Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=2[C:24]#[C:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C=O.[C:34]([BH3-])#N.[Na+].Cl.[C:39]([OH:46])(=[O:45])/[CH:40]=[CH:41]/[C:42]([OH:44])=[O:43]>CO.CC(O)C>[C:39]([OH:46])(=[O:45])/[CH:40]=[CH:41]/[C:42]([OH:44])=[O:43].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH3:34])[CH2:14][CH2:15][C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=2[C:24]#[C:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C#Cc2ccccc2)c(CCNCCc2ccc(OC)c(OC)c2)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC(C)O
Solvent: CO
Product: COc1ccc(C#Cc2ccccc2)c(CCN(C)CCc2ccc(OC)c(OC)c2)c1
Reaction time: 6 h

Procedure:
A solution of 1.7 g (4.09 mmole) of N-[2-(3,4-dimethoxyphenyl)ethyl]-5-methoxy-2-(phenylethynyl)benzeneethanamine in 30 ml of methanol was treated with 0.85 ml (10.2 mmole) of 37% aqueous formaldehyde solution and 0.95 g (15.1 mmole) of sodium cyanoborohydride. The mixture was stirred under an atmosphere of nitrogen for six hours, methanolic hydrogen chloride was added to pH 1, and the mixture stirred overnight at room temperature. The solvent was evaporated in vacuo and the residue partitioned between 3N sodium hydroxide and ether. The organic phase was separated, washed with brine, dried over anhydrous potassium carbonate and evaporated in vacuo to yield crude free base of the product. The free base was combined with one equivalent of fumaric acid in 2-propanol and allowed to crystallize overnight with cooling. Filtering afforded 1.73 g of nearly pure product which was recrystallized from a mixture of 95% ethanol and 2-propanol to yield pure N-[2-(3,4-dimethoxyphenyl)ethyl]-5-methoxy-N-methyl-2-(phenylethynyl)benzeneethanamine (E)-2-butenedioate (1:1 ), mp 152.5°-154° C.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:8]([CH:9]2[CH2:11][CH2:10]2)[C:7]2[C:12]([C:16]([NH:18][CH3:19])=[O:17])=[CH:13][CH:14]=[CH:15][C:6]=2[N:5]=1)[CH3:3].Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]([NH2:27])[C:22]=1[C:28]([F:31])([F:30])[F:29].CCN(C(C)C)C(C)C>C(O)CCC>[NH2:27][C:23]1[N:24]=[CH:25][N:26]=[C:21]([NH:1][C@H:2]([C:4]2[N:8]([CH:9]3[CH2:10][CH2:11]3)[C:7]3[C:12]([C:16]([NH:18][CH3:19])=[O:17])=[CH:13][CH:14]=[CH:15][C:6]=3[N:5]=2)[CH3:3])[C:22]=1[C:28]([F:31])([F:30])[F:29]
Reactant: CNC(=O)c1cccc2nc([C@H](C)N)n(C3CC3)c12
Reactant: Nc1ncnc(Cl)c1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CNC(=O)c1cccc2nc([C@H](C)Nc3ncnc(N)c3C(F)(F)F)n(C3CC3)c12
Temperature: 120 °C
Reaction time: 42 h

Procedure:
A mixture of (S)-2-(1-aminoethyl)-1-cyclopropyl-N-methyl-1H-benzo[d]-imidazole-7-carboxamide (Prepared in Example 20, 150 mg, 0.581 mmol), 6-chloro-5-(trifluoromethyl)pyrimidin-4-amine (172 mg, 0.871 mmol) and 1,1′-dimethyltriethylamine (202 μL, 1.161 mmol) in n-butanol (2 mL) was stirred at 120° C. After 42 h, the mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by column chromatography on a silica gel column using 0 to 10% gradient of MeOH in DCM-EtOAc (1:1) with 0.2% NH4OH as eluent to give 2-((1S)-1-((6-amino-5-(trifluoromethyl)-4-pyrimidinyl)amino)ethyl)-1-cyclopropyl-N-methyl-1H-benzimidazole-7-carboxamide: 1H NMR (400 MHz, DMSO-d6) δ 8.50-8.41 (m, 1H), 8.05 (s, 1H), 7.66 (d, J=8 Hz, 1H), 7.28-7.18 (m, 2H), 6.90-6.78 (m, 2H), 5.89-5.81 (m, 1H), 3.40-3.33 (m, 1H), 2.82 (d, J=4 Hz, 3H), 1.60 (d, J=8 Hz, 3H), 1.16-1.03 (m, 2H), 0.95-0.75 (m, 2H); LC-MS (ESI) m/z 420.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.C(N(C(C)C)CC)(C)C.[CH3:30][NH:31][C:32]([CH3:35])([CH3:34])[CH3:33]>ClCCl>[C:32]([N:31]([C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1)[CH3:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Reactant: CNC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(F)c2oc(N(C)C(C)(C)C)nc2c1C#N
Yield: 92.9 %

Procedure:
2-Chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (0.20 g, 0.70 mmol) was dissolved in dichloromethane (10 ml), and diisopropylethylamine (0.15 ml, 0.88 mmol) and N-methyl-tert-butylamine (0.10 ml, 0.84 mmol) were added. After heating under reflux for 3 hours, N-methyl-tert-butylamine (50.0 μl, 0.42 mmol) was added, followed by heating under reflux for 2 hours. This was diluted with dichloromethane, washed with water, and dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane) to obtain a pale yellow solid (0.22 g, 0.65 mmol, 93%).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][CH:16]([CH:19]=O)[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:22][NH:23][CH3:24]>>[CH3:22][N:23]([CH3:24])[CH2:19][CH:16]1[CH2:17][CH2:18][N:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:8][CH:9]=2)[CH2:14][CH2:15]1
Reactant: O=CC1CCN(c2ccc(CN3CCCC3)cc2)CC1
Reactant: CNC
Agent: Cl
Product: CN(C)CC1CCN(c2ccc(CN3CCCC3)cc2)CC1

Procedure:
Prepared from the product of Example 16 and dimethylamine hydrochloride.
Reaction SMILES: [NH2:1][C:2]1([C:5]([O:7][CH3:8])=[O:6])[CH2:4][CH2:3]1.C([O-])(O)=O.[Na+].Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>C(Cl)Cl.O>[C:19]1([CH2:18][O:17][C:15]([NH:1][C:2]2([C:5]([O:7][CH3:8])=[O:6])[CH2:4][CH2:3]2)=[O:16])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)C1(N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C1(NC(=O)OCc2ccccc2)CC1
Reaction time: 2 h
Yield: 46.1 %

Procedure:
Methyl 1-aminocyclopropanecarboxylate (15.83 g, 104.43 mmol) was dissolved in a mixture of CH2Cl2 (150 mL) and water (150 mL). To this mixture was added NaHCO3 (35.09 g, 417.72 mmol) followed by benzyl chloroformate (15.43 mL, 109.64 mmol). The mixture was stirred vigorously for 2 hours, and after separation of the two layers, the aqueous layer was extracted with 100 mL of CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to provide methyl 1-({[(phenylmethyl)oxy]carbonyl}amino)cyclopropanecarboxylate (12.0 g, 46%). LCMS: (M+H)+: 206.1.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([Cl:12])=[C:7]([O:13][CH2:14][CH3:15])[N:6]=1)=[O:4].[Li+].[OH-].Cl>C(O)C.O>[NH2:11][C:9]1[C:8]([Cl:12])=[C:7]([O:13][CH2:14][CH3:15])[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=1
Reactant: CCOc1nc(C(=O)OC)cc(N)c1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1nc(C(=O)O)cc(N)c1Cl
Yield: 70 %

Procedure:
This material from step A was treated with LiOH in ethanol/water (5:3, 1 M, 2 mL) at ambient temperature for 2 h. HCl(aq) was added after 30 min to adjust pH value to 1. The precipitates were collected to afford the titled compound (130 mg, 70%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[N:16][N:17]([CH2:20][O:21]CC[Si](C)(C)C)[C:18](=[O:19])[C:13]=2[C:12](O)=[C:11]1CC1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:36](OCN1C2C=NNC(=O)C=2C(C(O)(C)C)=C1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:36]([C:12]1[C:13]2[C:18](=[O:19])[N:17]([CH2:20][OH:21])[N:16]=[CH:15][C:14]=2[N:10]([CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:11]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(O)c1cn(COCc2ccccc2)c2cn[nH]c(=O)c12
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(O)c(Cc3ccccc3)n2COCc2ccccc2)c1=O
Product: O=c1c2c(Cc3ccccc3)cn(COCc3ccccc3)c2cnn1CO
Yield: 71 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Reference example 21-(e) except for using 3.08 g (6.26 mmol) of 1-benzyloxymethyl-3-hydroxyphenylmethyl-5-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo-[2,3-d]pyridazin-4-one obtained in Reference example 33-(e) in place of 1-benzyloxymethyl-3-(1-hydroxy-1-methylethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one, whereby 1.68 g of the title compound was obtained as a pale yellowish solid. (Yield: 71%)
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[O:9])[C:5]([O:19]C)=[CH:4][CH:3]=1.[Cl-].[Li+]>CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[O:9])[C:5]([OH:19])=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)nc1C(=O)NCc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1nc(Br)ccc1O
Temperature: 130 °C
Yield: 91.1 %

Procedure:
To a solution of 6-bromo-N-(4-chlorobenzyl)-3-methoxypicolinamide (800 mg, 2.25 mmol) in DMF (10 mL) was added lithium chloride (954 mg, 22.5 mmol), and the mixture was heated at 130° C. for 16 h. The mixture was concentrated in vacuo and the residue was suspended in water. Finally, the crude 6-bromo-N-(4-chlorobenzyl)-3-hydroxypicolinamide (700 mg, yield: 91%) was obtained by filtration. 1H-NMR (DMSO-d6, 400 MHz) δ 12.47 (br s, 1H), 9.67 (s, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.34˜7.42 (m, 5H), 4.46 (d, J=6.0 Hz, 2H). MS (M+H)+: 341/343.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13](O)[N:12]2[N:16]=[CH:17][N:18]=[C:11]2[CH:10]=1.P(Cl)(Cl)([Cl:21])=O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Cl:21][C:13]1[N:12]2[N:16]=[CH:17][N:18]=[C:11]2[CH:10]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(-c2ccc(Cl)cc2Cl)cc2ncnn12
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Product: Clc1ccc(-c2cc3ncnn3c(Cl)n2)c(Cl)c1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
2.07 g (7.4 mmol) of 7-[2,4-dichlorophenyl][1,2,4]triazolo[1,5-c]pyrimidin-5-ol (Example 137A) are introduced into phosphoryl chloride (20 ml), 5.0 g (22 mmol) of benzyltriethylammonium chloride are added, and the reaction mixture is stirred at 120° C. for 16 h. The reaction mixture is concentrated and cautiously poured onto ice, while stirring vigorously, and the mixture is stirred for 10 min. The solid is filtered off with suction. 1100 mg (50% of theory) of the product are obtained.
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([Cl:7])[C:3]=1[C:8]([OH:10])=[O:9].S(=O)(=O)(O)O.[CH3:16]O>>[Cl:7][C:4]1[C:3]([C:8]([O:10][CH3:16])=[O:9])=[C:2]([Cl:1])[S:6][N:5]=1
Reactant: CO
Reactant: O=C(O)c1c(Cl)nsc1Cl
Agent: O=S(=O)(O)O
Product: COC(=O)c1c(Cl)nsc1Cl

Procedure:
Into a 50-mL round-bottom flask, was placed dichloro-1,2-thiazole-4-carboxylic acid (400 mg, 2.02 mmol, 1.00 equiv), methanol (10 mL), sulfuric acid (2 mL). The resulting solution was heated to reflux overnight. The resulting mixture was concentrated under vacuum. The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (5:100). This resulted in 350 mg (82%) of methyl 3,5-dichloro-1,2-thiazole-4-carboxylate as yellow oil.
Reaction SMILES: C(OC([NH:8][C@:9]([CH3:29])([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:17][CH:16]=1)[C:10]([OH:12])=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C@:9]([CH3:29])([CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:19][CH:20]=1)[C:10]([OH:12])=[O:11]
Reactant: CCCCCCCOc1ccc(CC[C@@](C)(NC(=O)OC(C)(C)C)C(=O)O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCOc1ccc(CC[C@@](C)(N)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (R)-2-tert-butoxycarbonylamino-4-(4-heptyloxy-phenyl)-2-methyl-butyric acid (43 mg, 0.11 mMol) in CH2Cl2 (2 ml) is added trifluoroacetic acid (0.1 ml). The mixture is stirred at RT for 8 hours. After that time, the reaction mixture is concentrated under reduced pressure. Column chromatography eluting with 5%→25% MeOH in CH2Cl2 gives the title compound as a colourless oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.I[CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:10]([O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)[CH2:11][CH3:12]
Reactant: Oc1ccc(I)cc1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1ccc(I)cc1
Yield: 91.6 %

Procedure:
A mixture of 4-iodophenol (6.6 g), 1-iodopropane (5.1 g), anhydrous potassium carbonate (13.8 g) and acetone (100 ml) was stirred at reflux for 6 hours. Two further portions of 1-iodopropane were added after one hour (5.1 g) and two hours (5.1 g). The acetone was removed by evaporation, the residue was treated with water (100 ml) and the mixture extracted with dichloromethane (2×30 ml). The organic extracts were combined, dried (MgSO4) and evaporated. The residue, an oil, was distilled at 150° C. and 0.5 mm pressure (using a Kugelrohr oven) to give 4-n-propoxyiodobenzene as a colourless oil (7.2 g), NMR(CDCl3): 0.9-1.08(3H,t), 1.7-1.9(2H,m), 3.82-3.92(2H,t), 6.62-6.72(2H,d), 7.5-7.6(2H,d); m/z 262 (M).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[OH:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[OH:22])[CH:17]=O.Cl.CO>O>[OH:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=3)[C:8]2=[O:12])[CH:19]=[CH:20][C:21]=1[OH:22]
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: O=Cc1ccc(O)c(O)c1
Agent: Cl
Solvent: O
Solvent: CO
Product: O=C1C(=Cc2ccc(O)c(O)c2)CCc2cc(O)ccc21
Temperature: 25 °C
Yield: 72 %

Procedure:
After 6-hydroxy-1-tetralone 1.0 g and 3,4-dihydroxybenzaldehyde 0.85 g were added to a mixture of concentrated hydrochloric acid 50 ml and methanol 75 ml, the mixture was refluxed for 2.5 hours and cooled to room temperature, and water 357 ml was added. The precipitated crystals were filtered. The crystals were dried over phosphorous pentoxide for six hours under reduced pressure to obtain the desired compound 1.25 g.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH:25]=[O:26])[CH2:23][CH2:22][C:21]([C:27]([O:29]C)=[O:28])=[CH:20][C:19]=3[CH:31]=2)=[CH:11][CH:10]=1)[CH2:7][CH3:8])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:3][CH2:4][CH2:5][N:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH:25]=[O:26])[CH2:23][CH2:22][C:21]([C:27]([OH:29])=[O:28])=[CH:20][C:19]=3[CH:31]=2)=[CH:11][CH:10]=1)[CH2:7][CH3:8])[CH3:2]
Reactant: CCOCCN(CC)c1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOCCN(CC)c1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
In methanol (25 ml) and THF (25 ml) was dissolved methyl 7-[4-[N-(2-ethoxyethyl)-N-ethylamino]phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.23 g). To the solution was added 1N sodium hydroxide solution (5.5 ml), and the mixture was stirred at room temperature overnight and concentrated. To the residue was added water, and the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 7-[4-[N-(2-ethoxyethyl)-N-ethylamino]phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.2 g) as pale green crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[OH:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:22][CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCN1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2OCCN2CCCC2)CC1

Procedure:
The title compound was prepared by using Mitsunobu condition from 4-(2-hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester and 2-hydroxyethyl pyrrolidine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH2:9]I)=[CH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH2:9][NH:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[CH:4][N:3]=1
Reactant: Clc1ncc(CI)c(Cl)n1
Reactant: COc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(NCc2cnc(Cl)nc2Cl)cc1
Reaction time: 0.5 h

Procedure:
A 500-mL, three-necked flask equipped with a magnetic stirrer, thermometer, and nitrogen-inlet bubbler was charged with a solution of 2,4-dichloro-5-(iodomethyl)pyrimidine (85 g, ca. 253.2 mmol) (from Example 1c supra) in toluene (13.7 mL) from the previous step and toluene (96.3 mL, thus, a total of ca. 110 mL of toluene). After cooling with an ice-water bath, p-anisidine (31.18 g, 253.2 mmol) (Aldrich) was added. After stirring for 30 minutes, a solution of sodium hydroxide (13.54 g, 331.7 mmol) in water (50 mL) was added dropwise over 8 minutes, while maintaining the temperature of the reaction mixture at 10–15° C. hexanes (55 mL) was added and the mixture was stirred at 10–15° C. for 45 minutes, then at room temperature for 22 hours to give a slurry. TLC analysis of the supernatant indicated complete reaction. The slurry was diluted with water (100 mL) and the solid was collected by filtration, washed with cold water and cold (−50° C.) methanol (100 mL), and dried by suction to give [(2,4-dichloropyrimidin-5-yl)methyl](4-methoxyphenyl)amine as an off-white solid, 97% pure by HPLC analysis. (Yield 59.87 g, 83.2%).
Reaction SMILES: C[O-].[Na+].CO.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[SH:13].Cl[C:15]1[S:19][C:18]([C:20](=[O:22])[CH3:21])=[CH:17][C:16]=1[N+:23]([O-:25])=[O:24]>>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][C:15]1[S:19][C:18]([C:20](=[O:22])[CH3:21])=[CH:17][C:16]=1[N+:23]([O-:25])=[O:24]
Reactant: Sc1ccccc1Cl
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)c1cc([N+](=O)[O-])c(Sc2ccccc2Cl)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.6 %

Procedure:
To a 0.1 M stock solution of sodium methoxide in anhydrous methanol (11 mL, 1.1 mmol) was added the 2-chlorobenzenethiol (0.144 g, 1 mmol) and the resulting mixture stirred at ambient temperature for 15 minutes. 1-(5-Chloro-4-nitro-2-thienyl)ethanone (206 mg, 1 mmol) was added and the mixture was stirred at ambient temperature for 2 hours. After this time the reaction was quenched by the addition of water (15 mL) and the resulting precipitate was collected by filtration, washed with water (10 mL) and dried in vacuo at 40° C. overnight. The solid was then crystallized from acetonitrile to afford the title compound as a dark orange solid (165 mg, 52.6% yield). 1H NMR (300 MHz, CDCl3) δ: 8.09 (1H, s), 7.77 (1H, ddd, J=7.58, 1.58, 0.36 Hz), 7.40-7.67 (3H, m), 2.49 (3H, s).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]#[N:6].CC([O-])(C)C.[K+].COCCOC.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[C:41]3[C:36](=[CH:37][C:38](F)=[CH:39][CH:40]=3)[N:35]=[CH:34][N:33]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>C(Cl)Cl.CC(C)=O>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[C:41]3[C:36](=[CH:37][C:38]([O:1][CH2:2][CH2:3][CH2:4][C:5]#[N:6])=[CH:39][CH:40]=3)[N:35]=[CH:34][N:33]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: N#CCCCO
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)ccc23)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCCC#N)ccc23)CC1
Temperature: 25 °C
Yield: 42 %

Procedure:
A mixture of 4-hydroxybutyronitrile (24.2 mg, 285 μmol) [Organometallics (1996), 15(4), 1236-41], KOtBu (34.8 mg, 311 μmol), and DME was stirred at rt, followed by the addition of 4-(7-Fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (48.8 mg, 147 μmol) (prepared as described in Example 65b). The resulting homogeneous solution was stirred at rt for 2 hr, and was then directly loaded onto a 5 g Jones silica cartridge pre-equilibrated with 9:1 DCM/acetone, and eluted with 9:1→8:2 DCM/acetone to afford the title intermediate (24.5 mg, 42%) as a colorless oil. LC/MS (ESI) calcd mass 396.2, found 397.1 (MH)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][CH:33]=3)=[C:4]2[N:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:48][C:49]1([C:64]([O:66][CH2:67][CH3:68])=[O:65])[CH2:54][CH2:53][C:52](B2OC(C)(C)C(C)(C)O2)=[CH:51][CH2:50]1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[CH3:14][Si:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:10][CH2:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]1[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][CH:33]=3)=[C:4]2[N:3]=[C:2]([C:52]2[CH2:53][CH2:54][C:49]([CH3:48])([C:64]([O:66][CH2:67][CH3:68])=[O:65])[CH2:50][CH:51]=2)[CH:7]=1
Reactant: CCOC(=O)C1(C)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)C1(C)CC=C(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n2)CC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To a 40 mL vial charged with 5-chloro-3-(6-phenylpyridin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (Int-18e, 582 mg, 1.0 mmol), Pd(dppf)Cl2 (82 mg, 0.1 mmol), K3PO4 (636 mg, 3.0 mmol), and ethyl 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate (441 mg, 1.5 mmol) was added dioxane (20 mL including 1 mL water). The mixture was thoroughly degassed by alternately evacuating the flask under vacuum, then placing it under an argon atmosphere numerous times. The reaction was then heated to 90° C. and stirred overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (30 mL) and filtered through celite. The solvent was removed under reduced pressure and the residue was purified with column (silica gel, 0-30% ethyl acetate in hexane) gave ethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-methylcyclohex-3-enecarboxylate (Int-18f) (630 mg). HPLC-MS tR=2.89 min (UV254 nm); mass calculated for formula C39H55N5O4Si2 713.4, observed LCMS m/z 714.4 (M+H).