Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([S:10]([OH:13])(=O)=[O:11])[C:4]=2[N:3]=[N:2]1.[Cl:14]S(O)(=O)=O>>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([S:10]([Cl:14])(=[O:13])=[O:11])[C:4]=2[N:3]=[N:2]1
Reactant: O=S(=O)(O)c1cccc2[nH]nnc12
Reactant: O=S(=O)(O)Cl
Product: O=S(=O)(Cl)c1cccc2[nH]nnc12

Procedure:
Benzotriazole-4-sulphonic acid (5 g, 23 mM) was added, in portions, to chlorosulphonic acid (50 ml), whilst keeping the temperature of the acid below 0°. The resulting solution was heated at 120° overnight, cooled and carefully poured onto ice (1000 g). The solid which formed was collected by filtration, washed well with water and dried in vacuo. This material was dissolved in boiling ethyl acetate and decolorized using a small quantity of charcoal. The product crystallized from the ethyl acetate solution after petroleum ether (40° to 60°) was added, as a white solid (3.94 g, 72 percent), m.p. 173° to 175° (uncorr).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH2:18]([N:22]=[C:23]=[O:24])[CH2:19][CH2:20][CH3:21]>>[CH2:18]([NH:22][C:23]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:24])[CH2:19][CH2:20][CH3:21]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: CCCCN=C=O
Product: CCCCNC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Yield: 78.5 %

Procedure:
Beginning with 0.15 gm (0.65 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.088 mL (0.78 mMol) butyl isocyanate, 0.168 gm (78%) of the title compound were recovered essentially by the procedure of Example 122. An analytical sample was crystallized from aqueous ethanol.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[C:15]([Br:16])=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:17])C)(C)(C)C.Cl.C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(O)C>[Br:16][C:15]1[C:10]([CH2:9][NH:7][CH3:6])=[C:11]([NH2:17])[CH:12]=[CH:13][CH:14]=1
Reactant: CN(Cc1c(N)cccc1Br)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCc1c(N)cccc1Br
Temperature: 100 °C
Yield: 765.5 %

Procedure:
(2-Amino-6-bromo-benzyl)-methyl-carbamic acid tert-butyl ester (371 mg) was dissolved in 50 ml ethanol. To this solution was added 2M ethanolic hydrochloride acid solution (10 ml). The reaction mixture was heated at 100° C. for 30 minutes, at which time the deprotection was completed. The solution was allowed to cool to room temperature and poured into the mixture of saturated NaHCO3 solution and ethyl acetate. The aqueous layer was extracted with EtOAc three times and the organic fractions were concentrated to give 3-bromo-2-methylaminomethyl-phenylamine as a brown oil (1.938 g, 76%). MS: (M+H)+217.1.
Reaction SMILES: Br[CH:2]([CH3:16])[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][C:11](=[O:14])[NH:10][C:9]=2[CH:15]=1)=O.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[CH3:16][C:2]1[N:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]2=[N:17][C:3]=1[C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][C:11](=[O:14])[NH:10][C:9]=2[CH:15]=1
Reactant: Nc1ccccn1
Reactant: CC(Br)C(=O)c1ccc2c(c1)NC(=O)CO2
Product: Cc1c(-c2ccc3c(c2)NC(=O)CO3)nc2ccccn12
Yield: 38.1 %

Procedure:
6-(3-Methylimidazo[1,2-a]pyridin-2-yl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (0.75 g) was prepared in substantially the same manner as that of Example 16 from 6-(2-bromopropionyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (2.0 g) and 2-aminopyridine (1.8 g). mp. 280°-282° C.
Reaction SMILES: [O:1]1[C@@:5]2([CH:10]3[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]3)[CH2:6]2)[CH2:4][NH:3][C:2]1=[O:13].Br[C:15]1[CH:16]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[S:18][CH:19]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:17]1[S:18][CH:19]=[C:15]([N:3]2[CH2:4][C@:5]3([CH:10]4[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]4)[CH2:6]3)[O:1][C:2]2=[O:13])[CH:16]=1
Reactant: O=C1NC[C@@]2(CN3CCC2CC3)O1
Reactant: Brc1csc(-c2ccccn2)c1
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1csc(-c2ccccn2)c1

Procedure:
The title compound was prepared by a method analogous to that described in Preparation 3 from (S)-spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 4-bromo-2-(2-pyridyl)thiophene. The title compound (140 mg) was obtained as a pale-yellow solid, m/z 342 (MH+).
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:37].C(O)C.C(=O)([O-])[O-].[NH4+:45].[NH4+]>ClCCl.C(O)C>[ClH:37].[C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:45])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C#N)cc1)n2C)c1ccccc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Yield: 86 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[2-(4-cyanophenyl)ethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 86% of theory, C29H31N5O3 (497.6) Rf value: 0.11 (silica gel; dichloromethane/ethanol=4:1) ##EQU40##
Reaction SMILES: C[C:2]1[C:3]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.C[CH2:24][N:25]=[C:26]=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CNC>CO.CN(C)C=O>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:15]=[C:11]([C:3]3[CH:2]=[N:10][CH:9]=[CH:8][C:4]=3[C:5]([N:25]([CH3:26])[CH3:24])=[O:7])[S:12][CH:13]=2)=[CH:21][CH:20]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1nccc(C(=O)O)c1-c1nc(-c2ccc(Cl)cc2)cs1
Agent: CNC
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CO
Product: CN(C)C(=O)c1ccncc1-c1nc(-c2ccc(Cl)cc2)cs1
Temperature: 40 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
The compound (141) (170 mg, 0.5 mmol) was dissolved in methanol (10 ml)-1N NaOH aq. (10 ml) and the mixture was stirred at 40° C. for one hr. The pH of the reaction mixture was adjusted to around 6, and the precipitated solid was collected by filtration, which was dried in vacuo and dissolved in dimethylformamide (3 ml) together with WSC (117 mg, 0.6 mmol), HOBt (85 mg, 0.6 mmol) and dimethylamine (27 mg, 0.6 mmol). The mixture was stirred at 30° C. for 2 hrs. The reaction mixture was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined and dried (MgSO4). The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as white crystals (120 mg, 35%).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.C=O.[OH:8][CH2:9][C:10]1[N:14]2CCCCC2=[CH:12][N:11]=1>>[CH3:12][N:11]1[CH:3]=[C:2]([CH3:1])[N:14]=[C:10]1[CH2:9][OH:8]
Reactant: OCc1ncc2n1CCCC2
Reactant: [Li]CCCC
Agent: C=O
Product: Cc1cn(C)c(CO)n1

Procedure:
The reaction of 1,4-dimethylamidazole (5.65 g.) with n-butyl lithium followed by treatment with formaldehyde (according to the method described for the preparation of 3-hydroxymethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine in Example 243) gave 1,4-dimethyl-2-hydroxymethylimidazole (2.71 g.), m.p. 125°-126° (ethyl acetate-petroleum ether).
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:13]([N:14]3[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]3=[O:26])=[CH:12][CH:11]=[C:10]([Cl:27])[C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:28]N(Cl)C(OCC)=O.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.Cl>[C:1]([C:5]1[O:6][C:7]2[C:13]([N:14]3[C:19](=[O:20])[C:18]([Cl:28])=[C:17]([C:21]([F:23])([F:22])[F:24])[N:16]([CH3:25])[C:15]3=[O:26])=[CH:12][CH:11]=[C:10]([Cl:27])[C:8]=2[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)N(Cl)Cl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c3nc(C(C)(C)C)oc23)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(C(F)(F)F)c(Cl)c(=O)n(-c2ccc(Cl)c3nc(C(C)(C)C)oc23)c1=O
Reaction time: 0.25 h
Yield: 130.7 %

Procedure:
A stirred solution of 0.84 gram (2.1 mmole) of 3-(2-t-butyl-4-chlorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione (prepared as described in Example 2) in 20 mL of acetic acid had 0.16 gram (1.0 mmole) of N,N-dichlorourethane added via syringe. Upon completion of the addition the clear reaction mixture was stirred for 15 minutes, then one drop of concentrated hydrochloric acid was added, and the reaction mixture was stirred at ambient temperature for 72 hours. After this time the reaction mixture was poured into 100 mL of water, and 10 grams of sodium carbonate were added. The mixture was extracted with three 50 mL portions of methylene chloride. The organic extracts were combined and washed with one 50 mL portion of an aqueous 5% sodium carbonate solution. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrate under reduced pressure, yielding a pale yellow oil which was subjected to column chromatography on silica gel. Elution was accomplished with 9:1 heptane:ethyl acetate, followed by 2:1 heptane:ethyl acetate. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.57 gram of 3-(2-t-butyl-4-chlorobenzoxazol-7-yl)-1-methyl-5-chloro-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione, m.p. 83°-86° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2=[CH:16][S:17][C:18]([CH3:19])=[C:5]12)=[O:3].[N:20]1([CH2:26][CH2:27][CH:28]2[O:33][CH2:32][CH2:31][NH:30][CH2:29]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.Cl>>[CH3:19][C:18]1[S:17][CH:16]=[C:6]2[C:7](=[O:15])[NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:4]([C:2]([N:30]3[CH2:31][CH2:32][O:33][CH:28]([CH2:27][CH2:26][N:20]4[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]4)[CH2:29]3)=[O:3])[C:5]=12
Reactant: Cc1scc2c1N(C(=O)Cl)c1ccccc1NC2=O
Reactant: C1CCN(CCC2CNCCO2)CC1
Agent: Cl
Product: Cc1scc2c1N(C(=O)N1CCOC(CCN3CCCCC3)C1)c1ccccc1NC2=O
Yield: 74 %

Procedure:
Prepared analogously to Example 4 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 2-[2-(1-piperidinyl)ethyl]morpholine in a yield of 74% of theory. Rf 0.48 (conditions as in Example 58). The colourless hydrochloride melted at 254°-256° C. (D.).
Reaction SMILES: C(O[C:4](=[O:18])[CH2:5][C@H:6]1[CH2:11][CH2:10][CH2:9][C@@H:8]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7]1)C.[H-].[Na+]>COCCOC>[CH2:16]([O:15][C:13]([CH:12]1[C:4](=[O:18])[CH2:5][CH:6]2[CH2:7][CH:8]1[CH2:9][CH2:10][CH2:11]2)=[O:14])[CH3:17]
Reactant: CCOC(=O)C[C@H]1CCC[C@@H](CC(=O)OCC)C1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C1C(=O)CC2CCCC1C2
Temperature: 94 °C
Reaction time: 16 h

Procedure:
Cis-cyclohexane-1,3-diacetic acid diethyl ester QU was dissolved in dry DME (300 mL). To this solution, sodium hydride (15 g) was added and the suspension stirred at 94° C. for 16 h. After cooling, the reaction mixture was slowly poured into ice-water (500 mL) and extracted four times with EtOAc (200 mL each). The combined organic layer was washed with brine, and concentrated to give 3-oxo-bicyclo[3.3.1]nonane-2-carboxylic acid ethyl ester QV which was used without purification in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH2:11][S:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[K+].[CH2:19]1OCCOCCOCCOCCOCCOC1.CI.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH3:19])[C@@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH2:11][S:12][CH3:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CSCC[C@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reaction time: 22 h

Procedure:
A solution of N-(tert-butyloxycarbonyl)-D-methionine (20 g.) in tetrahydrofuran was added dropwise with stirring to a suspension of potassium hydride (35% in mineral oil, 27.5 g.) in tetrahydrofuran (160 ml.) containing 18-crown-6 ether (1 g.) maintained at ice bath temperature. Stirring was continued for one and one quarter hours. Methyl iodide (5 ml.) was added, stirring was continued, and the temperature was allowed to rise to room temperature during 22 hours. The pH was adjusted to 3 with aqueous citric acid (1 M) with cooling. The mixture was partitioned between ether and water. The ether layer was extracted with aqueous sodium bicarbonate. The aqueous sodium bicarbonate layer was extracted with ether. The latter ether layer was washed with water, dried and stripped of ether, affording N-(tert-butyloxycarbonyl)-N-methyl-D-methionine as a syrup (15.5 g.).
Reaction SMILES: ClC[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[CH:7][C:6]=1[CH3:21])=[O:4].ClCC(C1C=CC(C)=CC=1NC(=O)C1C=CC=CC=1C)=[O:25].Cl>C1(C)C=CC=CC=1>[CH3:21][C:6]1[CH:7]=[C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH:9]=[CH:10][C:5]=1[C:3]([OH:4])=[O:25]
Reactant: Cc1cc(NC(=O)c2ccccc2C)ccc1C(=O)CCl
Reactant: Cc1ccc(C(=O)CCl)c(NC(=O)c2ccccc2C)c1
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=O)c2ccccc2C)ccc1C(=O)O
Yield: 86 %

Procedure:
A toluene solution of a mixture of 2-chloro-2′-methyl-4′-(2-methyl-benzoylamino)acetophenone and 2-chloro-4′-methyl-2′-(2-methylbenzoylamino)acetophenone obtained in the above Reference Example 5 is concentrated and to the residue is added isopropyl alcohol (twice volume). To the mixture is added dropwise an aqueous sodium hypochlorite solution (twice molar amount) at 10-20° C. After completion of the reaction (30 minutes to one hour), the reaction mixture is acidified with hydrochloric acid, and the precipitated crystals are separated by filtration to give a crude product of 2-methyl-4-(2-methylbenzoylamino)benzoic acid in a yield of 86-100%. This crude product is recrystallized from methanol to give the desired product (yield 57%, purity by HPLC 99.3%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24]([O:26][CH:27]2[CH2:31][CH2:30][NH:29][CH2:28]2)=[O:25])=[N:13][CH:14]=1.[C:33]1(=O)[CH2:37][CH2:36][CH2:35][CH2:34]1.C([BH3-])#N.[Na+]>>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24]([O:26][CH:27]2[CH2:31][CH2:30][N:29]([CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[CH2:28]2)=[O:25])=[N:13][CH:14]=1
Reactant: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)OC1CCNC1
Reactant: O=C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)OC1CCN(C2CCCC2)C1
Yield: 86.2 %

Procedure:
Using a similar procedure to that described in Example 9-C, N-(5-chloropyridin-2-yl)-2-[(pyrrolidin-3-yloxycarbonyl)amino]benzamide trifluoroacetate (100 mg, 0.211 mmol), cyclopentanone (0.095 mL, 1.05 mmol), and sodium cyanoborohydride (53 mg, 0.84 mmol) yielded 78 mg (87%) of the title compound.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH2:20]([S:22](Cl)(=[O:24])=[O:23])[CH3:21].CCN(CC)CC>C(Cl)Cl>[C:16]([C:15]1[CH:14]=[CH:13][C:12]([C:7]2[C:6]3[CH2:5][CH2:4][CH2:3][CH:2]([NH:1][S:22]([CH2:20][CH3:21])(=[O:24])=[O:23])[C:11]=3[CH:10]=[N:9][CH:8]=2)=[CH:19][CH:18]=1)#[N:17]
Reactant: N#Cc1ccc(-c2cncc3c2CCCC3N)cc1
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)NC1CCCc2c(-c3ccc(C#N)cc3)cncc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A cooled (0° C.) solution of (rac)-4-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)benzonitrile (example 1) (62.3 mg, 250 μmol) in CH2Cl2 (3.6 ml) was treated with ethanesulfonyl chloride (26.6 μL, 275 μmol) and Et3N (41.8 μL, 300 μmol). After ½ h the mixture was stirred at room temperature for 3 h, cooled down (0° C.) and treated again with ethanesulfonyl chloride (7.3 μL, 75 μmol) and Et3N (11.5 μL, 82.5 μmol). After 2 h at room temperature, the mixture was concentrated in vacuo and purified by flash chromatography (20 g SiO2, Telos-cartridge, CH2Cl2/MeOH (0.5 to 1.5%)) to give after precipitation from CH2Cl2 with n-pentane the pure title compound (43 mg, 50%) as a off-white powder. MS: 342.1 (M+H+).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[C:32]([CH3:40])[CH:31]=4)[N:21]=3)[CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:40][C:32]1[CH:31]=[C:30]([C:22]2[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[N:25]=[C:20]([C:16]3[CH:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=4)[CH:19]=[CH:18][CH:17]=3)[N:21]=2)[CH:35]=[CH:34][C:33]=1[C:36]([F:37])([F:39])[F:38]
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(-c4ccc(S(=O)(=O)NC(C)(C)C)s4)c3)n2)ccc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(-c4ccc(S(N)(=O)=O)s4)c3)n2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 50.4 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-5-{3-[6-(3-methyl-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide (0.46 g) in dichloromethane (6 mL) was added TFA (6 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration and further purified by flash chromatography (heptane/ethyl acetate) and crystallization (dichloromethane/MeOH) to yield the title compound as an off-white solid (0.21 g, 38%). MS (ISN) 542.1 [(M−H)−]; mp 216° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]=[O:18])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:19]1[C:20]2[S:33][CH:32]=[CH:31][C:21]=2[N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[N:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:34]1([Mg]Br)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]([OH:18])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:19]1[C:20]2[S:33][CH:32]=[CH:31][C:21]=2[N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[N:23]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2sccc21
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1nc(-c2cc3cc(C(O)c4ccccc4)ccc3n2C(=O)OC(C)(C)C)c2sccc21
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-5-formyl-indole-1-carboxylic acid tert-butyl ester [100 mg, 0.214 mmol, Intermediate (11)] in anhydrous tetrahydrofuran (5 mL) is added phenylmagnesium bromide (1M in tetrahydrofuran, 1 mL) at −78° C. The resulting reaction mixture is stirred at the same temperature for 1 h then quenched it by the addition of water at 0° C. (4 mL). The reaction mixture is extracted three times with ethyl acetate (30 mL). Combined ethyl acetate phases are washed with brine, dried over sodium sulfate and filtered. Evaporation of the solvent in vacuo yielded 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-5-(hydroxy-phenyl-methyl)-indole-1-carboxylic acid tert-butyl ester [99 mg, 85%, Intermediate (12)] as a white foam; LC/MS: (M+H, 546).
Reaction SMILES: Br[CH:2]([C:8]#[N:9])[C:3]([N:5]([CH3:7])[CH3:6])=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C.O>[C:8]([CH:2]([S:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4])#[N:9]
Reactant: CN(C)C(=O)C(Br)C#N
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN(C)C(=O)C(C#N)Sc1ccccc1
Temperature: 50 °C

Procedure:
A suspension of 2-bromo-2-cyano-N,N-dimethylacetamide (3.80 g, 20 mmol), potassium carbonate (2.902 g, 21 mmol) and thiophenol (2.314 g, 21 mmol, 2.16 mL) in acetonitrile (20 mL) was heated to 50° C. for 3 days. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (2×50 mL). The combined extracts were combined and concentrated. The concentrate was purified by column chromatography on silica gel with 0-50% ethyl acetate/hexanes to provide the desired product. MS (ESI(+)) m/e 221 (M+H)+.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[N:20]([CH2:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:19]([CH2:28][CH3:29])=[N:18][C:12]=3[C:13]([NH2:17])=[N:14][C:15]=2[CH:16]=1.C(N(CC)CC)C.[C:37](OC(=O)C)(=[O:39])[CH3:38]>ClCCl>[NH2:17][C:13]1[C:12]2[N:18]=[C:19]([CH2:28][CH3:29])[N:20]([CH2:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:11]=2[C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][NH:3][C:37](=[O:39])[CH3:38])=[CH:16][C:15]=2[N:14]=1
Reactant: CCc1nc2c(N)nc3cc(OCCN)ccc3c2n1CC1CCOCC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(N)nc3cc(OCCNC(C)=O)ccc3c2n1CC1CCOCC1
Reaction time: 0.17 h
Yield: 75.3 %

Procedure:
7-(2-Aminoethoxy)-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine dihydrochloride (0.480 g, 1.03 mmol; prepared as in Example 552), dichloromethane (10 mL), and triethylamine (0.430 mL, 3.09 mmol) were combined and stirred for 10 minutes. Acetic anhydride (0.097 mL, 1.03 mmol) was added and the reaction was stirred for an additional 16 hours. The reaction mixture was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 2-20% CMA in chloroform). Fractions containing product were combined and concentrated. Trituration of the product in acetonitrile provided 0.319 g of N-(2-{[4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}ethyl)acetamide as fine white crystals, mp 165-167° C.
Reaction SMILES: Cl[C:2]1[C:7]2[S:8][CH2:9][C:10](=[O:13])[N:11]([CH3:12])[C:6]=2[N:5]=[C:4]([CH2:14][CH3:15])[N:3]=1.O.[NH2:17][NH2:18]>C(O)CCC>[CH2:14]([C:4]1[N:3]=[C:2]([NH:17][NH2:18])[C:7]2[S:8][CH2:9][C:10](=[O:13])[N:11]([CH3:12])[C:6]=2[N:5]=1)[CH3:15]
Reactant: NN
Reactant: CCc1nc(Cl)c2c(n1)N(C)C(=O)CS2
Solvent: CCCCO
Solvent: O
Product: CCc1nc(NN)c2c(n1)N(C)C(=O)CS2
Yield: 81.2 %

Procedure:
4-Chloro-6,7-dihydro-2-ethyl-8-methylpyrimido[5,4 b][1,4]thiazin-7-one from Example 119 (2.4g, 9.93 mmole) was suspended in approximately 100ml of n-butanol. Hydrazine monohydrate (0.99g, 19.9 mmole) was added and the resultant mixture was refluxed for about 20 hours. The reaction mixture was allowed to cool and the precipitate was separated by filtration, washed with water and dried, providing 1.93g (81%) of 6,7-dihydro-2-ethyl-4-hydrazino-8-methylpyrimido[5,4-b}[1,4]thiazin-7-one. Infrared and nuclear magnetic resonance spectral analyses confirmed the structural assignment.