Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][N:19]=4)[CH:17]=3)=[C:11]([CH3:27])[N:10]=[N:9]2)=[CH:4][CH:3]=1.C1N=C[N:30](C(N2C=NC=C2)=O)C=1.[OH-].[NH4+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[CH:26]=[CH:25][C:21]([C:22]([NH2:30])=[O:23])=[CH:20][N:19]=4)[CH:17]=3)=[C:11]([CH3:27])[N:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1nnn(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(N)=O)cn2)cn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
To a solution of 6-(4-(1-(4-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (70 mg, 0.192 mmol) in DMF (2 mL) was added CDI (38 mg, 0.231 mmol) and the resulting mixture stirred at 60° C. for 1 h. After cooling to room temperature ammonium hydroxide (300 μL, 1.92 mmol) was added and reaction mixture was stirred for 16 h and then evaporated. Purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (61 mg, 87%) as an off white solid. MS: m/e=364.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:16][CH2:17][CH3:18]>CN(C=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[N:7]([CH2:16][CH2:17][CH3:18])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCCI
Reactant: O=c1[nH]cnc2cc(Br)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1cnc2cc(Br)ccc2c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 7-bromoquinazolin-4(3H)-one (0.2 g, 0.89 mmol) and DMF (20 mL) was added sodium hydride (85 mg, 3.5 mmol) in portions. The reaction mixture was stirred at room temperature for 15 min. 1-iodopropane (0.18 g, 1.1 mmol) was added dropwise. After stirring for 30 min., the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give the desired product. MS (ESI): 267, 269 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[C:17]([NH:19][CH3:20])[C:16]([N+:21]([O-:23])=[O:22])=[CH:15][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12](O)=[O:13])[CH:7]=1.C[N:25](C)CCCN=C=NCC.N1C2C(=NC=CC=2)N(O)N=1.C(NC(C)C)(C)C.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:18]=[C:17]([NH:19][CH3:20])[C:16]([N+:21]([O-:23])=[O:22])=[CH:15][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([NH2:25])=[O:13])[CH:7]=1
Reactant: CNc1cc(OC)c(Oc2ccnc(C(=O)O)c2)cc1[N+](=O)[O-]
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CNc1cc(OC)c(Oc2ccnc(C(N)=O)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture containing 4-(2-methoxy-4-(methylamino)-5-nitrophenoxy)pyridine-2-carboxylic acid (1 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2 eq), 3H-1,2,3-triazolo[4,5-b]pyridine-3-ol (1.5 eq), and diisopropylamine (5 eq) in tetrahydrofuran was stirred at room temperature for 1 hour. To this was then added ammonium chloride (2 eq) and the resulting mixture was stirred together for 48 hours. Reaction concentrated. Purification on silica gel, 50% acetone in hexanes to yield 4-(2-methoxy-4-(methylamino)-5-nitrophenoxy)pyridine-2-carboxamide as a bright yellow solid. HPLC=3.70 min; MS: MH+=319.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[C:13]([OH:20])=[CH:14][CH:15]=[C:16]([C:17]([OH:19])=[O:18])[C:10]=3[N:9]=2)=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:26]O>>[CH3:26][O:18][C:17]([C:16]1[C:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[NH:12][C:11]=2[C:13]([OH:20])=[CH:14][CH:15]=1)=[O:19]
Reactant: O=C(O)c1ccc(O)c2[nH]c(-c3ccc(F)cc3)nc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)c2[nH]c(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Yield: 76 %

Procedure:
2-(4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid (500 mg, 1.84 mmol) obtained in step 3 was dissolved in methanol, H2SO4 (0.49 ml, 9.20 mmol) was added dropwise thereto and refluxed for 15 hours. The resulting solution was cooled to room temperature, concentrated under a reduced pressure to remove methanol, and the residue was neutralized with NaHCO3. Then, the neutralized residue was extracted with ethyl acetate and concentrated under a reduced pressure to obtain a residue which was purified by silica gel chromatography to obtain the title compound (397 mg, 1.39 mmol) in a yield of 76%.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[Na].Br[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1>C(O)C>[CH2:8]([O:7][C:1]([CH:2]([C:3](=[O:4])[CH3:5])[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)=[O:6])[CH3:9]
Reactant: BrCc1ccc2ccccc2c1
Reactant: CCOC(=O)CC(C)=O
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc2ccccc2c1)C(C)=O
Reaction time: 6 h
Yield: 114.1 %

Procedure:
In a four-necked flask equipped with a thermometer, dropping funnel and stirrer were placed 179 g (1.375 moles) of ethyl acetoacetate and 500 ml of ethanol, and then 31.5 g (1.375 moles) of sodium was added in portions thereto to form a solution. Then, a solution of 276.4 g (1.25 moles) of 2-bromomethylnaphthalene in 1000 ml of ethanol was added dropwise to the above solution at room temperature over a period of 2 hours. After completion of the addition, the resulting mixture was brought up to 65° C. and stirred at the same temperature for 6 hours. After completion of the reaction ethanol was distilled off under reduced pressure, the residue obtained was extracted by addition of 1500 ml of toluene, and the organic layer was separated. The organic layer was washed with 10% hydrochloric acid, water, 5% aqueous sodium bicarbonate solution and water in said order and then concentrated under reduced pressure to obtain 385.4 g of 2-(2-ethoxycarbonyl-3-oxobutyl)naphthalene as a crude product.
Reaction SMILES: [F:1][C:2]([CH3:32])([CH3:31])[CH:3]=[CH:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:22]3[C:17](=[CH:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[N:16]=[C:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[OH:30])[N:14]=2)[CH2:9][CH2:8]1)=[O:6].[H][H]>CO.[Pd]>[F:1][C:2]([CH3:32])([CH3:31])[CH2:3][CH2:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([C:13]2[C:22]3[C:17](=[CH:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[N:16]=[C:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[OH:30])[N:14]=2)[CH2:11][CH2:12]1)=[O:6]
Reactant: Cc1ccc2c(N3CCN(C(=O)C=CC(C)(C)F)CC3)nc(-c3ccccc3O)nc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc2c(N3CCN(C(=O)CCC(C)(C)F)CC3)nc(-c3ccccc3O)nc2c1

Procedure:
To 4-fluoro-1-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-methyl-pent-2-en-1-one (228 mg) in 1.5 mL of methanol was added Pd/C (34 mg, 10% weight Pd on carbon), and the reaction mixture was hydrogenated with a hydrogen balloon for 1 h. The resulting mixture was filtered through Celite, and the solvent was removed to give 4-fluoro-1-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-methyl-pentan-1-one. LC/MS: m/z 437.4 (M+H)+ at 2.86 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [C:1]1([CH:7]2[N:11]=[CH:10][C:9](=[O:12])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[S:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1>C(Cl)Cl>[C:7]([NH:11][CH2:10][C:9]([C:18]1[S:17][CH:21]=[CH:20][CH:19]=1)=[O:12])(=[O:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccsc1
Reactant: O=C1C=NC(c2ccccc2)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(NCC(=O)c1cccs1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 42.2 %

Procedure:
A 500 mL, round-bottomed, 3-necked flask was charged with 23.0 g (142.7 mmol) of 2-phenyl-5-oxazolone, and 250 mL of dried methylene chloride, and cooled in an ice bath under a nitrogen atmosphere. Using a powder addition funnel, 57.0 g (3.0 equiv.) of aluminum chloride was added over a period of 1 hour to the stirred reaction mixture. After holding for 20 minutes the gradual addition of thiophene (14.4 mL, 1.22 equiv.) was carried out over a 1 hour period. The reaction mixture was then stirred overnight (15 hours) at room temperature, and the reaction was then quenched by the addition of iced water. The product was extracted several times with methylene chloride, and the combined extracts were dried over anhydrous sodium sulfate, filtered, then stripped on a rotary evaporator. After drying at the pump the crude product (33.96 g) was recrystallized from hot methanol with activated charcoal treatment to yield 14.77 g (42.2%) of α-N-benzoylamino-2-acetylthiophene was a white solid; mp 153°-154° C. Re-work of the mother liquor afforded a second batch of product (mp 140°-146° C.), bringing the total yield of product to 47.3%.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]([CH3:21])=[CH:19][C:18]3[C:17]([CH3:23])([CH3:22])[CH2:16][CH2:15][C:14]([CH3:25])([CH3:24])[C:13]=3[CH:12]=2)=[CH:7][C:6]=1[C:26](=[CH2:30])[C:27]([OH:29])=[O:28].CO.[CH2:33]1COCC1.S(=O)(=O)(O)O>O>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]([CH3:21])=[CH:19][C:18]3[C:17]([CH3:23])([CH3:22])[CH2:16][CH2:15][C:14]([CH3:25])([CH3:24])[C:13]=3[CH:12]=2)=[CH:7][C:6]=1[C:26](=[CH2:30])[C:27]([O:29][CH3:33])=[O:28]
Reactant: C=C(C(=O)O)c1cc(-c2cc3c(cc2C)C(C)(C)CCC3(C)C)ccc1OCOC
Reactant: C1CCOC1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: C=C(C(=O)OC)c1cc(-c2cc3c(cc2C)C(C)(C)CCC3(C)C)ccc1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1.9 g (4.35 mmol) of 2-methoxymethoxy-5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenylacrylic acid, 20 ml of methanol and 30 ml of THF are introduced into a round-bottomed flask. 2.8 ml of concentrated sulphuric acid are added and the mixture is stirred at room temperature for 12 hours. The reaction medium is poured into water and extracted with ethyl ether, and the organic phase is separated out after settling has taken place, washed with water, dried over magnesium sulphate and evaporated. 1.63 g (95%) of methyl 2-hydroxy-5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenylacrylate are collected.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[C:7]([CH:12]2[CH2:14][CH2:13]2)[N:6]=1)=[O:4].Br[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1>>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:9][CH:8]=[C:7]([CH:12]2[CH2:14][CH2:13]2)[N:6]=1)=[O:4]
Reactant: Brc1cccnc1
Reactant: COC(=O)c1nc(C2CC2)cnc1N
Product: COC(=O)c1nc(C2CC2)cnc1Nc1cccnc1

Procedure:
The product was obtained starting from 3-amino-6-cyclopropylpyrazine-2-carboxylic acid methyl ester (200 mg, 1.04 mmol; intermediate A-10, step 2) and 3-bromopyridine (142 μl, 1.45 mmol) according to the method described in example A-1, step 2 as yellow solid (192 mg, 68%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10](=[NH:12])[NH2:11].C[O:14][C:15](=O)/[C:16](/[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[C:17](\O)/[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C[O-].[Na+].Cl>CO>[C:21]([O:20][C:18]([C:17]1[NH:12][C:10]([CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[Br:2])=[N:11][C:15](=[O:14])[C:16]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: N=C(N)Cc1ccccc1Br
Reactant: COC(=O)/C(OCc1ccccc1)=C(\O)C(=O)OC(C)(C)C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)c1[nH]c(Cc2ccccc2Br)nc(=O)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 71.3 %

Procedure:
2-(2-Bromophenyl)acetimidamide hydrochloride (2 g, 8.01 mmol, Eq: 1.00) and 4-tert-butyl 1-methyl 2-(benzyloxy)-3-hydroxyfumarate (4) (3.44 g, 11.2 mmol, Eq: 1.39) were dissolved in methanol (40.0 ml) and cooled down to 0° C. At that temperature sodium methoxide (1.37 g, 24.0 mmol, Eq: 3) was added. After another 15 minutes at this temperature, the resulting suspension was allowed to warm to room temperature overnight. A little methanol (˜5 ml) was added and the yellow suspension was cooled to 0° C. 1M HCl (˜50 ml) was added and a precipitate formed. The suspension was stirred for −20 minutes. The solid was collected by filtration, washed with water and a little methanol/water 9/1 and dried to afford 5-(benzyloxy)-2-(2-bromobenzyl)-6-oxo-3,6-dihydro-pyrimidine-4-carboxylic acid tert-butyl ester (2.69 g, 5.71 mmol, 71.2% yield) (67) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=O)[CH:19]=3)=[O:17])[CH:9]=2)=[CH:4][C:3]=1[CH2:26][N:27]1[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[C@@H:29]([CH3:40])[CH2:28]1.[NH2:41][CH2:42][C:43]1[C:48]([CH2:49][CH3:50])=[N:47][C:46]2[N:51]([CH2:54][CH3:55])[N:52]=[CH:53][C:45]=2[C:44]=1[NH:56][CH:57]1[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCl.O>[CH2:54]([N:51]1[C:46]2=[N:47][C:48]([CH2:49][CH3:50])=[C:43]([CH2:42][NH:41][CH2:24][C:20]3[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=3)[C:16]([NH:15][CH2:14][C:10]3[CH:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH2:26][N:27]5[CH2:32][CH2:31][NH:30][C@@H:29]([CH3:40])[CH2:28]5)[CH:4]=4)[CH:13]=[CH:12][CH:11]=3)=[O:17])[C:44]([NH:56][CH:57]3[CH2:58][CH2:59][O:60][CH2:61][CH2:62]3)=[C:45]2[CH:53]=[N:52]1)[CH3:55]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: C[C@H]1CN(Cc2cc(-c3cccc(CNC(=O)c4cccc(C=O)c4)c3)ccc2F)CCN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNCc1cccc(C(=O)NCc2cccc(-c3ccc(F)c(CN4CCN[C@@H](C)C4)c3)c2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1,1-dimethylethyl (2S)-4-{[4-fluoro-3′-({[(3-formylphenyl)-carbonyl]amino}methyl)-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (195 mg, 0.36 mmol) in dichloromethane (5 mL) was added 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine, and (110 mg, 0.36 mmol) and sodium triacetoxyborohydride (115 mg. 0.54 mmol) and the resulting solution was stirred at ambient temperature for 16 h and then treated with aqueous hydrochloric acid (2M, 2 mL) and stirred for a further 2 h. The mixture was treated with water (20 mL) and extracted with dichloromethane (25 mL). The organic phase was concentrated to dryness and the residue dissolved in methanol (5 mL), treated with aqueous hydrochloric acid (2M, 2 mL) and stirred at ambient temperature for 16 h. The mixture was then concentrated to dryness and the product purified by mass-directed automated preparative HPLC. Product-containing fractions were concentrated to dryness to afford 25 mg of the title compound. LC-MS m/z 733 (M+H)+, 0.79 min (ret time).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[Cl:26])[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1Cl
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(Cc1cc(-c2ccccc2Cl)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (2-chlorophenyl)boronic acid (218 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-blue oil (yield 171 mg, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=CN=3)[N:12]=[C:11]([C:20]([OH:22])=[O:21])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[N:24]1C=CC=C(NN)[CH:25]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:25]=[N:24][CH:17]=[CH:18][CH:19]=3)[N:12]=[C:11]([C:20]([OH:22])=[O:21])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: NNc1cccnc1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: Cl
Product: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2cccnc2)n1

Procedure:
807 mg (2.90 mmol) of the compound of Example 1A is reacted analogously to the synthesis of the compound of Example 20A with 464 mg (3.19 mmol) of 3-pyridylhydrazine hydrochloride. After hydrolysis, 353 mg (38% of theory) of the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][CH2:12]O)=[C:9]([Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[NH:8][C:5]2=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:40]C(Br)(Br)Br>C1COCC1>[Br:40][CH2:12][CH2:11][C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[NH:8][C:9]=1[Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16]
Reactant: CC[Si](CC)(CC)c1[nH]c2ncc(Cl)cc2c1CCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1[nH]c2ncc(Cl)cc2c1CCBr
Reaction time: 0.5 h
Yield: 44.9 %

Procedure:
3-(2-bromoethyl)-5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridine was prepared according to method D Step III with 2-(5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanol (2.0 g; 6.43 mmol) in THF (30 mL) and triphenyl phosphine (2.56 g; 9.65 mmol) and perbromomethane (3.27 g, 9.65 mmol) in THF (40 mL) pre-stirred for 30 minutes. The crude mixture was purified by flash chromatography on silica gel (eluent 5 to 40% of ethyl acetate in heptanes) to yield 1.08 g (45%) of 3-(2-bromoethyl)-5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridine as a white solid.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH:22]([OH:23])[C:21]3[S:24][CH2:25][CH:26]([O:29][CH3:30])[CH2:27][S:28][C:20]=3[C:19]2=[O:31])=[N:16][CH:17]=1>N1C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH:19]([O:31][C:2]([O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[O:3])[C:20]3[S:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25][S:24][C:21]=3[C:22]2=[O:23])=[N:16][CH:17]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COC1CSC2=C(SC1)C(O)N(c1ccc(Cl)cn1)C2=O
Solvent: c1ccncc1
Product: COC1CSC2=C(SC1)C(OC(=O)Oc1ccccc1)N(c1ccc(Cl)cn1)C2=O
Yield: 60.9 %

Procedure:
By reacting phenyl chloroformate (16.7 g) with 7-(5-chloropyrid-2-yl)-6-hydroxy-3-methoxy-8-oxo-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]-pyrrole (prepared as described in Example 1; 12.3 g) in anhydrous pyridine (100 cc) at between -10° C. and +20° C., 7-(5-chloropyrid-2-yl)-3-methoxy-8-oxo-6-phenoxycarbonyloxy-3,4,7,8-tetrahydro-2H,6H-1,4-dithiepino[2,3-c]pyrrole (m.p. 167° C.; 10.1 g) is obtained.
Reaction SMILES: [N:1]1([C:7]2[N:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]#[N:10])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:16]1[CH:21]=[C:20]([NH:22][CH:23]2[CH2:25][CH2:24]2)[N:19]2[N:26]=[CH:27][C:28]([CH:29]=[O:30])=[C:18]2[N:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:23]1([NH:22][C:20]2[N:19]3[N:26]=[CH:27][C:28]([CH:29]=[O:30])=[C:18]3[N:17]=[C:16]([N:4]3[CH2:3][CH2:2][N:1]([C:7]4[N:14]=[CH:13][CH:12]=[CH:11][C:8]=4[C:9]#[N:10])[CH2:6][CH2:5]3)[CH:21]=2)[CH2:24][CH2:25]1
Reactant: O=Cc1cnn2c(NC3CC3)cc(Cl)nc12
Reactant: N#Cc1cccnc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cccnc1N1CCN(c2cc(NC3CC3)n3ncc(C=O)c3n2)CC1
Temperature: 95 °C
Yield: 35 %

Procedure:
In a reaction flask, 2-(piperazin-1-yl)nicotinonitrile (22 mg, 0.11 mmol) was mixed with 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (27 mg, 0.11 mmol) in DMF (0.5 mL) along with potassium carbonate (32 mg, 0.23 mmol). The reaction was heated at 95° C. for 12 hours then partitioned between water and ethyl acetate. The organic layer was washed with water then saturated NaCl solution. The ethyl acetate layer was isolated, dried of anhydrous sodium sulfate, filtered, and evaporated to dryness. The product, 2-(4-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)piperazin-1-yl)nicotinonitrile, was recovered in 35% yield (16 mg) after recrystallization from ethyl acetate/hexanes. LCMS (M+1=389)
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([N:8]=[N:9][N:10]=2)[CH:5]=[CH:6][N:7]=1.[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)CC)C>CCO>[N:10]1[N:9]=[N:8][N:4]2[CH:5]=[CH:6][N:7]=[C:2]([N:14]3[CH2:13][CH2:12][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]3)[C:3]=12
Reactant: Clc1nccn2nnnc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2nccn3nnnc23)CC1
Yield: 89.7 %

Procedure:
A 3 L round bottom flask was charged with 8-chlorotetrazolo[1,5-a]pyrazine (350 g, 2.3 mol), tert-butyl piperazine-1-carboxylate (420 g, 2.3 mol), triethylamine (460 g, 4.5 mol), and EtOH (2 L). The mixture was heated at reflux for 1 h. Work-up: the reaction mixture was concentrated in vacuo. The residue was mixed with saturated aqueous NaHCO3 (1 L) and then extracted with CH2Cl2 (1 L×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 8% EtOAc in CH2Cl2 (containing 2% Et3N), to afford 630 g (91%) of the product as a white solid. MS m/z: 306 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[N:13](OCCC(C)C)=[O:14].Cl>CO>[OH:14]/[N:13]=[C:8]1/[C:9](=[O:12])[C:10]2[C:6]([CH2:7]/1)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=2
Reactant: COc1ccc2c(c1)C(=O)CC2
Reactant: CC(C)CCON=O
Agent: Cl
Solvent: CO
Product: COc1ccc2c(c1)C(=O)/C(=N/O)C2
Temperature: 40 °C
Reaction time: 2 h
Yield: 49.3 %

Procedure:
6-methoxy-2,3-dihydro-1H-inden-1-one (17.2 g, 106 mmol) was dissolved in methanol (700 mL). The mixture was heated to 40° C., then isoamyl nitrite (30 mL, 220 mmol) and concentrated hydrochloric acid (17 mL) were added. The reaction mixture was stirred at 40° C. for 2 hours. After cooled to room temperature, the precipitate was collected by filtration and dried under high vacuum to obtain product (10.0 g, yield 50%).
Reaction SMILES: [ClH:1].[OH:2][C@H:3]1[CH2:7][NH:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4]1.[CH3:11]COCC>CO>[ClH:1].[CH3:11][O:9][C:8](=[O:10])[C@@H:5]1[CH2:4][C@@H:3]([OH:2])[CH2:7][NH:6]1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: CCOCC
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H](O)CN1
Reaction time: 8 h
Yield: 93 %

Procedure:
Anhydrous HCl was bubbled through a stirred suspension of trans-4-hydroxy-L-proline (80 g, 0.61 mol) in 500 ml anhydrous methanol until the mixture was homogeneous. The reaction was heated to reflux for five hours, and the volume of the solvent then reduced by one half. Ether (100 ml) was added, and the mixture kept in a freezer overnight. The resulting precipitate was filtered, washed with ether and dried under reduced pressure to yield 111 g of present title product (93% yield). mp 170°-172° C.