or reduction tank 15 to purge other impurities that build-up over time in the process.
Reaction SMILES: Cl[C:2](OC1C=CC([N+]([O-])=O)=CC=1)=[O:3].[NH2:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=1.[F:22][C:23]([F:27])([F:26])[CH2:24][NH2:25].CCN(C(C)C)C(C)C>C1COCC1>[Cl:21][C:17]1[CH:16]=[C:15]([NH:14][C:2]([NH:25][CH2:24][C:23]([F:27])([F:26])[F:22])=[O:3])[CH:20]=[CH:19][N:18]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCC(F)(F)F
Reactant: Nc1ccnc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NCC(F)(F)F)Nc1ccnc(Cl)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 46.8 %

Procedure:
To 4-nitrophenyl chloroformate (2.91 g, 14.5 mmol) in THF (35 mL) was added 4-amino-2-chloropyridine (2.08 g, 16.2 mmol) and the reaction stirred at 60° C. for 2 hours. After cooling to room temperature 2,2,2-trifluoroethylamine (1.26 mL, 15.9 mmol) and DIPEA (7.5 mL, 43.4 mmol) were added and the reaction stirred at room temperature for 18 hours. The reaction was concentrated in vacuo and the residue partitioned between 1M NaOH (40 mL) and EtOAc (2×50 mL). The combined organic phases were washed with brine (60 mL), dried over MgSO4, filtered and concentrated in vacuo. The resulting yellow solid was suspended in CH2Cl2, filtered and washed with CH2Cl2 to give the product as a pale yellow solid (1.72 g).