Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[CH:31]1([NH2:41])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][CH2:32]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:41][CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33][CH2:32]1)=[O:29]
Reactant: COc1cc2c(c(OC)c1)C(Cc1ccc(OC)c(OC)c1)NCC2
Reactant: NC1CCCc2ccccc21
Reactant: O=C(Br)CBr
Product: COc1cc2c(c(OC)c1)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCCc3ccccc31)CC2

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1,2,3,4-tetrahydro-1-naphthylamine
Reaction SMILES: CS(OS(C)(=O)=O)(=O)=O.CCN(CC)CC.[CH2:17]([O:19][C:20]([C:22]1[C:23]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[C:24]([CH2:43][CH2:44][CH2:45]O)[N:25]2[C:30]=1[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH:28][C:27]([N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)=[N:26]2)=[O:21])[CH3:18].[Na+].[I-].[P:54]([O:61]CC)([O:58][CH2:59][CH3:60])[O:55][CH2:56][CH3:57]>C(Cl)Cl>[CH2:17]([O:19][C:20]([C:22]1[C:23]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[C:24]([CH2:43][CH2:44][CH2:45][P:54]([O:58][CH2:59][CH3:60])([O:55][CH2:56][CH3:57])=[O:61])[N:25]2[C:30]=1[C:29]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[CH:28][C:27]([N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)=[N:26]2)=[O:21])[CH3:18]
Reactant: CCOC(=O)c1c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCOCC3)nn2c1CCCO
Reactant: CCOP(OCC)OCC
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCOCC3)nn2c1CCCP(=O)(OCC)OCC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Methanesulfonic anhydride (136 mg, 0.78 mmol) and NEt3 (145 μL, 1.04 mmol) were added to a solution of 41 (125 mg, 0.26 mmol) in CH2Cl2 (15 mL) at 0° C. under a nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 30 min. and at ambient temperature for 8 h. The reaction mixture was diluted with CH2Cl2 (20 mL) and washed with saturated aqueous NaHCO3, brine, dried (MgSO4), filtered, and concentrated in vacuo to provide a yellow oil. A mixture of the oil (68.5 mg, 0.122 mmol) and NaI (183 mg, 1.22 mmol) in P(OEt)3 (5 mL) was heated at 120° C. for 24 h. The P(OEt)3 was removed in vacuo and the residue was purified by flash chromatography (silica gel, 0-4% MeOH/CH2Cl2) to provide the title compound. 1H NMR (DMSO-d6) δ 0.89 (t, J=7.2 Hz, 3H), 1.20 (m, 9H), 1.85 (m, 2H), 3.24 (m, 2H), 3.52 (m, 6H), 3.71 (m, 4H), 3.94 (m, 6H), 4.17 (q, J=7.1 Hz, 2H), 6.79 (s, 1H), 7.40 (m, 2H), 7.46 (m, 3H). Mass Spectrum (ESI+) m/e=602.2 (M+H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=2)[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:22]1[S:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1>C(OCC)(=O)C>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=2)[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:22]2[S:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCCCOc1cccc(CN2CCCCC2)c1
Reactant: Clc1nc2ccccc2s1
Solvent: CCOC(C)=O
Product: c1cc(CN2CCCCC2)cc(OCCCCCNc2nc3ccccc3s2)c1

Procedure:
5-(3-(Piperidinomethyl)phenoxy]pentylamine (0.8 g) and 2-chlorobenzthiazole (0.53 g) were fused at 140° C. for 3 hours. The cooled residue was subjected to medium pressure column chromatography on silica using ethyl acetate as eluant to give the title compound as an oil. This was converted to 2-[5-[3-piperidinomethyl)phenoxy]pentylamino]benzthiazole dihydrochloride (0.18 g), m.p. 140°-145° C. (recrystallised from ethanol/ether).
Reaction SMILES: [CH2:1]1[CH2:6]CCC[CH2:2]1.C1(C)C=C[C:10]([S:13](O)(=O)=O)=CC=1.[CH3:18][CH:19]([OH:23])[CH:20]([OH:22])[CH3:21].CCCC=S>O>[CH3:21][CH:20]1[CH:19]([CH3:18])[O:23][CH:2]([CH2:1][CH2:6][S:13][CH3:10])[O:22]1
Reactant: CC(O)C(C)O
Reactant: C1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CCCC=S
Solvent: O
Product: CSCCC1OC(C)C(C)O1
Reaction time: 0.5 h

Procedure:
Into a 100 ml reaction flask equipped with spin bar, reflux condenser, heating mantle and hot plate with magnetic stirring apparatus is placed 5 ml cyclohexane, 0.2 grams para-toluenesulfonic acid and 3.5 grams (0.04 moles) of 2,3-butanediol. Over a period of 30 minutes, 4.1 grams (0.04 moles) of 3-methylthiopropionaldehyde is added to the reaction mass. The reaction mass is then heated to reflux and refluxed for a period of 7 hours during which water of reaction is removed.
Reaction SMILES: [H][H].N[CH:4]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][CH2:14][CH2:13][C:12]=2[CH:16]=1)[C:5]([OH:7])=[O:6].N([O-])=[O:18].[Na+].N([O-])=O.[K+]>C(O)(=O)C>[OH:18][CH:4]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][CH2:14][CH2:13][C:12]=2[CH:16]=1)[C:5]([OH:7])=[O:6]
Reactant: O=N[O-]
Reactant: [H][H]
Reactant: NC(C(=O)O)c1ccc2c(c1)CCO2
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)C(O)c1ccc2c(c1)CCO2

Procedure:
The compound of formula 3 wherein W is a hydroxyl group may be prepared from the corresponding amine compound of formula 3, W is --NHR4 and R4 is hydrogen. One equivalent of α-amino(2,3-dihydro-5-benzofuranyl)acetic acid in a suitable acid such as hydrochloric, hydrobromic, sulfuric, phosphoric or acetic acid is reacted with 1 to 3 equivalents of an alkali metal nitrite such as sodium nitrite or potassium nitrite at a temperature of from 30° to 70° C. for from 2 to 8 hours to give the desired α-hydroxy(2,3-dihydro-5-benzofuranyl)acetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12](Cl)[N:13]=1)[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6].[CH3:15][O-:16].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([O:16][CH3:15])[N:13]=1)[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6]
Reactant: O=C(NC1CC1)c1cc(Cl)nc(Cl)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(=O)NC2CC2)cc(Cl)n1
Temperature: 105 °C

Procedure:
To a solution of 2,6-dichloro-N-cyclopropylisonicotinamide from the previous step (1 eq.) in methanol (0.2 M) was added sodium methoxide (6 eq.). The reaction vessel was sealed and the resulting solution was heated in the microwave at 105° C. for 30 min. The volatiles were removed in vacuo and the resulting residue was partitioned between sat. aq. NH4Cl and EtOAc. The organic layer was separated and washed further with brine. Drying over Na2SO4, filtration and concentration of the filtrate in vacuo afforded the title compound as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2([CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([CH2:17][CH2:18][OH:19])[C:11]([CH3:21])([CH3:20])[CH2:10]2)[NH:6][C:5]1=[O:22].[C:23]([C:27]1[CH:28]=[C:29]([CH2:38][CH2:39][C:40](OC)=[O:41])[CH:30]=[C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])[C:32]=1[OH:33])([CH3:26])([CH3:25])[CH3:24].[CH3:44][O-:45].[Na+]>C1(C)C(C)=CC=CC=1>[C:34]([C:31]1[CH:30]=[C:29]([CH2:38][CH2:39][C:40]([O:1][CH2:2][CH2:3][N:4]2[C:8](=[O:9])[C:7]3([CH2:14][C:13]([CH3:15])([CH3:16])[N:12]([CH2:17][CH2:18][O:19][C:40](=[O:41])[CH2:39][CH2:38][C:29]4[CH:28]=[C:27]([C:23]([CH3:25])([CH3:26])[CH3:24])[C:32]([OH:33])=[C:31]([C:34]([CH3:36])([CH3:37])[CH3:35])[CH:30]=4)[C:11]([CH3:21])([CH3:20])[CH2:10]3)[NH:6][C:5]2=[O:22])=[O:41])[CH:28]=[C:27]([C:23]([CH3:25])([CH3:24])[CH3:26])[C:44]=1[OH:45])([CH3:37])([CH3:35])[CH3:36]
Reactant: C[O-]
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CC1(C)CC2(CC(C)(C)N1CCO)NC(=O)N(CCO)C2=O
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CC(C)(C)c1cc(CCC(=O)OCCN2C(=O)NC3(CC(C)(C)N(CCOC(=O)CCc4cc(C(C)(C)C)c(O)c(C(C)(C)C)c4)C(C)(C)C3)C2=O)cc(C(C)(C)C)c1O

Procedure:
A mixture of 2.9 g of 3,8-bis(2-hydroxyethyl)-7,7,9,9-tetramethyl-2,4-dioxo-1,3,8-triazaspiro [4.5]decane, 6.4 g of methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate and 0.3 g of sodium methoxide was refluxed for 8 hours in 300 ml of xylene, while removing 250 ml of xylene together with methanol formed in situ. After completion of the reaction, xylene was evaporated from the reaction under reduced pressure and the resulting residue was recrystallized from ligroin, giving the desired compound in the form of white crystals melting at 178°-179° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[N:15][N:14]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])[C:13]=2[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:28]([O-])([O-])=O.[K+].[K+]>CO.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[N:15][N:14]([CH:17]([CH3:21])[C:18]([O:20][CH3:28])=[O:19])[C:13]=2[CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C(=O)O)n1nnc2ccc(OCc3ccccc3)cc21
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C(C)n1nnc2ccc(OCc3ccccc3)cc21

Procedure:
A mixture of 6-(benzyloxy)-α-methyl-1H-benzotriazole-1-acetic acid (36.6 g, 0.123 mole) and concentrated sulfuric acid (2.7 ml) in methanol is stirred at reflux temperature for 6 hours, cooled in an ice bath and treated with K2CO3 (25 g). The resulting mixture is stirred vigorously until a thick slurry results, diluted with methylene chloride and filtered. The filtrate is concentrated in vacuo to give a solid residue. Recrystallization of the residue from methanol affords the title product as a white solid, 27 g, mp 88°-91.5° C., identified by NMR and elemental analyses. Another 4.2 g (81.7% total yield) of the title product is obtained form the mother liquor.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:36]=[CH:35][C:25]2[N:26]([CH3:34])[C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]=2[CH:23]=1.Cl>O1CCOCC1.COCCO>[Cl:20][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:21][C:22]2[CH:36]=[CH:35][C:25]3[N:26]([CH3:34])[C:27](=[O:33])[CH2:28][CH2:29][C:30]([CH3:32])([CH3:31])[C:24]=3[CH:23]=2)=[N:3][CH:4]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: CN1C(=O)CCC(C)(C)c2cc(N)ccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: COCCO
Product: CN1C(=O)CCC(C)(C)c2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)ccc21
Yield: 19.9 %

Procedure:
Combined N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (85 mg, 0.251 mmol), 7-Amino-1,5,5-trimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (80 mg, 0.251 mmol), 4 N HCl in dioxane (80 ul) and 2-methoxyethanol (3 mL). Heated reaction to 120° C. for 4 hours. Added CH2Cl2/MeOH/NH4OH, evaporated off solvent and purified with normal phase chromatography eluting with 1% to 3% MeOH in CH2Cl2 to yield a yellow solid, N-{(1R,2R)-2-[5-Chloro-2-(1,5,5-trimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide (26 mg, 20%). mp 165° C.; LCMS: m/z=521.59 (M+H+), 1H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.68 (m, 2H), 7.25 (s, 1H), 7.06 (d, 1H, J=8.6 Hz), 6.06 (d, 1H, J=6.6 Hz), 5.73 (d, 1H, J=7.3 Hz), 3.83 (m, 1H), 3.26 (s, 3H), 2.85 (s, 3H), 2.11 (m, 7H), 1.80 (s, 2H), 1.30 (m, 10H).
Reaction SMILES: [Br:1]Br.[CH:3]([S:6][C:7]1[CH:11]=[C:10]([Si](C)(C)C)[O:9][C:8]=1[C:16]([NH:18][C:19]1[NH:23][N:22]=[N:21][N:20]=1)=[O:17])([CH3:5])[CH3:4].O>C(Cl)(Cl)Cl.C(O)(=O)C>[Br:1][C:10]1[O:9][C:8]([C:16]([NH:18][C:19]2[NH:23][N:22]=[N:21][N:20]=2)=[O:17])=[C:7]([S:6][CH:3]([CH3:5])[CH3:4])[CH:11]=1
Reactant: BrBr
Reactant: CC(C)Sc1cc([Si](C)(C)C)oc1C(=O)Nc1nnn[nH]1
Solvent: CC(=O)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)Sc1cc(Br)oc1C(=O)Nc1nnn[nH]1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A solution of 3.1 g (19.5 mmol, 1.6 equiv) of bromine in 7 mL of chloroform is added dropwise to a room temperature solution of 3.98 g (12.22 mmol) of 3-isopropylthio-5-trimethylsilyl-N-1H-tetrazol-5-yl-2-furancarboxamide in 13 mL of chloroform and 20 mL of glacial acetic acid under nitrogen atmosphere. The resulting mixture is stirred at room temperature for 23 hours then poured onto 200 mL of water. The aqueous mixture is extracted with ethyl acetate (3x). The combined extracts are washed with 10% aqueous sodium thiosulfate and saturated aqueous sodium chloride, dried over sodium sulfate and concentrated in vacuo to give a yellow solid. Recrystallization from isopropanol/water gave 1.58 g (4.06 g theo., 38%) of the desired product as a yellow solid; mp 200°-210° C. (dec).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Br:14])(=O)=O.[CH2:15]([NH2:20])[CH2:16][CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].O1CCCC1>C(OCC)(=O)C.O>[Br:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH2:7][CH2:6][NH:20][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCN
Reactant: CS(=O)(=O)OCCc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCNCCc1ccccc1Br
Reaction time: 0.08 h

Procedure:
7 g of 2-(2-bromophenyl)ethyl methanesulfonate, 14.5 cm3 of 1-pentanamine, 17.33 g of potassium carbonate and 200 cm3 of tetrahydrofuran are stirred at a temperature between 65° C. and 70° C. under an inert atmosphere for 72 h. The reaction mixture is brought to 30° C. in order to be poured over a mixture of water, ice and ethyl acetate. The phases are stirred for 5 min, then are separated. The aqueous phase is extracted 3 times with ethyl acetate. The organic phases are combined, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). The 6.6 g of oil obtained are purified by flash chromatography over silica (column: 200 g; particle size: 15-40 μm; eluent: 95% dichloromethane/5% methanol to 90% dichloromethane/10% methanol gradient). After concentrating the fractions under reduced pressure, 4.56 g of N-[2-(2-bromophenyl)ethyl]pentan-1-amine are obtained in the form of a white oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:14]=[CH:15][C:16]([F:20])=[C:17]([CH:19]=3)[NH2:18])[C:8]([CH3:12])=[N:9]2)=[CH:4][N:3]=1.[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][NH:28][CH3:29])=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CCOC(C)=O>[NH2:18][C:17]1[CH:19]=[C:13]([C:7]2[C:8]([CH3:12])=[N:9][C:10]3[C:5]([CH:6]=2)=[CH:4][N:3]=[C:2]([N:28]([CH2:27][C:26]2[CH:30]=[CH:31][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[CH3:29])[CH:11]=3)[CH:14]=[CH:15][C:16]=1[F:20]
Reactant: Cc1nc2cc(Cl)ncc2cc1-c1ccc(F)c(N)c1
Reactant: CNCc1ccc(OC)cc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN(C)c2cc3nc(C)c(-c4ccc(F)c(N)c4)cc3cn2)cc1
Temperature: 170 °C
Yield: 67.6 %

Procedure:
Treat a solution of 5-(7-chloro-2-methyl-1,6-naphthyridin-3-yl)-2-fluoroaniline (0.353 g, 1.227 mmol) and 4-methoxy-N-methylbenzylamine (0.371 g, 2.454 mmol) in NMP (6 mL) in a sealed tube with N,N-diispropylethylamine (DIEA) (0.429 mL, 2.454 mmol), sparge with argon and heat at 170° C. overnight. Add additional 4-methoxy-N-methylbenzylamine (0.371 g, 2.454 mmol) and heat at 185° C. for 24 h. Add more 4-methoxy-N-methylbenzylamine (0.15 g, 1 mmol) and heat the mixture overnight at 185° C. Cool to RT, dilute with EtOAc and wash with satd. NaHCO3, water, and then brine. Dry the organics over MgSO4, concentrate to dryness and purify via silica gel chromatography (EtOAc/Hex) to afford the title compound (334 mg, 68%). 1H NMR (400 MHz, DMSO-d6): δ 8.95 (s, 1H), 7.95 (s, 1H), 7.15 (d, J=8.4 Hz, 2H), 7.05 (dd, J=11.5, 8.2 Hz, 1H), 6.85 (m, 2H), 6.78 (dd, J=8.8, 2.3 Hz, 1H), 6.71 (s, 1H), 6.54 (ddd, J=8.2, 4.4, 2.2 Hz, 1H), 5.24 (s, 2H), 4.85 (s, 2H), 3.69 (s, 3H), 3.08 (s, 3H), 2.47 (s, 3H); MS (ESI) m/z: 403.2 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][NH2:26]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:26][CH3:25])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: CN
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: CNC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3C)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 74 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and methanamine 1H NMR (400 MHz, DMSO-d6) δ ppm 2.36 (s, 3 H) 2.76 (d, J=4.55 Hz, 3 H) 7.59 (dd, J=7.96, 1.39 Hz, 1 H) 7.66 (s, 1 H) 7.71 (d, J=7.83 Hz, 1 H) 8.11 (br. s., 1 H) 8.33 (d, J=6.32 Hz, 2H) 8.61 (d, J=4.55 Hz, 1 H) 8.79-8.89 (m, 1 H) 12.66-13.53 (m, 1 H). MS m/z [M+H]+334.1.
Reaction SMILES: [CH2:1]([O:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:15](Cl)(=[O:19])[C:16](Cl)=O.[CH3:21][N:22]([CH3:25])C=O>ClCCl>[CH2:10]([O:9][CH:1]([O:19][CH2:15][CH3:16])[CH2:25][N:22]([CH2:21][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:12](=[O:14])[CH2:11][CH2:10][O:9][CH2:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[CH3:11]
Reactant: CN(C)C=O
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCOCCc1ccccc1
Solvent: ClCCl
Product: CCOC(CN(CCc1ccccc1)C(=O)CCOCCc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Phenethyloxypropanoic acid (0.34 g) was dissolved in dichloromethane (20 mL) and treated with oxalyl chloride (0.32 g) and a drop of dimethylformamide at ambient temperature. The resultant solution was stirred at ambient temperature for 2 hours. The solution was then concentrated and azeotroped with dichloromethane (2×20 mL). The collected residue was dissolved in dichloromethane and added, portionwise, to a stirred solution of 2,2-diethoxy-N-phenethyl-ethanamine (0.41 g) and triethylamine (0.6 mL), dissolved in dichloromethane (20 mL), at ambient temperature. The resultant solution was stirred at ambient temperature for 2 hours. The mixture was then concentrated, taken up in ethyl acetate (50 mL), washed with water (2×25 mL), washed with brine (50 mL), dried over anhydrous magnesium sulphate, filtered and concentrated to give the sub-titled compound (0.53 g) as a viscous oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.[H][H]>C(O)C.[Pd]>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: O=C(O)/C=C/c1ccc(Cn2ccnc2)c(Cl)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=C(O)CCc1ccc(Cn2ccnc2)c(Cl)c1

Procedure:
A mixture of (E)-3-[3-chloro-4-(imidazol-1-ylmethyl)phenyl]prop-2-enoic acid hydrochloride (0.07 g) and 5% palladium on barium sulphate (0.01 g) in ethanol was stirred under an atmosphere of hydrogen until the theoretical amount of hydrogen had been consumed. The catalyst was then filtered off (Hyflo) and the reaction mixture was concentrated to affored a colourless oil. N.M.R. spectroscopy of the product showed that it was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]3)=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[CH:30]2.Cl>CC(O)CCC.C(O)(C)C>[ClH:1].[C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]1)[N:5]=[CH:4][CH:3]=[C:2]2[NH:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[CH:30]2)#[N:13]
Reactant: N#Cc1cc2c(Cl)ccnc2cc1OCCCN1CCS(=O)(=O)CC1
Reactant: Nc1ccc2[nH]ccc2c1
Agent: Cl
Solvent: CCCC(C)O
Solvent: CC(C)O
Product: N#Cc1cc2c(Nc3ccc4[nH]ccc4c3)ccnc2cc1OCCCN1CCS(=O)(=O)CC1
Temperature: 120 °C
Yield: 96.7 %

Procedure:
A solution of 4-chloro-6-cyano-7-(3-(1,1-dioxothiomorpholino)propoxy)quinoline (80 mg, 0.21 mmol) and 5-aminoindole (33 mg, 0.25 mmol) in 2-pentanol (2.5 ml) containing 6.2N HCl in isopropanol (40 μl) was heated at 120° C. for 3 hours. After cooling, the solid was collected by filtration, washed with isopropanol followed by ether and dried under vacuum to give 6-cyano-7-(3-(1,1-dioxothiomorpholino)propoxy)-4-(indol-5-ylamino)quinoline hydrochloride (104 mg, 90%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[O:11][CH:12]([C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1)[CH2:13][CH2:14][CH2:15][OH:16].C(N(CC)CC)C.O>C(Cl)Cl>[CH3:1][S:2]([O:16][CH2:15][CH2:14][CH2:13][CH:12]([C:17]1[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=1)[O:11][C:10]1[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:8]([O:7][CH3:6])[CH:9]=1)(=[O:4])=[O:3]
Reactant: COc1ccc(OC(CCCO)c2ccc(C#N)cc2)cc1OC
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(OC(CCCOS(C)(=O)=O)c2ccc(C#N)cc2)cc1OC
Yield: 100 %

Procedure:
A solution of methanesulfonyl chloride (3.4 mL, 5.0 g, 44 mmol) in DCM (15 mL) was added slowly to a cooled (−5° C.) mixture of 4-[1-(3,4-dimethoxyphenoxy)-4-hydroxybutyl]benzonitrile (see step (ii) above; 11 g, 34 mmol) and triethylamine (7 mL, 5.2 g, 50.6 mmol) in DCM (50 ML), during which addition the temperature did not rise above 2° C. Stirring was continued at between 0 and 5° C. for a further 2 h before water was added. The resulting organic layer was separated, and washed with water, separated again and then dried to give the subtitle compound in 100% yield.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[NH:7][N:6]=1)(=[O:3])[CH3:2].[Br:14]Br.O>C(O)(=O)C>[C:10]([C:8]1[NH:7][N:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[C:9]=1[Br:14])([CH3:13])([CH3:12])[CH3:11]
Reactant: BrBr
Reactant: CC(=O)Nc1cc(C(C)(C)C)[nH]n1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1n[nH]c(C(C)(C)C)c1Br
Temperature: 60 °C
Yield: 80 %

Procedure:
4.5 g (0.025 mole) of 3-acetylamino-5-t-butylpyrazole prepared in Example 3 was dissolved in 20 ml of acetic acid, and 4.0 g of bromine was added dropwise thereto while stirring. The reaction solution was heated at 60° C. for one hour and then cooled. 50 ml of water was added to the resulting solution and allowed to stand, whereby crystals were precipitated. The crystals were collected by filtration, washed with water and then dried to obtain 5.2 g of 5-t-butyl-4-bromo-3-acetylaminopyrazole. This product was recrystallized from methanol and found to have a melting point of 234° to 235° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[C:4]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[N:3][CH:2]=1.N1C=CN=C1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN(C=O)C.O>[Si:26]([O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][NH:11][C:4]2[C:5]3[C:10](=[N:9][CH:8]=[CH:7][N:6]=3)[N:1]=[CH:2][N:3]=2)=[CH:15][CH:16]=1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: Oc1ccc(CCNc2ncnc3nccnc23)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CCNc2ncnc3nccnc23)cc1
Temperature: 2.5 °C
Reaction time: 20 h
Yield: 92.1 %

Procedure:
4-[2-(Pteridin-4-ylamino)-ethyl]-phenol (1.0 g, 3.7 mmol) was partially dissolved in dry DMF (75 mL), treated with imidazole (630 mg, 9.3 mmol), cooled to 0-5° C. and treated dropwise with a solution of t-butyldimethylsilyl chloride (680 mg, 4.5 mmol) in DMF (15 mL). After warming to 25° C. the mixture was stirred for 20 h, diluted with H2O (75 mL) and extracted with EtOAc. The extracts were washed with H2O, brine, dried (Na2SO4), filtered and concentrated in vacuo to give {2-[4-(tert-butyldimethylsilanyloxy)-phenyl]-ethyl}-pteridin-4-yl-amine (1.3 g) as a white solid: mp 164-165° C.; 1H NMR (300 MHz, CDCl3) δ 8.99 (s, 1H), 8.61 (s, 1H), 8.59 (s, 1H), 8.26 (d, J=5.9 Hz, 1H), 6.8-7.2 (m, 5H), 3.98 (t, J=6.2 Hz, 2H), 2.99 (t, 6.3 Hz, 2H), 1.02 (s, 6H), 0.18 (s, 9H).