Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33](O)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:36][C@H:37]1[C@H:41]([OH:42])[CH2:40][N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:38]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33]([NH:36][C@H:37]4[C@H:41]([OH:42])[CH2:40][N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:38]4)=[O:34])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](O)C1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3c(OCC4CC4)ccc4c3OCO4)c2n1COCC[Si](C)(C)C
Product: Cc1c(C(=O)N[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2O)c2ncnc(-c3c(OCC4CC4)ccc4c3OCO4)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c1) and commercially available tert-butyl(3R*,4R*)-3-amino-4-hydroxy-pyrrolidine-1-carboxylate the title compound is obtained as pale yellow foam.
Reaction SMILES: C1N2CN3CN(C2)CN1C3.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[OH:19].FC(F)(F)[C:22](O)=[O:23]>>[Cl:11][C:12]1[CH:17]=[C:16]([CH:15]=[C:14]([CH3:18])[C:13]=1[OH:19])[CH:22]=[O:23]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cccc(Cl)c1O
Agent: C1N2CN3CN1CN(C2)C3
Product: Cc1cc(C=O)cc(Cl)c1O
Temperature: 85 °C
Reaction time: 0.33 h
Yield: 35 %

Procedure:
Hexamethylenetetramine (19.60 g, 139.8 mmol) was added in portions to a solution of 2-chloro-6-methylphenol (20.00 g, 117.2 mmol) in trifluoroacetic acid (200 mL). There was a slight exotherm and effervescence was noted. The reaction mixture was heated in an oil-bath at 84-86° C. for 5 h, then it was cooled and evaporated (˜50° C., 0.2 mm). The residue was evaporated from hexane, then ice-water (500 mL) was added and the mixture was stirred for 20 min. Ether (100 mL) was added and the reaction was brought to approx. pH 5 by the careful portionwise addition of solid sodium hydrogen carbonate (49 g). The resulting mixture was extracted with ether (2×250 mL), and the ether layers were washed with brine, dried (MgSO4), filtered and concentrated to about 100 mL. The mixture was then left to crystallize over the weekend to give a solid which was filtered off and washed with ice-cold ether to give 3-chloro-4-hydroxy-5-methylbenzaldehyde (6.9 g, 35%) as a yellow solid. The mother liquor was evaporated and dichloromethane (30 mL) was added. The yellow solid was filtered off (2.9 g, 14%). The remaining solution was purified by HPLC (7% ethyl acetate/hexanes) to give a yellow solid (7.8 g, 39%). The overall yield was17.6 g (88%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[C:27]([O:31][C:32](=[O:42])[CH2:33][O:34][CH:35]1[CH2:40][CH2:39][CH:38](O)[CH2:37][CH2:36]1)([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[C:27]([O:31][C:32](=[O:42])[CH2:33][O:34][CH:35]1[CH2:40][CH2:39][CH:38]([I:25])[CH2:37][CH2:36]1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)COC1CCC(O)CC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COC1CCC(I)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triphenylphosphine (1.18 g, 4.49 mmol), imidazole (0.31 g, 4.49 mmol) and iodine (1.14 g, 4.49 mmol) are added to a solution of (4-hydroxy-cyclohexyloxy)-acetic acid tert-butyl ester (cis:trans=ca. 1:1) (0.86 g, 3.74 mmol) in a mixture of CH2Cl2 (10 ml)/CCl4 (20 ml) at 0° C. The cooling bath is removed and the reaction mixture is stirred at room temperature for 18 hours. Saturated aq. Na2S2O3 (10 ml) is added and the mixture is stirred for 15 minutes. The layers are separated and the aqueous layer is re-extracted with CH2Cl2 (×3). The combined organic extracts are washed with brine (×1), dried (Na2SO4), filtered and concentrated. Purification by chromatography on silica gel, eluting with 5% ethyl acetate in isohexane, gives the product.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2([OH:19])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.CCN(CC)CC>C(Cl)Cl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([C:13]2([OH:19])[CH2:18][CH2:17][N:16]([CH2:25][C:24]3[CH:27]=[CH:28][C:21]([F:20])=[CH:22][CH:23]=3)[CH2:15][CH2:14]2)=[O:12])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: Fc1ccc(CBr)cc1
Reactant: CC(C)c1ccc(NC(=O)C2(O)CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1ccc(NC(=O)C2(O)CCN(Cc3ccc(F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 25.6 mg (0.09 mmol) 4-Hydroxy-piperidine-4-carboxylic acid (4-isopropyl-phenyl)-amide, 19.9 mg (0.1 mmol) 4-fluorobenzyl bromide and 27 mg (0.27 mmol) NEt3 in 2 ml DCM was stirred for 3 h at room temperature. The mixture was concentrated and subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3 to yield after evaporation of the product containing fractions 5.4 mg (17%) of the title compound as off-white solid. MS (m/e): 371.3 [(M+H)+].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[S:24][CH:25]=[CH:26][C:27]=2[Cl:28])[O:21][CH:22]=1>>[Cl:28][C:27]1[CH:26]=[CH:25][S:24][C:23]=1[C:20]1[O:21][CH:22]=[C:18]([CH2:17][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)=[CH:4][CH:3]=2)[N:19]=1
Reactant: ClCc1coc(-c2sccc2Cl)n1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: Clc1ccsc1-c1nc(COc2ccc(CCCn3ccnc3)cc2)co1
Yield: 77 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(3-chloro-2-thienyl)oxazole to give 2-(3-chloro-2-thienyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 77%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 69-70° C.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([OH:23])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1.[CH2:34](Br)[CH2:35][CH2:36][CH3:37]>>[CH2:34]([O:23][C:20]1[CH:21]=[C:22]2[C:17]([CH2:16][CH2:15][CH2:14][CH:13]2[C:11]([N:10]([CH2:9][C:6]2[CH:7]=[CH:8][C:3]([N:2]([CH3:33])[CH3:1])=[CH:4][CH:5]=2)[C:24]2[CH:25]=[CH:26][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:29]=2)=[O:12])=[CH:18][CH:19]=1)[CH2:35][CH2:36][CH3:37]
Reactant: CCCCBr
Reactant: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3ccc(O)cc32)cc1
Product: CCCCOc1ccc2c(c1)C(C(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(C(C)C)cc1)CCC2

Procedure:
By the reaction and treatment in the same manner as in Example 110 using N-[(4-dimethylaminophenyl)methyl]-7-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.5 g) and butyl bromide (0.18 mL) as starting materials, 7-butoxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.15 g) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14](Cl)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].[CH:16]1([CH2:19][O:20][C:21]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=2B2OC(C)(C)C(C)(C)O2)[CH2:18][CH2:17]1>>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([C:22]3[CH:23]=[C:24]([F:29])[C:25]([O:27][CH3:28])=[CH:26][C:21]=3[O:20][CH2:19][CH:16]3[CH2:18][CH2:17]3)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: COc1cc(OCC2CC2)c(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: CCOC(=O)c1c[nH]c2c(Cl)ncnc12
Product: CCOC(=O)c1c[nH]c2c(-c3cc(F)c(OC)cc3OCC3CC3)ncnc12

Procedure:
Starting from 4-chloro-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid ethyl ester and 2-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example A42) the title compound is obtained as pale yellow solid.
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[F:7][C:8]1[C:9]([C:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CC(O)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(O)C#Cc1c(F)ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2

Procedure:
Using Method C above, 1-pentyn-3-ol (28.5 mg, 0.34 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (50 mg, 0.135 mmol) (Starting Material 3 supra) using (Ph3P)2PdCl2 (9.5 mg) and CuI (2.6 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 6 h to give rac-(Z)-1,3-dihydro-5-fluoro-4-(3-hydroxy-1-pentynyl)-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 17 mg, 39%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:25]([OH:27])=O)[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][O:16][C:15]2=[O:24])[CH2:10][CH2:9]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:40][CH:41]([NH2:44])[CH2:42][OH:43]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:25]([NH:44][CH:41]([CH3:40])[CH2:42][OH:43])=[O:27])[CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][O:16][C:15]2=[O:24])[CH2:10][CH2:9]1
Reactant: CC(N)CO
Reactant: O=C(O)c1cnc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(CO)NC(=O)c1cnc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1

Procedure:
The title compound was prepared from the product of example 148 step (i) (0.14 g), carbonyldiimidazole (0.064 g) and DL-2-amino-1-propanol (0.05 g) using the method of example 115 step (i). Purification was by chromatography eluting with 20% ethyl acetate/isohexane. Yield 0.04 g as a solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:17])=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[F:18][C:19]1[CH:31]=[CH:30][C:22]([CH2:23][N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:21][CH:20]=1.C(N(CC)CC)C>C(#N)C>[F:18][C:19]1[CH:31]=[CH:30][C:22]([CH2:23][N:24]2[CH2:29][CH2:28][N:27]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([CH3:17])=[C:9]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[N:10]=4)[N:7]=3)[CH2:26][CH2:25]2)=[CH:21][CH:20]=1
Reactant: Fc1ccc(CN2CCNCC2)cc1
Reactant: Cc1c(-c2ccccc2)nc2ccc(Cl)nn12
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccccc2)nc2ccc(N3CCN(Cc4ccc(F)cc4)CC3)nn12
Temperature: 180 °C
Yield: 47 %

Procedure:
A solution of 6-chloro-3-methyl-2-phenylimidazo[1,2-b]pyridazine (1.00 g, 4.35 mmol) and 1-(4-fluorobenzyl)piperazine (Sigma-Aldrich, 1.54 g, 4.35 mmol) in acetonitrile (50 mL) containing triethylamine (13.0 mmol) is heated at 180° C. in the microwave for 5 hours. The reaction mixture is concentrated to dryness and then purified via chromatography (hexanes to EtOAc) to afford the title product (0.82 g, 81%) as an off-white solid: Rf 0.30 (EtOAc); LCMS (m/z)=402.4 [M+H]+, tR=1.74 min. (compound same as Example 134)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([OH:13])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[C:14](Cl)(=O)C(Cl)=O>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: O=C(O)c1cnc2cc(Br)ccn12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cnc2cc(Br)ccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 246.5 %

Procedure:
A 50 mL flask equipped with a reflux condenser and a nitrogen line was charged with 7-bromoimidazo[1,2-a]pyridine-3-carboxylic acid (1.00 g, 4.15 mmol), DCM (20 mL), oxalyl chloride (0.72 mL, 1.46 mmol), and chilled in a ice-water bath. Four drops of DMF were added to the reaction, and the flask was stirred at ambient temperature overnight. The reaction mixture was concentrated to dryness, chilled in an ice water bath, and 30 mL MeOH were added under a nitrogen atmosphere. The reaction mixture was stirred at ambient temperature overnight, concentrated to dryness, and re-suspended in saturated, aqueous sodium bicarbonate solution. The suspension was extracted with DCM and EtOAc, the combined organic extracts were dried over anhydrous sodium sulfate, and concentrated to afford the desired product (0.918 g) as a tan solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([SH:12])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].[CH2:13]([O:15][C:16](=[O:28])[CH:17]([C:23](OCC)=[O:24])[C:18](OCC)=[O:19])[CH3:14].[Sn](Cl)(Cl)(Cl)Cl>C(OCC)(=O)C>[CH2:13]([O:15][C:16]([C:17]1[C:18](=[O:19])[S:12][C:8]2[C:9]([C:23]=1[OH:24])=[CH:10][CH:11]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:7]=2)=[O:28])[CH3:14]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Reactant: CCCCOc1cccc(S)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CCCCOc1ccc2c(O)c(C(=O)OCC)c(=O)sc2c1
Temperature: 210 °C
Reaction time: 2 h
Yield: 6.6 %

Procedure:
3-Butoxy-benzenethiol (1.2 g, 6.58 mmol) was dissolved in 2-ethoxycarbonyl-malonic acid diethyl ester (2.1 mL, 9.87 mmol). Tin tetrachloride (26 μL, 0.224 mmol) was added and the reaction was sealed and heated to 210° C. After 2 h, the reaction was cooled and directly subjected to silica gel chromatography (5%-50% ethyl acetate in hexanes) to provide 7-butoxy-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid ethyl ester (140 mg, 7%). MS ESI(−) m/e: 321.249 (M−1).
Reaction SMILES: C([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH2:18][O:19][CH3:20])C1C=CC=CC=1>O1CCCC1>[OH:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH2:18][O:19][CH3:20]
Reactant: COCOc1cc(C=O)ccc1OCc1ccccc1
Solvent: C1CCOC1
Product: COCOc1cc(C=O)ccc1O
Yield: 50.8 %

Procedure:
4-Benzyloxy-3-methoxymethoxybenzaldehyde (32.60 g) 5% palladium on carbon (30.0 g) and tetrahydrofuran (500 mL) were subjected to catalytic reduction under a hydrogen atmosphere and atmospheric pressure. The catalyst was filtered off and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1:3, v/v) to give 4-hydroxy-3-methoxymethoxybenzaldehyde as a colorless oil (11.08 g, yield 51%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18](O)=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.S(Cl)(Cl)=O.[CH3:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH:28]([CH3:32])[NH:27]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18]([N:27]2[CH:28]([CH3:32])[CH2:29][CH2:30][CH2:31][CH:26]2[CH3:25])=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: CC1CCCC(C)N1
Reactant: O=C(O)c1cc(-c2ccccc2Cl)nc2ccccc12
Solvent: O=S(Cl)Cl
Product: CC1CCCC(C)N1C(=O)c1cc(-c2ccccc2Cl)nc2ccccc12

Procedure:
2-(2-Chlorophenyl)-quinoline-4-carboxylic acid (5.7 g) and thionyl chloride (15 ml) are heated under reflux for 1 hour. The thionyl chloride is evaporated off, the residue is taken up in toluene (40 ml) and the toluene is also evaporated off. Toluene (50 ml) is then added to the residue obtained, followed by the dropwise introduction of 2,6-dimethylpiperidine (6.78 g), with stirring. The mixture is stirred for 1 hour at ambient temperature, the precipitate is filtered off and the filtrate is evaporated under reduced pressure. The residue is taken up in water (50 ml) and chloroform (50 ml). The organic phase is decanted and the aqueous phase is extracted with chloroform (50 ml). The organic phases are combined, dried over magnesium sulphate and evaporated under reduced pressure.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:6][CH2:7][C:8]#[N:9])#[N:2].[H][H]>O1CCOCC1>[NH2:2][CH2:1][CH2:3][CH2:4][N:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:6][CH2:7][CH2:8][NH2:9]
Reactant: CCCCCCCCCCCCN(CCC#N)CCC#N
Reactant: [H][H]
Solvent: C1COCCO1
Product: CCCCCCCCCCCCN(CCCN)CCCN
Yield: 103.7 %

Procedure:
19.7 g of N,N-bis(2-cyanoethyl)dodecylamine, 1.97 g of RaneyCo, 80 ml of 1,4-dioxane was charged to an autoclave, and hydrogen addition reaction was carried out by supplying hydrogen at an initial pressure of 8.2 MPa at 120° C. for 2 hours. After removing a catalyst by filtration, the obtained filtrate was concentrated and dried to obtain 21.0 g of a target compound as pale red oily product. The same procedure was carried out to obtain a total amount of 40.8 g of the target compound as a pale red oily product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]([CH3:17])[CH2:9][C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]#[CH:29])=[CH:24][CH:23]=1)[CH3:20].ClCCl>C(#N)C.[Cu]I>[C:1]([O:5][C:6](=[O:18])[NH:7][CH:8]([CH3:17])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:29]#[C:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH2:19][CH3:20])=[CH:23][CH:24]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccc(OCC)cc1
Reactant: CC(Cc1ccc(I)cc1)NC(=O)OC(C)(C)C
Agent: [Cu]I
Solvent: ClCCl
Solvent: CC#N
Product: CCOc1ccc(C#Cc2ccc(CC(C)NC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C

Procedure:
To 5.00 g (13.8 mmol) [2-(4-iodo-phenyl)-1-methyl-ethyl]-carbamic acid tert-butyl ester (I52.5) and 2.02 g (13.8 mmol) 4-ethoxyphenylacetylene in 80 mL ACN are added 4.46 mL (32.2 mmol) TEA, 135.6 mg (0.17 mmol) [1,1′-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) complex with dichloromethane and 32.3 mg (0.17 mmol) CuI, and the reaction mixture is stirred at r.t. over night. The precipitate is filtered and washed with ACN. The resulting crude product is purified by column chromatography (CyH/EtOAc 100/0→90/10).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:3]=1[CH2:4][O:5][CH2:6][C@H:7]1[O:11][CH:10]([O:12][CH3:13])[C@H:9](CC([O-])=O)[C@H:8]1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27].C[O-:34].[Na+]>CO>[Cl:1][C:2]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:3]=1[CH2:4][O:5][CH2:6][C@H:7]1[O:11][CH:10]([O:12][CH3:13])[C@H:9]([OH:34])[C@@H:8]1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[Cl:27]
Reactant: C[O-]
Reactant: COC1O[C@H](COCc2ccc(Cl)cc2Cl)[C@H](OCc2ccc(Cl)cc2Cl)[C@H]1CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: COC1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@H]1O
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To (3R,4R,5R)-5-(2,4-dichlorobenzyloxymethyl)-4-(2,4-dichlorobenzyloxy)-2-methoxy-tetrahydrofuran-3-acetate (10 g, 19.1 mmol) in MeOH (150 ml) is added a solution of 30% NaOMe in MeOH (5.37 ml, 28.6 mmol) and the reaction is stirred at 20° C. for 30 mins. The reaction mixture is concentrated and dissolved in IPAC (100 ml), washed with 1 N HCl solution (50 mL) and water (50 mL) and concentrated to give (3R,4S,5R)-5-(2,4-Dichlorobenzyloxymethyl)-4-(2,4-dichlorobenzyloxy)-2-methoxy-tetrahydrofuran-3-ol as a yellowish oil. The obtained crude compound is used for the next step without further purification. 1H-NMR (CDCl3, 400 MHz): δ 7.43 (d, J=8.1 Hz, 1H), 7.35-7.31 (m, 3H), 7.23 (dd, J=2.1, 4.0 Hz, 1H), 7.21-7.10 (dd, J=2.1, 4.0 Hz, 1H), 4.92 (d, J=4.6 Hz 1H), 4.77 (d, J=13.4 Hz, 1H), 4.68 (d, J=13.4 Hz, 1H); 4.60 (d, J=13.0 Hz, 1H), 4.56 (d, J=13.0 Hz, 1H), 4.25 (q, J=4.0 Hz, 1H), 4.19 (dd, J=6.8, 4.8 Hz, 1H) 3.86 (dd J=6.9, 7.0 Hz 1H), 3.60 (d, J=10.5 Hz, 2H), 3.48 (s, 3H); 13C-NMR (CDCl3, 100 MHz): δ 134.2, 134.1, 133.9, 133.5, 133.4, 129.9, 129.8, 129.1, 129.08, 127.11, 127.08, 102.8, 81.6, 77.4, 72.0, 70.8, 70.0, 69.5, 55.6 (one carbon overlapped); ESI-MS: calcd. for C20H20Cl4O5 (M+NH4+, 480.0). found: 498.0.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1Br)([O-])=O.Br[C:12]1[N:17]=[CH:16][CH:15]=[CH:14][N:13]=1>>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:12]1[N:17]=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: Brc1ncccn1
Reactant: O=[N+]([O-])c1ccccc1Br
Product: Nc1ccccc1-c1ncccn1

Procedure:
2-Nitrobromobenzene (2.02 g) and 2-bromopyrimidine (0.80 g) were coupled as in Example 83, and the product reduced as in Example 64 to give 2-(2-aminophenyl)pyrimidine. This was reacted with CMI under conditions described in the general procedure for CMI couplings to give N-(4,5-dihydro-1H-imidazol-2-ylmethyl)-2-(2-pyrimidinyl)aniline.
Reaction SMILES: [H-].[Na+].[NH2:3]/[C:4](/[C:11]([F:14])([F:13])[F:12])=[CH:5]\[C:6]([O:8]CC)=O.[Cl:15][C:16]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][C:17]=1[C:18]([O:20][C:21]([CH3:28])([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:19].Cl>C(OCC)C.CN(C)C=O>[Cl:15][C:16]1[CH:32]=[CH:31][C:30]([N:33]2[C:6](=[O:8])[CH:5]=[C:4]([C:11]([F:12])([F:13])[F:14])[NH:3][C:34]2=[O:35])=[CH:29][C:17]=1[C:18]([O:20][C:21]([CH3:27])([CH3:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:19]
Reactant: CCOC(=O)C(C)(C)OC(=O)c1cc(N=C=O)ccc1Cl
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)C(C)(C)OC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)ccc1Cl
Temperature: -5 °C

Procedure:
4.9 g of sodium hydride (50% dispersion in white oil) are added to 120 ml of dimethylformamide while stirring and the mixture is cooled to -5° C. At this temperature a solution of 22.4 g of ethyl 3-amino-4,4,4-trifluorocrotonate in 180 ml of diethyl ether is added dropwise during 30 minutes. The reaction mixture is stirred at room temperature for one hour and thereafter cooled to -65° C. A solution of 28 g of ethyl 2-(2-chloro-5-isocyanato-benzoyloxy)-2-methylpropionate in 100 ml of dimethylformamide is now added dropwise during 30 minutes. The reaction mixture is stirred at -65° C. for 2 hours; thereafter it is left to warm to room temperature. The reaction mixture is introduced into 300 ml of 1N hydrochloric acid at 0° C. The mixture is extracted twice with 300 ml of ethyl acetate each time. The organic phases are back-washed once with 200 ml of water and once with 200 ml of saturated sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue is recrystallized from ethyl acetate/n-hexane. There is obtained ethyl 2-{2-chloro-5-[3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2H)-pyrimidinyl]-benzoyloxy}-2-methylpropionate, m.p. 176°-177° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:20]3[N:21]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)=[CH:27][CH:26]=4)[N:23]=[C:19]3[CH:18]=[CH:17][CH:16]=2)[CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[NH2:7][CH2:8][C:9]1[CH:10]=[C:11]([C:15]2[N:20]3[N:21]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]5[CH2:35][CH2:36][CH2:37][CH2:38]5)=[CH:27][CH:26]=4)[N:23]=[C:19]3[CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Reaction time: 2 h

Procedure:
(3-{2-[4-(2-Pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-benzyl)-carbamic acid tert-butyl ester (1.78 g, 3.37 mmol) was dissolved in dichloromethane (20 ml). Trifluoroacetic acid (20 ml) was added and the reaction was stirred for 2 hours. Neutralisation was performed by adding saturated aqueous sodium hydrogencarbonate. The aqueous phase was extracted twice with dichloromethane, and the combined organics washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the desired compound. Yield: 460 mg, 32%. 50 mg was purified by preparatory HPLC.