Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]3[O:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[O:21][CH2:20]3)=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.[CH:30](=O)[CH3:31].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][N:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]3[O:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[O:21][CH2:20]3)=[CH:15][CH:14]=2)[CH2:30][CH3:31])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(CNCc2ccc([C@H]3COc4ccccc4O3)cc2)cc1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCN(Cc1ccc(C(=O)OC)cc1)Cc1ccc([C@H]2COc3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-{[(S)-4-(2,3-dihydro-benzo[1,4]dioxin-2-yl)-benzylamino]-methyl}-benzoic acid methyl ester (prepared according to General Method E) (130 mg, 0.33 mmol), acetaldehyde (0.03 mL, 0.50 mmol), and sodium cyanoborohydride (42 mg, 0.67 mmol) in MeOH (15 mL) is treated with 2 drops of acetic acid. The mixture is stirred at room temperature for 16 h, and concentrated. The residue is purified by flash chromatography eluting with a gradient of 0-10% MeOH in DCM to give 4-({[(S)-4-(2,3-dihydro-benzo[1,4]dioxin-2-yl)-benzyl]-ethyl-amino}-methyl)-benzoic acid methyl ester.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[N:16]=[N:17][N:18]([CH:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[CH:19]=2)=[CH:11][C:10]=1[C:33]1[O:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1>ClCCl>[O:34]1[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=[C:33]1[C:10]1[C:9]([NH2:8])=[N:14][CH:13]=[C:12]([C:15]2[N:16]=[N:17][N:18]([CH:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]3)[CH:19]=2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)nn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncc(-c2cn(C3CCNCC3)nn2)cc1-c1nc2ccccc2o1
Reaction time: 2 h
Yield: 99.5 %

Procedure:
TFA (0.771 ml) was added to a stirred suspension of tert-butyl 4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]triazol-1-yl]piperidine-1-carboxylate (231 mg) dissolved in dichloromethane (5 ml) at room temperature. The resulting solution was stirred for 2 hours. Excess TFA was removed by azeotropic concentration with toluene. The residue was taken off with dichloromethane-methanol and treated with methanolic ammonia (7 M). The mixture was concentrated to dryness and the resulting solid was triturated with diethyl ether. The resultant solid was collected by filtration, washed with diethyl ether followed by petroleum ether and dried under vacuum at 60° C. to give 3-(1,3-benzoxazol-2-yl)-5-[1-(4-piperidyl)triazol-4-yl]pyridin-2-amine (180 mg) as a solid; NMR Spectrum: (DMSOd6+TFAd) 2.20-2.32 (m, 2H), 2.38-2.48 (m, 2H), 3.7-3.30 (m, 2H), 3.47-3.58 (m, 2H), 4.92-5.02 (m, 1H), 7.54 (ddd, 1H), 7.59 (ddd, 1H), 7.90 (d, 1H), 7.95 (dd, 1H), 8.84 (d, 1H), 8.96 (s, 1H), 9.24 (d, 1H); Mass spectrum: M+H+: 362
Reaction SMILES: [OH:1][C:2]([CH3:36])([CH3:35])[CH2:3][C@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:10][CH2:9][CH2:8][N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[C:6](=[O:28])[NH:5]1.Br[C:38]1[CH:39]=[CH:40][C:41](=[O:47])[N:42]([CH:44]2[CH2:46][CH2:45]2)[CH:43]=1>>[CH:44]1([N:42]2[C:41](=[O:47])[CH:40]=[CH:39][C:38]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:8][CH2:9][CH2:10][C@:4]([CH2:3][C:2]([OH:1])([CH3:35])[CH3:36])([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[NH:5][C:6]4=[O:28])[CH3:12])=[CH:18][CH:17]=3)=[CH:43]2)[CH2:46][CH2:45]1
Reactant: O=c1ccc(Br)cn1C1CC1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CCC[C@](CC(C)(C)O)(c2ccccc2)NC1=O
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C3CC3)c2)cc1)N1CCC[C@](CC(C)(C)O)(c2ccccc2)NC1=O

Procedure:
The title compound was prepared from (S)-4-(2-hydroxy-2-methylpropyl)-4-phenyl-1-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-diazepan-2-one and 5-bromo-1-cyclopropylpyridin-2(1H)-one following a procedure analogous to that described in Example 11 Step 2. LC-MS Method 1 tR=1.66 min; m/z=500 (M+1). 1H NMR (CD3OD) δ 7.78 (s, 1H), 7.56 (d, 3H), 7.37 (m, 5H), 7.27 (t, 1H), 7.17 (d, 2H), 6.61 (d, 1H), 5.46 (q, 1H), 3.37 (m, 1H), 2.92 (m, 1H), 2.74 (dt, 1H), 2.39 (d, 1H), 1.53 (d, 3H), 1.16 (s, 3H), 0.58 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][N:5]=[CH:6][C:7]1[C:8]([F:30])=[C:9]([F:29])[C:10]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[F:28])=[C:11]([CH:19]=1)[C:12]([NH:14][O:15][CH2:16][CH2:17][OH:18])=[O:13].CON(C(C)=O)[C:34](=[O:36])[CH3:35]>CN(C)C=O.CO>[C:34]([NH:1][CH2:2][CH2:3][O:4][N:5]=[CH:6][C:7]1[C:8]([F:30])=[C:9]([F:29])[C:10]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[F:28])=[C:11]([CH:19]=1)[C:12]([NH:14][O:15][CH2:16][CH2:17][OH:18])=[O:13])(=[O:36])[CH3:35]
Reactant: NCCON=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Reactant: CON(C(C)=O)C(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)NCCON=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 69.8 %

Procedure:
To a solution of 5-[(2-amino-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide (8.14 mg, 0.02 mmol) described in Example 22 in a mixture of dimethylformamide (1 ml) and methanol (5 ml), N-methoxy-diacetamide (100 mg, 0.76 mmol) was added, and the mixture was stirred at room temperature for 14 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the resulting residue was purified with Mega Bond Elut silica gel (5 g, Varian, Inc.). From the fractions eluted with 6% methanol/methylene chloride, 5-[(2-acetylamino-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide (8.10 mg, 92% yield) was obtained as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:12]([O:16][C:17](=[O:29])[NH:18][CH2:19][C:20]1[C:25]([O:26][CH3:27])=[CH:24][C:23]([NH2:28])=[CH:22][N:21]=1)([CH3:15])([CH3:14])[CH3:13].N1C=CC=CC=1>C(Cl)Cl>[C:12]([O:16][C:17](=[O:29])[NH:18][CH2:19][C:20]1[C:25]([O:26][CH3:27])=[CH:24][C:23]([NH:28][S:8]([C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=2)(=[O:10])=[O:9])=[CH:22][N:21]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: COc1cc(N)cnc1CNC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(NS(=O)(=O)c2cccnc2Cl)cnc1CNC(=O)OC(C)(C)C
Yield: 99 %

Procedure:
The title compound (2.21 g, 5.15 mmol) was prepared from 2-chloropyridine-3-sulfonyl chloride (1.10 g, 5.20 mmol), tert-butyl(5-amino-3-methoxypyridin-2-yl)methylcarbamate (IntC16) (1.45 g, 5.72 mmol) and pyridine (1.26 mL, 15.6 mmol) in DCM (20 mL) at rt using the methods of (IntC1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[C:9]([NH:10][CH:11]([CH2:15][CH3:16])[CH:12]([OH:14])[CH3:13])=[CH:8][C:7]([CH3:17])=[N:6][C:5]=1[O:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([Cl:26])=[CH:21][C:20]=1[CH3:27].[H-].[Na+].[CH2:31]1COCC1>>[CH3:1][O:2][C:3](=[O:28])[C:4]1[C:9]([NH:10][CH:11]([CH2:15][CH3:16])[CH:12]([O:14][CH3:31])[CH3:13])=[CH:8][C:7]([CH3:17])=[N:6][C:5]=1[O:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([Cl:26])=[CH:21][C:20]=1[CH3:27]
Reactant: C1CCOC1
Reactant: CCC(Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC)C(C)O
Agent: [H-]
Agent: [Na+]
Product: CCC(Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC)C(C)OC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-hydroxy-propylamino)-6-methyl-nicotinic acid methyl ester (50 mg, 0.123 mmol) in dry THF was added NaH and stirred for 20 min. An excess of Mel was added and the resulting mixture was stirred at rt overnight. The mixture cooled to rt and quenched with water and extracted with ethyl acetate. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to give an oil. The oil was purified through silica gel column chromatography using 20% ethyl acetate in hexane asan eluent to give the title compound as a clear oil. 1H NMR(CDCl3) d 8.20(d,1H), 7.00(s,2H), 6.14&6.10(two sets of s,1H), 3.859s,3H), 3.47(m,1H), 3.39&3.37(two sets of s,3H), 2.08(s,3H), 2.06(s,6H), 1.75(m,1H), 1.58(m,1H), 1.14(t,3H), 0.95(t,3H)ppm.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:21])=[C:4]([C:13]([NH:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8].[C:22](Cl)(=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>CC(N(C)C)=O>[C:22]([NH:1][C:2]1[C:3]([I:21])=[C:4]([C:13]([NH:15][C:16]([CH3:19])([CH3:20])[CH2:17][OH:18])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8])(=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([NH:1][C:2]1[C:3]([I:21])=[C:4]([C:13]([NH:15][C:16]([CH3:19])([CH3:20])[CH2:17][OH:18])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8])=[O:28]
Reactant: O=C(Cl)CCCCC(=O)Cl
Reactant: CC(C)(CO)NC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Solvent: CC(=O)N(C)C
Product: CC(C)(CO)NC(=O)c1c(I)c(NC(=O)CCCCC(=O)Nc2c(I)c(C(=O)O)c(I)c(C(=O)NC(C)(C)CO)c2I)c(I)c(C(=O)O)c1I

Procedure:
Analogously to Example 10, 5-amino-N-(2-hydroxy-1,1-dimethylethyl)-2,4,6-triiodoisophthalamic acid is reacted with hexanedioic acid dichloride in dimethylacetamide, and the reaction mixture is worked up. The thus-obtained product melts at 280°-281° C., with decomposition.
Reaction SMILES: C(OCC)(=O)[CH2:2][C:3](OCC)=[O:4].[Na].[CH2:13]1[O:21][C:20]2[CH:19]=[CH:18][C:17]([CH:22]=[CH:23][C:24](=[O:26])[CH3:25])=[CH:16][C:15]=2[O:14]1.[OH-].[K+]>C(O)C>[OH:4][C:3]1[CH2:2][CH:22]([C:17]2[CH:18]=[CH:19][C:20]3[O:21][CH2:13][O:14][C:15]=3[CH:16]=2)[CH2:23][C:24](=[O:26])[CH:25]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(=O)C=Cc1ccc2c(c1)OCO2
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Product: O=C1C=C(O)CC(c2ccc3c(c2)OCO3)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Diethyl malonate (17.34 g) was added to a solution of sodium metal (2.35 g) in anhydrous absolute ethanol (40 ml). 1-(3,4-methylenedioxyphenyl)-but-1-en-3-one (20 g) was added to the solution and the volume of ethanol was made up to 80 ml. The mixture was heated under reflux with stirring for 2-4 hr. An aqueous solution of potassium hydroxide (25.0 g in 120 ml of water) was added and the mixture was heated under reflux for a further 6 hours. Subsequently, the ethanol was distilled off and the aqueous residue was acidified with dilute hydrochloric acid. After cooling to room temperature, the mixture was extracted with ethyl acetate and the organic phase was washed consecutively with water and an aqueous 10% sodium hydroxide solution. The basic extract was acidified with dilute aqueous hydrochloric acid and the resulting solution was extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated to give 3-hydroxy-5-(3,4-methylenedioxyphenyl)cyclohex-2-en-1-one as a crystalline solid, mp 181° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([C:21]([NH:23][CH2:24][C:25]3[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=3[CH3:31])=[O:22])[C:12]3[CH:17]=[N:16][N:15]([CH:18]([CH3:20])[CH3:19])[C:13]=3[N:14]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:34][N:35](C=O)[CH3:36].CNC.O>CCOC(C)=O>[CH3:31][C:30]1[CH:29]=[C:28]([CH3:32])[NH:27][C:26](=[O:33])[C:25]=1[CH2:24][NH:23][C:21]([C:11]1[C:12]2[CH:17]=[N:16][N:15]([CH:18]([CH3:19])[CH3:20])[C:13]=2[N:14]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][N:35]([CH3:36])[CH3:34])[CH:4]=2)[CH:10]=1)=[O:22]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(CBr)c3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CN(C)C=O
Agent: CNC
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(CN(C)C)c3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 8 h
Yield: 40 %

Procedure:
To a stirred solution of 6-(3-(bromomethyl)phenyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.) in a DMF, dimethylamine (5 equiv.) was added at 0° C. & resulting reaction mixture stirred for overnight. After completion of reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain the crude material which was purified by column chromatography to give pure final compounds (40% yield). LCMS: 473.20 (M+1)+; HPLC: 99.89% (@ 254 nm) (Rt; 5.325); 1H NMR (DMSO-d6, 400 MHz) δ 11.52 (s, 1H), 8.96 (bs, 1H), 8.35 (s, 1H), 8.13-8.10 (m, 3H), 7.50 (t, J=8.4 Hz, 1H), 7.43-7.41 (m, 1H), 5.89 (s, 1H), 5.34-5.31 (m, 1H), 4.41 (d, J=4 Hz, 2H), 3.50 (s, 2H), 2.23 (s, 3H), 2.19 (s, 6H), 2.12 (s, 3H), 1.54 (d, J=6.8 Hz, 6H).
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[OH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:29]=1[CH:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]([CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[C:39]1=[O:52]>>[OH:16][CH2:5][C:38]1([C:29]2[CH:30]=[C:31]([C:34]([F:35])([F:36])[F:37])[CH:32]=[CH:33][C:28]=2[OH:27])[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]([CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[C:39]1=[O:52]
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Reactant: CCCCCN1C(=O)C(c2cc(C(F)(F)F)ccc2O)c2ccccc21
Product: CCCCCN1C(=O)C(CO)(c2cc(C(F)(F)F)ccc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 3-[2-hydroxy-5-(trifluoromethyl)phenyl]-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained: MS (ES+) m/z 376 (M−17), 416 (M+23).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([NH2:12])[CH2:8][C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.[ClH:13].[C:14](OCC)(=O)[CH3:15]>C(O)C>[ClH:13].[NH2:12][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH2:8][C:9]([O:11][CH2:14][CH3:15])=[O:10]
Reactant: CCOC(C)=O
Reactant: NC(CC(=O)O)c1ccccc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC(N)c1ccccc1
Yield: 98.6 %

Procedure:
DL-3-amino-3-phenylpropionic acid (5.4 g, 0.032 moles) was added to saturated HCl (100 ml) in ethanol. The reaction mixture was stirred for 4 hours at room temperature under nitrogen. HCl in ethanol was removed under vacuum to afford a residue. The concentrated residue was trituated with ethyl acetate. The ethyl acetate was then removed in vacuum and the procedure was repeated twice. The resulting residue was dried under high vacuum to give a yellow solid (7.4 g, 98.6% yield). 1H NMR (400 MHz, CD3OD) δ 7.46-7.41 (m, 5H), 4.70 (m, 1H), 4.16-4.11 (m, 2H), 3.11-2.96 (m, 2H), 1.19 (t, 3H, 7.18 Hz). HRMS (M+H) calculated for C11H15N1O2 194.1176, found 194.1210.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([OH:15])=[C:13]([C:16]([OH:18])=O)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].Cl.[NH:20]1[CH2:25][CH2:24][C:23]2([C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26]2)[CH2:22][CH2:21]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([OH:15])=[C:13]([C:16]([N:20]3[CH2:25][CH2:24][C:23]4([C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH2:27][CH2:26]4)[CH2:22][CH2:21]3)=[O:18])[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: c1ccc2c(c1)CCC21CCNCC1
Reactant: CCOC(=O)c1cnn2c(O)c(C(=O)O)cnc12
Agent: Cl
Product: CCOC(=O)c1cnn2c(O)c(C(=O)N3CCC4(CCc5ccccc54)CC3)cnc12
Yield: 65.1 %

Procedure:
In the same manner as in Example 1, step 2 and using 3-ethoxycarbonyl-7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.27 g, 1.06 mmol) obtained in Example 19, step 2 and spiro[indane-1,4′-piperidine]hydrochloride (0.3 g, 1.32 mmol), the title compound (0.29 g, 64%) was obtained.
Reaction SMILES: F[C:2]1[C:7]([CH:8]=O)=[C:6]([I:10])[C:5]([CH3:11])=[CH:4][N:3]=1.O.[NH2:13][NH2:14]>O1CCOCC1>[I:10][C:6]1[C:5]([CH3:11])=[CH:4][N:3]=[C:2]2[NH:13][N:14]=[CH:8][C:7]=12
Reactant: Cc1cnc(F)c(C=O)c1I
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: Cc1cnc2[nH]ncc2c1I

Procedure:
2-fluoro-4-iodo-5-methyl-pyridine-3-carbaldehyde (510 mg, 1.924 mmol) was dissolved in dry Dioxane (10 mL) and Hydrazine monohydrate (288.9 mg, 280.8 μL, 5.772 mmol) was added in one portion
Reaction SMILES: [CH3:1][O:2][C:3](=[O:62])[NH:4][CH:5]([C:9]([N:11]1[CH:17]([C:18]2[NH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[C:34]([C:39]6[NH:40][C:41]([CH:44]7[CH:49]8[CH2:50][CH:46]([CH2:47][CH2:48]8)[N:45]7C(=O)C(C7CC7)NC(OC)=O)=[N:42][CH:43]=6)[CH:35]=5)[CH:30]=4)=[CH:25][CH:24]=3)=[CH:21][N:22]=2)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:63][O:64][C:65]([CH3:76])([CH3:75])[CH:66]([NH:70][C:71]([O:73][CH3:74])=[O:72])[C:67]([OH:69])=O>>[CH3:74][O:73][C:71](=[O:72])[NH:70][CH:66]([C:67]([N:45]1[CH:44]([C:41]2[NH:40][C:39]([C:34]3[CH:33]=[CH:32][C:31]4[C:36](=[CH:37][CH:38]=[C:29]([C:26]5[CH:27]=[CH:28][C:23]([C:20]6[NH:19][C:18]([CH:17]7[CH2:16][C:13]8([CH2:14][CH2:15]8)[CH2:12][N:11]7[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:62])[CH:6]([CH3:7])[CH3:8])=[N:22][CH:21]=6)=[CH:24][CH:25]=5)[CH:30]=4)[CH:35]=3)=[CH:43][N:42]=2)[CH:49]2[CH2:50][CH:46]1[CH2:47][CH2:48]2)=[O:69])[C:65]([O:64][CH3:63])([CH3:76])[CH3:75]
Reactant: COC(=O)NC(C(=O)O)C(C)(C)OC
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6C7CCC(C7)N6C(=O)C(NC(=O)OC)C6CC6)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Product: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6C7CCC(C7)N6C(=O)C(NC(=O)OC)C(C)(C)OC)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Yield: 35 %

Procedure:
This compound was prepared using the procedure used to prepare [1-(6-{5-[4-(6-{2-[2-(2-Cyclopropyl-2-methoxycarbonylamino-acetyl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (example from JJC) using 3-Methoxy-2-methoxycarbonylamino-3-methyl-butyric acid (0.020 g, 0.096 mmol) to provide [2-Methoxy-1-(3-{5-[6-(4-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.019 g, 35%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:10]([OH:12])=[O:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.S(=O)(=O)(O)O.[CH3:18]O>>[Br:1][C:2]1[C:3]([C:10]([O:12][CH3:18])=[O:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1
Reactant: CSc1ncc(Br)c(C(=O)O)n1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1nc(SC)ncc1Br
Reaction time: 24 h
Yield: 80 %

Procedure:
A solution of 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid (7.64 g, 30.7 mmol) in MeOH (60 mL) was treated with sulfuric acid (2 mL) and boiled for 24 hours. The mixture was poured onto ice water and extracted with DCM. The DCM phase was washed with saturated aqueous sodium hydrogen carbonate solution, dried and evaporated to give the title compound (6.42 g, 80%).
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([S:14][CH3:15])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)(Cl)Cl>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([S:14]([CH3:15])=[O:24])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc2c(c1)CN(C(C)=O)CC2
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCc2ccc(S(C)=O)cc2C1
Temperature: 25 °C

Procedure:
A solution of N-acetyl-7-methylthio-1,2,3,4-tetrahydroisoquinoline, (2 gm., 0.009 m.) in 20 ml. of chloroform was cooled to -20° C. and treated with (1.6 gm., 0.009 m.) m-chloroperbenzoic acid. The reaction mixture was allowed to warm to 25° C. and was washed with 10% aqueous sodium carbonate, dried over sodium sulfate and evaporated to yield N-acetyl-7-methylsulfinyl-1,2,3,4-tetrahydroisoquinoline. This compound was hydrolyzed following the procedure set forth in Example 1 to yield 7-methylsulfinyl-1,2,3,4-tetrahydroisoquinoline hydrochloride, m.p. 200°-202° C. from ethanol-ethyl acetate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.O1CCOCC1.[OH-].[Na+].Cl[CH:24]([F:26])[F:25]>O>[F:25][CH:24]([F:26])[O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: FC(F)Cl
Reactant: CC(C)C(C(=O)O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)C(C(=O)O)c1ccc(OC(F)F)cc1
Temperature: 0 °C
Yield: 43 %

Procedure:
To a stirred mixture of 2-(4-hydroxyphenyl)-3-methylbutyric acid (10.0 g; 0.0515 mol), dioxane (65 ml), sodium hydroxide (19.08 g, 18.56 g real; 0.464 mol), and water (30 ml) is bubbled chlorodifluoromethane (46 g; 0.532 mol) at 80° C. over a four-hour period. The reaction mixture is then poured into 250 ml of ice water, washed with ether, acidified with concentrated hydrochloric acid to pH 3, and extracted with 200 ml of ether. The ether extract is washed with 100 ml of water, dried with sodium sulfate, filtered, and evaporated to a white paste. A mixture of hexane and methylene chloride is added. The resulting mixture is filtered to remove the solid which is the starting material. The filtrate is evaporated to give 5.41 g of product as a clear brown oil. The product is at least 85% pure as calculated by NMR. NMR (CDCl3 -d5 pyridine): δ6.57 (t, J=74.3 Hz, 1 H); δ3.63 (s, imp.); δ3.25 (d, J=10 Hz, 1H); δ2.37 (m, 1H); δ1.19 (d, J=6.5 Hz, 3H); δ0.78 (d, J=6.5 Hz, 3H); δ13.82 (s, 1H).
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[NH2:16][C:17]1[N:22]=[C:21]([NH2:23])[C:20]([NH2:24])=[N:19][C:18]=1[NH2:25]>N1C=CC=CC=1>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:7]([C:4]3[CH:3]=[CH:2][C:1]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)=[CH:6][CH:5]=3)=[O:8])[C:20]([NH:24][C:7]([C:4]3[CH:3]=[CH:2][C:1]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)=[CH:6][CH:5]=3)=[O:8])=[N:19][C:18]=2[NH:25][C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:2][CH:3]=2)=[O:8])=[O:8])=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: Nc1nc(N)c(N)nc1N
Solvent: c1ccncc1
Product: O=C(Nc1nc(NC(=O)c2ccc(-c3ccccc3)cc2)c(NC(=O)c2ccc(-c3ccccc3)cc2)nc1NC(=O)c1ccc(-c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1

Procedure:
In the same way, reaction of 4-biphenylcarbonyl chloride with tetraaminopyrazine in excess pyridine will give tetrakis(4-biphenylcarboxamido)pyrazine. Heating this compound at or near its Tp will give 2,6-bis(4-biphenylyl)-1H,5H-diimidazo[4,5-b:4',5'-e]pyrazine.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:11][N:12]([CH:14](OC)OC)[CH3:13]>CN(C=O)C>[CH3:11][N:12]([CH3:14])/[CH:13]=[CH:1]/[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1ncccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
A modified procedure of Cash et al. (Org. Biomol. Chem. 2005, 3. 3701-3706) was used. 2-Methyl-3-nitropyridine (0.7 g, 5.1 mmol) was dissolved in 15 ml dry DMF and stirred under nitrogen. Dimethylformamiddimethylacetal (DMF-DMA) (1.35 ml, 1.22 g, 10.2 mmol) was added dropwise. The reaction was heated to 90° C. for 4 h. After approximately 15 min a deep redish color appeared. After evaporating the solvent (E)-N,N-Dimethyl-2-(3-nitropyridin-2-yl)ethenamine is obtained as a red oil (0.16 g, 0.8 mmol, 73%) which can be used without further purification. 1H NMR (300 MHz, CDCl3) 8.40 (pdd; 3J=1.7 Hz; 3J=4.4 Hz; 1H; H-6); 8.16 (pdd; 3J=1.7 Hz; 3J=8.3 Hz; 1H; H-4); 8.04 (d; 3JAX=12.5 Hz; 1H; H-8); 6.76 (pdd; 3J=4.4 Hz; 3J=8.3 Hz; 1H; H-5); 6.15 (d; 3JAX=12.5 Hz; 1H; H-7); 3.01 (s; 6H; CH3).