Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([O:15][C:16]3[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=3[F:26])(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:27][C:28]1[CH:29]=[C:30]([C:35]2[CH:40]=[CH:39][C:38](B(O)O)=[C:37]([O:44][CH3:45])[CH:36]=2)[CH:31]=[C:32]([F:34])[CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>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>[F:27][C:28]1[CH:29]=[C:30]([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[C:11]4[C:6](=[CH:7][C:8]([S:12]([O:15][C:16]5[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=5[F:26])(=[O:14])=[O:13])=[CH:9][CH:10]=4)[CH:5]=[CH:4][N:3]=3)=[C:37]([O:44][CH3:45])[CH:36]=2)[CH:31]=[C:32]([F:34])[CH:33]=1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Cl)nccc2c1
Reactant: COc1cc(-c2cc(F)cc(F)c2)ccc1B(O)O
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: [K+]
Product: COc1cc(-c2cc(F)cc(F)c2)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Yield: 65.5 %

Procedure:
A round-bottom flask was charged with perfluorophenyl 1-chloroisoquinoline-6-sulfonate (see EXAMPLE 73, STEP 1, 4.40 g, 10.74 mmol), (3′,5′-difluoro-3-methoxy-[1,1′-biphenyl]-4-yl)boronic acid (INTERMEDIATE JJJJJ; 3.40 g, 12.89 mmol), potassium carbonate (4.45 g, 32.2 mmol), and Pd(Ph3P)4 (1.241 g, 1.074 mmol). The flask was flushed with Ar (g), then 1,4-dioxane (40.3 ml) and water (13.42 ml) were added in sequence. The flask was fitted with a reflux condenser and lowered into a 50° C. heating bath for 1 h. The mixture was diluted with water and extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. TLC showed two major spots. The residue was purified by chromatography on silica gel (100-g SNAP Ultra column, 0-50% EtOAc/Heptane). Fractions containing the desired product were combined and concentrated to give perfluorophenyl 1-(3′,5′-difluoro-3-methoxy-[1,1′-biphenyl]-4-yl)isoquinoline-6-sulfonate (4.179 g, 7.04 mmol, 65.6% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.93 (d, J=1.6 Hz, 1H), 8.84 (d, J=5.6 Hz, 1H), 8.20 (d, J=5.7 Hz, 1H), 8.07 (dd, J=1.9, 9.0 Hz, 1H), 7.95 (d, J=8.9 Hz, 1H), 7.70-7.62 (m, 2H), 7.59-7.50 (m, 3H), 7.36-7.27 (m, 1H), 3.79 (s, 3H). m/z (ESI) 594.0 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O>>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1B(O)O
Reactant: Nc1nc2c(Br)cccn2n1
Product: COc1ccccc1-c1cccn2nc(N)nc12

Procedure:
8-(2-Methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (1.0 g, 0.0047 mol) and 2-methoxybenzeneboronic acid (1.1 g, 0.0070 mol) in a manner analogous to Step 2c. The reacting product was isolated as a brown solid (1.0 g) and was used without further purification. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.50 (d, J=6.5 Hz, 1H), 7.51 (dd, J=7.6, 1.5 Hz, 1H), 7.43-7.36 (m, 2H), 7.13 (d, J=8.1 Hz, 1H), 7.02 (t, J=7.3 Hz, 1H), 6.91 (t, J=7.0 Hz, 1H), 5.96 (br s, 2H), 3.73 (s, 3H). MS=241 (MH)+.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9]CC)=O.[NH2:12][C:13]([NH2:15])=[O:14]>>[NH:12]1[C:2]2[CH2:6][CH2:5][CH2:4][C:3]=2[C:7](=[O:9])[NH:15][C:13]1=[O:14]
Reactant: NC(N)=O
Reactant: CCOC(=O)C1CCCC1=O
Product: O=c1[nH]c2c(c(=O)[nH]1)CCC2

Procedure:
Similarly, compounds of this invention can be prepared as illustrated by the exemplary reaction in Scheme 3. Reaction of cyclopentanone with diethyl carbonate in THF in the presence of NaH produced ethyl 2-oxocyclopentanecarboxylate. Reaction of ethyl 2-oxocyclopentanecarboxy late with urea at 175-185° C. produced 6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione. Reaction of 6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione with hexamethyldisilazane (HMDS) in toluene in the presence of concentrated sulfuric acid, produced the intermediate 2,4-di(trimethylsilyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidine. Reaction of 2,4-di(trimethylsilyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidine with methyl 3-(bromomethyl)benzoate in DMF, followed by treatment with 1,4-dioxane and methanol, produced 1-(3-methoxycarbonylbenzyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione. Treatment of the ester with NaOH in water-methanol produced 1-(3-carboxybenzyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione. Coupling of the acid with a substituted amine, such as 1-(pyrimidin-2-yl)piperazine, in the presence of coupling agents, such as HATU and DIPEA in DMF, produced the targeted compound 1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([OH:17])=[CH:7][CH:8]=2)[N:3]=1.[CH2:18](Br)[CH:19]=[CH2:20]>>[CH2:20]([O:17][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:11][C:2]([CH3:1])=[N:3]2)=[CH:8][CH:7]=1)[CH:19]=[CH2:18]
Reactant: Cc1cc(N2CCCC2)c2ccc(O)cc2n1
Reactant: C=CCBr
Product: C=CCOc1ccc2c(N3CCCC3)cc(C)nc2c1

Procedure:
In analogy to example 6 there was prepared: on reaction of 2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with allyl bromide, whereby the product was isolated as free base, 7-allyloxy-2-methyl-4-pyrrolidin-1-yl-quinoline as a light yellow solid. EI mass spectrum, m/e: 268.2 (M calculated for C17H20N2O: 268).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[CH:8][C:7]=1[O:17][CH3:18]>C(O)(=O)C>[OH:5][C:6]1[C:11]([N+:1]([O-:4])=[O:2])=[CH:10][C:9]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[CH:8][C:7]=1[O:17][CH3:18]
Reactant: CCCC(=O)c1ccc(O)c(OC)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCCC(=O)c1cc(OC)c(O)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
6.5 ml of 11.2N nitric acid are added dropwise to a solution of 12.7 g of 4'-hydroxy-3'-methoxybutyrophenone in 250 ml of glacial acetic acid while stirring within 10 minutes. The reaction mixture is subsequently stirred for 15 minutes, poured into ice-water, the separated precipitate is filtered under suction, washed with ice-water and taken up in methylene chloride. The methylene chloride solution is filtered over 50 g of silica gel. The material obtained is recrystallized from methylene chloride/n-hexane. There is obtained 4'-hydroxy-3'-methoxy-5'-nitrobutyrophenone in the form of yellow crystals of m.p. 92°-93°.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([O:18][CH3:19])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:20][C:21]1[NH:22][C:23]2[C:28]([C:29]=1[CH3:30])=[CH:27][C:26]([NH2:31])=[CH:25][CH:24]=2>CCO>[CH3:20][C:21]1[NH:22][C:23]2[C:28]([C:29]=1[CH3:30])=[CH:27][C:26]([NH:31][C:2]1[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]([N:13]4[CH2:17][CH2:16][C@@H:15]([O:18][CH3:19])[CH2:14]4)=[O:12])[S:10][C:3]=13)=[CH:25][CH:24]=2
Reactant: Cc1[nH]c2ccc(N)cc2c1C
Reactant: CO[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Solvent: CCO
Product: CO[C@@H]1CCN(C(=O)c2cc3nccc(Nc4ccc5[nH]c(C)c(C)c5c4)c3s2)C1
Yield: 96.1 %

Procedure:
A solution of (3R)-(7-chloro-thieno[3,2-b]pyridin-2-yl)-(3-methoxy-pyrrolidin-1-yl)-methanone (139 mg, 0.47 mmol) and 2,3-dimethyl-1H-indol-5-ylamine (75 mg, 0.47 mmol) in EtOH (10 mL) was heated to reflux. After 12 h the reaction mixture was concentrated onto silica gel (5 mL) and purified on silica gel by flash column chromatography CH2Cl2/MeOH/NH4OH (98.5/1/0.5) to afford the title compound as a yellow solid, (190 mg). MS: 421.3 (MH+); HPLC Rf: 4.708 min.; HPLC purity: 99%.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:20](O)(=[O:24])[C:21]([CH3:23])=[CH2:22].Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[Br:19][C:15]1[CH:14]=[C:13]([NH:12][C:6]2[C:5]3[C:10](=[CH:11][C:2]([NH:1][C:20](=[O:24])[C:21]([CH3:23])=[CH2:22])=[CH:3][CH:4]=3)[N:9]=[CH:8][N:7]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Reactant: C=C(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: C=C(C)C(=O)Nc1ccc2c(Nc3cccc(Br)c3)ncnc2c1
Reaction time: 8 h
Yield: 23.4 %

Procedure:
To a stirred solution of 7-amino-4-[(3-bromophenyl)amino]quinazoline (J Med Chem, 1995;38:3482) (150 mg, 0.48 mmol) in dry DMF (20 mL) was added methacrylic acid (200 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI.HCl) (2.5 mol, 228 mg), the reaction mixture was stirred overnight then further amounts of EDCI.HCl (230 mg) and methacrylic acid (200 mg) were added. After a further 2 days stirring the solvent was removed under vacuum and the residue diluted with saturated NaHCO3, extracted with ethyl acetate (EtOAc) and then the combined organic extracts were dried over anhydrous Na2SO4, concentrated under reduced pressure and chromatographed on silica gel eluting with MeOH/CH2Cl2/EtOAc (5:45:50) to MeOH/CH2Cl2/EtOAc (10:40:50) to give N-[4-[(3-bromophenyl)amino]quinazolin-7-yl]-2-methyl-acrylamide (43 mg, 24%) as a pale brown solid, np (CH2Cl2/hexane) 255-259° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[Cl:9].C([Li])CCC.C[O:16][B:17](OC)[O:18]C.Cl>O1CCCC1.O>[Cl:9][C:3]1[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=1[B:17]([OH:18])[OH:16]
Reactant: Clc1cccc(Br)c1Cl
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: OB(O)c1cccc(Cl)c1Cl
Temperature: -78 °C
Reaction time: 1.25 h

Procedure:
A solution of 1-bromo-2,3-dichlorobenzene (20 g, 0.088 mole, Aldrich) in dry tetrahydrofuran (44.24 ml) was added dropwise to a solution of n-butyllithium (1.6M in hexane, 66.36 ml, 0.11 mole) in anhydrous tetrahydrofuran (16 ml), maintaining the temperature below −65° C. The resulting pale yellow suspension was stirred at −78° C. for 75 min. Trimethylborate (13.28 ml, 12.16 g, 0.12 mole) was added dropwise maintaining the temperature below −55° C. The resulting pale yellow solution was warmed to room temperature overnight. Excess n-butyllithium was decomposed with water (30 ml) and the reaction mixture was evaporated in vacuo. The residue obtained was suspended in water and acidified with 2M hydrochloric acid (10 ml). The insoluble solid was filtered, washed well with water and dried. The solid was suspended in 60-80° C. petroleum ether, stirred at room temperature for 10 min, filtered dried in vacuo. Yield 8.42 g (50%), M.p. 235-238° C.
Reaction SMILES: Cl.CN([CH2:5][C:6]1[C:7](=[O:13])[NH:8][C:9](=[O:12])[NH:10][CH:11]=1)C.[CH:14]([C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[C:18]=1[NH2:19])([CH3:16])[CH3:15]>C(O)CO>[NH2:19][C:18]1[C:20]([CH:24]([CH3:25])[CH3:26])=[CH:21][C:22]([CH2:5][C:6]2[C:7](=[O:13])[NH:8][C:9](=[O:12])[NH:10][CH:11]=2)=[CH:23][C:17]=1[CH:14]([CH3:16])[CH3:15]
Reactant: CN(C)Cc1c[nH]c(=O)[nH]c1=O
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: Cl
Solvent: OCCO
Product: CC(C)c1cc(Cc2c[nH]c(=O)[nH]c2=O)cc(C(C)C)c1N

Procedure:
A mixture of 5-dimethylaminomethyluracil hydrochloride (10.28 g, 50.0 mmol) and 2,6-diisopropylaniline (10.64 g, 60.0 mmol) in ethylene glycol (75 mL) was heated for 41/2 hours at 134°-137° C. After cooling, the title compound was filtered, washed with ethanol, and dried (5.55 g, 37%). A second crop was obtained from the mother liquor upon standing (3.24 g, 21.5%). The two crops were combined and recrystallized from methanol to give the purified title compound (5.84 g, 38.8%).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:11]([OH:23])[CH:10]=1)(=[O:4])[NH:2][NH2:3].[CH3:24][C:25]1([CH3:41])[CH2:30][CH:29]([NH:31][C:32](=[O:38])[C:33](OCC)=[O:34])[CH2:28][C:27]([CH3:40])([CH3:39])[NH:26]1>CO>[CH3:24][C:25]1([CH3:41])[CH2:30][CH:29]([NH:31][C:32](=[O:38])[C:33]([NH:3][NH:2][C:1]([O:5][CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:11]([OH:23])[CH:10]=2)=[O:4])=[O:34])[CH2:28][C:27]([CH3:40])([CH3:39])[NH:26]1
Reactant: NNC(=O)OCCOc1ccc(C(=O)c2ccccc2)c(O)c1
Reactant: CCOC(=O)C(=O)NC1CC(C)(C)NC(C)(C)C1
Solvent: CO
Product: CC1(C)CC(NC(=O)C(=O)NNC(=O)OCCOc2ccc(C(=O)c3ccccc3)c(O)c2)CC(C)(C)N1
Temperature: 70 °C

Procedure:
Into a 100 ml 3-neck flask was added 6.4 grams (0.027 mole) of 2-(3-hydroxy-4-benzoylphenoxy)ethyl carbazate from (A), 8.1 grams (0,027 mole) of a 60% solution of ethyl N-(2,2,6,6-tetramethyl-4-piperidinyl)oxamate and 25 ml of methanol. The flask was equipped with a magnetic stirrer, thermometer and a Dean Stark trap with a reflux condenser. The reaction was heated in an oil bath and the methanol was slowly distilled off through the Dean Stark trap. After the methanol stopped coming over, the reaction was heated one hour, a vacuum was applied to the system to remove any residual methanol and the reaction was heated for another 11/2 hours at 70° C. The reaction was dissolved in 50 ml of hot methanol. The solution was filtered to remove a small amount of insoluble material. The methanol was stripped from the filtrate on a rotating evaporator, leaving 9.4 grams of a yellow crystalline solid. Liquid chromatography indicated the product was about 85-90% pure.
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([O:10][CH2:11][CH2:12][C@@H:13]3[CH2:15][C@@H:14]3[CH:16]3[CH2:21][CH2:20][N:19]([C:22]#[N:23])[CH2:18][CH2:17]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[OH:26][NH:27][C:28](=N)[CH:29]([CH3:31])[CH3:30]>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][C@@H:13]3[CH2:15][C@@H:14]3[CH:16]3[CH2:17][CH2:18][N:19]([C:22]4[O:26][N:27]=[C:28]([CH:29]([CH3:31])[CH3:30])[N:23]=4)[CH2:20][CH2:21]3)=[CH:24][CH:25]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: N#CN1CCC([C@H]2C[C@H]2CCOc2ccc(-n3cnnn3)cc2)CC1
Reactant: CC(C)C(=N)NO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CCOc3ccc(-n4cnnn4)cc3)CC2)n1
Temperature: 25 °C
Yield: 38.3 %

Procedure:
To a solution of 4-((1R,2S)-2-(2-(4-(1H-tetrazol-1-yl)phenoxy)ethyl)cyclopropyl)piperidine-1-carbonitrile (Step A, Example 83; 150 mg, 0.444 mmol) and N-hydroxyisobutyrimidamide (54 mg, 0.53 mmol) in tetrahydrofuran (5 mL) was added zinc chloride (1.1 mL, 0.5 M in tetrahydrofuran, 0.53 mmol). The mixture was refluxed for 2 h, cooled to RT, and concentrated to dryness under reduced pressure. The residue was dissolved in 2 mL of 4N HCl ethanol and water (1:1). The solution was refluxed for 1 hour, cooled to RT, and concentrated to dryness under reduced pressure. The residue was dissolved in methanol (5 mL), neutralized by the addition of excess potassium carbonate, mixed with silica gel (2 g), and concentrated to dryness under reduced pressure. The residue was loaded on a silica gel column (15 g of silica gel) and eluted with dichloromethane/methanol (199:1, 1 L) to provide impure product (72 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)=[N:10]1.Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[C:34]([OH:36])=[O:35]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)[NH:12][C:13]([CH2:20][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[C:34]([OH:36])=[O:35])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(n2cncn2)=NC1c1ccc(F)cc1Br
Reactant: O=C(O)C1COCCN1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(n2cncn2)=NC1c1ccc(F)cc1Br
Yield: 31 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(1H-1,2,4-triazol-1-yl)-1,4-dihydropyrimidine-5-carboxylate (1.75 g, 3.6 mmol) was reacted with morpholine-3-carboxylic acid hydrochloride (0.6 g, 3.6 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a pale yellow solid (0.6 g, 31%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].[Cl:15][C:16]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:17]=1[O:18][CH2:19][C:20]([OH:22])=[O:21].Cl>C(=S)=S>[Cl:15][C:16]1[C:26]([Cl:27])=[C:25]([C:8](=[O:9])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[F:5])[CH:24]=[CH:23][C:17]=1[O:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: O=C(O)COc1cccc(Cl)c1Cl
Reactant: O=C(Cl)c1ccccc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C(O)COc1ccc(C(=O)c2ccccc2F)c(Cl)c1Cl
Temperature: 0 °C

Procedure:
To a mixture of 12.5 g of aluminum chloride and 45 ml of carbon disulfide there is added dropwise 7.1 g of 2-fluorobenzoyl chloride while maintaining the temperature below 0° C. This low temperature is maintained for 1.5 hours. While maintaining this same low temperature, 5 g of 2,3-dichlorophenoxyacetic acid is added incrementally. After addition is complete, the reaction mixture is maintained at this low temperature for 30 minutes and then permitted to reach ambient temperature after which it is refluxed for 28 hours. The carbon disulfide is decanted from the refluxed solution leaving dark orange residue which is poured onto a mixture of 500 ml of ice/water and 100 ml of concentrated hydrochloric acid. The resulting pink precipitate is collected by filtration, rinsed with 300 ml of warm water (50° C.) and dried in vacuum oven. The dried product is recrystallized twice from aqueous ethyl alcohol to form the product 2,3-dichloro-4-(2-fluorobenzoyl)phenoxyacetic acid having a melting point of 153° to 156° C.
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]2[CH:8]=[CH:9][N:10]3[CH:16]=[CH:15][CH:14]=[C:11]3[C:12](=[O:13])[C:6]=2[CH:5]=1)(=[O:3])N.S(=O)(=O)(O)[OH:20].N([O-])=O.[Na+]>O>[C:1]([C:4]1[CH:18]=[CH:17][C:7]2[CH:8]=[CH:9][N:10]3[CH:16]=[CH:15][CH:14]=[C:11]3[C:12](=[O:13])[C:6]=2[CH:5]=1)([OH:20])=[O:3]
Reactant: O=S(=O)(O)O
Reactant: NC(=O)c1ccc2ccn3cccc3c(=O)c2c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc2ccn3cccc3c(=O)c2c1

Procedure:
To 9-carbamoyl-11H-pyrrolo[2,1-b][3]benzazepin-11-one (27 g., 0.112 moles) in 300 ml. of 50% sulfuric acid maintained at 50° C. is added slowly 25 g. of sodium nitrite in 75 ml. of water. At the end of the addition, the solid is filtered, washed with water and air-dried to yield 9-carboxy-11H-pyrrolo[2,1-b][3]benzazepin-11-one.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7])=[O:2].S(Cl)([Cl:14])=O.CN(C)C=O>C1(C)C=CC=CC=1>[CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([Cl:14])=[O:7])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=Cc1cccc(C(=O)O)c1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=Cc1cccc(C(=O)Cl)c1
Reaction time: 2 h

Procedure:
A mixture of 3-formylbenzoic acid (84 grams (g), 0.558 moles), thionyl chloride (80.5 g, 0.71 moles), and dimethylformamide (3 milliliters (ml)), in toluene (500 ml) was slowly warmed to 70° C. and stirred at that temperature for 2 hours. The toluene was eliminated in the rotavap to yield 97.7 g of 3-formylbenzoyl used in the next step as such.
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:13]3[O:14][CH2:15][CH2:16][CH2:17][C:12]3=[N:11][C:4]=1[CH:5]=[N:6]2.ClC1C=C(C=CC=1)C(OO)=[O:23]>ClCCl>[CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:13]3[O:14][CH2:15][CH2:16][CH2:17][C:12]3=[N:11][C:4]=1[CH:5]=[N+:6]2[O-:23]
Reactant: c1ccc2c(c1)ncc1nc3n(c12)OCCC3
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1cc2nc3n(c2c2ccccc21)OCCC3
Reaction time: 1 h
Yield: 101.8 %

Procedure:
9,10-Dihydro-8H-[1,2]oxazino[2′,3′:1,2]imidazo[4,5-c]quinoline (0.3339 g, 1.482 mmol) was dissolved in 5 mL of dichloromethane and treated with 3-chloroperoxybenzoic acid (0.95 g, 57-86% purity). After stirring for 1 hour, the reaction mixture was diluted with 15 mL of dichloromethane, washed successively with dilute aqueous K2CO3, H2O, and brine, dried over Na2SO4, and concentrated under reduced pressure to give 0.364 g of 9,10-dihydro-8H-[1,2]oxazino[2′,3′:1,2]imidazo[4,5-c]quinoline 5-oxide as a tan solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:7]=1[CH2:23]Br)=[O:5])[CH3:2].[CH2:25]([O:27][C:28](=[O:38])[CH2:29][NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH3:26]>>[CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[N:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[C:7]=1[CH2:23][N:30]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:29][C:28]([O:27][CH2:25][CH3:26])=[O:38])=[O:5])[CH3:2]
Reactant: CCOC(=O)CNC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1c(Br)c(C(C)(C)C)n(-c2ccc(F)cc2)c1CBr
Product: CCOC(=O)CN(Cc1c(C(=O)OCC)c(Br)c(C(C)(C)C)n1-c1ccc(F)cc1)C(=O)OC(C)(C)C

Procedure:
Prepared in analogy to that of Example 1(c) from 4-bromo-2-bromomethyl-5-tert-butyl-1-(4-fluoro-phenyl)-1H-pyrrole-3-carboxylic acid ethyl ester and tert-butoxycarbonylamino-acetic acid ethyl ester. The title compound, ESI MS (m/z): 605 (M+Na+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([C:15]([NH:17][NH2:18])=O)[CH2:14][CH2:13]1.O.C([O-])(O)=O.[Na+]>O=P(Cl)(Cl)Cl>[Br:11][C:8]1[CH:7]=[C:3]([C:4]2[O:6][C:15]([CH:12]3[CH2:14][CH2:13]3)=[N:17][N:18]=2)[C:2]([NH2:1])=[N:10][CH:9]=1
Reactant: Nc1ncc(Br)cc1C(=O)O
Reactant: NNC(=O)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1ncc(Br)cc1-c1nnc(C2CC2)o1
Temperature: 0 °C
Yield: 95.4 %

Procedure:
A solution of 2-amino-5-bromo-nicotinic acid (300 mg, 1.38 mmol) and cyclopropanecarboxylic acid hydrazide (300 mg, 3.0 mmol) in POCl3 (30.0 mL,) was stirred for 18 h at 65° C. The reaction mixture was distilled under reduced pressure to obtain a residue, which was cooled to 0° C. by adding iced water and neutralizing with saturated NaHCO3 solution (100 mL). The aqueous layer was extracted with ethyl acetate. The ethyl acetate layer was separated, dried over anhydrous Na2SO4 and evaporated to afford 370 mg of crude 5-bromo-3-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)-pyridin-2-ylamine. Crude compound was purified by column chromatography using silica gel (100-200 mesh). The column was eluted with 15% EtOAc in petroleum ether to afford the title compound as a pale yellow solid used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=[O:10])=[N:6][C:7]=1[CH3:8].OS(O)(=O)=O.[CH3:17]O>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([O:11][CH3:17])=[O:10])=[N:6][C:7]=1[CH3:8]
Reactant: CO
Reactant: Cc1nc(C(=O)O)ccc1N
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(N)c(C)n1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 5-amino-6-methylpicolinic acid (31D, 240 mg, 1.5 mmol) in methanol was added conc. H2SO4. The solution was stirred at 60° C. overnight, when LC-MS showed that s.m. was consumed. Then the mixture was concentrated and neutralized with Na2CO3 solution to pH=7. The mixture was extracted with DCM (10 mL×3). The organic layer was dried and concentrated to give the title compound 31E. LC-MS: m/z 167 (M+H)+