Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][C:6]2[C:8]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:9][CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.C(N(CC)CC)C.[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=[O:32]>C(Cl)Cl>[CH3:18][N:15]1[CH2:14][CH2:13][N:12]([C:8]2[C:6]3[CH2:7][C@H:2]([NH:1][C:31]([C:27]4[O:26][CH:30]=[CH:29][CH:28]=4)=[O:32])[CH2:3][O:4][C:5]=3[CH:11]=[CH:10][CH:9]=2)[CH2:17][CH2:16]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CO3)CC1
Reactant: O=C(Cl)c1ccco1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccco2)CO3)CC1
Temperature: 0 °C
Yield: 78.4 %

Procedure:
To an ice-cooled stirred solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (230 mg, 0.930 mmol) and triethylamine (194 μL, 1.39 mmol) in anhydrous methylene chloride (10 mL) was added 2-furoyl chloride (101 μL, 1.02 mmol) under nitrogen. The ice-bath was removed, and the reaction mixture was allowed to reach room temperature. The mixture was washed with a 2 M NH3 solution, dried (MgSO4), and the solvent was removed in vacuo. The remains was purified on a chromatotron (accelerated thin layer chromatography, eluent: chloroform/ethanol; 92:8+0.5% conc. NH3) affording 249 mg (79% yield) of the title compound as a white solid: mp sinters >50° C.; [α]21D−83° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 341 (52, M+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[CH:9][C:8]2[C:11](Br)=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[S:13][C:7]=2[C:6]=1[OH:22])=[O:4].[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C[O-].[Na+]>O1CCOCC1.C(OCC)(=O)C.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>[CH3:1][O:2][C:3]([C:5]1[N:10]=[CH:9][C:8]2[C:11]([C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[S:13][C:7]=2[C:6]=1[OH:22])=[O:4]
Reactant: COC(=O)c1ncc2c(Br)c(-c3ccc(F)cc3)sc2c1O
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ncc2c(-c3ccc(F)cc3)c(-c3ccc(F)cc3)sc2c1O
Temperature: 120 °C
Yield: 50.6 %

Procedure:
3-Bromo-2-(4-fluoro-phenyl)-7-hydroxy-thieno[3,2-c]pyridine-6-carboxylic acid methyl ester (0.34 g, 0.89 mmol), example 36-g, 4-fluoro-phenyl boronic acid (0.373 mg, 2.67 mmol), sodium methoxide (0.433 g, 8.01 mmol), and tetrakis(triphenylphosphine)palladium(0) (257 mg, 0.22 mmol) were suspended in 15 mL of 1,4-dioxane. The reaction mixture was heated at 120° C. for 30 min. using a CEM microwave reactor (CEM, Matthews, N.C.). The reaction mixture was diluted with ethyl acetate, and washed with saturated sodium bicarbonate and brine solutions. The organic fraction was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-60% ethyl acetate in hexanes to produce 0.179 g of a yellow solid. MS: (+) m/z 398.0 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC(C)([O-])C.[K+]>CS(C)=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:3][CH:4]=1
Reactant: Oc1ccccc1
Reactant: Brc1ccc(Br)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Brc1ccc(Oc2ccccc2)nc1
Temperature: 160 °C
Reaction time: 4 h
Yield: 70.5 %

Procedure:
A mixture of 2,5-dibromo pyridine (25 g, 106 mmol), phenol (10.5 g, 111 mmol), potassium tert-butoxide (12.5 g, 111 mmol) and dimethyl sulfoxide (250 mL) was stirred for 4 hours at 160° C. This mixture was cooled to room temperature, and partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried with anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=10:1) to obtain the title compound (18.7 g, 70%).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([CH2:10][CH:11]([C:13]2[N:14]([CH3:25])[N:15]=[N:16][C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)O)=[N:7][C:6]=1[CH3:26])=[O:4]>S(=O)(=O)(O)O>[F:24][C:21]1[CH:20]=[CH:19][C:18]([C:17]2[N:16]=[N:15][N:14]([CH3:25])[C:13]=2/[CH:11]=[CH:10]/[C:8]2[S:9][C:5]([C:3]([OH:4])=[O:2])=[C:6]([CH3:26])[N:7]=2)=[CH:23][CH:22]=1
Reactant: COC(=O)c1sc(CC(O)c2c(-c3ccc(F)cc3)nnn2C)nc1C
Agent: O=S(=O)(O)O
Product: Cc1nc(/C=C/c2c(-c3ccc(F)cc3)nnn2C)sc1C(=O)O
Temperature: 160 °C
Yield: 88.7 %

Procedure:
A suspension of 2-{2-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-2-hydroxy-ethyl}-4-methyl-thiazole-5-carboxylic acid methyl ester (204 mg, 0.54 mmol) in sulfuric acid (conc., 3.19 mL) was heated at 160° C. under Ar for 2 h. After cooling to room temperature the mixture was poured into ice and extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated to afford the title compound (165 mg, 88%) as an off white solid. MS: m/e=343.0 [M−H]−.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][C:11]([NH:13][CH2:14][C:15]#[C:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[O:12])[CH:8]=2)[CH:3]=[CH:2]1.[CH2:27]([O:29][C:30](=[O:33])[CH2:31]Br)[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>C(#N)C>[CH2:27]([O:29][C:30](=[O:33])[CH2:31][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][C:11](=[O:12])[NH:13][CH2:14][C:15]#[C:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][CH:18]=3)[CH:8]=2)[CH:3]=[CH:2]1)[CH3:28]
Reactant: CCOC(=O)CBr
Reactant: O=C(Cc1ccc2cc[nH]c2c1)NCC#Cc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: CCOC(=O)Cn1ccc2ccc(CC(=O)NCC#Cc3ccc(C(F)(F)F)cc3)cc21

Procedure:
In analogy to the procedure described for example 1 b], 2-(1H-indol-6-yl)-N-[3-(4-trifluoromethyl-phenyl)-prop-2-ynyl]-acetamide was reacted with bromo-acetic acid ethyl ester in the presence of cesium carbonate and potassium iodide in acetonitrile under reflux conditions to give the title compound as colorless oil.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(OC([N:15]1[CH2:18][CH:17]([NH:19][C:20](=[O:36])[CH2:21][NH:22][C:23](=[O:35])[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([C:31]([F:34])([F:33])[F:32])[CH:25]=2)[CH2:16]1)=O)(C)(C)C>>[OH:7][C:1]([C:3]([F:6])([F:5])[F:4])=[O:2].[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:21][NH:22][C:23](=[O:35])[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([C:31]([F:33])([F:34])[F:32])[CH:25]=2)=[O:36])[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CNC(=O)c2ccc(F)c(C(F)(F)F)c2)C1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNC(=O)c1ccc(F)c(C(F)(F)F)c1)NC1CNC1

Procedure:
The title compound was prepared as colorless oil from the TFA de-protection of 3-[2-(4-fluoro-3-trifluoromethyl-benzoylamino)-acetylamino]-azetidine-1-carboxylic acid tert-butylester (as prepared in the previous step) using the procedure described in Step E of Example 1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][CH2:20][C:21]2[CH:25]=[CH:24][S:23][CH:22]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15]CC=C)=[CH:10][CH:9]=2)=[O:5])[CH3:2]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClCCl.N1CCOCC1.O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][CH2:20][C:21]2[CH:25]=[CH:24][S:23][CH:22]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: C=CCOc1ccc2c(c1)cc(C(=O)OCC)n2CCc1ccsc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cc2cc(O)ccc2n1CCc1ccsc1
Reaction time: 18 h
Yield: 108.5 %

Procedure:
To 5-allyloxy-1-[(2-thiophen-3-yl)ethyl]-1H-indole-2-carboxylic acid ethyl ester (1.36 g, 3.8 mmol) was added a mixture of dichloromethane:morpholine:water (100:10:2, 50 mL) followed by the addition of tetrakis(triphenylphosphine) palladium (0) (300 mg). After stilling at room temperature for 18 h, the reaction was partitioned between dichloromethane and water. The organic layer was washed with HCl (3N), NaHCO3, brine and dried over Na2SO4. Purification by flash column chromatography (silica gel, 10-30% EtOAc/hexanes) yielded the desired product as a off-white solid (1.3 g, 86%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([CH2:18][OH:19])[C:12]=2[O:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1.O=[Mn]=O>[C:1]([O:5][C:6]([N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([CH:18]=[O:19])[C:12]=2[O:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCOc2c(CO)cccc21
Agent: O=[Mn]=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCOc2c(C=O)cccc21
Temperature: 80 °C
Yield: 84.9 %

Procedure:
To a solution of 8-hydroxymethyl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester (591.2 mg, 2.2 mmol) in dioxane (4 mL) was added preactivated MnO2 (2.00 g, 22.3 mmol), and the resulted mixture was heated at 80° C. for overnight. The resulted mixture was then cooled to r.t., and filtered. The solid was washed with EtOAc (20 mL×3). EtOAc washing solution was combined with dioxane filtrate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to provide 8-formyl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester (491.5 mg) as a white solid. MS m/z: 286.0 (M+Na)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[C:15]([F:18])([F:17])[F:16])[CH2:3][CH2:2]1.C1(N(C2N=C(C)ON=2)C)CC1.[CH:30]1([CH2:33][C@H:34]([NH2:41])[C:35]2[N:39]=[C:38]([CH3:40])[O:37][N:36]=2)[CH2:32]C1>>[CH:33]1([CH:34]([NH:41][C:12]([C:10]2[CH:9]=[CH:8][C:7]([C:15]([F:18])([F:17])[F:16])=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[C:35]2[N:39]=[C:38]([CH3:40])[O:37][N:36]=2)[CH2:30][CH2:32]1
Reactant: O=C(O)c1ccc(C(F)(F)F)c(OCC2CC2)n1
Reactant: Cc1nc([C@@H](N)CC2CC2)no1
Agent: Cc1nc(N(C)C2CC2)no1
Product: Cc1nc(C(NC(=O)c2ccc(C(F)(F)F)c(OCC3CC3)n2)C2CC2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Example 113 d) and cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methylamine (which can e.g. be prepared in a similar manner than (S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 38 e)) as starting materials, MS (EI): m/e=397.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:5]([N:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[O:22][CH3:23])[CH3:8])=[O:6].[CH3:31][Si:32]([CH3:37])([CH3:36])[CH2:33][CH2:34][SH:35].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CCN(C(C)C)C(C)C.[NH4+].[Cl-]>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].CCOC(C)=O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:7]([CH3:8])[C:5](=[O:6])[C:4]2[CH:3]=[C:2]([S:35][CH2:34][CH2:33][Si:32]([CH3:37])([CH3:36])[CH3:31])[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=2)=[C:16]([O:22][CH3:23])[CH:17]=1
Reactant: C[Si](C)(C)CCS
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(Br)cc(C(F)(F)F)c1
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: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(SCC[Si](C)(C)C)cc(C(F)(F)F)c1
Temperature: 120 °C

Procedure:
A solution of 3-bromo-N-(4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)-N-methyl-5-(trifluoromethyl)benzamide (0.135 g, 279 μmol) and 2-(trimethylsilyl)ethanethiol (37.5 mg, 44.1 μL, 279 μmol) in dioxane (2 mL) was stirred under argon for 5 minutes in a sealed tube. To the clear light yellow solution were added tris(dibenzylideneacetone)dipalladium(0) (6.4 mg, 6.98 μmol, CAS RN 52409-22-0) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (8.08 mg, 14.0 μmol, CAS RN 161265-03-8) and DIPEA (72.2 mg, 97.6 μL, 559 μmol) and the reaction mixture was stirred at 120° C. After stirring for 4 hours in a sealed tube, heating was stopped. The reaction mixture was poured on saturated aqueous NH4Cl solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 20 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless solid (0.116 g; 77%). MS (ESI): m/z=537.17 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[C:11]([CH2:12][OH:13])=[CH:10][N:9]=[C:8]2S)=[CH:4][CH:3]=1.C(O)C.OO.[OH-].[Na+]>O.[O-]S([O-])(=O)=O.O=[V+2].O>[Br:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[C:11]([CH2:12][OH:13])=[CH:10][N:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: OCc1cnc(S)n1Cc1ccc(Br)cc1
Agent: O=[V+2]
Agent: O=S(=O)([O-])[O-]
Agent: OO
Solvent: O
Solvent: CCO
Product: OCc1cncn1Cc1ccc(Br)cc1
Temperature: 45 °C
Yield: 80.4 %

Procedure:
1-(4-Bromobenzyl)-2-mercapto-5-hydroxymethylimidazole(40 g, 0.134 mol) and vanadyl sulfate hydrate(21.9 mg, 0.1 mol %) were introduced into a mixed solution of 240 ml of ethanol and 240 ml of water. The mixture was warmed to 45° C. and stirred. After a short time, 30% hydrogen peroxide(51.6 g, 3.4 molar eq.) was slowly added dropwise thereto and the internal temperature was kept at about 50° C. When the initial white suspension turned to a pale yellow solution, the solution was further stirred for about 30 minutes to which was added 6 N sodium hydroxide solution to adjust pH of the solution to about 10. Then, ethanol was distilled under reduced pressure The precipitated crystal was filtered, washed with distilled water and dried to the constant weight to give 28.7 g(Yield 80.4%, HPLC=97%) of the title compound as a white powder.
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[N:5][CH:4]=1.[F:25][C:26]1[CH:32]=[C:31]([CH3:33])[C:30]([OH:34])=[CH:29][C:27]=1[NH2:28].Cl>CC(O)CCC.C(O)(C)C>[F:25][C:26]1[CH:32]=[C:31]([CH3:33])[C:30]([OH:34])=[CH:29][C:27]=1[NH:28][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[N:5][CH:4]=1
Reactant: Cc1cc(F)c(N)cc1O
Reactant: COc1cc2c(Cl)cnnc2cc1OCCCN1CCOCC1
Agent: Cl
Solvent: CCCC(C)O
Solvent: CC(C)O
Product: COc1cc2c(Nc3cc(O)c(C)cc3F)cnnc2cc1OCCCN1CCOCC1

Procedure:
A solution of 4-chloro-6-methoxy-7-(3-morpholinopropoxy)cinnoline hydrochloride (132 mg, 0.33 mmol), (prepared as described for the starting material in Example 12), and 2-fluoro-5-hydroxy-4-methylaniline (56 mg, 0.39 mmol), (prepared as described for the starting material in Example 11), in 2-pentanol (2.5 ml) containing 7M hydrogen chloride in isopropanol (9drops) was heated at reflux for 30 minutes. After cooling, the solid was filtered off, washed with isopropanol, ether and dried under vacuum to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(3-morpholinopropoxy)cinnoline as an hydrochloride salt (yellow solid, 143 mg, 84%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8]C=CC=2.[CH3:16][Al](C)C>O1CCOCC1>[CH3:8][C:9]1[CH:4]=[N:3][CH:16]=[C:2]([CH3:1])[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: C[Al](C)C
Reactant: CCOC(=O)c1c(C)[nH]c2ccccc12
Solvent: C1COCCO1
Product: CCOC(=O)c1c(C)cncc1C
Yield: 78 %

Procedure:
To a solution of ethyl 2-methyl-1H-indole-3-carboxylate (2 g, 6.15 mmol), Pd(PPh3)-4(0.36 g, 0.31 mmol) in dioxane (20 mL) was added Me3Al (2 M in THF, 7.69 ml, 15.37 mmol) under N2. The mixture was stirred at reflux overnight. After the complete of the reaction, the reaction was quenched by addition of 5 mL of water and extracted with EtOAc. The extractions were combined, washed with H2O, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash column (Eluent: PE/EtOAc=15:1) to give ethyl 3,5-dimethylisonicotinate as a yellow solid. (0.9 g, yield 78%). LRMS (M+H+) m/z: calcd 180.2. found 179.01.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:27])=[C:5]([C@@H:10]2[O:15][CH2:14][C@H:13]3[CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][CH2:19][N:12]3[CH2:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]>C(O)(C(F)(F)F)=O>[F:9][C:8]1[C:3]([C:1]#[N:2])=[C:4]([CH3:27])[C:5]([C@@H:10]2[O:15][CH2:14][C@H:13]3[CH2:16][NH:17][CH2:18][CH2:19][N:12]3[CH2:11]2)=[CH:6][CH:7]=1
Reactant: Cc1c([C@H]2CN3CCN(C(=O)OC(C)(C)C)C[C@@H]3CO2)ccc(F)c1C#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1c([C@H]2CN3CCNC[C@@H]3CO2)ccc(F)c1C#N
Reaction time: 1 h

Procedure:
tert-butyl(3S,9aR)-3-(3-cyano-4-fluoro-2-methylphenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (1-17C) (3.00 g, 7.99 mmol) was dissolved in TFA (10 mL) and stirred for 1 hr. The trifluoroacetic acid was removed under reduced pressure and azeotroped with dichloroethane (3×) then was dried over high vacuum to yield the title compound: LC-MS (IE, m/z): 276 [M+1]+; 1H-NMR (500 MHz, DMSO) δ ppm 7.755 (dd, J=8.75, 6.2 Hz, 1H), 7.38 (t, J=8.85 Hz, 1H), 4.80 (d, J=10.1 Hz, 1H), 3.98 (dd, J=11.25, 2.5 Hz, 1H), 3.456 (t, J=10.7 Hz, 1H), 3.354 (d, J=12.6 Hz, 1H), 3.273 (d, J=11.8 Hz, 1H), 2.984-3.089 (m, 3H), 2.715 (t, J=11.37 Hz, 1H), 2.639 (t, J=10 Hz, 1H), 2.50 (s, 3H), 2.46 (b, 1H), 2.337 (t. J=10.9 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([OH:13])[CH2:10][C:11]#[N:12].B.O1CCCC1.[ClH:20]>CO>[ClH:20].[NH2:12][CH2:11][CH2:10][CH:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[OH:13]
Reactant: N#CCC(O)c1ccc(F)cc1F
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: NCCC(O)c1ccc(F)cc1F
Temperature: 70 °C
Yield: 94 %

Procedure:
3-(2,4-Difluoro-phenyl)-3-hydroxy-propionitrile (960 mg, 5.24 mmol) was slowly treated with a solution of borane-tetrahydrofuran complex (11.53 mL, 11.53 mmol, 1M in tetrahydrofuran) at 0° C. After bubbling ceased, the reaction mixture was heated to 70° C. for 3 hours. The reaction mixture was then concentrated. The white solid obtained was treated with methanol (11.5 mL), followed by HCl (2M in ether, 11.5 mL). The resulting mixture was heated to reflux for 2 hours, allowed to cool to ambient temperature and then concentrated at reduced pressure. The white solid obtained was triturated with diethyl ether and dried in vacuum oven to provide a white solid (1.10 g, 94%). LC-MS: t=2.20 min, (M+H)+ at 188.08.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([OH:18])=O)[NH:13][C:12]1=[O:19])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[SH:20][C@H:21]1[CH2:25][CH2:24][N:23]([C:26](=[N:28][C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])[CH3:27])[CH2:22]1.C1(N=C=NC2CCCCC2)CCCCC1>C1C=CC=CC=1.CN(C)C1C=CN=CC=1>[Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16]([S:20][C@H:21]2[CH2:25][CH2:24][N:23]([C:26](=[N:28][C:29]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=3)=[O:30])[CH3:27])[CH2:22]2)=[O:18])[NH:13][C:12]1=[O:19])[CH3:10])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CC[C@H](S)C1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: c1ccccc1
Product: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CC[C@H](SC(=O)C[C@H]2NC(=O)[C@@H]2[C@@H](C)O[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
2.67 mg (0.93 mmole) of (3S, 4R)-3-[(R)-1-t-butyldimethylsilyloxyethyl]-4-carboxymethyl-2-azetidinone and 330 mg (1.02 mmole) of (S)-3-mercapto-1-[N-(p-nitrobenzyloxycarbonyl)acetimidoyl]pyrrolidine were dissolved in 5 ml of benzene. 210 mg (9.02 mmole) of dicyclohexylcarbodiimide and 5 mg (0.04 mmole) of 4-dimethylaminopyridine were added, and the mixture was stirred at room temperature for 1 hour, after which insolubles were filtered off. The filtrate was concentrated to dryness by evaporation under reduced pressure and the resulting oily residue was purified by column chromatography through 15 g of silica gel eluted with mixtures of benzene and ethyl acetate in volume ratios from 1:2 to 1:5, to give 495 mg (yield 90%) of the title product in the form of an oil.
Reaction SMILES: [C:1]([NH:4][NH2:5])([NH2:3])=[NH:2].Cl.C([O-])(=O)C.[Na+].[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>O.C(O)(=O)C>[C:12]([NH:5][NH:4][C:1]([NH2:3])=[NH:2])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N=C(N)NN
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N=C(N)NNC(=O)c1ccccc1
Temperature: 10 °C

Procedure:
A four neck flask (2 liters) equipped with a thermometer and a stirrer was charged with 88.5 g (1.0 mol) of aminoguanidine hydrochloride, 205 g (2.5 mol) of sodium acetate and 1 liter of acetic acid and cooled down to 10° C. Dropwise added thereto was 154.5 g (1.1 mol) of benzoyl chloride while stirring, and stirring was continued at room temperature (20° C.) for 12 hours. After filtering off crystal, the mother liquid was concentrated to obtain an oily substance. This was dissolved in 1 liter of deionized water, and a 48% sodium hydroxide aqueous solution was dropwise added until the pH became 13 or higher. Crystal deposited was filtered off and washed with 200 ml of deionized water, and then the crystal was dried under reduced pressure to obtain slightly brown crystal.
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1/[CH:10]=[CH:11]/[C@H:12]([N:21]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20].[OH-].[Li+].Cl>O1CCOCC1.O>[CH2:29]([N:21]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C@H:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])/[CH:11]=[CH:10]/[C:5]1[N:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([OH:36])=[O:2])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)c1cccnc1/C=C/[C@@H](Cc1ccccc1F)N(Cc1ccccc1)Cc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cccnc1/C=C/[C@@H](Cc1ccccc1F)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 24 h

Procedure:
To a solution of 2-[(E)-(R)-3-dibenzylamino-4-(2-fluoro-phenyl)-but-1-enyl]-nicotinic acid methyl ester (0.7 g, 1.4 mmol) in 5 mL of a 1:1 dioxane:water solution is added lithium hydroxide (0.07 g, 2.8 mmol). After stirring for 24 hours, the reaction is diluted with water and is neutralized by addition of 1N HCl. Filtration gives the title compound.