Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].[F:10][C:11]1[CH:12]=[C:13]([S:18](Cl)(=[O:20])=[O:19])[CH:14]=[CH:15][C:16]=1[F:17]>C(Cl)Cl>[F:10][C:11]1[CH:12]=[C:13]([S:18]([NH:6][C@@H:5]([CH2:7][OH:8])[C:4]([O:3][CH3:2])=[O:9])(=[O:19])=[O:20])[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@H](CO)NS(=O)(=O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
A suspension of L-serine-methyl ester hydrochloride (1.5 g, 9.5 mmol) in CH2Cl2 (70 mL) was added with TEA (1.1 mol eq, 1.45 mL) and the mixture was stirred at r.t. for 10 minutes. Then 3,4-difluorobenzensulfonyl chloride (1 mol eq, 2.0 g) and additional TEA (1.1 mol eq) were added and the solution hated at 60° C. overnight. The solvent was removed under reduced pressure, water was added to the residue (100 mL) and the aqueous phase extracted with EtOAc (3×40 mL). The recombined organic phases were dried over Na2SO4 and evaporated to reduced pressure. The residue was recrystallized from ethylic ether to afford 2G as a pale orange solid (2.85 g, 94% yield). 1HNMR (DMSO, 200 MHz) δ 3.45 (s, 3H), 3.54 (m, 2H), 3.95 (m, 1H), 5.01 (t, 1H), 7.66 (m, 2H), 7.88 (m, 1H), 8.46 (d, 1H, J=8).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10].Cl.[C:14](O)(=[O:16])[CH3:15]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:14](=[O:16])[CH3:15])=[CH:5][C:4]=1[C:9]([F:10])([F:11])[F:12]
Reactant: CC(=O)O
Reactant: COc1ccccc1C(F)(F)F
Agent: Cl
Product: COc1ccc(C(C)=O)cc1C(F)(F)F
Temperature: 0 °C

Procedure:
A solution 1-methoxy-2-(trifluoromethyl)benzene (3.52 g) was dissolved in glacial acetic acid (30 ml) and treated with boron trifluoride acetic acid complex (30 ml) and the resulting solution maintained at 55° for 48 hours. The solution was poured into dilute hydrochloric acid (100 ml) and ice (100 g) added and the mixture extracted with chloroform (2×200 ml). The combined organic extracts were washed with sodium bicarbonate solution (3×100 ml), then water (100 ml), dried and evaporated to dryness to give an oily black solid. This was chromatographed on silica (40 g) eluting with ether:light petroleum (bp.60°-80°) (1:4) to give a solid which was crystallised from light petroleum (bp.60°-80°) to give the title compound (0.3 g), m.p.56°-57°
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][C:14]=3[F:25])=[O:9])=[CH:4][CH:3]=1.[CH:28](O)=[O:29]>>[CH:28]([O:24][CH2:23][C:22]#[C:21][C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([F:25])[CH:15]=1)[N:12]=[CH:11][C:10]([C:8]([NH:7][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:27][CH:26]=1)=[O:9])=[C:19]2[OH:20])=[O:29]
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(C#CCO)cc2c1O
Reactant: O=CO
Product: O=COCC#Cc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 25 °C
Yield: 44 %

Procedure:
A solution of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Example No. 53 (0.15 g) in 6 mL formic acid is heated at 100° C. for 6 hours. Once the reaction is cooled to room temperature, it is partitioned between CH2Cl2 and water. The organic layer is washed with water, saturated NaHCO3, and water again. The organic layer is dried over MgSO4, filtered and concentrated under reduced pressure to give a residue which is crystallized with CH2Cl2 /hexanes to give the product (0.070 g, 44%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[C:4]([OH:9])=[N:5][CH:6]=[CH:7][CH:8]=1.OS(O)(=O)=O.[N+:17]([O-])([OH:19])=[O:18]>>[N+:17]([C:7]1[CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[C:4]([OH:9])=[N:5][CH:6]=1)([O-:19])=[O:18]
Reactant: Oc1ncccc1C(F)(F)F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cnc(O)c(C(F)(F)F)c1
Temperature: 26 °C
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
To an ice-cooled solution of 3-(trifluoromethyl)pyridin-2-ol (4 g, 24.53 mmol) in H2SO4 (26.1 mL, 491 mmol) was added nitric acid (1.206 mL, 27.0 mmol) dropwise. After 30 min, the ice bath was removed and the reaction was stirred at 26° C. for 10 h. The reaction mixture was added to 120 g ice. The resulting precipitate was collected by filtration, rinsed with additional H2O and air-dried to afford the first batch of product. Another crop of product was obtained after evaporating the mother liquor to less than 100 mL, cooling on an ice bath, and adding NaOH to adjust to pH=8. The mixture was extracted by EA (100 mL). The organic layer was dried and concentrated to give the product, which was combined with the first batch to yield a yellow solid of 5-nitro-3-(trifluoromethyl)pyridin-2-ol (2.63 g, 12.64 mmol, 51.5% yield): 1H NMR (400 MHz, CD3OD) δ: 8.86 (d, J=3.1 Hz, 1H), 8.55 (d, J=2.6 Hz, 1H); ES-LCMS m/z 209.0 (M+H).
Reaction SMILES: Cl[C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[F:18][C:19]([F:23])([F:22])[CH2:20][OH:21]>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:2]([O:21][CH2:20][C:19]([F:23])([F:22])[F:18])=[N:3][CH:4]=[C:5]([CH:9]=2)[C:6]([OH:8])=[O:7])=[CH:12][CH:13]=1
Reactant: O=C(O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Reactant: OCC(F)(F)F
Product: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 5c, using 6-chloro-5-(4-chloro-phenyl)-nicotinic acid and 2,2,2-trifluoro-ethanol as starting materials, MS (ISP) 330.3 (M−H).
Reaction SMILES: [S:1]([CH:13]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]([NH2:20])[CH2:14]1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[C:21](OC(=O)C)(=[O:23])[CH3:22].O>CO>[S:1]([CH:13]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]([NH:20][C:21](=[O:23])[CH3:22])[CH2:14]1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: NC1CCCCC(S[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)C1
Reactant: CC(=O)OC(C)=O
Solvent: CO
Solvent: O
Product: CC(=O)NC1CCCCC(S[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)C1

Procedure:
In one example, the primary amine group of compound B5 can optionally be acylated by contacting B5 with an excess of acetic anhydride in methanol containing a trace of water. Generally, this reaction is conducted at about 25° C. to about 30° C. for about 2 to about 24 hours to provide for 3-acetamidocycloheptyl 1-thio-β-galactopyranoside, C5.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:35])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][N:9]2[C:28](NCC(O)=O)=O)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.C[N:46]([C:48]([O:52]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+]>CN(C)C=O>[Cl:1][C:2]1[C:3]([F:35])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH2:10][N:9]2[CH2:28][C:48]([NH2:46])=[O:52])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C[C@@H]1CN(C(=O)NCC(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1CN(CC(N)=O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.37 h
Yield: 70.7 %

Procedure:
To a mixture rac-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-acetic acid (25.4 mg, 0.048 mmol, example 17) in N,N-dimethyl formamide (2.5 mL) was added DIPEA (44.5 mg, 0.344 mmol) and HATU (30.3 mg, 0.080 mmol). After it was stirred at rt for 22 min, ground ammonium chloride (6.6 mg, 0.12 mmol,) was added. After 3 hrs the reaction mixture was extracted with EtOAc, and washed with water, 10% ammonium chloride, saturated sodium bicarbonate, water, and saturated NaCl. The organic phase was separated, and dried over Na2SO4. The reaction mixture was then purified by flash column to give rac-2-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetamide (16.3 mg, 64.3%).
Reaction SMILES: [NH2:1][CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1)[C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[CH:9]2)=[O:4].[C:22]([O:26][C:27]([NH:29][CH2:30][C:31](O)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C1COCC1>[C:22]([O:26][C:27](=[O:28])[NH:29][CH2:30][C:31](=[O:32])[NH:1][CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1)[C:3](=[O:4])[NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[CH:9]2)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: NC(C(=O)Nc1ccc2[nH]ncc2c1)c1cccc(Cl)c1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCC(=O)NC(C(=O)Nc1ccc2[nH]ncc2c1)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of 2-amino-2-(3-chloro-phenyl)-N-(1H-indazol-5-yl)-acetamide (0.17 mmol) and tert-butoxycarbonylamino-acetic acid (0.17 mmol) in THF (2 mL) was added HOBt (0.18 mmol). The reaction mixture was cooled to 0° C. and EDC (0.18 mmol) was added and the reaction mixture was left to stir overnight. The reaction mixture was then concentrated in vacuo and the residue was was partitioned between EtOAc and brine. The organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with EtOAc:hexanes (80:20) to give the title compound in 55% yield.
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:54]=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[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][C:56]1[C:60]([S:61](Cl)(=[O:63])=[O:62])=[C:59]([CH3:65])[O:58][N:57]=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:54]=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[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:61]([C:60]2[C:56]([CH3:55])=[N:57][O:58][C:59]=2[CH3:65])(=[O:63])=[O:62])[CH2:49][CH2:48]1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc(C)c1S(=O)(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 17 %

Procedure:
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro-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-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 3,5-dimethylisoxazole-4-sulfonyl chloride as starting materials in 17% yield. LCMS for C29H32ClN8O4S (M+H)+: m/z=623.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[CH:5]=[C:6]([CH:8](O)[CH3:9])[CH:7]=1.C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCC>O1CCCC1>[Br:20][CH:8]([C:6]1[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[CH:3]=[C:2]([Cl:1])[CH:7]=1)[CH3:9]
Reactant: CC(O)c1cc(Cl)cc(-c2ccc(C#N)cc2)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(Br)c1cc(Cl)cc(-c2ccc(C#N)cc2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of (±)-3′-chloro-5′-(1-hydroxyethyl)biphenyl-4-carbonitrile (171 mg, 0.664 mmol) and carbon tetrabromide (264 mg, 0.796 mmol) in tetrahydrofuran (2 mL) at 0° C. was added triphenylphosphine (209 mg, 0.796 mmol). The resulting solution was stirred at room temperature for 45 min. The reaction was diluted with ca. 2 volumes of pentane and filtered to remove the undissolved solids which were discarded. The organics were concentrated and purified by column chromatography (3%→8% ethyl acetate/hexanes) to give 201 mg (94%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 7.74 (d, J=8.2 Hz, 2H), 7.66 (d, J=8.2 Hz, 2H), 7.50 (s, 1H), 7.47 (s, 2H), 5.18 (q, J=6.7 Hz, 1H), 2.06 (d, J=7.0 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ ppm 146.1, 143.8, 141.5, 135.4, 132.8, 127.9, 127.3, 127.1, 124.2, 118.6, 112.1, 47.4, 26.8.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][NH:26]C(=O)OC(C)(C)C)[CH:21]=4)[CH2:16][CH2:15][N:14]=3)[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][NH2:26])[CH:21]=4)[CH2:16][CH2:15][N:14]=3)[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Agent: Cl
Solvent: ClCCl
Product: NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Reaction time: 14 h
Yield: 77.9 %

Procedure:
After adding HCl dissolved in isopropanole (15 ml, 6 molar solution) to a solution of tert-butyl 2-(1-(1-(4-chlorophenyl)cyclobutyl)-3,4-dihydroisoquinolin-7-yloxy)ethylcarbamate (6.20 g, 13.6 mmol) in dichloromethane (200 ml) the mixture was stirred for 14 h. The resulting precipitate was removed by filtration and washed with diisopropylether. After drying the filtrate was dissolved in water and basified with 2N NaOH. Extraction with dichloromethane the combined organic layers were washed with water and saturated NaCl solution. Drying with MgSO4 and removal of the solvent gave 2-(1-(1-(4-chlorophenyl)cyclobutyl)-3,4-dihydroisoquinolin-7-yloxy)ethanamine (3.77 g, 10.6 mmol, 78%).
Reaction SMILES: [H][H].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]=[CH:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)[CH:4]=1>[Pd]>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=2)[CH:4]=1
Reactant: COC(=O)c1ccc(C=Cc2cccnc2)cc1
Reactant: [H][H]
Agent: [Pd]
Product: COC(=O)c1ccc(CCc2cccnc2)cc1
Yield: 93.7 %

Procedure:
Hydrogen gas was slowly bubbled through a vigorously stirred mixture of methyl 4-(2-(3-pyridyl)ethenyl)benzoate (952 mg, 3.98 mmol) and 10% palladium on carbon (95 mg) at room temperature for 4 h. The reaction mixture was filtered through Kieselguhr which was then washed with excess ethyl acetate. The combined organics were evaporated under reduced pressure to give methyl 4-(2-(3-pyridyl)ethyl)benzoate (900 mg, 94%) as an oil which crystallised on standing.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[C:4](=[O:13])[C:5](=[O:12])[NH:6]2.C(O)(=[O:16])C>C(OC(=O)C)(=O)C.O.[O-2].[O-2].[O-2].[Cr+6]>[Cl:1][C:2]1[C:3]2[C:4](=[O:13])[O:12][C:5](=[O:16])[NH:6][C:7]=2[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: O=C1Nc2cc(Cl)cc(Cl)c2C1=O
Reactant: CC(=O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=c1[nH]c2cc(Cl)cc(Cl)c2c(=O)o1
Yield: 72 %

Procedure:
To a stirred solution of 4,6-dichloro-1H-indole-2,3-dione (5.00 g, 23.2 mM) in acetic acid (21 mL) and acetic anhydride (21 mL) at 80° C. was added in small portions chromium trioxide (4.12 g, 41.3 mM). The temperature of the reaction mixture was maintained between 80°-90° C. during the addition of the chromium trioxide. After the addition was complete, the reaction mixture was diluted with water (100 mL) and then filtered to separate the precipitated solids. The solids were washed thoroughly with water and then dried to obtain the title compound as a yellow solid (4.13 g, 72%); MS(CI): 232 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:20](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH3:20])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Cl)cc(NC2CCOCC2)c1C
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1cc(Cl)cc(N(C)C2CCOCC2)c1C
Temperature: 80 °C
Yield: 65.2 %

Procedure:
To a stirred solution of methyl 5-chloro-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate (700 mg, 2.473 mmol) in acetonitrile (10 mL), cesium carbonate (1.61 g, 4.946 mmol) and methyl iodide (1.82 g, 0.8 ml, 12.36 mmol) were added; resulting reaction mass was heated at 80° C. for 13 h. On completion, reaction mass was cooled to room temperature and filtered, residue was washed with ethyl acetate and filtrate was concentrated and then purified by column chromatography to afford desired compound (480 mg, 65%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[C:24]([F:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[C:24]([F:28])[C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: Cc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)c(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f42) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:6][N:7]=[CH:8][C:9]1[S:19][C:12]2[N:13]=[CH:14][N:15]=[C:16]([S:17][CH3:18])[C:11]=2[CH:10]=1.CO[C:27]1[CH:28]=[C:29]([CH:42]=[CH:43][C:44]=1OC)[CH2:30][N:31]=[CH:32]C1SC2N=CN=CC=2C=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:6][N:7]1[C:8]([C:9]2[S:19][C:12]3[N:13]=[CH:14][N:15]=[C:16]([S:17][CH3:18])[C:11]=3[CH:10]=2)=[C:30]([C:29]2[CH:42]=[CH:43][CH:44]=[CH:27][CH:28]=2)[N:31]=[CH:32]1
Reactant: COc1ccc(CN=Cc2cc3cncnc3s2)cc1OC
Reactant: COc1ccc(CN=Cc2cc3c(SC)ncnc3s2)cc1OC
Product: COc1ccc(Cn2cnc(-c3ccccc3)c2-c2cc3c(SC)ncnc3s2)cc1OC
Yield: 55 %

Procedure:
The title compound was prepared in 55% yield using a procedure similar to the one described for example 6 above but starting from N-(3,4-dimethoxybenzyl)-N-{[4-(methylthio)thieno[2,3-d]pyrimidin-6-yl]methylidene}amine (intermediate 18) (76 mg), in place of N-(3,4-dimethoxybenzyl)-N-[thieno[2,3d]pyrimidin-6-ylmethylidene]amine (intermediate 14);
Reaction SMILES: Cl.CO.[N:4]1[N:8]2[CH2:9][CH2:10][NH:11][CH2:12][C:7]2=[CH:6][C:5]=1[CH2:13][OH:14].CS[C:17]1[S:18][CH2:19][CH2:20][N:21]=1>C(OCC)C>[S:18]1[CH2:19][CH2:20][N:21]=[C:17]1[N:11]1[CH2:10][CH2:9][N:8]2[N:4]=[C:5]([CH2:13][OH:14])[CH:6]=[C:7]2[CH2:12]1
Reactant: OCc1cc2n(n1)CCNC2
Reactant: CSC1=NCCS1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: OCc1cc2n(n1)CCN(C1=NCCS1)C2

Procedure:
Hydrogen chloride (2 mol/l) solution in diethyl ether (0.7 ml) was added to the methanol (20 ml) solution of (4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-methanol (1.08 g) and 2-methylsulfanyl-4,5-dihydrothiazole (1.03 g). The reaction mixture was refluxed for 4 days. The mixture was quenched with small amount of saturated potassium carbonate solution, dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure. The residue was applied to silica-gel column chromatography, then the column was eluted with 10% methanol in chloroform. The titled compound was obtained as a white solid (1.49 g, 89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.Cl.[Cl:20][CH2:21][C:22]1[C:23]([NH:34][CH2:35][CH3:36])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH3:33])=[CH:27][CH:26]=2.[Cl:37]CC1C(NCC)=NC2C(C=1)=CC(OC)=CC=2.[Li+].[OH-]>C1(C)C=CC=CC=1.C(Cl)Cl>[ClH:20].[ClH:37].[CH2:35]([NH:34][C:23]1[C:22]([CH2:21][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]=2[OH:18])=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:32][CH3:33])[CH:29]=2)[N:24]=1)[CH3:36]
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: CCNc1nc2ccc(OC)cc2cc1CCl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCc1nc(O)c(Cc2cc3cc(OC)ccc3nc2NCC)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 6 %

Procedure:
To a stirred solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35142 (250 mg, 1.01 mmol) in toluene (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-N-ethyl-6-methoxyquinolin-2-amine hydrochloride SLA 28166 (290 mg, 1.01 mmol) followed by a 2 N aq. LiOH solution (1.01 mL, 2.02 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 95:5) followed by a second purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 92:8) provided, after evaporation and drying, 25 mg of 4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.45 mL). The reaction mixture was stirred for 5 min at RT, concentrated at 40° C. under vacuum, to afford 4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol dihydrochloride 50 as a yellow solid (30 mg, 6% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:12][C:13](=O)[CH3:14])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:16][NH:17]C=O.CN.Cl>O.C(O)=O>[ClH:1].[CH3:16][NH:17][CH:13]([CH3:14])[CH2:12][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: CNC=O
Reactant: CC(=O)CC1(c2ccc(Cl)cc2)CCC1
Agent: CN
Agent: Cl
Solvent: O
Solvent: O=CO
Product: CNC(C)CC1(c2ccc(Cl)cc2)CCC1

Procedure:
The ketone prepared as described above (5.4 g) was mixed with N-methylformamide (18 ml), 98% formic acid (4 ml) and 25% aqueous methylamine (0.6 ml) and the mixture heated under reflux for sixteen hours. The mixture was poured into water and extracted with dichloromethane. The extract was washed, dried and evaporated to give a residue which was heated under reflux with concentrated hydrochloric acid (10 ml) for six hours. The mixture was evaporated to dryness and the residue dried by repeated addition and vacuum evaporation of an industrial methylated spirit/toluene mixture. The solid residue was recrystallised from propan-2-ol to give N-methyl-2-[1-(4-chlorophenyl)-cyclobutyl]-1-methylethylamine hydrochloride (m.p. 193°-194° C.) (Formula I R1, R2 =H; R3 =Me; R4 =H; R5 =4-Cl; R6 =H; R7 =Me; R8 =H).