Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([SH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[F:13][C:14]1[CH:21]=[N:20][CH:19]=[CH:18][C:15]=1[CH:16]=O.CS(C)=O>O>[F:13][C:14]1[CH:21]=[N:20][CH:19]=[CH:18][C:15]=1[C:16]1[S:12][C:3]2[C:2]([N:1]=1)=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][N:4]=2
Reactant: Nc1cc(C(F)(F)F)cnc1S
Reactant: O=Cc1ccncc1F
Solvent: O
Solvent: CS(C)=O
Product: Fc1cnccc1-c1nc2cc(C(F)(F)F)cnc2s1
Temperature: 170 °C
Reaction time: 2 h
Yield: 39.7 %

Procedure:
A mixture of 0.90 g of 3-amino-5-(trifluoromethyl)-pyridine-2-thiol, 0.58 g of 3-fluoroisonicotinaldehyde and 5 ml of DMSO was stirred at 170° C. for 2 hours. The reaction mixture was cooled down to room temperature, then, to the reaction mixture was added water, and the resultant mixture was extracted with ethyl acetate twice. The combined organic layers were washed with water and saturated saline, dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, to obtain 0.55 g of 2-(3-fluoropyridin-4-yl)-6-(trifluoromethyl)thiazolo[5,4-b]pyridine (hereinafter, referred to as the present compound 9).
Reaction SMILES: [Mg].BrC(Br)C.[CH2:6](Br)[C:7]#[CH:8].Cl[CH2:11][CH2:12][CH2:13][C:14](=[O:16])[CH3:15].[Cl-:17].[NH4+]>CCOCC>[Cl:17][CH2:6][CH2:7][CH2:8][C:14]([OH:16])([CH3:15])[CH2:13][C:12]#[CH:11]
Reactant: C#CCBr
Reactant: CC(=O)CCCCl
Reactant: [Cl-]
Agent: CC(Br)Br
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: C#CCC(C)(O)CCCCl
Temperature: -5 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 6.69 g. of magnesium in 20 ml. of ether under argon, is added 0.1 g. of mercuric chloride and 0.1 g. of dibromoethane. The mixture is stirred for 10 minutes and 0.5 ml. of propargyl bromide is added. A 50 ml. portion of ether is added, followed by a solution of 30 g. of 5-chloro-2-pentanone and 32.55 g. of propargyl bromide in 45 ml. of ether with stirring, at a rate to maintain vigorous reflux. The mixture is stirred an additional 15 minutes, cooled to -5° C. and an ice cold saturated solution of ammonium chloride is added dropwise. The ether layer is decanted and filtered. The solids are washed with ether which is also filtered. The combined ether filtrates are washed with water, dried over magnesium sulfate and the solvent removed giving the product as an orange oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH2:12])[CH2:9][CH2:10][NH2:11].CC1C=CC=CC=1C(N)CCN.ClC1C=CC=CC=1C(N)CCN>>[C:3]1([CH:8]([NH2:12])[CH2:9][CH2:10][NH2:11])[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: NCCC(N)c1ccccc1F
Agent: Cc1ccccc1C(N)CCN
Agent: NCCC(N)c1ccccc1Cl
Product: NCCC(N)c1ccccc1

Procedure:
Analogously, 1-(2-fluorophenyl)-1,3-propanediamine, 1-(2-methylphenyl)-1,3-propanediamine and 1-(2-chlorophenyl)-1,3-propanediamine have been prepared.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:8]([O:10][CH2:11][CH3:12])=[O:9].[P:13]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16].Cl>C(#N)C.O.ClCCl>[CH2:11]([O:10][C:8]([N:1]1[CH:6]=[CH:5][CH:4]([P:13]([O:17][CH2:18][CH3:19])(=[O:20])[O:14][CH2:15][CH3:16])[CH:3]=[CH:2]1)=[O:9])[CH3:12].[P:13]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])=[O:9]
Reactant: CCOP(OCC)OCC
Reactant: c1ccncc1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CCOC(=O)N1C=CC(P(=O)(OCC)OCC)C=C1
Product: CCOP(=O)(OCC)OCC
Temperature: -5 °C
Reaction time: 2 h

Procedure:
A solution of pyridine (16.1 L, 0.2 kmol) in acetonitrile (160 L) is cooled to −10° C. Ethyl chloroformate (19.1 L, 0.2 kmol) is added at such a rate that the temperature does not rise above 0° C. The suspension is then stirred at −10 to 0° C. for 2 hours to ensure complete N-acylation. The batch is cooled to −30° C., and triethyl phosphite (34.3 L, 0.2 kmol) is added at such a rate that the temperature does not rise above −20° C. (ranging from −30 to −20° C.). The solution is stirred in this range for 2 hours, and then warmed to ambient temperature over several hours (or overnight). The acetonitrile is stripped under Sihi vacuum to a temperature not exceeding 80° C. and the residual liquid is cooled to 30° C. Dichloromethane (140 L) is added, followed by a mixture of water (60 L) and concentrated HCl (10 L). The mixture is stirred at ambient temperature for 1 hour, and the lower organic phase is pumped to a separate vessel and washed with water (100 L). After pumping back to the original (water-washed) vessel, it is washed with 1% potassium carbonate solution and finally with water to neutrality. The dichloromethane is then stripped to leave crude (about 92% pure) diethyl N-ethoxycarbonyl-1,4-dihydropyridine-4-phosphonate containing about 5% 1,2-isomer and traces of triethyl phosphate (oxidation of corresponding phosphite). The yield is about 48.4 kg of a light yellow liquid which is stored under nitrogen because it is slightly unstable to air.
Reaction SMILES: C[O:2][C:3](=[O:15])[CH:4]=[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)[CH3:6].[OH-].[Na+]>O.CO.C1COCC1>[CH3:14][O:13][C:9]1[CH:8]=[C:7]([C:5]([CH3:6])=[CH:4][C:3]([OH:15])=[O:2])[CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)C=C(C)c1cccc(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cccc(C(C)=CC(=O)O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.9 %

Procedure:
3-(3-Methoxy-phenyl)-but-2-enoic acid methyl ester (2 g, 7.9 mmol) and sodium hydroxide (0.78 g, 19.4 mmol) were dissolved in a mixture of water (50 ml), methanol (50 ml) and THF (50 ml). The mixture was stirred at ambient temperature for 16 hours and then concentrated under reduced pressure. The remaining aqueous solution was diluted with water and extracted with EtOAc twice. The aqueous was collected and acidified to pH 4 and extracted with EtOAc three times. The organics were combined, dried (magnesium sulphate) and concentrated in vacuo to give 3-(3-Methoxy-phenyl)-but-2-enoic acid as a white crystalline solid (1 g, 55%).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.Cl.Cl[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][S:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1
Reactant: ClCc1ccccn1
Reactant: O=C(O)c1ccc(S)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(SCc2ccccn2)cc1
Yield: 40.9 %

Procedure:
An ethanol/water mixed solution (2/1, 60 mL) of 4-mercaptobenzenecarboxylic acid (1.0 g), 2-chloromethylpyridine hydrochloride (2.1 g) and potassium carbonate (4.5 g) was heated under reflux for 4 hours. The organic solvent was evaporated off under reduced pressure, and aqueous 5 N hydrochloric acid solution was added to the residue until it became acidic. Water was evaporated off under reduced pressure, and DMF was added to the resulting residue and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (chloroform/methanol=9/1 to 4/1) to obtain the entitled compound (650 mg).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]=[CH:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([OH:64])[CH2:5][C:4]1=[O:65])[CH3:2].[H][H]>[Rh]>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH2:52][CH2:53][C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([OH:64])[CH2:5][C:4]1=[O:65])[CH3:2]
Reactant: [H][H]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC=Cc4ccccc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: [Rh]
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCCCc4ccccc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.6 %

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-cinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (37 mg in 2 ml ethanol) was added 4 mg of 5% rhodium on carbon catalyst. The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 1.5 hours, the mixture was filtered over Celite, concentrated and purified by preparative TLC on silica gel (ethyl acetate:hexane (1:2)+1% methanol) to give the title compound (19.5 mg).
Reaction SMILES: C1([N:7](C(=O)CNC(OC(C)(C)C)=O)[C@H]2CCNC2)CCCCC1.[C:24]([NH:31][C@H:32]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:33]([OH:35])=O)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].[CH:44]1([NH:50][CH:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1>>[C:24]([NH:31][C@H:32]([CH2:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:33]([NH:7][N:54]1[CH2:53][CH2:52][CH:51]([NH:50][CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)[CH2:56][CH2:55]1)=[O:35])([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25]
Reactant: C1CCC(NC2CCNCC2)CC1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: CC(C)(C)OC(=O)NCC(=O)N(C1CCCCC1)[C@H]1CCNC1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)NN1CCC(NC2CCCCC2)CC1

Procedure:
The title compound was prepared following the procedure described in Intermediate 129 using (2R)-2-(BOC)amino-3-(4-chlorophenyl)propionic acid and 4-[(cyclohexyl)amino]piperidine.
Reaction SMILES: [NH:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3].[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25].O>CS(C)=O>[CH2:25]([N:1]1[C:12](=[O:13])[C:11]2[N:9]([CH3:10])[CH:8]=[N:7][C:6]=2[N:4]([CH3:5])[C:2]1=[O:3])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=[CH2:17]
Reactant: C=CCCCCCCCBr
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reaction time: 0.25 h
Yield: 81.6 %

Procedure:
A mixture of theobromine (17.64 g, 98 mmol) and sodium hydride (2.35 g, 98 mmol) in dimethylsulfoxide (250 ml) was stirred for 15 minutes. 9-Bromo-1-nonene (20.0 g, 98 mmol) was added and stirring continued for 3 days. The reaction mixture was poured into water (300 ml) and extracted with dichloromethane (4×200 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution (2×150 ml), dried over sodium sulfate, and the solvents evaporated under vacuum. The residue was crystallized (dichloromethane-ether) to give 1-(8-nonenyl)-3,7-dimethylxanthine (24.34 g, 99% yield) as white crystals.
Reaction SMILES: C(C1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:4]=1)#N.[C:21]([OH:24])(=[O:23])[CH3:22]>Cl>[CH3:9][C:7]1[CH:6]=[C:5]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=2)[N:4]=[C:22]([C:21]([OH:24])=[O:23])[CH:8]=1
Reactant: Cc1cc(C#N)nc(Oc2cccc(C(F)(F)F)c2)c1
Reactant: CC(=O)O
Agent: Cl
Product: Cc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)O)c1

Procedure:
2-cyano-4-methyl-6-[3-(trifluoromethyl)phenoxy] pyridine (2.055 g, 0.0074 mol) was heated and stirred in 10 ml of concentrated hydrochloric acid and 6 ml of acetic acid at 110° C. for 5 hours. Thereafter, the obtained reaction solution was concentrated under reduced pressure. The obtained residues were mixed with water. The precipitated solids were filtered out, washed with water and then dried, thereby obtaining an aimed product.
Reaction SMILES: [N:1]1([C:7]#[N:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:9][OH:10]>>[OH:10][NH:9][C:7]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[NH:8]
Reactant: NO
Reactant: N#CN1CCOCC1
Product: N=C(NO)N1CCOCC1

Procedure:
The title compound was prepared from the reaction of morpholine nitrile and hydroxylamine (equimolar amounts) by a route analogous to that used for the preparation of Example 412A to yield 419A in quantitative yield. 1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 5.18 (S, 2H), 3.57 (m, 4H), 2.93 (m, 4H)
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][CH:8]=[CH:9][N:10]=1.CCCCCC.C([Li])CCC.[CH3:22][O:23][CH2:24][C:25](OC)=[O:26].O>O1CCCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][C:8]([C:25](=[O:26])[CH2:24][O:23][CH3:22])=[CH:9][N:10]=1
Reactant: c1csc(C2OCCO2)n1
Reactant: COCC(=O)OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: COCC(=O)c1cnc(C2OCCO2)s1
Temperature: -70 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
To a solution of 2-(1,3-dioxolan-2-yl)-1,3-thiazole (2.20 g) in tetrahydrofuran (50 mL) was slowly added a 1.6M n-butyllithium hexane solution (9.6 mL) at −70° C. under a nitrogen atmosphere. The reaction mixture was stirred at −70° C. for 1 hr, and methyl methoxyacetate (2.91 g) was added. The reaction mixture was warmed to room temperature, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (2.00 g, yield 62%) was obtained as yellow crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). melting point 65-66° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:13][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH2:12])[CH:10]=[C:5]2[CH:4]=1.Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]([C:23](=[O:25])[CH3:24])[CH:18]=1.CCN(C(C)C)C(C)C>CN1CCCC1=O.C(OCC)(=O)C>[F:15][C:2]([F:1])([F:14])[C:3]1[NH:13][C:6]2=[N:7][CH:8]=[C:9]([CH2:11][NH:12][C:17]3[N:22]=[CH:21][N:20]=[C:19]([C:23](=[O:25])[CH3:24])[CH:18]=3)[CH:10]=[C:5]2[CH:4]=1
Reactant: NCc1cnc2[nH]c(C(F)(F)F)cc2c1
Reactant: CC(=O)c1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(=O)c1cc(NCc2cnc3[nH]c(C(F)(F)F)cc3c2)ncn1
Temperature: 25 °C
Reaction time: 7 h
Yield: 8 %

Procedure:
1-[2-(Trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methanamine (Intermediate 5, 32 mg, 0.149 mmol), 1-(6-chloro-4-pyrimidinyl)ethanone (Intermediate 18, 34.9 mg, 0.223 mmol) and DIPEA (0.052 mL, 0.297 mmol) were added together in N-methyl-2-pyrrolidone (1 mL) and the resulting mixture was stirred at room temperature for 7 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by MDAP. Product containing fractions were combined and evaporated under reduced pressure. The resulting solid was dried under high vacuum at 45° C. for 18 hours to give the title compound as a white solid (4 mg);
Reaction SMILES: C(C1[C:11]2[C:6](=[N:7][C:8](CC)=[CH:9][C:10]=2CC)N(C2C3C(=CC=CC=3)CC2)C=1/C=C/C(NC1CCOC(C)(C)C1)=O)#N.[C:38]([C:40]1[C:48]2[C:43](=[N:44][C:45]([CH2:51][CH3:52])=[CH:46][C:47]=2[CH2:49][CH3:50])[N:42]([CH:53]2[C:61]3[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=3)[CH2:55][CH2:54]2)[C:41]=1/[CH:62]=[CH:63]/[C:64]([NH:66]C1C=NC=CC=1)=[O:65])#[N:39].C(C1C2C(=NC(CC)=CC=2CC)N(C2C3C(=CC=CC=3)CC2)C=1/C=C/C(O)=O)#N.NC1C=CN=CC=1>>[C:38]([C:40]1[C:48]2[C:43](=[N:44][C:45]([CH2:51][CH3:52])=[CH:46][C:47]=2[CH2:49][CH3:50])[N:42]([CH:53]2[C:61]3[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=3)[CH2:55][CH2:54]2)[C:41]=1/[CH:62]=[CH:63]/[C:64]([NH:66][C:10]1[CH:9]=[CH:8][N:7]=[CH:6][CH:11]=1)=[O:65])#[N:39]
Reactant: CCc1cc(CC)c2c(C#N)c(/C=C/C(=O)NC3CCOC(C)(C)C3)n(C3CCc4ccccc43)c2n1
Reactant: CCc1cc(CC)c2c(C#N)c(/C=C/C(=O)Nc3cccnc3)n(C3CCc4ccccc43)c2n1
Agent: CCc1cc(CC)c2c(C#N)c(/C=C/C(=O)O)n(C3CCc4ccccc43)c2n1
Agent: Nc1ccncc1
Product: CCc1cc(CC)c2c(C#N)c(/C=C/C(=O)Nc3ccncc3)n(C3CCc4ccccc43)c2n1

Procedure:
In the same manner described in (4) of Example 2, (E)-3-[3-cyano-1-(2,3-dihydro-1H-inden-1-yl)-4,6-diethyl-1H-pyrrolo[2,3-b]pyridin-2-yl]-N-(3-pyridinyl)-2-propenamide was synthesized from (E)-3-[3-cyano-1-(2,3-dihydro-1H-inden-1-yl)-4,6-diethyl-1H-pyrrolo[2,3-b]pyridin-2-yl]-2-propenoic acid and 4-aminopyridine.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][CH2:7][C@H:8]([OH:12])[C:9]([OH:11])=[O:10].[CH3:13][C:14](=[CH2:16])[CH3:15]>C(COC)OC>[NH2:6][CH2:7][C@H:8]([O:12][C:14]([CH3:16])([CH3:15])[CH3:13])[C:9]([O:11][C:14]([CH3:15])([CH3:13])[CH3:16])=[O:10]
Reactant: C=C(C)C
Reactant: NC[C@H](O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)[C@H](CN)OC(C)(C)C
Temperature: -78 °C
Reaction time: 48 h

Procedure:
The following reaction was carried out in a Fischer-Porter tube. Dimethoxyethane (76 ml) and 3.2 ml of concentrated sulfuric acid were added in that order to 4.0 g of 3-amino-(2S)-hydroxypropionic acid (L-isoserine), and the mixture was then cooled to −78° C. Isobutylene (38 ml) was added thereto, and the tube was sealed, followed by shaking at room temperature for 48 hr. The tube was then slowly opened, and isobutylene was removed by distillation at room temperature. The reaction mixture was then added dropwise to 128 ml of ice water, and the mixture was washed twice with 250 ml of ether, was cooled to 0° C., and was then neutralized with a 6 N aqueous sodium hydroxide solution. Further, solid sodium chloride was added to prepare a saturated solution, and the mixture was extracted four times with 100 ml of chloroform. The chloroform layers were combined, and the combined chloroform layers were dried over anhydrous sodium sulfate and were then concentrated under the reduced pressure to give 640 mg of a yellow oil. The yellow oil was purified by column chromatography on silica gel (64 g, chloroform-methanol-concentrated aqueous ammonia=20:1:0.05→10:1:0.1) to give 191 mg of intermediate 1 and 430 mg of intermediate 2.
Reaction SMILES: Br[CH2:2][C:3]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[N+:11]([C:10]1[C:3]([CH2:2][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6])([O-:13])=[O:12]
Reactant: C1CCNC1
Reactant: N#Cc1cccc([N+](=O)[O-])c1CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cccc([N+](=O)[O-])c1CN1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a stirred solution of 2-(bromomethyl)-3-nitrobenzonitrile (1.10 g, 4.56 mmol) and pyrrolidine (0.65 g, 9.13 mmol) in CH2Cl2 (15 mL) was added triethylamine (1.85 g, 18.25 mmol) dropwise at 0° C. The mixture was stirred at room temperature for 2 h and evaporated to dryness under reduced pressure. The residue was diluted with water (10 mL) and extracted with CH2Cl2 (3×50 mL). The CH2Cl2 solution was dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of EtOAc and hexane as eluent to give 3-nitro-2-(pyrrolidin-1-ylmethyl)benzonitrile (0.96 g, 91%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.90 (d, 1 H, J=7.6 Hz), 7.83 (dd, 1H, J=7.6, 0.8 Hz), 7.52 (t, 1H, J=7.6 Hz), 4.14 (s, 2H), 2.52 (br s, 4H), 1.72 (br s, 4H).
Reaction SMILES: [F:1][CH:2]([F:8])[C:3](OCC)=[O:4].C[O-].[Na+].[CH2:12]1[O:20][C:19]2[CH:18]=[CH:17][C:16]([C:21](=[O:23])[CH3:22])=[CH:15][C:14]=2[O:13]1.Cl>CCOCC>[O:20]1[C:19]2[CH:18]=[CH:17][C:16]([C:21](=[O:23])[CH2:22][C:3](=[O:4])[CH:2]([F:8])[F:1])=[CH:15][C:14]=2[O:13][CH2:12]1
Reactant: CCOC(=O)C(F)F
Reactant: CC(=O)c1ccc2c(c1)OCO2
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: O=C(CC(=O)C(F)F)c1ccc2c(c1)OCO2
Reaction time: 16 h

Procedure:
Ethyl difluoroacetate (1.72 g, 11 mmol) was dissolved in ether (25 mL). To the stirred solution was added 25% sodium methoxide (2.38 g, 11 mmol) followed by 3′,4′-(methylenedioxy)acetophenone (1.64 g, 10 mmol). After stirring 16 hours, 1N HCl (25 mL) was added. The organic layer was collected and washed with water (2×25 mL), dried over magnesium sulfate, filtered, and concentrated. The resulting crude dione was used in the next step without further purification of characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][CH:11]=1.[Br:18]N1C(=O)CCC1=O>C(#N)C>[Br:18][C:10]1[CH:11]=[C:6]([O:5][CH2:4][C:3]2[C:13]([Cl:17])=[CH:14][CH:15]=[CH:16][C:2]=2[Cl:1])[C:7]([NH2:12])=[N:8][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ncccc1OCc1c(Cl)cccc1Cl
Solvent: CC#N
Product: Nc1ncc(Br)cc1OCc1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.6 %

Procedure:
A stirring solution of 3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine (32.4 g, 0.11 mol) in acetonitrile was cooled to 0° C. using an ice bath. To this solution was added N-bromosuccinimide (19.5 g, 0.11 mol) portionwise. The reaction was stirred at 0° C. for 15 min. The reaction was concentrated to dryness under vacuum. The resulting dark oil was dissolved in EtOAc (500 mL) and partitioned with H2O (250 mL). The organic was then washed with sat'd NaHCO3 (2×200 mL) and brine (1×200 mL). Activated charcoal was added to the organic layer and warmed to reflux. The solution was then cooled to room temperature and filtered through a pad of celite. The organic was then concentrated to dryness under vacuum to one third the original volume. The solids were then filtered off to yield 5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine (22.0 g, 0.07 mol, 64%) as a tan solid. The remaining filtrate was concentrated under vacuum to yield crude 5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine (12.19, 0.04 mol, 35%) as a brown solid.
Reaction SMILES: [OH-:1].[Li+].[N+:3]([C:6]1[N:7]=[C:8]([C:11]([CH:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21]C=2)C(OCC)=O)=O)[NH:9][CH:10]=1)([O-:5])=[O:4].O.[CH2:26]([OH:28])C>>[N+:3]([C:6]1[N:7]=[C:8]([CH:11]([C:13]2[CH:19]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26]([OH:28])=[O:1])[NH:9][CH:10]=1)([O-:5])=[O:4]
Reactant: [OH-]
Reactant: CCOC(=O)C(C(=O)c1nc([N+](=O)[O-])c[nH]1)c1ccccc1
Reactant: CCO
Agent: [Li+]
Solvent: O
Product: O=C(O)C(c1ccccc1)c1nc([N+](=O)[O-])c[nH]1
Temperature: 12 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
Lithium hydroxide (18.1 g, 750 mm, 2 eq) was added to a stirred slurry of ethyl 2-(4-nitroimidazoyl)-2-phenylacetate (Preparation 11 from Examples Part 1) (104 g, 379 mm) in 250 mL of ethanol. Deionized water was added to the resulting mixture and the stirring was continued for 4 hours. The ethanol was removed under vacuum and the resulting aqueous solution was washed with 100 mL of diethyl ether. The aqueous layer was diluted with 100 mL of deionized water and the pH was adjusted to 1.8 with concentrated HCl after cooling to 12° C. The resulting slurry was stirred for 30 minutes at less than 5 degrees and filtered. The wet cake was washed with 100 mL of deionized water and dried under a stream of air on the filter overnight to yield 90.34 g (96%) of a brown solid. The product may be recrystallized from isopropyl alcohol to give 72.31 g (80% recovery, 77% overall yield) of a tan solid. Elemental analysis: Calculated: % C 53.45, % H 3.67. % N 16.97; Found: % C 53.67, % H 3.79, % N 16.65. MS: 247 (M+): IR (cm−1) 1719; H1 nmr (d6 DMSO): d 6.51 (s, 1H), 7.43-7.55 (m, 5H), 7.95 (s, 1H), 8.40 (s, 1H)