Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:25]=[CH:24][C:15](/[CH:16]=[CH:17]/[C:18]4[N:22]([CH3:23])[N:21]=[N:20][N:19]=4)=[CH:14][CH:13]=3)=[C:9]([C:26]3[CH:31]=[CH:30][C:29]([O:32]C)=[CH:28][CH:27]=3)[S:8][C:7]=2[CH:34]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:32][C:29]1[CH:28]=[CH:27][C:26]([C:9]2[S:8][C:7]3[CH:34]=[C:3]([OH:2])[CH:4]=[CH:5][C:6]=3[C:10]=2[O:11][C:12]2[CH:25]=[CH:24][C:15](/[CH:16]=[CH:17]/[C:18]3[N:22]([CH3:23])[N:21]=[N:20][N:19]=3)=[CH:14][CH:13]=2)=[CH:31][CH:30]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(/C=C/c3nnnn3C)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1nnnc1/C=C/c1ccc(Oc2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.1 %

Procedure:
To a 30 mL vial containing (E)-5-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)styryl)-1-methyl-1H-tetrazole (12 mg, 0.03 mmol) in DCM (1 mL) was added BBr3 (1 M in heptane, 0.077 mL, 0.08 mmol) and the reaction was stirred for 1 h at room temperature. The reaction mixture was quenched with 4 mL MeOH and stirred for 10 min at room temperature. The reaction mixture was concentrated to 50% volume and the crude product was purified by reverse phase HPLC (acidic condition, 0.1% TFA in 1-100% CH3CN/H2O) to afford (E)-2-(4-hydroxyphenyl)-3-(4-(2-(1-methyl-1H-tetrazol-5-yl)vinyl)phenoxy)benzo[b]thiophen-6-ol (4 mg, 9.04 μmol, 35% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm=7.52 (d, J=16.67 Hz, 1 H), 7.38-7.48 (m, 4 H), 7.09 (d, J=2.02 Hz, 1 H), 7.06 (d, J=8.59 Hz, 1 H), 6.96 (d, J=16.67 Hz, 1 H), 6.81-6.90 (m, 2 H), 6.61-6.73 (m, 3 H), 4.24 (s, 3 H), LC/MS (m/z, MH+): 443.3.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([CH3:10])[CH3:9])[CH:3]=1.P(Cl)(Cl)(Cl)=O.[C:16]([N:19]1[CH2:23][CH2:22][NH:21][C:20]1=O)(=[O:18])[CH3:17]>>[C:16]([N:19]1[CH2:23][CH2:22][N:21]=[C:20]1[NH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([CH3:10])[CH3:9])[CH:3]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)N1CCNC1=O
Reactant: CC(C)c1cc(N)n(C)n1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)N1CCN=C1Nc1cc(C(C)C)nn1C
Reaction time: 40 h

Procedure:
5-amino-3-isopropyl-1-methyl pyrazole (described in British Pat. No. 1,057,740) (19.3 g) was dissolved in 180 ml. phosphorus oxychloride (POCl3). 1-Acetyl-2-imidazolidinone (J. Chem Soc 1964, 178) (20.1 g) was added. This reaction mixture was stirred at 55° for 40 hr. The solvents were concentrated in vacuum, ice and methylene chloride were added and the mixture neutralized with 25% sodium hydroxide in water. The methylene chloride layer was dried over MgSO4 and then concentrated and the residue crystallized from isopropyl alcohol and ether to give 12.73 g. of product, mp 145°-147° C.
Reaction SMILES: C[O-].[Na+].[C:4]1([C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][O:6]1)=[O:5].[CH:14]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20])=O.C(OCC)(=O)CC>CO>[O:5]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:6])[CH:14]1[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20]
Reactant: O=C1OCc2ccccc21
Reactant: N#Cc1cccc(C=O)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(=O)CC
Solvent: CO
Product: N#Cc1cccc(C2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 67.3 %

Procedure:
A mixture of 27% sodium methoxide solution in methanol (400 g, 2 mol) and methanol (150 ml) was added dropwise between ambient temperature and 30° C. over 15 minutes to a stirred mixture of phthalide (67 g, 0.5 mol), 3-formylbenzonitrile (65.5 g, 0.5 mol) and ethyl propionate (250 ml), the mixture was stirred at ambient temperature for 40 minutes and at reflux temperature for 1 hour, then it was allowed to cool to ambient temperature. The resulting red solid was collected by filtration, washed with ethyl acetate (2×50 ml) and dissolved in water (1800 ml). The solution was acidified by the addition of acetic acid (60 ml) and the resulting red solid was collected by filtration, washed with water (2×200 ml) and dried in vacuo to give 3-(1,3-dioxoindan-2-yl)benzonitrile (83.2 g) as a dark red solid, m.pt. 179-182° C., m/z (M+H)+• 248, which was used without further purification.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][C:52]([O:59][CH3:60])=[C:53]([Br:58])[CH:54]=4)[O:49][C:48]=3[C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][C:52]([O:59][CH3:60])=[C:53]([Br:58])[CH:54]=4)[O:49][C:48]=3[C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)=[CH:45][CH:46]=2)[CH2:38][CH2:39][CH2:40]1
Reactant: COc1cc2oc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(=O)c2cc1Br
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: COc1cc2oc(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)c(=O)c2cc1Br
Yield: 76 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(6-bromo-7-methoxy-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as a white solid (27 mg, 76%). 1H NMR (400 MHz, DMSO-d6): δ 8.19 (s, 1H), 7.46 (s, 1H), 7.44-7.31 (m, 7H), 7.14-7.10 (m, 2H), 4.02 (s, 3H), 2.40-2.32 (m, 2H), 2.12-2.04 (m, 2H), 2.04-1.94 (m, 1H), 1.69-1.60 (m, 1H). LCMS (Method E): RT=3.87 min, [M+H]+=476/478.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:27])[CH2:7][CH2:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]23[CH2:26][CH:21]4[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]4)[CH2:18]2)[CH2:24]3)=[CH:13][CH:12]=1)C>C(O)C.O1CCCC1>[C:17]12([C:14]3[CH:13]=[CH:12][C:11]([S:10][CH2:9][CH2:8][CH2:7][C:6]([OH:27])=[O:5])=[CH:16][CH:15]=3)[CH2:18][CH:19]3[CH2:25][CH:23]([CH2:22][CH:21]([CH2:20]3)[CH2:26]1)[CH2:24]2
Reactant: CCOC(=O)CCCSc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCCSc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reaction time: 72 h

Procedure:
100 ml of 2 N sodium hydroxide solution are added to a solution of 6 g of crude 4-[4-(1-adamantyl)-phenylthio]-butyric acid ethyl ester in 300 ml of ethanol and 100 ml of tetrahydrofurane and the mixture is left to stand for 3 days at about 25° C with exclusion of air. The reaction solution is then evaporated in vacuo to a volume of about 100 ml and partitioned between 3 times 200 ml of methylene chloride and 200 ml of 2 N hydrochloric acid. The organic phases are washed until neutral, dried over sodium sulphate and evaporated in vacuo. Crystallisation of the evaporation residue from benzene/petroleum ether gives 4-[4-(1-adamantyl)-phenylthio]-butyric acid of melting point 136°-138° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:4]([C:19](=[S:21])[NH2:20])[N:3]=1.Cl[CH2:23][C:24](=O)[CH3:25]>C(O)(C)C>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH2:1])=[N:3][C:4]=2[C:19]1[S:21][CH:23]=[C:24]([CH3:25])[N:20]=1
Reactant: CC(=O)CCl
Reactant: NC(=S)c1nc(N)nc2c1ncn2Cc1ccccc1F
Solvent: CC(C)O
Product: Cc1csc(-c2nc(N)nc3c2ncn3Cc2ccccc2F)n1
Temperature: 80 °C
Yield: 12 %

Procedure:
A stirred suspension of 2-amino-9-(2-fluorobenzyl)-9H-purine-6-thiocarboxamide (200 mg, 0.5 mmol) and chloroacetone (1 mL) in isopropanol (5 mL) was heated at 80° C. for 2 h, filtered and the filtrate concentrated in vacuo and purified by chromatography [SiO2; EtOAc] to give the title compound (26 mg, 12%) as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH:19]([OH:40])[CH2:20][N:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[C:23]([C:30]([O:32]CC5C=CC=CC=5)=[O:31])=[CH:22]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCCC1>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH:19]([OH:40])[CH2:20][N:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[C:23]([C:30]([OH:32])=[O:31])=[CH:22]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1csc(-c2cc3cc(C(O)Cn4cc(C(=O)OCc5ccccc5)c5ccccc54)ccc3o2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1csc(-c2cc3cc(C(O)Cn4cc(C(=O)O)c5ccccc54)ccc3o2)n1
Yield: 85.4 %

Procedure:
A solution of benzyl 1-{2-[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]-2-hydroxyethyl}indole-3-carboxylate (70 mg) and 1N sodium hydroxide (0.13 ml) in tetrahydrofuran (7 ml) was stirred at 50° C. for 1 day. After removal of solvent, the residue was dissolved into water and the solution was acidified with diluted hydrochloric acid. The resulting precipitates were collected by filtration and washed with water to give 1-{2-[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]-2-hydroxyethyl}indole-3-carboxylic acid (50 mg).
Reaction SMILES: [CH3:1][C:2]1[C@H:7]([C:8]([O:10]C(C)(C)C)=[O:9])[N:6]2[C:15](=[O:27])[C@@H:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:5]2[S:4][CH:3]=1.Cl>ClCCl.O.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[C@H:7]([C:8]([OH:10])=[O:9])[N:6]2[C:15](=[O:27])[C@@H:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@H:5]2[S:4][CH:3]=1
Reactant: CC1=CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)OC(C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC1=CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 82.7 %

Procedure:
A stirred solution of tert-butyl (4R,6R,7R)-3-methyl-7-phenylacetamido-ceph-2-em-4-carboxylate (0.776 g, 2.0 mmol) in dichloromethane (30 ml) was cooled to 0° C. Titanium tetrachloride (0.6 ml, 5.5 mmol) was added in 1 min. After stirring for 2.5 h at 0° C., the suspension was mixed with a chilled 2M solution of hydrochloric acid in water (40 ml). The organic-phase was separated and washed with a 1M solution of hydrochloric acid in water (20 ml), water (20 ml), and brine (20 ml). The organic phase was concentrated to give 0.55 g of (4R,6R,7R)-3-methyl-7-phenylacetamido-ceph-2-em-4-carboxylic acid (yield 82.7%).
Reaction SMILES: [C@@H]1([NH:10][C:11]2[C:20]3[CH:19]=[N:18][CH2:17][N:16]([NH2:21])[C:15]=3[N:14]=[CH:13][N:12]=2)O[C@H](CO)[C@@H](O)[C@H]1O.P(Cl)(Cl)(Cl)=O>COP(OC)(OC)=O>[N:14]1[C:15]2[N:16]([NH2:21])[CH2:17][N:18]=[CH:19][C:20]=2[C:11]([NH2:10])=[N:12][CH:13]=1
Reactant: NN1CN=Cc2c(N[C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)ncnc21
Solvent: O=P(Cl)(Cl)Cl
Solvent: COP(=O)(OC)OC
Product: Nc1ncnc2c1C=NCN2N

Procedure:
The method of this invention comprises the steps of a) reacting 6-cyanopurine with bis(trimethylsilyl)trifluoroacetamide in acetonitrile under reflux and thereafter with tetra-O-acetyl-β-D-ribofuranose in the presence of trimethylsilyltrifluoromethanesulfonate to stereospecifically produce 9-(tri-O-acetyl-β-D-ribofuranosyl)-6-cyanopurine in high yield; b) reacting said 9-(tri-O-acetyl-β-D-ribofuranosyl)-6-cyanopurine with methanolic ammonia in a sealed pressure vessel at ambient temperature to produce N4 -(β-D-ribofuranosyl)pyrimido[4,5-d]pyrimidine-4,8-diamine; c) reacting said N4 -(β-D-ribofuranosyl)pyrimido[4,5-d]pyrimidine-4,8-diamine with phosphoryl chloride in trimethylphosphate at a temperature below about 10° C. to produce N4 -5-O-phosphono-β-D-ribofuranosyl)pyrimido[4,5-d]pyrimidine-4,8-diamine or, alternatively reacting said N4 -(β-D-ribofuranosyl)pyrimido[4,5-d]pyrimidine-4,8-diamine with acetic anhydride in the presence of an acid scavenger to produce N4 -(2,3,5-tri-O-acetyl-β-D-ribofuranoxyl)pyrimido[4,5-d]pyrimidine-4,8-diamine.
Reaction SMILES: OO.S(=O)(=O)(O)O.[Cl:8][C:9]1[CH:31]=[CH:30][C:12]2[C:13]3[C:14](=[CH:25][NH:26][C:27]=3[CH2:28][CH3:29])[CH2:15][N:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]=2[CH:10]=1.S(=O)(O)[O-:33].[Na+]>C(O)(=O)C>[Cl:8][C:9]1[CH:31]=[CH:30][C:12]2[C:13]3[CH:27]([CH2:28][CH3:29])[NH:26][C:25](=[O:33])[C:14]=3[CH2:15][N:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]=2[CH:10]=1
Reactant: CCc1[nH]cc2c1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reactant: O=S([O-])O
Agent: O=S(=O)(O)O
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CCC1NC(=O)C2=C1c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reaction time: 1 h

Procedure:
In one portion, 0.9 ml (7.9 mmol) of 30% hydrogen peroxide was added to 40 ml of a 1% solution of concentrated sulfuric acid in acetic acid. After stirring for 1 hour, 2.0 g (5.6 mmol) of 8-chloro-6-(2-chlorophenyl)-1-ethyl-2H,4H-pyrrolo[3,4-d][2]benzazepine were added, and the resulting mixture was stirred for 20 minutes. The excess peracid was discharged by the addition of saturated aqueous sodium bisulfite solution, and the mixture was concentrated at reduced pressure. The residue was partitioned between methylene chloride and water and neutralized with concentrated ammonium hydroxide solution. The methylene chloride solution was washed with brine, dried over anhydrous sodium sulfate, and concentrated at reduced pressure. The resulting oil was crystallized from ether to give 8-chloro-6-(2-chlorophenyl)-1-ethyl-1,4-dihydropyrrolo[3,4-d][2]benzazepin-3(2H)-one as yellow prisms, mp 233°-235° C. Recrystallization from a mixture of ethyl acetate and methanol gave colorless prims, mp 236°-237° C.
Reaction SMILES: N12CCCN=C1CCCC[CH2:2]2.[CH3:12][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[C:16]=1[NH:24][C:25]([NH:27][S:28]([N:31]([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH2:34][CH3:35])(=[O:30])=[O:29])=[O:26])[CH3:14].CI>C(#N)C>[CH3:12][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:22])[CH3:23])[C:16]=1[NH:24][C:25](=[O:26])[N:27]([S:28]([N:31]([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH2:34][CH3:35])(=[O:30])=[O:29])[CH3:2])[CH3:14]
Reactant: CCCCN(CCCC)S(=O)(=O)NC(=O)Nc1c(C(C)C)cccc1C(C)C
Reactant: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: CI
Product: CCCCN(CCCC)S(=O)(=O)N(C)C(=O)Nc1c(C(C)C)cccc1C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (1.6 mL, 10.7 mmol) was added dropwise to a solution of N-[2,6-bis(1-methylethyl)phenyl]-N'-[(dibutylamino)sulfonyl]urea (4.0 g, 9.7 mmol) and methyl iodide (1.52 g, 10.7 mmol) in 100 mL acetonitrile at -15° C. The resulting mixture was warmed to room temperature and stirred for 16 hours. Concentrated in vacuo and partitioned between 1N HCl and ethyl acetate. The organic layer was dried with MgSO4, filtered, and concentrated to give an orange oil. Chromatography gave the title compound as a clear oil; 1H NMR (DMSO-d6) θ 8.57 (s, 1H), 7.31-7.15 (m, 3H), 3.33-3.21 (m, 7H), 3.05 (heptet, 2H), 1.57-1.46 (m, 4H), 1.35-1.20 (m, 4H), 1.13 (d, 12H), 0.90 (t, 6H). ##STR14##
Reaction SMILES: [CH2:1]([N:3]([CH2:5][CH:6]([N:8]1[C:21]2[CH:20]=[C:19]([C:22](=[S:24])[NH2:23])[CH:18]=[CH:17][C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:7])[CH3:4])[CH3:2].[CH3:25][CH:26]([CH3:30])[CH2:27][CH2:28]N.S>C(O)C>[CH3:25][CH:26]([CH3:30])[CH2:27][CH2:28][NH:23][C:22]([C:19]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH:6]([CH3:7])[CH2:5][N:3]([CH2:1][CH3:2])[CH3:4])[C:21]=2[CH:20]=1)=[S:24]
Reactant: CCN(C)CC(C)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Reactant: CC(C)CCN
Agent: S
Solvent: CCO
Product: CCN(C)CC(C)N1c2ccccc2Sc2ccc(C(=S)NCCC(C)C)cc21
Temperature: 100 °C

Procedure:
A solution of 10-[(2RS)-1-(N-ethyl-N-methyl-amino)-2-propyl]-2-phenothiazinecarbothioamide (1 g) and 3-methylbutylamine (4.9 cc) in absolute ethanol (15 cc) is saturated with hydrogen sulphide and heated for 16 hours to a temperature in the region of 100° C. After being cooled, the orange solution obtained is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual orange oil is purified by chromatography on a column (height: 25 cm; diameter 2 cm) of silica gel (0.04-0.063 mm) under a slight excess pressure of nitrogen (40 kPa), eluting with a mixture (80:20 by volume) (500 cc) of ethyl acetate and cyclohexane and collecting 30-cc fractions. Fractions 4 to 8 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. N-(3-Methylbutyl)-10-[(2RS)-1-(N-ethyl-N-methylamino)-2-propyl]-2-phenothiazinecarbothioamide (1.3 g) is thereby obtained in the form of an orange-yellow oil.
Reaction SMILES: CN(C)S([N:6]1[CH:10]=[C:9]([CH:11]([C:13]2[C:18]([CH2:19][CH3:20])=[CH:17][C:16]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:15][C:14]=2[CH2:28][CH3:29])O)[N:8]=[C:7]1[Si](C(C)(C)C)(C)C)(=O)=O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH2:28]([C:14]1[CH:15]=[C:16]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:17]=[C:18]([CH2:19][CH3:20])[C:13]=1[CH2:11][C:9]1[N:8]=[CH:7][NH:6][CH:10]=1)[CH3:29]
Reactant: CCc1cc(Oc2ccccc2)cc(CC)c1C(O)c1cn(S(=O)(=O)N(C)C)c([Si](C)(C)C(C)(C)C)n1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(Oc2ccccc2)cc(CC)c1Cc1c[nH]cn1

Procedure:
Prepared in analogy to Example 57(e) from rac-2-(tert-butyl-dimethyl-silanyl)-4-[(2,6-diethyl-4-phenoxy-phenyl)-hydroxy-methyl]-imidazole-1-sulfonic acid dimethylamide, triethylsilane and trifluoroacetic acid in dichloromethane in a pressure tube at 100° C. for 16 h. White crystalline solid. MS (ISP): 307.3 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C@H:12]1[CH2:31][N:15]2[C:16](=[O:30])[N:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[CH2:18][C@@H:14]2[CH2:13]1.CCN(C(C)C)C(C)C.O>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C@H:12]1[CH2:31][N:15]2[C:16](=[O:30])[N:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:27])[F:28])=[CH:21][CH:20]=3)[CH2:18][C@@H:14]2[CH2:13]1)=[O:5]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: N[C@@H]1C[C@H]2CN(c3ccc(OC(F)(F)F)cc3)C(=O)N2C1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(N[C@@H]1C[C@H]2CN(c3ccc(OC(F)(F)F)cc3)C(=O)N2C1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
2-Chloro-benzoyl chloride (40.5 mg, 0.23 mmol) was dropped into a solution of (6R,7aS)-6-Amino-2-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[1,2-c]imidazol-3-one (70 mg, 0.23 mmol) and DIPEA (23 mg, 0.23 mmol) in anhydrous dichloromethane (3 mL), the mixture was stirred at room temperature for 4 hours. Then the mixture was poured into water (10 mL) extracted with ethyl acetate (3×10 mL), the organic layers was combined, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5:1) to give 85 mg (83%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.70-7.67 (m, 1H), 7.60 (d, 2H, J=9.3 Hz), 7.43-7.32 (m, 3H), 7.20 (d, 2H, J=9.0 Hz), 6.49 (d, 1H, J=6.6 Hz), 4.76-4.68 (m, 1H), 4.26 (dd, 1H, J1=12.6 Hz, J2=7.2 Hz), 4.18-4.02 (m, 2H), 3.76 (dd, 1H, J1=9 Hz, J2=2.1 Hz), 3.13 (dd, 1H, J1=12.9 Hz, J2=3.3 Hz), 2.35-2.28 (m, 1H), 1.93-1.83 (m, 1H); LC-MS: 440.1 [M+1]+.
Reaction SMILES: C(NC1CCCCC1)(C)C.C([Li])CCC.[CH2:16]([O:18][C:19](=[O:27])[CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)[CH3:17].[Cl:28][C:29]1[N:34]=[C:33]([Cl:35])[C:32]([CH2:36]I)=[CH:31][N:30]=1>O1CCCC1.C(OCC)(=O)C>[CH2:16]([O:18][C:19](=[O:27])[CH:20]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)[CH2:36][C:32]1[C:33]([Cl:35])=[N:34][C:29]([Cl:28])=[N:30][CH:31]=1)[CH3:17]
Reactant: CCOC(=O)Cc1ccncc1
Reactant: Clc1ncc(CI)c(Cl)n1
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1cnc(Cl)nc1Cl)c1ccncc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-isopropylcyclohexylamine (720 mg, 5.0 mmol) (Aldrich) in dry tetrahydrofuran (10 mL) was added n-butyllithium (2.5 M in hexanes, 2.0 mL, 5.0 mmol) (Aldrich) at −78° C. under argon. After 30 minutes, a solution of 4-pyridylacetic acid ethyl ester (826 mg, 5.0 mmol) (Lancaster) in tetrahydrofuran (3 mL) was added by injection via a syringe and the reaction mixture was stirred at −78° C. for another 30 minutes. To the reaction mixture was added a solution of 2,4-dichloro-5-iodomethyl-pyrimidine (722.5 mg, 2.5 mmol) (from Example 1c supra) in tetrahydrofuran (3 mL) at −78° C. and the reaction mixture was stirred at the same temperature for 1 hour then slowly allowed to warm up to −30° C. and stirred for 10 minutes. The reaction mixture was diluted with ethyl acetate (100 mL) and successively washed with saturated aqueous ammonium chloride solution (50 mL), water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude 3-(2,4-dichloro-pyrimidin-5-yl)-2-pyridin-4-yl-propionic acid ethyl ester which was used in the next step without further purification. (Yield 1.43 g, 83.6%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C@@H:7]([C:12]([OH:14])=[O:13])[NH:8][CH2:9]2)=[CH:4][CH:3]=1.[ClH:15].[CH3:16]O>>[ClH:15].[CH3:16][O:13][C:12]([C@@H:7]1[CH2:6][C:5]2[C:10](=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)[CH2:9][NH:8]1)=[O:14]
Reactant: CO
Reactant: O=C(O)[C@@H]1Cc2ccc(O)cc2CN1
Agent: Cl
Product: COC(=O)[C@@H]1Cc2ccc(O)cc2CN1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-7-hydroxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (19.3 g) in 100 mL MeOH was added hydrochloric acid (100 mL, 4M solution in dioxane) at room temperature and the reaction mixture was heated to reflux and stirred at 70° C. for 16 hours. After completion of the reaction, the reaction mixture was concentrated in vacuo to give (S)-7-hydroxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid methyl ester hydrochloride salt. The product was used in a subsequent step without further purification.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH:16]=[C:15]3[C:10]([CH:11]=[C:12]([C:17]4[CH:18]=[C:19]([CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[N:20]5[C:25]=4[C:24]([NH2:26])=[N:23][CH:22]=[N:21]5)[CH:13]=[CH:14]3)=[N:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:34][C:35](N(C)C)=[O:36]>>[C:35]([N:30]1[CH2:29][CH2:28][CH:27]([C:19]2[N:20]3[C:25]([C:24]([NH2:26])=[N:23][CH:22]=[N:21]3)=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:16]=4)[CH:18]=2)[CH2:32][CH2:31]1)(=[O:36])[CH3:34]
Reactant: CN(C)C(=O)CCl
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(CC5CCCCC5)nc4c3)c12
Product: CC(=O)N1CCC(c2cc(-c3ccc4cn(CC5CCCCC5)nc4c3)c3c(N)ncnn23)CC1
Yield: 16 %

Procedure:
In a manner similar to the procedure described for Example 369 and using 5-[2-(cyclohexylmethyl)-2H-indazol-6-yl]-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine and substituting methane sulfonyl chloride for 2-chloro-N,N-dimethylacetamide as starting materials, 11 mg (16%) of the desired product was isolated. 1H NMR (400 MHz, CD3OD) δ 8.25 (s, 1 H) 7.79-7.84 (m, 2 H) 7.65 (s, 1 H) 7.23 (d, 1 H) 6.63 (s, 1 H) 4.29 (d, 2 H) 3.85 (d, 2 H) 3.35-3.40 (m, 1 H) 2.94 (td, 2 H) 2.88 (s, 3 H) 1.58-2.24 (m, 10 H) 1.07-1.30 (m, 5 H). LC-MS [M+H]+=508.3, RT=2.86 min.