Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:4]([NH2:6])=[S:5].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[CH2:20]=O>CO>[CH3:1][N:2]([CH3:13])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)[C:4]([NH:6][CH2:20][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[S:5]
Reactant: C1COCCN1
Reactant: C=O
Reactant: CN(C)C(C(N)=S)c1ccccn1
Solvent: CO
Product: CN(C)C(C(=S)NCN1CCOCC1)c1ccccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1.8 g. (0.0091 mole) of 2-dimethylamino-2-(2-pyridyl)thioacetamide in 25 ml. of methanol is added 0.9 g. (0.0015 mole) of morpholine in 2 ml. of methanol and 0.9 g. (0.0015 mole) of 37% aqueous formaldehyde solution in 2 ml. of methanol. The resulting solution is stirred at room temperature for 18 hours. The solvent is removed under reduced pressure and ether is added to the residue. The mixture is cooled at -20°C. for 4 hours and then filtered. The solvent is evaporated from the filtrate to give 2-dimethylamino-N-morpholinomethyl-2-(2-pyridyl)-thioacetamide.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([S:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[NH:27][C:26](=[O:28])[O:25][C:24]([CH:35]5[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]5)([CH:29]5[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]5)[C:23]=4[CH:41]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:42]O>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([S:13]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[NH:27][C:26](=[O:28])[O:25][C:24]([CH:29]5[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]5)([CH:35]5[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]5)[C:23]=4[CH:41]=3)=[O:42])=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1Nc2ccc(OCCCCSc3ccc(C4CCCCC4)cc3)cc2C(C2CCCCC2)(C2CCCCC2)O1
Reactant: OO
Product: O=C1Nc2ccc(OCCCCS(=O)c3ccc(C4CCCCC4)cc3)cc2C(C2CCCCC2)(C2CCCCC2)O1

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-cyclohexyl-phenylmercapto)-butoxy]-4,4-dicyclohexyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[NH:9][CH:8]=[CH:7][C:6]2=O.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:6]1[C:5]2[C:10](=[CH:11][C:12]([CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2c(=O)cc[nH]c2cc1C
Product: COc1cc2c(Cl)ccnc2cc1C
Temperature: 25 °C
Yield: 71 %

Procedure:
6-Methoxy-7-methyl-1H-quinolin-4-one (73.9 g) was added to phosphorus oxychloride (160 ml), and the mixture was heated under reflux for 2 hr. The reaction solution was cooled to room temperature, and the solvent was then removed by distillation under the reduced pressure. Chloroform and water were added to the reaction solution, and the aqueous layer was neutralized with an aqueous potassium hydroxide solution. The organic layer was washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, hexane was added to the residue, and the precipitated crystal was collected by filtration to give 4-chloro-6-methoxy-7-methyl-quinoline (12.7 g, yield 71%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5](C#N)=[N:6][CH:7]=1.[CH2:10]1[CH2:14][O:13]CC1.C[Mg+].[Br-]>CCOCC>[F:1][C:2]1[CH:3]=[N:4][C:5]([C:14](=[O:13])[CH3:10])=[N:6][CH:7]=1
Reactant: C1CCOC1
Reactant: N#Cc1ncc(F)cn1
Agent: C[Mg+]
Agent: [Br-]
Solvent: CCOCC
Product: CC(=O)c1ncc(F)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
A round-bottom-flask containing 5-fluoropyrimidine-2-carbonitrile (Method 59, 1.50 g, 12.19 mmol) was charged with anhydrous THF (30 ml) under N2. The solution was cooled to 0° C., and a solution of MeMgBr (4.90 ml of a 3.0 M solution in ether, 14.62 mmol) was added dropwise. After 2 hours at 0° C., the reaction mixture was quenched with ice water and extracted with EtOAc. The organic extract was washed with brine, dried over Na2SO4, and evaporated to dryness to give the title compound as an oil (0.778 g, yield 46%). GC-MS, 140 (M); 1H NMR (CDCl3) δ 8.65 (s, 2H), 2.65 (s, 2H).
Reaction SMILES: [N:1]1([C:7]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][N:10]=[C:9]3[NH:17][CH:18]=[CH:19][C:8]=23)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:20]([O:24][C:25]([NH:27][C@H:28]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:29](O)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.C(N(CC)CC)C>C(Cl)Cl>[C:20]([O:24][C:25]([NH:27][C@H:28]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:29]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][N:10]=[C:9]3[NH:17][CH:18]=[CH:19][C:8]=23)[CH2:6][CH2:5]1)=[O:30])=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: COC(=O)c1cnc2[nH]ccc2c1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cnc2[nH]ccc2c1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.4 %

Procedure:
Methyl 4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.23 g, 0.69 mmol) and (R)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (0.227 g, 0.759 mmol) were placed in DCM (5 mL) at room temperature. HOBT-H2O (0.147 g, 0.966 mmol), EDCI (0.172 g, 0.897 mmol) and triethylamine (0.48 mL, 3.45 mmol) were then added, and the reaction was stirred at room temperature for 18 hours. The reaction was then quenched with saturated Na2CO3 and extracted with DCM. The combined organic fractions were dried, filtered, and concentrated to give a crude residue. The residue was purified by column chromatography (500:7 DCM:MeOH) to give (R)-methyl 4-(4-(2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoyl)piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.11 g, 29.4% yield).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH3:17])([CH3:16])[C:12]([O:14]C)=O)=[CH:6][C:5]=1[F:18])(=[O:3])[NH2:2].[F:19][C:20]([F:33])([F:32])[C:21]1[CH:28]=[C:27]([N:29]=[C:30]=[S:31])[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]>CS(C)=O.O>[C:23]([C:22]1[CH:25]=[CH:26][C:27]([N:29]2[C:12](=[O:14])[C:11]([CH3:17])([CH3:16])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([F:18])[CH:6]=3)[C:30]2=[S:31])=[CH:28][C:21]=1[C:20]([F:19])([F:32])[F:33])#[N:24]
Reactant: COC(=O)C(C)(C)Nc1ccc(C(N)=O)c(F)c1
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(C(N)=O)c(F)c1
Reaction time: 0.03 h

Procedure:
A solution of methyl 2-(4-carbamoyl-3-fluorophenylamino)-2-methylpropanoate and 2-(trifluoromethyl)-4-isothiocyanatobenzonitrile (1.5 equivalents) in dry DMSO (5 mL per mmol) was heated to 80-82° C. for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 40% Acetone-Hexanes. MS (m/z): 451 (M+1). HPLC: Column, YMC ODS A, 4.6×150 mm, 5 μm, Mobile Phase A: 10 mM Ammonium acetate, Mobile Phase B: Acetonitrile, Gradient, 10% B up to 2 min, 10% to 90% B in 3 min, hold for 3 min, 90% to 10% B in 5 min, Retention time, 2.782 min, HPLC Purity, 99.4%, Flow Rate, 1 mL/min. 1H NMR (CDCl3, Freebase): δ (ppm) 8.3 (t, 1H), 8.0 (d, 1H) 7.98 (s, 1H), 7.8 (d, 1H), 7.27 (d, 1H), 7.2 (d, 1H), 6.65 (d, 1H), 6.0 (s, 1H), 1.62 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]=1.C=O.Cl.[C:15]12([NH2:25])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2.[C:26](O)(=O)[CH3:27]>>[C:15]12([N:25]3[CH2:5][CH2:6][C:11]4[C:10]5[CH:9]=[CH:8][CH:7]=[CH:27][C:26]=5[CH2:4][CH2:3][C:2]=4[CH2:1]3)[CH2:22][CH:21]3[CH2:20][CH:19]([CH2:18][CH:17]([CH2:23]3)[CH2:16]1)[CH2:24]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: CC(=O)O
Reactant: CC1=CCCc2ccccc21
Agent: C=O
Agent: Cl
Product: c1ccc2c(c1)CCC1=C2CCN(C23CC4CC(CC(C4)C2)C3)C1

Procedure:
Following the procedure of Example 1, step 3, 2.05 g (14.0 mmol) of 1-methyl-3,4-dihydronaphthalene in 14 ml of acetic acid was reacted with 4.54 ml of 37% formaldehyde solution and 6.03 g of 1-adamantanamine hydrochloride. Work up gave 5.58 g of crude 3-(1-adamantyl)-1,2,3,4,5,6-hexahydrobenz[f]isoquinoline. Following the procedure of Example 2, this was reacted with 1.02 g of lithium wire in 400 ml of liquid ammonia, 100 ml of anhydrous THF and 2 ml of aniline. Chromatography on flash silica, eluting with 5-20% methanol/dichloromethane, then on alumina, eluting with 2-7% ethyl acetate/petroleum ether, afforded 0.54 g (12%) of the title product as a white solid. The hydrochloride salt was made using ethereal hydrogen chloride. Upon evaporation of the solvent and recrystallisation from methanol/petroleum ether, the title product hydrochloride was obtained as a white solid, m.p. 252°-255° C. NMR δ(D2O, CD3CN) 1.56 (1H, m), 1.68-1.92 (9H, m), 2.02-2.04 (6H, m), 2.27 (3H, s), 2.61 (1H, m), 2.74 (1H, d of d), 2.82 (1H, t, J=12.0 Hz), 2.92-2.95 (2H, m), 3.08 (1H, t of d), 3.65 (1H, m), 3.82 (1H, m), 7.19-7.23 (3H, m), 7.29-7.30 (1H, m). m/z (CI+, NH3) 322 (M+H)+, 195. Analysis calcd. for C23H32ClN: C, 77.17; H, 9.01; N, 3.91%. Found: C, 77.09; H, 8.95; N, 3.89%.
Reaction SMILES: [CH3:1][CH2:2][O:3][CH2:4]C.[OH-].[K+].N(CNC(N)=O)=[O:9].[CH3:15][O:16][C:17]1[CH:25]=[C:24]([O:26][CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)[CH:23]=[CH:22][C:18]=1C(Cl)=O>C1COCC1>[CH3:15][O:16][C:17]1[CH:25]=[C:24]([O:26][CH:27]2[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[CH2:31][CH2:32]2)[CH:23]=[CH:22][C:18]=1[CH2:1][C:2]([O:3][CH3:4])=[O:9]
Reactant: COc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)Cl
Reactant: NC(=O)NCN=O
Reactant: CCOCC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1OC
Reaction time: 0.5 h

Procedure:
A mixture of ether (66 ml) and 40% aqueous potassium hydroxide (20 ml) was cooled in ice. N-Nitrosomethylurea (6.6g) was added in portions with gentle swirling over 30 min. The ether layer was decanted and dried over solid potassium hydroxide for 15 min. The ether solution was decanted, and the decanted solution was cooled in an ice bath. A solution of 2-methoxy-4-(1-Boc-4-piperidyloxy)benzoyl chloride (3.26 g, 8.8 mmol) in THF (6 ml) was added dropwise and the mixture was stirred in the cold for 15 min and at ambient temperature for 3.5 hours. Nitrogen was passed through the mixture for 1 hour, and the solution was then concentrated in vacuo. A portion (930 mg) of the residue was dissolved in methanol and heated to reflux, and a solution of silver benzoate (200 mg) in triethylamine (2 ml) was added in five 0.1 ml portions at intervals of eight minutes. A sixth portion was added after an additional forty minutes' reflux, and after another five minutes, a seventh portion. After a final 30 minutes' reflux, the mixture was cooled and filtered, and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel eluted with 3%, followed by 5% methanol in methylene chloride. The product fractions were combined and evaporated to dryness in vacuo to give methyl 2-methoxy-4-(1-Boc-4-piperidyloxy)-phenylaceate.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][N:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:4][C:3]1=O.P(Cl)(Cl)([Cl:16])=O>C(#N)C>[Cl:16][C:3]1[CH:2]([CH3:1])[CH2:6][N:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:4]=1
Reactant: CC1CN(c2cccnc2)NC1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC1CN(c2cccnc2)N=C1Cl
Temperature: 75 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
Crude 4-methyl-1-(pyridin-3-yl)pyrazolidin-3-one (35.2 g, ˜82.4 mmol) was introduced into a 250 mL three-neck round bottom flask equipped with a reflux condenser. Acetonitrile (100 mL) was then added. To this yellow mixture was added phosphoryl chloride (11.56 mL, 124 mmol) slowly. The yellow slurry was stirred at 75° C. for 1 hour. The mixture was cooled down and concentrated to remove volatiles. The brown residue was carefully quenched with water (120 mL), and basified with NaOH (50 wt % in water) to pH 10 while keeping the temperature below 60° C. The mixture was then extracted with ethyl acetate (3×150 mL). The combined organic extracts were washed with water (80 mL) and concentrated under reduced pressure to afford the crude product as dark purple oil. The crude product was purified by flash column chromatography using 0-70% ethyl acetate/hexanes as eluent to provide the title compound as a brown oil (12.3 g, 76% over two steps): 1H NMR (400 MHz, CDCl3) δ 8.27 (dd, J=2.8, 0.7 Hz, 1H), 8.15 (dd, J=4.6, 1.4 Hz, 1H), 7.38 (ddd, J=8.4, 2.9, 1.4 Hz, 1H), 7.18 (ddd, J=8.4, 4.7, 0.7 Hz, 1H), 4.17-4.06 (m, 1H), 3.47 (t, J=8.9 Hz, 1H), 3.44-3.34 (m, 1H), 1.37 (d, J=6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 148.17, 142.07, 141.10, 134.74, 123.39, 119.92, 56.62, 43.62, 16.16; EIMS m/z 195 ([M]+).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[C:54]1([N:60]=[C:61]=[O:62])[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:61]([NH:60][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[O:62])[CH2:51][CH2:52]1
Reactant: Clc1cnc2nc1Nc1ccc(OCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Reactant: O=C=Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccccc1)N1CCC(CCOc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 50 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and phenyl isocyanate as the starting materials in 50% yield. LCMS for C31H33ClN7O2 (M+H)+: m/z=570.1.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[C:4]2[N:10]([CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:9]([OH:16])=[N:8][C:5]2=[N:6][CH:7]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O1CCOCC1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.O>[Cl:1][C:2]1[C:3]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:4]2[N:10]([CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:9]([OH:16])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: CCC(CC)n1c(O)nc2ncc(Cl)c(I)c21
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCC(CC)n1c(O)nc2ncc(Cl)c(-c3ccccc3)c21
Temperature: 135 °C
Yield: 36.5 %

Procedure:
6-Chloro-7-iodo-1-(pentan-3-yl)-1H-imidazo[4,5-b]pyridin-2-ol (190 mg, 0.52 mmol), phenylboronic acid (76 mg, 0.63 mmol), and (DPPF)PdCl2 (38 mg, 0.052 mmol) were added to a microwave vial equipped with stirbar. A septum was affixed to the vial and the vessel was purged with nitrogen for 5 min. Degassed dioxane (5 mL), and degassed 2 M K2CO3 (aq.) (1 mL, 2 mmol) were added by syringe, and the septum was replaced with a crimped vial cap. The reaction was heated to 135° C. for 20 min. The reaction mixture was diluted with EtOAc and water, and the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Purification by preparative LCMS provided the title compound as a white solid (60 mg). The compound was characterized by LCMS (m/z=316.1 [M+H]+) and 1H NMR.
Reaction SMILES: Cl[C:2]1[C:3]2[S:20][C:19]([NH2:21])=[N:18][C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:7]=1.[NH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25]>>[NH2:21][C:19]1[S:20][C:3]2[C:2]([NH:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25])=[N:7][C:6]([S:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=3[F:17])=[N:5][C:4]=2[N:18]=1
Reactant: Nc1nc2nc(SCc3cccc(F)c3F)nc(Cl)c2s1
Reactant: CC(C)(N)CO
Product: CC(C)(CO)Nc1nc(SCc2cccc(F)c2F)nc2nc(N)sc12

Procedure:
Prepared by the method of example 2 step a), using the product of example 4, step b) and 2-amino-2-methylpropanol.
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([O:20][CH3:21])[CH:19]=3)=[CH:13][C:8]=2[N:7]=[C:6]1[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26])([CH3:4])([CH3:3])[CH3:2].[NH2:30][OH:31]>C(O)C>[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([O:20][CH3:21])[CH:19]=3)=[CH:13][C:8]=2[N:7]=[C:6]1[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]([NH:30][OH:31])=[NH:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: NO
Reactant: COc1cncc(-c2ccc3c(c2)nc(-c2cccc(C#N)c2)n3C(C)(C)C)c1
Solvent: CCO
Product: COc1cncc(-c2ccc3c(c2)nc(-c2cccc(C(=N)NO)c2)n3C(C)(C)C)c1
Yield: 100 %

Procedure:
3-[1-tert-Butyl-5-(5-methoxy-pyridin-3-yl)-1H-benzimidazol-2-yl]-benzonitrile (0.480 g, 1.255 mmol) is dissolved in ethanol (5 mL). Hydroxylamine (1.0 mL, 50% in water) is added. The reaction mixture is heated under reflux for 6 hours. The solvent is removed in vacuum to give 3-[1-tert-butyl-5-(5-methoxy-pyridin-3-yl)-1H-benzimidazol-2-yl]-N-hydroxy-benzamidine (0.531 g, 100%) as a yellow solid.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[CH3:25][O-:26].[Na+].Cl.[OH2:29]>CCO>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:6][CH2:5][C@H:14]([CH3:13])[C:25]([OH:29])=[O:26])=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: C[O-]
Reactant: O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: C[C@@H](CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Yield: 28 %

Procedure:
To a mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (50 mg, 0.16 mmol) and 3-amino-2-(S)-methyl-propionic acid, trifluoroacetic acid salt (48 mg, 0.47 mmol) in EtOH (2 mL) was added NaOMe solid (60 mg) (amount needed to adjust the pH of the mixture to 8-9). The resultant mixture was microwaved at 140° C. for 1 h. Reaction mixture was diluted with water (60 mL) and acidified by 1 N HCl to pH=3-4. It was extracted with EtOAc. Organic layer was dried over MgSO4, filtered and concentrated. Crude product was purified by silica gel chromatography, eluting with 5-100% EtOAc/CH2Cl2, to provide the title compound 16.8 mg (0.043 mmol) in 28% yield. 1H NMR (200 MHz) in DMSO-d6, δ ppm: 14.78 (s, 1H), 12.37 (s, 1H), 9.29 (br s, 1H), 8.41 (d, J=9.2 Hz, 1H), 7.73 (br d, J=10.6 Hz, 1H), 7.54 (m, 2H), 7.30 (m, 4H), 3.58 (m, 1H), 3.43 (m, 1H), 2.81 (m, 1H), 1.10 (d, J=7.0 Hz, 3H).
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].N1C(C)=CC(C)=CC=1C.[OH:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([C@@H:26]1[CH2:30][S:29][C:28](=[O:31])[NH:27]1)=[O:25]>>[N+:7]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([C@@H:26]1[CH2:30][S:29][C:28](=[O:31])[NH:27]1)=[O:25])([O-:8])=[O:6]
Reactant: O=C1N[C@H](C(=O)NCCCCO)CS1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Product: O=C1N[C@H](C(=O)NCCCCO[N+](=O)[O-])CS1
Yield: 20.9 %

Procedure:
Following a procedure similar to that described in Example 16(b), but using 195 mg of nitronium tetrafluoroborate, 157 mg of 2,4,6-collidine and 218 mg of (4R)-N-(4-hydroxybutyl)-2-oxothiazolidine-4-carboxamide [prepared as described in step (a) above], 55 mg of the title compound were obtained as colorless needles, melting at 68°-70° C.
Reaction SMILES: CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.[CH3:25][NH:26][CH2:27][C:28]1([N:34]([CH3:36])[CH3:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[CH:37]([OH:39])=O>>[CH:37]([N:26]([CH3:25])[CH2:27][C:28]1([N:34]([CH3:36])[CH3:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:39]
Reactant: O=CO
Reactant: CNCC1(N(C)C)CCCCC1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Product: CN(C=O)CC1(N(C)C)CCCCC1
Reaction time: 1 h
Yield: 77.7 %

Procedure:
Formic acid (6.9 g, 0.15 mole) and acetic anhyride (15.3 g, 0.15 mole) were mixed without cooling and kept at room temperature for 1 hr. 1-methylaminomethylcyclohexyldimethylamine (5.9 g, 0.034 mole) was dissolved in formic acid (12 ml) and the formylating mixture (16 ml) added slowly. This produced vigorous effervescence and a temperature rise to 75°. The mixture was then left at room temperature for 2 hr. and then heated on a water bath at 55° for 0.75 hr. The solvents were removed under reduced pressure to give an amber oil (5.32 g, 77.7%) which crystallised as colourless prisms of 1-(N-formyl-1-methylaminomethyl) cyclohexyldimethylamine from light petroleum (b.p. 60°-80°), m.p. 59°-60°.
Reaction SMILES: [H-].[Na+].[O:3]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:24]3[C:23]([NH2:25])=[N:22][CH:21]=[N:20][C:19]=3[NH:18][CH:17]=2)=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H].S(O[CH:39]1[CH2:48][CH2:47][C:42]2([O:46][CH2:45][CH2:44][O:43]2)[CH2:41][CH2:40]1)(C1C=CC(C)=CC=1)(=O)=O.O1C2(CCC(=O)CC2)OCC1>CN(C)C=O>[O:3]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[C:24]3[C:23]([NH2:25])=[N:22][CH:21]=[N:20][C:19]=3[N:18]([CH:39]3[CH2:48][CH2:47][C:42]4([O:46][CH2:45][CH2:44][O:43]4)[CH2:41][CH2:40]3)[CH:17]=2)=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CCC3(CC2)OCCO3)cc1
Reactant: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: [H][H]
Agent: O=C1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC2(CC1)OCCO2
Temperature: 120 °C

Procedure:
Sodium hydride (0.26 g of a 60% dispersion in mineral oil) was added to a mixture of 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (1.94 g) in dimethylformamide 950 ml) at ambient temperature with stirring. The mixture was stirred until the evolution of hydrogen ceased and then 8-tosyloxy-1,4-dioxaspiro[4,5]decane (2.0 g, prepared as described in U.S. Pat. No. 4,360,531 from 1,4-dioxaspiro[4,5]decan-8-one, (which was prepared according to J. Med. Chem. 1992, 22460) was added. The mixture was heated at 120° C. for 5 hours under nitrogen, cooled to ambient temperature, quenched with water and extracted with ethyl acetate to give a residue which was purified by flash column chromatography on silica using ethyl acetate followed by ethyl acetate containing increasing amounts of methanol up to 6% to give 5-(4-phenoxyphenyl)-7-(1,4-dioxaspiro[4,5]decan-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine, m.p. 193-194° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:11]1[C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]2[N:7]=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[CH:24]=3)[CH2:21][C:20](=[O:36])[NH:19][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1NC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3ccncc3)c2)=Nc2cc(C(F)(F)F)c(Cl)cc2N1

Procedure:
The title compound was prepared from {4-chloro-2-[3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-5-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M92) (0.44 g, 0.82 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light orange solid (120 mg, 35%).