Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([P:11]([O:16][CH2:17][CH3:18])(=[O:15])[O:12][CH2:13][CH3:14])([P:3]([O:8][CH2:9][CH3:10])(=[O:7])[O:4][CH2:5][CH3:6])[CH3:2].CCCCCC.C([Li])CCC.CSC1C=CC(S[Cl:39])=CC=1>O1CCCC1>[Cl:39][C:1]([P:3]([O:4][CH2:5][CH3:6])(=[O:7])[O:8][CH2:9][CH3:10])([P:11]([O:16][CH2:17][CH3:18])(=[O:15])[O:12][CH2:13][CH3:14])[CH3:2]
Reactant: CSc1ccc(SCl)cc1
Reactant: CCOP(=O)(OCC)C(C)P(=O)(OCC)OCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(C)(Cl)P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 13.29 g (40 mmol) of tetraethyl ethane-1,1-diphosphonate in 120 ml of dry tetrahydrofuran was cooled to -78° C. in an argon atmosphere followed by the addition of 24.24 ml (40 mmol) of a n-butyllithium hexane solution (1.65 mmol/ml) and stirring for 30 minutes. After adding a solution of 7.63 g (40 mmol) of 4-methylthiobenzenesulfenyl chloride in 50 ml of dry tetrahydrofuran to this mixture, the reaction mixture was allowed to warm up to room temperature followed by stirring for 3 hours. After pouring the resulting mixture into icewater, the mixture was extracted with ethyl acetate (3×150 ml). The solvent was distilled off under reduced pressure after the combined organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. A mixture of tetraethyl 1-methylthiophenyl)thio]ethane-1,1-diphosphonate and tetraethyl 1-chloroethane-1,1-diphosphonate was obtained as the residue. This mixture was then carefully purified with column chromatography (developing solvent: ethanol: ethyl acetate=5:95) to obtain 7.12 g of the target compound in the form of a yellow oily substance.
Reaction SMILES: [F:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:14]([C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1[O:18][CH2:19][CH:20]1[O:22][CH2:21]1)#[N:15]>C(O)(C)C.CCCCCC>[C:14]([C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1[O:18][CH2:19][CH:20]([OH:22])[CH2:21][N:11]1[CH2:10][CH2:9][N:8]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:13][CH2:12]1)#[N:15]
Reactant: N#Cc1ccccc1OCC1CO1
Reactant: Fc1cccnc1N1CCNCC1
Solvent: CCCCCC
Solvent: CC(C)O
Product: N#Cc1ccccc1OCC(O)CN1CCN(c2ncccc2F)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
To a solution of 1-(3-fluoro-2-pyridyl)piperazine (453 mg, 2.5 mmol) in 5 ml of isopropanol stirred at 70° C. under nitrogen was added portionwise 2-cyanophenoxy-2,3-epoxypropane (438 mg, 2.5 mmol) and the mixture stirred for 21/2 hours at 70° C. The solvent was removed in vacuo at room temperature and the residual oil was chromatographed on silica gel eluting with 5% methanol-chloroform. The product was obtained as a colorless oil which slowly solidified upon trituration in hexane to yield 0.66 g of 1-[3-(2-cyanophenoxy)-2-hydroxypropyl]-4-(3-fluoro-2-pyridyl)piperazine; m.p. 68°-70° C. Analysis satisfactory for C19H21FN4O2.
Reaction SMILES: [C:1]([C:11]1[O:12][C:13]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:14]=2[C:15]=1[NH2:16])(=[O:10])/[CH:2]=[CH:3]\[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O>CC(O)=O.OP(O)(O)=O>[Br:21][C:18]1[CH:19]=[CH:20][C:13]2[O:12][C:11]3[C:1](=[O:10])[CH2:2][CH:3]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=4)[NH:16][C:15]=3[C:14]=2[CH:17]=1
Reactant: Nc1c(C(=O)/C=C\c2ccccc2)oc2ccc(Br)cc12
Agent: O=P(O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C1CC(c2ccccc2)Nc2c1oc1ccc(Br)cc21
Temperature: 25 °C
Yield: 85 %

Procedure:
A solution of (Z)-2-cinnamoyl-3-amino-5-bromo-benzofuran (28 g, 81.83 mmol) in AcOH (70 mL) and H3PO4 (70 mL) was refluxed for 2 hours. TLC showed the reaction completed. The mixture was cooled to room temperature and poured into water (250 mL) The yellow solids precipitated out were collected by filtration to give 8-bromo-2-phenyl-2,3-dihydro-benzofuro[3,2-b]pyridin-4(1H)-one (6C) (23.8 g, 85% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:13][CH2:14][NH:15][CH2:16][CH2:17][OH:18])[N:8]=[C:7]3[C:19]4[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=4[S:21][C:5]=1[C:6]=23)([O-:3])=[O:2].[C:26](=O)(OC1C=CC=CC=1)[O:27]C1C=CC=CC=1.CC([O-])=O.[Na+].C1(O)C=CC=CC=1>>[N+:1]([C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:13][CH2:14][N:15]3[CH2:16][CH2:17][O:18][C:26]3=[O:27])[N:8]=[C:7]3[C:19]4[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=4[S:21][C:5]=1[C:6]=23)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c3c(nn2CCNCCO)-c2ccccc2Sc13
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Oc1ccccc1
Product: O=C1OCCN1CCn1nc2c3c(c([N+](=O)[O-])ccc31)Sc1ccccc1-2
Temperature: 25 °C

Procedure:
A mixture of 1.0 g (0.0025 mol) of 2-[[2-(5-nitro-2H[1]benzothiopyrano[4,3,2-cd]indazol-2-yl)-ethyl]amino]ethanol, 10.0 g (0.045 mol) of diphenyl carbonate, 0.3 g (0.0036 mol) of NaOAc and 10.0 g of phenol was treated at 110° C. for 16 hours, allowed to cool to room temperature, and triturated twice in a small amount of acetone. The insoluble material was recrystallized to give the product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20][SH:21])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:30]=[C:31]([NH:34][CH2:35][CH:36]3[CH2:38][CH2:37]3)[S:32][CH:33]=2)=[CH:25][CH:24]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(N(C(C)C)CC)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20][S:21][C:23]3[CH:24]=[CH:25][C:26]([C:29]4[N:30]=[C:31]([NH:34][CH2:35][CH:36]5[CH2:37][CH2:38]5)[S:32][CH:33]=4)=[CH:27][CH:28]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CS)c2CC1
Reactant: Brc1ccc(-c2csc(NCC3CC3)n2)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSc3ccc(-c4csc(NCC5CC5)n4)cc3)c2CC1
Temperature: 100 °C
Yield: 97.6 %

Procedure:
To a solution of 3-tert-butoxycarbonyl-7-chloro-6-mercaptomethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.051 g, 0.155 mmol) in dry dioxane (0.7 mL) add N-[4-(4-bromo-phenyl)-thiazol-2-yl]-cyclopropylmethylamine (0.043 g, 0.14 mmol), tris(dibenzylideneacetone)dipalladium(0) (3.2 mg, 0.0035 mmol), Xantphos (4.1 mg, 0.014 mmol) and diisopropylethylamine (0.049 mL, 0.28 mmol) at room temperature. Purge the reaction mixture with nitrogen and heat the mixture at 100° C. overnight. Cool the reaction mixture to room temperature, dilute with DCM (50 mL) and filter through Celite®. Concentrate the filtrate in vacuo. Dissolve the residue in DCM, load the solution on to a RediSep® column (40 g) and purify the crude mixture by preparative liquid chromatography (0:100 to 25:75 EtOAc/hexane over 33 min; 35 mL/min) to afford 3-tert-butoxycarbonyl-7-chloro-6-{4-[2-(cyclopropylmethyl-amino)-thiazol-4-yl]-phenylthiomethyl}-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.076 g, 97%) as a colorless oil.
Reaction SMILES: O.NN.[CH3:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-])=O)[CH2:7][CH2:6]1>C(O)C.[Ni]>[CH3:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[CH2:7][CH2:6]1
Reactant: CN1CCN(Cc2ccccc2[N+](=O)[O-])CC1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: CN1CCN(Cc2ccccc2N)CC1
Reaction time: 2 h

Procedure:
In 30 volume parts of ethanol is dissolved 1.87 parts of N1 -methyl-N4 -(2-nitrobenzyl)piperazine, followed by the addition of 3.0 parts of Raney nickel. Then, 3.0 parts of hydrazine hydrate is further added to the mixture and the entire mixture is kept at room temperature for 2 hours. Following this reaction, the Raney nickel is filtered off and the solvent is distilled off under reduced pressure. The residual oily substance is recrystallized from aqueous methanol. The procedure gives pale yellow crystals melting at 78° to 79° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C:15](=[O:26])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].N(OC(C)C)=O.[C:33]1([CH:39](N)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(#N)C.CC(N(C)C)=O>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C:15](=[O:26])[N:10]2[C:11]=1[C:12]([O:14][CH:39]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:13])(=[O:3])[CH3:2]
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Agent: CC(C)ON=O
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reaction time: 3 h

Procedure:
3-Acetoxymethyl-7β-(2-thienylacetamido)ceph-3-em-4-carboxylic acid (3.96 g, 10 m.moles) was dissolved in acetonitrile (50 ml) and dimethylacetamide (5ml). To this solution was added a mixture of isopropyl nitrite (2.4 g, 27 m.moles) and diphenylmethylamine (2.21 g, 12 m.moles) dissolved-suspended in acetonitrile (20 ml). The resulting slurry was stirred for 3 hours at 35°, after which time a solution resulted. The solvents were removed in vacuo and the gum redissolved in chloroform (50 ml). The resulting solution was washed with 5% sodium bicarbonate solution (50 ml), then water (50 ml) and the chloroform removed in vacuo. The gum was crystallised from hot isopropyl alcohol (28 ml), the crystals washed with cold isopropyl alcohol (25 ml) and then dried in vacuo at room temperature to give the title compound. Yield 3.19 g (56.8% based on the input acid); m. pt. and mixed m. pt. 140° - 140.5° with an authentic sample of the ester. The bicarbonate extract was washed with ethyl acetate (10 ml) and then acidified with 2N sulphuric acid at 5° to pH 1.2. The suspension was stirred for 30 minutes, filtered and washed with cold water (70 ml). The recovered starting material was dried in vacuo at room temperature, (0.9 g, single spot on t.l.c. by u.v. detection).
Reaction SMILES: BrC1C=CC=C2C=1C=CN2.[CH3:11][O:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15](=[O:23])[C:16](=[O:22])[NH:17]2.BrCCCCC.Br[CH2:31][C:32]1[O:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=1>>[CH3:11][O:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15](=[O:23])[C:16](=[O:22])[N:17]2[CH2:31][C:32]1[O:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=1
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: COc1cccc2c1C(=O)C(=O)N2
Agent: Brc1cccc2[nH]ccc12
Solvent: CCCCCBr
Product: COc1cccc2c1C(=O)C(=O)N2Cc1ccc(C(F)(F)F)o1

Procedure:
Following the procedure as described in PREPARATION 1A, and making non-critical variations to replace 4-bromoindole with 4-methoxy-1H-indole-2,3-dione, and 1-bromopentane with 2-(bromomethyl)-5-(trifloromethyl)furan, the title compound was obtained (26%): MS (ES+) m/z 348.2 (M+23).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH3:14])=[CH:7][C:6]=1[F:28].[CH3:29][NH2:30]>CO>[F:28][C:6]1[CH:7]=[C:8]([C:11]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH3:14])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][NH:30][CH3:29]
Reactant: CN
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCBr)c(F)c1)c1ccccc1
Solvent: CO
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCNC)c(F)c1)c1ccccc1
Temperature: 85 °C
Yield: 57 %

Procedure:
To a stirred solution of 4-(1-(4-(2-bromoethoxy)-3-fluorophenyl)-2-phenyl but-1-enyl)phenol (111 mg, 0.25 mmol) in 5 mL MeOH was added 1 mL CH3NH2 (30% aq) and the mixture was heated at 85° C. for 18 h. The mixture was extracted with EtOAc. The extract was washed with water and brine, dried over Na2SO4, filtered, concentrated, and purified by column chromatography (CH2Cl2/MeOH (NH3 gas)=10/1) to give the desired product (56 mg, 57% yield, Z/E=1/1) as a beige solid. 1H NMR (400 MHz, CDCl3) δ 7.08-7.11 (m, 5H), 7.03 & 6.77 (d, J=8.6 Hz, 2H), 6.91-6.96 (m, 1H), 6.76 & 6.44 (d, J=8.4 Hz, 2H), 6.51-6.58 (m, 2H), 4.17 & 4.01 (t, J=5.0 Hz, 2H), 3.03 & 2.93 (t, J=5.0 Hz, 2H), 2.55 & 2.48 (s, 3H), 2.47 (q, J=7.6 Hz, 2H), 0.91 (t, J=7.6 Hz, 3H); m/z=392[M+1]+.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[N:9]1(C(OC(C)(C)C)=O)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:11][CH2:10]1.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[Br:8][C:14]1[CH:13]=[C:12]2[C:17](=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:15]=1)[NH:9][CH2:10][CH2:11]2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cccc2c1N(C(=O)OC(C)(C)C)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(Br)cc2c1NCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 164.8 %

Procedure:
NBS (51.3 g, 0.29 mol) was added in several portions to a solution of 1-(1,1-dimethylethyl) 7-ethyl 2,3-dihydro-1H-indole-1,7-dicarboxylate (140.3 g, 0.48 mol) in CH2Cl2 (1200 mL) and the reaction mixture was stirred at room temperature overnight. The reaction solution was washed with 2 M NaOH (500 mL) and water (500 mL), and was then dried (Na2SO4). The solution was concentrated in vacuo to 500 mL and TFA (130 mL, 1.69 mol) was added. The mixture was stirred at room temperature overnight. A solution of 2 M NaOH was added to bring the reaction mixture to pH>8. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3×300 mL). The combined organic layers were dried (Na2SO4) and the solvent was evaporated, giving 129.1 g (99%) of the title compound.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]3[CH:24]=[CH:25][C:26]([C:28]#[N:29])=[CH:27][C:16]=3[N:15]=2)[C:5]1=[O:30])([CH3:3])[CH3:2].Cl.[NH2:32][OH:33].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[OH:33][NH:32][C:28]([C:26]1[CH:25]=[CH:24][C:17]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:14]([CH2:13][N:6]3[C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[N:4]([CH:1]([CH3:2])[CH3:3])[C:5]3=[O:30])=[N:15][C:16]=2[CH:27]=1)=[NH:29]
Reactant: NO
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(C#N)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(C(=N)NO)ccc21
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
A mixture containing 2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-5-carbonitrile (152 mg, 0.379 mmol), hydroxylamine hydrochloride (95 mg, 1.36 mmole) and potassium carbonate (105 mg, 0.758 mmole) in ethanol (4 mL) and water (2 mL) in a sealed tube was placed in a microwave oven (Smith Creator, Personal Chemistry) and heated at 140° C. for 15 min, followed by 150° C. for 10 min while stirring. The solvents were removed in vacuo and the residue was triturated with water. The white precipitate was collected by filtration, washed with water and dried in vacuo to give N-hydroxy-2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-5-carboxamidine (140 mg, 85%) as a white solid:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[F:12]F>C(#N)C>[Cl:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][C:5]([F:12])=[CH:6][N:7]=1
Reactant: FF
Reactant: COC(=O)c1nccnc1Cl
Solvent: CC#N
Product: COC(=O)c1nc(F)cnc1Cl
Temperature: 25 °C

Procedure:
In 15 mL of acetonitrile was dissolved 0.3 g of methyl 3-chloro-2-pyrazinecarboxylate. At an ice-cooled temperature, 10% fluorine gas (a fluorine gas diluted with nitrogen gas) was introduced at a rate of 45 ml per minute for a period of 18 minutes. Then, while elevating the temperature from the ice-cooled temperature to room temperature, nitrogen gas was introduced for one hour, and the reaction product was concentrated under reduced pressure. The oily product thus obtained was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=10:1] to obtain 0.03 g of methyl 3-chloro-6-fluoro-2-pyrazinecarboxylate as a colorless oily product.
Reaction SMILES: CSC1N=NC(C(NC(=O)OC(C)(C)C)C)=CN=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([NH:31][C:32]2[N:33]=[N:34][C:35]([CH:38]([NH:40]C(=O)OC(C)(C)C)[CH3:39])=[CH:36][N:37]=2)[CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28].[ClH:48]>CO.O1CCOCC1>[ClH:48].[NH2:40][CH:38]([C:35]1[N:34]=[N:33][C:32]([NH:31][C:23]2[CH:22]=[C:21]([O:20][CH3:19])[C:26]([O:27][CH3:28])=[C:25]([O:29][CH3:30])[CH:24]=2)=[N:37][CH:36]=1)[CH3:39]
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)OC(C)(C)C)nn2)cc(OC)c1OC
Agent: CSc1ncc(C(C)NC(=O)OC(C)(C)C)nn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Reaction time: 0.5 h

Procedure:
To a stirred solution of tert-butyl 1-[3-(methylthio)-1,2,4-triazin-6-yl]ethylcarbamate (Intermediate 8) (1.2 g, 3.1 mmol) in methanol (10 mL) was added 4N HCl in dioxane (10 mL). After stirring for 30 minutes the volatiles were removed under reduced pressure to provide 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine hydrochloride as a foam. The foam was dissolved in methanol, ammonium hydroxide was added to neutralize the acid, and silica gel (5 g) was added followed by evaporation of the volatiles under reduced pressure. The pre-adsorbed solids were loaded into a solid loading cartridge and subjected to an isocratic elution using dichloromethane: methanol: ammonium hydroxide (95:4:1) using a RediSep silica gel cartridge (40 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (680 mg) as a yellow solid. 1H NMR (CDCl3): δ8.42 (s, 1H), 7.38 (s, 1H), 6.97 (s, 2H), 4.38 (d, J=7.0 Hz, 1H), 3.90 (s, 6H), 3.84 (s, 3H), 1.62 (br, 2H), 1.52 (d, J=7.0 Hz, 3H), 1.43 (s, 9H). MS m/z 306 (M+1).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([N:16]2[C:20]([NH2:21])=[CH:19][C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])=[N:17]2)[CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.[F:29][C:30]1[C:35]([F:36])=[C:34]([F:37])[CH:33]=[CH:32][C:31]=1[N:38]=[C:39]=[O:40]>>[F:29][C:30]1[C:35]([F:36])=[C:34]([F:37])[CH:33]=[CH:32][C:31]=1[NH:38][C:39]([NH:21][C:20]1[N:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][OH:8])[CH:11]=2)[N:17]=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])[CH:19]=1)=[O:40]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(-n2nc(-c3ccccc3F)cc2N)c1
Reactant: O=C=Nc1ccc(F)c(F)c1F
Product: O=C(Nc1ccc(F)c(F)c1F)Nc1cc(-c2ccccc2F)nn1-c1cccc(CO)c1
Yield: 72.3 %

Procedure:
Using general method A, 1-(3-((t-butyldimethylsilyloxy)methyl)phenyl)-3-(2-fluorophenyl)-1H-pyrazol-5-amine (available from ethyl 3-(5-amino-3-(2-fluorophenyl)-1H-pyrazol-1-yl)benzoate using general method followed by protection with TBSCl) (0.4 g, 1.0 mmol) was combined with 2,3,4-trifluorophenyl isocyanate (0.32 g, 1.2 mmol) to yield 1-(2,3,4-trifluorophenyl)-3-(3-(2-fluorophenyl)-1-(3-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl)urea (330 mg, 72% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.14 (brs, 1H), 9.01 (s, 1H), 7.98 (dt, J=1.6, and 8.0 Hz, 1H), 7.86 (m, 1H), 7.2-7.6 (m, 8H), 6.96 (d, J=4.0 Hz, 1H), 5.39 (t, J=6.0 Hz, 1H), 4.62 (d, J=6.0 Hz, 2H); MS (EI) m/z: 457.0 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:19][CH:20]=[C:21]([C:27]#[N:28])[C:22](OCC)=O)C.C1(OC2C=CC=CC=2)C=CC=CC=1.C1(C2C=CC=CC=2)C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:15]=[C:14]2[C:12](=[CH:11][C:10]=1[F:16])[NH:13][CH:22]=[C:21]([C:27]#[N:28])[C:20]2=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: Nc1ccc(OCc2ccccc2)c(F)c1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: N#Cc1c[nH]c2cc(F)c(OCc3ccccc3)cc2c1=O
Temperature: 25 °C
Yield: 31.7 %

Procedure:
A mixture of 4-benzyloxy-3-fluoroaniline (6.06 g, 27.9 mmol) (U.S. Pat. No. 5,622,967) and ethyl (ethoxymethylene)cyanoacetate (5.08 g, 30.0 mmol) is heated at 120° C. for 45 minutes then cooled to room temperature. This solid is added in portions to a 3:1 mixture of diphenyl ether:biphenyl at 245° C. This mixture is heated at 245° C. for 3 hours then cooled and the solids are collected by filtration, washing with hexane and diethyl ether to provides 2.60 g of 6-benzyloxy-7-fluoro-4-oxo-1, 4-dihydro-3-quinolinecarbonitrile, mp>250° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([Br:9])[CH:5]=[C:4]([Br:10])[CH:3]=1.Br[CH2:12][C:13](=[C:15]([C:18]#[N:19])[C:16]#[N:17])[CH3:14]>C(O)(C)C.O1CCCC1>[NH2:19][C:18]1[N:8]([C:7]2[C:2]([Cl:1])=[CH:3][C:4]([Br:10])=[CH:5][C:6]=2[Br:9])[CH:12]=[C:13]([CH3:14])[C:15]=1[C:16]#[N:17]
Reactant: CC(CBr)=C(C#N)C#N
Reactant: Nc1c(Cl)cc(Br)cc1Br
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cc1cn(-c2c(Cl)cc(Br)cc2Br)c(N)c1C#N
Yield: 26.3 %

Procedure:
A mixture of 5.3 g of 6-chloro-2,4-dibromoaniline and 3.5 g of 2-(2-bromo-1-methylethylidene)malononitrile was dissolved in a mixed solution of 10 ml of isopropanol and 10 ml of tetrahydrofuran. The reaction mixture was heated for 2 hours while being concentrated at 120° C. Water was poured into the reaction mixture. The reaction mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure and was allowed to stand for crystallization to yield 1.9 g of 2-amino-4-methyl-1-(2,4-dibromo-6-chlorophenyl)pyrrole-3-carbonitrile.
Reaction SMILES: [CH3:1][CH:2]([SH:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19](F)[CH:18]=1>O>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([S:4][CH:2]([CH3:3])[CH3:1])[CH:18]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: CC(C)S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Sc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of propane-2-thiol (1.5 mL), potassium carbonate (3 g) and N,N-dimethylformamide (20 mL), 4-chloro-2-fluoronitrobenzene (2.5 g) was added and stirred at room temperature for 5 hours. After addition of water, the reaction mixture was extracted with ethyl acetate, and the extract was washed with water and saturated aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give 4-chloro-2-isopropylsulfanyl-1-nitrobenzene (3.30 g) as a yellow oil.
Reaction SMILES: C([NH:4][C:5]1[C:6]2[N:7]([C:11]([CH3:26])=[C:12]([CH2:14][CH2:15][C:16]3[CH:25]=[CH:24][C:19]4[N:20]=[C:21]([NH2:23])[O:22][C:18]=4[CH:17]=3)[N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=O)C.Cl.C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:23][C:21]1[O:22][C:18]2[CH:17]=[C:16]([CH2:15][CH2:14][C:12]3[N:13]=[C:6]4[C:5]([NH2:4])=[CH:10][CH:9]=[CH:8][N:7]4[C:11]=3[CH3:26])[CH:25]=[CH:24][C:19]=2[N:20]=1
Reactant: CC(=O)Nc1cccn2c(C)c(CCc3ccc4nc(N)oc4c3)nc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1c(CCc2ccc3nc(N)oc3c2)nc2c(N)cccn12
Yield: 85.3 %

Procedure:
A mixture of 6-[2-(8-acetylamino-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl]-2-aminobenzoxazole (0.6 g) and conc. hydrochloric acid (0.76 ml) in ethanol (12 ml) was refluxed for 7 hours. To the reaction mixture was added ethyl acetate (18 ml) and the resulting precipitate was collected by filtration. A solution of resulting precipitate in water was adjusted to pH 9.0 with 20% aqueous potassium carbonate solution and the precipitate was collected by filtration and dried to give 2-amino-6-[2-(8-amino-3-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (0.45 g).