Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:20])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19])CCC)C.C(OC([N:28]1[C:36]2[C:31](=[C:32]([Cl:37])[CH:33]=[CH:34][CH:35]=2)[C:30]([CH2:38]O)=[CH:29]1)=O)(C)(C)C.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:31]=1[C:30]([CH2:38][N:12]1[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:10]([CH2:6][CH2:5][C:4]([OH:3])=[O:20])[C:11]1=[O:19])=[CH:29][NH:28]2
Reactant: CCCC(CC(=O)OCC)n1c(=O)[nH]c2ccccc21
Reactant: CC(C)(C)OC(=O)n1cc(CO)c2c(Cl)cccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Product: O=C(O)CCn1c(=O)n(Cc2c[nH]c3cccc(Cl)c23)c2ccccc21
Temperature: 0 °C
Yield: 7.5 %

Procedure:
3-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-hexanoic acid ethyl ester (80 mg, 0.29 mmol), prepared as described above, 4-chloro-3-hydroxymethyl-indole-1-carboxylic acid tert-butyl ester (282 mg, 1 mmol) and triphenylphosphene (223 mg, 0.85 mmol) were combined in a reaction vial and THF (1 mL) was added. The mixture was stirred until complete solution was attained, then cooled to 0° C., and diisopropylazodicarboxylate (0.165 mL, 0.85 mmol) was added dropwise. The reaction mixture was heated in the microwave at 130° C. for 20 minutes, cooled, then diluted with THF (1 mL) and treated directly with the Amberlyst® resin (2.2 g, 2.95 mmol). This reaction mixture was agitated overnight and the resin was then filtered and washed with DMF (2×3 mL) and several portions of methanol. The product was eluted by treating the resin with a 20% solution of formic acid in methanol (2×3 mL) and washing with methanol (3 mL). The combined eluant and final wash was evaporated and redissolved in dichloromethane (1 mL). To this solution was added TFA (0.2 mL) and the reaction mixture was agitated for 1 h. The solvent was evaporated and the residue was purified by preparative HPLC using an acetonitrile/water/formic acid gradient providing the title compound (8 mg, 7%) LCMS (ESMS): m/z 412 (M+H+).
Reaction SMILES: C([O:5][C:6](=[O:35])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][C:16]3[N:17]([C:19]([C:22]4([C:25]5[CH:26]=[C:27]6[C:32](=[CH:33][CH:34]=5)[N:31]=[CH:30][CH:29]=[CH:28]6)[CH2:24][CH2:23]4)=[CH:20][N:21]=3)[CH:18]=2)=[CH:9][CH:8]=1)(C)(C)C.[ClH:36]>O1CCOCC1>[N:31]1[C:32]2[C:27](=[CH:26][C:25]([C:22]3([C:19]4[N:17]5[CH:18]=[C:13]([C:10]6[CH:11]=[CH:12][C:7]([C:6]([OH:35])=[O:5])=[CH:8][CH:9]=6)[CH:14]=[N:15][C:16]5=[N:21][CH:20]=4)[CH2:23][CH2:24]3)=[CH:34][CH:33]=2)[CH:28]=[CH:29][CH:30]=1.[ClH:36]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1

Procedure:
tert-Butyl-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoate (0.125 g, 0.27 mmol) was treated with 4M HCl in 1,4-dioxane (1.5 mL) at RT for 3 h. The mixture was decanted. The solid was washed with ether and dried to give the desired product as HCl salt (129 mg, 99.5%) which was directly used in next step without further purification. LCMS: (M+H)=407.1.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH:4]([OH:6])[CH3:5].[Cl:8][C:9]1[CH:14]=[C:13](Cl)[N:12]=[C:11]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=2[F:25])[N:10]=1.[H-].[Na+]>C1COCC1>[Cl:8][C:9]1[N:10]=[C:11]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=2[F:25])[N:12]=[C:13]([O:6][CH:4]([CH3:5])[CH2:3][N:2]([CH3:7])[CH3:1])[CH:14]=1
Reactant: CC(O)CN(C)C
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(CN(C)C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared according to the procedure outlined in Example 41 step i) using 1-dimethylamino-2-propanol (80 mg), 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of Example 1 step ii) (0.25 g) and 60% sodium hydride (30 mg) in THF (2 mL) at room temperature for 2 d to give the subtitle compound as a pale yellow gum. Yield: 0.29 g.
Reaction SMILES: [Mg].II.BrC(Br)C.[CH:8]([C:11]1[CH:12]=[C:13](Br)[CH:14]=[CH:15][CH:16]=1)([CH3:10])[CH3:9].[C:18]1(=[O:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>O1CCCC1>[CH:8]([C:11]1[CH:12]=[C:13]([C:18]2([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:14]=[CH:15][CH:16]=1)([CH3:10])[CH3:9]
Reactant: CC(C)c1cccc(Br)c1
Reactant: O=C1CCCCC1
Agent: CC(Br)Br
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)c1cccc(C2(O)CCCCC2)c1
Temperature: 70 °C
Yield: 63.2 %

Procedure:
To 1.2 g (50 mmol) of magnesium turnings in 15 mL of dry THF is added a small crystal of iodine followed by 40 μL of dibromoethane. This mixture is placed in a water bath at 50° C. and 3-isopropylbromobenzene (5.0 g, 25 mmol) in 15 mL of dry tetrahydrofuran (THF) is added dropwise over 20 min, while the bath temperature is raised to 70° C. The mixture is stirred and refluxed for 40 additional min. The solution is cooled in an ice-water bath and cyclohexanone (2.0 mL, 19 mmol) in 10 mL of dry THF is added dropwise over 15 min. The ice bath is removed and the mixture is allowed to warm to ambient temperature over 1 h. The solution is decanted into aqueous saturated NH4Cl, and combined with an ether wash of the residual magnesium turnings. The organic phase is washed twice more with aqueous NH4Cl, dried over anhydrous Na2SO4, filtered and concentrated. Chromatography on silica gel, eluting with 10% ethyl acetate in heptane, affords 2.7 g (12 mmol, 60%) of compound 1 as an oil: 1H NMR (CDCl3) δ 7.39 (m, 1 H), 7.3 (m, 2 H), 7.12 (m, 1 H), 2.92 (m, 1 H), 1.84-1.54 (m, 10 H), 1.26 (d, J=7 Hz, 6 H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=O)[C:11]([N:13]2[CH2:18][CH2:17][C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([OH:19])[CH2:15][CH2:14]2)=O)=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:19][C:16]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14][N:13]([CH2:11][CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:18][CH2:17]1
Reactant: O=C(C(=O)N1CCC(O)(c2ccccc2)CC1)c1c[nH]c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1(c2ccccc2)CCN(CCc2c[nH]c3ccccc23)CC1

Procedure:
A solution of 17.0 g. (0.049 mole) of 1-(indol-3-ylglyoxyloyl)-4-phenyl-4-piperidinol in 100 ml. of tetrahydrofuran was reduced in the usual way with 7.4 g. (0.195 mole) of lithium aluminum hydride in 200 ml. of tetrahydrofuran. After the usual workup 11.6 g. of oil was obtained which was crystallized from benzene-isooctane yielding 8.6 g. (55%) of product which melted at 133°-137° C. Another recrystallization from benzene raised the melting point to 137°-139° C. The analytical sample melted at 137°-139° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[CH:3]=1.[F:12][C:13]1[CH:14]=[CH:15][C:16]([O:22][CH3:23])=[C:17](B(O)O)[CH:18]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.CC(OC)(C)C.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>[Cl:11][C:4]1[CH:3]=[C:2]([C:15]2[CH:14]=[C:13]([F:12])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COc1ccc(F)cc1B(O)O
Reactant: O=C(O)c1ccc(Br)cc1Cl
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: [Na+]
Solvent: COC(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(F)cc1-c1ccc(C(=O)O)c(Cl)c1
Temperature: 75 °C
Yield: 97 %

Procedure:
4-Bromo-2-chlorobenzoic acid (205 g) and 5-fluoro-2-methoxyphenylboronic acid (161 g) were dissolved in toluene (2 L) and ethanol (2 L) in a 10 L reactor vessel. Sodium carbonate (2 L of a 2 M aqueous solution) was added followed by tetrakis(triphenylphosphine)palladium(0) (15.39 g). The reaction was heated at 75° C. for 16 h. The reaction was diluted with water (2.5 L) and TBME (2 L) and stirred. Further water (0.5 L) was added and the mixture stirred for a further 5 min to complete dissolution of the solids. The aqueous layer was separated, filtered through a Celite pad and cooled to 15° C. The solution was acidified to pH 1 over 1 h by the addition of conc. HCl (532 mL, final pH1). The solid was filtered off and washed with ice cold water (400 ml) to give a tan solid. This was dried for 72 h in a vacuum oven at 45° C. over CaCl2 to give the sub titled product (237 g).
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[N:16]=[CH:15][N:14]=[C:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)[CH:12]=1.[CH2:25]([C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1)[CH3:26]>C1COCC1>[Cl:10][C:11]1[N:16]=[CH:15][N:14]=[C:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:34]([NH:33][C:30]3[CH:31]=[CH:32][C:27]([CH2:25][CH3:26])=[CH:28][CH:29]=3)=[O:35])=[CH:20][CH:19]=2)[CH:12]=1
Reactant: Nc1ccc(Cc2cc(Cl)ncn2)cc1
Reactant: CCc1ccc(N=C=O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCc1ccc(NC(=O)Nc2ccc(Cc3cc(Cl)ncn3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 4 N solution of HCl in dioxane (1.2 mL, 4.96 mmol, 30 equiv) is added to a solution of [4-(6-chloro-pyrimidin-4-ylmethyl)-phenyl]-carbamic acid tert-butyl ester (50 mg, 0.156 mmol) in CH2Cl2 (0.67 mL), under an argon atmosphere. The resulting white suspension is stirred at rt for 4 h and concentrated in vacuo to afford 50.9 mg of crude 4-(6-chloro-pyrimidin-4-ylmethyl)-phenylamine as a white solid. DIEA (80 μL, 0.454 mmol, 2 equiv) is added to a suspension of crude 4-(6-chloro-pyrimidin-4-ylmethyl)-phenylamine (50 mg, 0.227 mmol) in THF (0.4 mL), under an argon atmosphere. 4-Ethyl-phenyl-isocyanate (40 μL, 0.250 mmol, 1.1 equiv) is then added. The resulting yellow solution is stirred at rt for 2 h and concentrated in vacuo. The residue is purified by silica gel (20 g) column chromatography (CH2Cl2/MeOH, 98/2). A second purification affords the title compound as a white solid: ES-MS: 367.0 [M+H]+; single peak at tR=8.94 min (System 2); Rf=0.32 (CH2Cl2/MeOH, 95/5).
Reaction SMILES: [C:1](OCC)(=[O:4])[CH2:2][CH3:3].[C:8]([I:12])(=[O:11])[CH2:9][CH3:10].C(I)C.C(I)(=[O:18])C.CI>>[C:8]([O:11][C:1](=[O:4])[CH2:2][CH3:3])(=[O:18])[CH2:9][CH3:10].[C:8]([I:12])(=[O:11])[CH2:9][CH3:10]
Reactant: CCOC(=O)CC
Reactant: CC(=O)I
Agent: CCC(=O)I
Solvent: CCI
Solvent: CI
Product: CCC(=O)OC(=O)CC

Procedure:
Examples 1-5 are repeated but using ethyl propionate, propionyl iodide and ethyl iodide in place of methyl acetate, acetyl iodide and methyl iodide, respectively. Propionic anhydride is produced in corresponding manner, with propionyl iodide also being produced in the procedures of runs 2-5.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[CH3:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][NH:29][CH3:30])=[CH:26][CH:25]=1>>[CH3:30][N:29]([CH2:28][C:27]1[CH:31]=[CH:32][C:24]([CH3:23])=[CH:25][CH:26]=1)[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Reactant: CNCc1ccc(C)cc1
Product: Cc1ccc(CN(C)CCn2cnc(-c3cc(C(=O)O)ccn3)c2)cc1
Yield: 71 %

Procedure:
The title compound was prepared in 71% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and 4-methyl-N-methylbenzylamine according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 2.33 (3H, s), 2.61 (3H, s), 2.69 (2H, t, J=6 Hz), 3.80 (2H, s), 4.00 (1H, t, J=5.7 Hz), 4.13 (1H, t, J=5.8 Hz), 7.23 (2H, t, J=8.9 Hz), 7.44 (1H, m), 7.51 (1H, d, J=6.9 Hz), 7.52 (1H, s), 7.73 (1H, d, J=5.1 Hz), 8.24 (1H, m), 8.35 (1H, s), 8.76 (1H, d, J=4.8 Hz). [M+H] Calc'd for C20H22N4O2, 351. Found, 351.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][C:33]1[CH:43]=[CH:42][C:36]([C:37]([O:39][CH2:40]C)=[O:38])=[CH:35][CH:34]=1.[CH2:44]([C:48]1[CH:55]=[CH:54][C:51]([CH2:52]O)=[CH:50][CH:49]=1)[CH2:45][CH2:46][CH3:47]>C1COCC1>[CH2:44]([C:48]1[CH:49]=[CH:50][C:51]([CH2:52][O:32][C:33]2[CH:43]=[CH:42][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)=[CH:54][CH:55]=1)[CH2:45][CH2:46][CH3:47]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CCCCc1ccc(CO)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCc1ccc(COc2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of triphenylphosphine (656 mg, 2.50 mmol) in THF (12 mL) at 0° C. was treated with diethyl azodicarboxylate (442 mg, 2.54 mmol), stirred for 20 minutes, treated with ethyl 4-hydroxybenzoate (350 mg, 2.30 mmol) and 4-butylbenzyl alcohol (414 mg, 2.52 mmol), warmed to room temperature, stirred for 16 hours, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 30% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(Cl)nc2s1
Reactant: c1cn[nH]c1
Product: Cc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]#[N:11])=[CH:4][CH:3]=1.[OH:12][NH2:13]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:10]([NH:13][OH:12])=[NH:11])=[CH:6][CH:7]=1
Reactant: N#CC=Cc1ccc(Cl)cc1
Reactant: NO
Solvent: CCO
Product: N=C(C=Cc1ccc(Cl)cc1)NO
Yield: 50.9 %

Procedure:
A solution of 3-(4-chloro-phenyl)-acrylonitrile (1.63 g, 10 mmol) and hydroxyamine (0.74 ml, 12 mmol) in ethanol (10 ml) was stirred at room temperature overnight. The solvent was evaporated, and the residue was purified by column chromatography (EtOAc:Hexane=1:3) to give 1.0 g (51%) of 3-(4-chloro-phenyl)-N-hydroxy-acrylamidine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[OH:18][CH:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH3:25])[CH2:20]1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][N:21]([CH3:25])[CH2:20]2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: CN1CCCC(O)C1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CN1CCCC(Oc2nc(N)nc(-c3ccco3)c2C#N)C1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 3-hydroxy-1-methylpiperidine and DBU in DME. ES-MS m/e (%): 300 (M+H+, 100).
Reaction SMILES: [CH:1]([O:4][CH:5]([CH3:7])[CH3:6])(C)C.[Na].BrC1[S:11][CH:12]=[CH:13][N:14]=1>CC(O)C>[CH:5]([O:4][C:1]1[S:11][CH:12]=[CH:13][N:14]=1)([CH3:7])[CH3:6]
Reactant: Brc1nccs1
Reactant: CC(C)OC(C)C
Agent: [Na]
Solvent: CC(C)O
Product: CC(C)Oc1nccs1
Reaction time: 15 h
Yield: 73.2 %

Procedure:
To a solution of sodium isopropyloxide (10.0 g) in 2-propanol (100 mL) was added 2-bromothiazol (10.0 g) at 85° C. and the mixture was stirred for 15 hours. After cooling, the reaction mixture was concentrated in vacuo and thereto was added water. The mixture was extracted with diethylether and the extract was washed with water and a saturated brine, dried over magnesium sulfate and concentrated in vacuo to give 2-isopropyloxythiazol (6.39 g, yield: 73%). MS(APCI) m/z: 144 [M+H]+
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][C:12]1[CH:13]=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:16][C:17]=1[CH3:18]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:11][C:12]1[CH:13]=[C:14]([C:19]([F:20])([F:21])[F:22])[CH:15]=[CH:16][C:17]=1[CH3:18]
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Cc1ccc(C(F)(F)F)cc1N
Product: Cc1ccc(C(F)(F)F)cc1Nc1nc2ccccc2[nH]1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 3-amino-4-methylbenzotrifluoride by Procedure A. The product was isolated upon basic work-up and purified by preparative LCMS to give the title compound as the free base. 1NMR (DMSO-d6) δ 2.40 (s, 3H), 6.95-7.03 (m, 2H), 7.20-7.25 (m, 1H), 7.31-7.42 (m, 3H), 8.63 (s, 1H), 8.88 (s, 1H), 10.9 (s, 1H). MS(ES+) m/z 292 ([M+1]+, 100).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][CH2:4]1.[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH:18]=[CH2:19].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.Cl>CO.C(O)C.C1C=CC=CC=1>[CH3:1][N:2]([CH3:16])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:19][CH2:18][C:17]([O:21][CH2:22][CH3:23])=[O:20])[C:6]=2[CH2:5][CH2:4]1
Reactant: CN(C)C1CCc2[nH]c3ccccc3c2C1
Reactant: C=CC(=O)OCC
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CO
Solvent: CCO
Product: CCOC(=O)CCn1c2c(c3ccccc31)CC(N(C)C)CC2

Procedure:
Following a procedure similar to that described in Example 256 and using 20 g. of 3-(dimethylamino)-1,2,3,4-tetrahydrocarbazole, 20 g. of ethyl acrylate, 1 ml. of 35% benzyltrimethylammonium hydroxide in methyl alcohol and 150 ml. of benzene and increasing the reflux time to three hours, there was obtained, on the evaporation of the reaction mixture to dryness, on oil, a solution of which in ethyl alcohol was treated with hydrogen chloride in ethyl alcohol. The resulting solids were filtered to give, after recrystallization from aqueous ethyl alcohol, 20.5 g. of ethyl 3-(dimethylamino)-1,2,3,4-tetrahydrocarbazole-9-propionate hydrochloride, m.p. 259°-261°C.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20]Cl)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[CH:7]([NH:22][C:23](=[O:27])[O:24][CH2:25][CH3:26])[CH2:6][CH:5]1[CH3:28])(=[O:3])[CH3:2].[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:22][C:23](=[O:27])[O:24][CH2:25][CH3:26])[CH2:6][C@@H:5]1[CH3:28])(=[O:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CCOC(=O)NC1CC(C)N(C(C)=O)c2ccc(-c3ccc(CCl)cc3)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)N[C@@H]1C[C@H](C)N(C(C)=O)c2ccc(-c3ccc(CN4CCCCC4)cc3)cc21
Temperature: 85 °C

Procedure:
(cis)-1-Acetyl-2-methyl-6-[4-(1-piperidinylmethyl)phenyl]-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation see Intermediate 2) (50 mg, 0.132 mmol) was dissolved in dichloromethane (DCM) (2 mL), mixed with ethyl chloridocarbonate (0.015 mL, 0.159 mmol), and DIPEA (0.046 mL, 0.265 mmol) and stirred under nitrogen for 2.5 days. Another sample of ethyl chloridocarbonate (0.015 mL, 0.159 mmol) was added to the reaction, along with a sample of DIPEA (0.046 mL, 0.265 mmol). LCMS analysis after 73 hours reaction time indicated that the reaction had produced a side-product. The reaction was allowed to stir overnight. The reaction mixture was loaded onto a 5 g SCX-column, eluting with MeOH (70 mL) followed by 2M MeOH/NH3 (70 mL). Fractions were evaporated to dryness to give a solid which was further purified on a 12+M Biotage silica columns, eluting with cyclohexane:EtOAc (1:0 to 1:1). Product-containing fractions were evaporated to dryness to give a white solid (38 mg) that was characterised as ethyl {1-acetyl-6-[4-(chloromethyl)phenyl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate. Some of this material (24 mg, 0.060 mmol) was added to a solution of piperidine (0.036 mL, 0.363 mmol) mixed with acetonitrile (4 mL), along with six equivalents of potassium carbonate (60.2 mg, 0.435 mmol) and the solution was refluxed under nitrogen at 85° C. for 15 hours then cooled and loaded onto a 5 g SCX-column, eluting with MeOH (70 mL) followed by 2M MeOH/NH3 (70 mL). Product-containing fractions were evaporated to dryness to give a clear, colourless solid (35 mg). This was purified on a 12+M Biotage silica column, eluting with DCM:2M MeOH/NH3 (1:0 to 49:1). Product-containing fractions were evaporated to dryness to give a clear, colourless solid (21 mg).
Reaction SMILES: O1CCCC1.[CH2:6]([C:8]1[C:16]([O:17]C2CCCCO2)=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[N:11][N:12]2C1CCCCO1)[CH3:7].FC(F)(F)C(O)=O.[OH-].[Na+]>O>[CH2:6]([C:8]1[C:16]([OH:17])=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[N:11][NH:12]2)[CH3:7]
Reactant: CCc1c(OC2CCCCO2)ccc2c1cnn2C1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCc1c(O)ccc2[nH]ncc12
Temperature: 25 °C
Yield: 45.7 %

Procedure:
In a mixed solvent of tetrahydrofuran (5.0 ml) and water (2.5 ml) was suspended 4-ethyl-1-tetrahydro-2H-pyran-2-yl-5-(tetrahydro-2H-pyran-2-yloxy)-1H-indazole (1.40 g), followed by adding thereto trifluoroacetic acid (10.0 ml), and the resulting mixture was stirred for 2.5 hours while being maintained at room temperature. The reaction mixture was neutralized with a 2N-aqueous sodium hydroxide solution and extracted with ethyl acetate, and the extract solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by a silica gel column chromatography (eluent: chloroform/ethyl acetate) to obtain 4-ethyl-1H-indazol-5-ol (314 mg, 47%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][CH2:12][O:13][CH2:14][CH3:15])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[NH2:20]>CN1CCCC1=O>[Cl:16][C:17]1[CH:18]=[C:19]([NH:20][C:2]2[C:3]3[N:10]([CH2:11][CH2:12][O:13][CH2:14][CH3:15])[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Reactant: CCOCCn1ccc2ncnc(Cl)c21
Solvent: CN1CCCC1=O
Product: CCOCCn1ccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c21
Yield: 53.2 %

Procedure:
To a solution of 4-chloro-5-(2-ethoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine (160 mg) in 1-methyl-2-pyrrolidone (1.4 mL) was added 3-chloro-4-(pyridin-2-ylmethoxy)aniline (250 mg). The title compound (160 mg) was obtained as pale-yellow needle crystals by the reaction in the same manner as in Example 42 (ii).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5](=[O:14])[C:6]2[S:11][C:10](=S)[N:9](C)[C:7]=2[N:8]=1)[CH3:2].Cl>[OH-].[Na+]>[CH2:1]([C:3]1[NH:4][C:5](=[O:14])[C:6]([SH:11])=[C:7]([NH:9][CH3:10])[N:8]=1)[CH3:2]
Reactant: CCc1nc2c(sc(=S)n2C)c(=O)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCc1nc(NC)c(S)c(=O)[nH]1
Temperature: 4 °C
Yield: 85.2 %

Procedure:
5-Ethyl-3-methyl-6H-thiazolo[4,5-d]pyrimidin-7-one-2-thione (9.5 g, 41.8 mmole) from Example 108 was suspended in approximately 500 ml of 4N sodium hydroxide solution. The resultant mixture was refluxed for 2 to 4 hours, followed by cooling at approximately 4° C. for about 20 hours. The mixture was slowly acidified with concentrated hydrochloric acid; the solid was separated by filtration and dried, providing 6.6 g (85%) of 2-ethyl-5-mercapto-6-methylamino-3H-pyrimidin-4-one. Infrared and nuclear magnetic resonance spectral analyses confirmed the structural assignment.