Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][CH:22]4[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]4)=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[Cl:37].[N:38]1[CH:43]=C[CH:41]=[CH:40][CH:39]=1.ClC(OC1C=CC=CC=1)=[O:46].C1(N)CC1.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Cl:37][C:3]1[CH:4]=[C:5]([CH:35]=[CH:36][C:2]=1[NH:1][C:43]([NH:38][CH:39]1[CH2:41][CH2:40]1)=[O:46])[O:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][CH:22]3[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:29])[CH2:26][CH2:27]3)=[C:14]([C:17]#[N:18])[CH:15]=2)[N:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2cc3nccc(Oc4ccc(N)c(Cl)c4)c3cc2C#N)CC1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: c1ccncc1
Agent: NC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCOc2cc3nccc(Oc4ccc(NC(=O)NC5CC5)c(Cl)c4)c3cc2C#N)CC1
Reaction time: 1 h
Yield: 60.9 %

Procedure:
After dissolving tert-butyl 4-(((4-(4-amino-3-chlorophenoxy)-6-cyano-7-quinolyl)oxy)ethyl)-1-piperidine carboxylate (486.5 mg, 0.930 mmol) in dimethylformamide (5 ml) under a nitrogen atmosphere, pyridine (0.170 ml, 2.09 mmol) and phenyl chloroformate (0.175 ml, 1.34 mmol) were added dropwise at room temperature, and the mixture was stirred for 1 hour. Cyclopropylamine (0.322 ml, 4.65 mmol) was added dropwise, and the mixture was further stirred overnight. The reaction solution was distributed between ethyl acetate and saturated aqueous sodium bicarbonate, and the organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was subjected to silica gel column chromatography (eluent-ethyl acetate), the fraction containing the target substance was concentrated, suspended in ethyl acetate and diluted with hexane, and the crystals were filtered out and blow-dried to obtain the title compound (343 mg, 0.566 mmol, 60.8%) as light yellow crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN.[C:21]([BH3-])#[N:22].[Na+]>>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:10]=1[CH2:11][NH:22][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: O=Cc1cc(Br)ccc1OCc1ccccc1
Agent: CN
Agent: Cl
Agent: [Na+]
Product: CNCc1cc(Br)ccc1OCc1ccccc1

Procedure:
In a manner similar to that of Example 75(b), by reacting 22.5 g (77 mmol) of 2-benzyloxy-5-bromobenzaldehyde, 26.1 g (386 mmol) of methylamine hydrochloride and 7.3 g (116 mmol) of sodium cyanoborohydride, and after purification by chromatography on a column of silica eluted with a dichloromethane/methanol mixture (9/1) and 0.5% isopropylamine, 12.2 g (51%) of the expected product are obtained in the form of a pale yellow oil.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][CH:6]=1)[CH3:4].F[C:14]1[N:19]=[C:18]([N:20]2[C@@H:24]([CH:25]([CH3:27])[CH3:26])[CH2:23][O:22][C:21]2=[O:28])[CH:17]=[CH:16][N:15]=1.CCN(C(C)C)C(C)C>CS(C)=O.CCOC(C)=O>[OH:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([C@@H:3]([NH:2][C:14]2[N:19]=[C:18]([N:20]3[C@@H:24]([CH:25]([CH3:26])[CH3:27])[CH2:23][O:22][C:21]3=[O:28])[CH:17]=[CH:16][N:15]=2)[CH3:4])=[CH:6][CH:7]=1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(F)n1
Reactant: C[C@H](N)c1ccc(CO)cc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(CO)cc2)n1
Yield: 83.9 %

Procedure:
A solution of (S)-(4-(1-aminoethyl)phenyl)methanol hydrochloride (4.0301 g, 21.47 mmol, purchased from NetChem), (S)-3-(2-fluoropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (5.3648 g, 23.82 mmol, 1.11 equiv) and DIPEA (38.0 mL, 218 mmol, 10.1 equiv) in DMSO (40 mL) was heated at 110° C. for 135 min. The reaction mixture was diluted with EtOAc (200 mL) and washed with water (200 mL). After separation, the aqueous phase was washed with EtOAc (2×150 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/heptane 30 to 100%) provided (S)-3-(2-((S)-1-(4-(hydroxymethyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one (6.42 g) in 84% yield.
Reaction SMILES: [CH2:1]([C:5]1[O:9][N:8]=[C:7]([C:10](F)=[O:11])[C:6]=1[C:13]([F:16])([F:15])[F:14])[CH:2]([CH3:4])[CH3:3].[OH:17][CH:18]([C:31]1[CH:36]=[CH:35][C:34](/[C:37](=[N:39]/O)/[NH2:38])=[CH:33][CH:32]=1)[CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][C@H:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:21]1.CCN(C(C)C)C(C)C>C(#N)C.ClCCl>[OH:17][CH:18]([C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:39]=[C:10]([C:7]3[C:6]([C:13]([F:16])([F:15])[F:14])=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[O:9][N:8]=3)[O:11][N:38]=2)=[CH:33][CH:32]=1)[CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][C@H:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:21]1
Reactant: CC(C)Cc1onc(C(=O)F)c1C(F)(F)F
Reactant: CCOC(=O)[C@H]1CCCN(CC(O)c2ccc(/C(N)=N/O)cc2)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)[C@H]1CCCN(CC(O)c2ccc(-c3noc(-c4noc(CC(C)C)c4C(F)(F)F)n3)cc2)C1
Yield: 54.5 %

Procedure:
A mixture of 5-isobutyl-4-(trifluoromethyl)isoxazole-3-carbonyl fluoride; Int-V-D (0.045 g, 0.188 mmol), (3S)-ethyl 1-(2-hydroxy-2-(4-((Z)—N′-hydroxycarbamimidoyl)phenyl)ethyl)piperidine-3-carboxylate (0.063 g, 0.188 mmol), and DIEA (0.043 mL, 0.245 mmol) in acetonitrile (1 mL) was stirred at room temperature for 4 days. The reaction was complete by HPLC. The reaction mixture was diluted with dichloromethane, washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated. The crude reaction mixture was purified by flash silica gel chromatography using a 20% mixture of ethyl acetate in hexane to give (3S)-ethyl 1-(2-hydroxy-2-(4-(5-(5-isobutyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidine-3-carboxylate (0.055 g, 0.103 mmol, 54.5% yield) as a clear, colorless oil. The product was >99% pure by HPLC with a ret. time=2.87 min.-Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=537.2.
Reaction SMILES: Cl.[NH:2]=[C:3](OC)[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.Cl.[F:17][C:18]([F:29])([F:28])[O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=1.N1C=CC=C[CH:31]=1>O>[F:17][C:18]([F:28])([F:29])[O:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH:31]=[N:2][C:3]([C:4]3[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=3)=[N:27]2)=[CH:24][CH:25]=1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Reactant: COC(=N)c1ccc(C(=O)OC)cc1
Reactant: c1ccncc1
Agent: Cl
Solvent: O
Product: COC(=O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C

Procedure:
To a magnetically stirred solution of methyl 4-(imino(methoxy)methyl)benzoate hydrochloride (1.15 g, 5.00 mmol) in anhydrous pyridine (5 mL) cooled by an ice bath was added (4-(trifluoromethoxy)phenyl)hydrazine hydrochloride (1.14 g, 5.00 mmol) in several portions. After warming to room temperature overnight (18 h), the yellow reaction mixture was diluted with water (25 mL) and washed with CH2CI2 (2×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to give an orange-yellow solid (1.60 g). The solid was dissolved in formic acid (15 mL), warmed to reflux, and stirred at reflux for 8 h. The reaction mixture was cooled to room temperature, diluted with water, and washed with diethyl ether (2×50 mL). The combined diethyl ether washes were washed with water (3×50 mL), washed with brine (50 mL), dried over MgSO4, filtered, and concentrated on a rotary evaporator to give the title compound as a tan solid (1.42 g, 78%). A sample was purified for analytical characterization by flash chromatography using 0-100% (v/v) EtOAc/hexanes as eluent to give the product as an off-white solid: mp 171-172° C.; 1H NMR (400 MHz, CDCI3) δ 8.60 (s, 1H), 8.27 (m, 2H), 8.15 (m, 2H), 7.81 (m, 2H), 7.40 (d, J=8.5 Hz, 2H), 3.95 (s, 3H); 13C NMR (101 MHz, CDCI3) δ 166.76, 162.61, 148.55, 141.77, 135.41, 134.46, 131.03, 130.02, 126.46, 122.44, 121.66, 121.31, 119.10; EIMS m/z 363 [M+].
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(Cl)(=O)C([Cl:26])=O>C1C=CC=CC=1>[CH2:1]([Cl:26])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Solvent: c1ccccc1
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCCl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Arachidonic acid (2.0 g, 6.6 mmol) was dissolved in benzene (20 ml). To this solution, oxalyl chloride (5.4 ml, 7.9 mmol) was added and the mixture was stirred at room temperature in a nitrogen atmosphere for 2.5 hours. Subsequently, the mixture was concentrated under reduced pressure to obtain arachidonyl chloride as an oily product. Meanwhile, L-ascorbic acid (1.4 g, 7.9 mmol) was added to a mixture of N-methylpyrrolidone (15 ml) and 4N-HCl/dioxane (2.4 ml) and the mixture was chilled on ice. To this solution, the arachidonyl chloride in methylene chloride (approx. 2 ml) was added, and the mixture was stirred overnight while chilled on ice. Upon completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water (twice), was dried over anhydrous magnesium sulfate, and was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluant=methanol/methylene chloride (1% to 20% methanol gradient)) and was dried under reduced pressure to give the desired product as a paste (2.7 g, 90% yield).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[Cl:5][C:6]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28]OS(C)(=O)=O)=[CH:22][C:7]=1[C:8]([NH:10][CH2:11][C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2)=[O:9]>O1CCCC1>[ClH:5].[Cl:5][C:6]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][NH:4][CH:1]([CH3:3])[CH3:2])=[CH:22][C:7]=1[C:8]([NH:10][CH2:11][C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2)=[O:9]
Reactant: CS(=O)(=O)OCCCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reactant: CC(C)N
Solvent: C1CCOC1
Product: CC(C)NCCCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Product: Cl
Temperature: 70 °C

Procedure:
Isopropylamine (0.5 ml) was added to a solution of 2-chloro-5-[3-[(methylsulfonyl)oxy]propyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.250 g, Example 6e) in tetrahydrofuran (20 ml) and heated at 70° C. in a sealed tube for 24 h. The mixture was concentrated under reduced pressure and the residue purified by solid phase extraction on SCX resin. The title product was isolated as the hydrochloric acid salt (0.10 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][OH:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH:13]=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCCO)cc1OC
Solvent: ClCCl
Product: COc1ccc(CCC=O)cc1OC
Reaction time: 0.5 h

Procedure:
A solution of 2.0 g (10.2 mmol) of the aldehyde prepared in step A in 40 ml CH2Cl2 is oxidised in the dark by the addition of 4.32 g (10.2 mmol) Dess-Marin periodinane. The reaction is complete after 30 minutes. The suspension formed is taken up into 50 ml CH2Cl2 and washed twice with sodium bicarbonate and 20% sodium thiosulphate solution. Concentration of the organic layer affords a beige crude product which is purified by chromatography (hexane/ethyl acetate) to yield a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[N:5]=1)([O-])=O.CO.[H][H]>C(OCC)(=O)C.[Pd]>[CH2:9]([N:6]1[CH:7]=[CH:8][C:4]([NH2:1])=[N:5]1)[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)CCn1ccc([N+](=O)[O-])n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)CCn1ccc(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.2 %

Procedure:
3-Nitro-1-iso-pentyl-1H-pyrazole (115 mg, 0.63 mmol) was dissolved in ethyl acetate (3 mL) and methanol (3 mL) was added. Palladium, 10 wt. % on activated carbon, wet (˜50 mg) was added to the reaction. The vial was charged with hydrogen gas (via balloon) and the reaction stirred for 16 h at 25° C. The reaction was passed through a plug of celite and concentrated in vacuo to afford 1-iso-pentyl-1H-pyrazol-3-ylamine (89 mg, 93%) as golden oil: ESI-LRMS m/e calcd for C8H15N3 [M+] 153.1, found 154.3 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=O)=[CH:16][CH:15]=1>O>[C:14]1([CH3:13])[CH:22]=[CH:21][C:17]([C:18]2[O:12][C:3]3[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=3[N:1]=2)=[CH:16][CH:15]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: COC(=O)c1cccc(N)c1O
Solvent: O
Product: COC(=O)c1cccc2nc(-c3ccc(C)cc3)oc12
Temperature: 180 °C
Yield: 30.2 %

Procedure:
Methyl 3-amino-2-hydroxybenzoate (4.4 g, 26 mmol) and 4-methylbenzoic acid (3.6 g, 26.0 mmol) were added to the polyphosphoric acid (20 g). The mixture was heated at 180° C. for 2 hr, and then cooled, poured into water, extracted with ethyl acetate, washed with saturated sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and condensed to obtain methyl 2-p-tolylbenzo[d]oxazole-7-carboxylate as a white solid (2.1 g, yield 30%). LC-MS (ESI) m/z 268 [M+1]+.
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:2]1.C(O)(=O)C.C(O[C:26]1(O[Si](C)(C)C)[CH2:28][CH2:27]1)C.[BH3-]C#N.[Na+].C1COCC1>CO>[CH:26]1([N:9]2[CH2:10][CH2:11][C:6]3([CH2:1][CH2:2][N:3]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4][CH2:5]3)[CH2:7][CH2:8]2)[CH2:28][CH2:27]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1CC1)CC2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
tert-Butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (250 mg, 0.98 mmol) were dissolved in 10 ml of absolute methanol. 3 g of molecular sieves (3 Å, which had been dried beforehand under high vacuum) were added to this solution. Under argon, glacial acetic acid (0.55 ml, 10 eq.), [(1-ethoxycyclopropyl)oxy]trimethylsilane (0.69 ml, 3.5 eq.) and 4.4 ml of a 1 M NaCNBH3 solution in THF (4.4 mmol, 4.5 eq.) were then added successively. After stirring at RT for 20 minutes, the mixture was heated to 60° C. and stirred at this temperature for about 15 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was taken up in dichloromethane, washed successively with 1 M NaOH solution and NaCl solution, and dried over MgSO4. After the solvent had been removed under reduced pressure, the product was obtained as a colorless oil.
Reaction SMILES: [C:1]([NH:9][C:10](=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H].CO>C(O)C>[C:1]([NH:9][C@@H:10]([C:11]([OH:13])=[O:12])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=C(O)C(=Cc1ccccc1)NC(=O)c1ccccc1
Solvent: CO
Solvent: CCO
Product: O=C(N[C@H](Cc1ccccc1)C(=O)O)c1ccccc1
Yield: 97.7 %

Procedure:
3.2 grams of α-benzamido-cinnamic acid were dissolved in 40 ml of absolute ethanol and treated with 0.3 ml of the catalyst solution produced in Example 19. The reaction mixture was sucked into a 100 ml autoclave. It was pressurized with 6 bars of hydrogen pressure. After taking up the theoretical amount of hydrogen it was worked up as customary (e.g. see Example 6). There were isolated 3.15 grams of N-benzoyl-(R)-phenylalanine having the rotary value of [α]D27 =+38.6° (c=1/CH3OH), corresponding to an optical yield of 95.8%.
Reaction SMILES: [N+:1]([O-])([OH:3])=[O:2].[CH2:5]([O:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[CH:10]=1)[CH3:6].[N:17]#[C:18][NH2:19]>C(O)C>[N:1]([OH:3])=[O:2].[CH2:5]([O:7][C:8]([C:9]1[CH:10]=[C:11]([NH:15][C:18]([NH2:19])=[NH:17])[CH:12]=[CH:13][CH:14]=1)=[O:16])[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: N#CN
Solvent: CCO
Product: CCOC(=O)c1cccc(NC(=N)N)c1
Product: O=NO
Temperature: 25 °C

Procedure:
Nitric acid (70%, 6.66 mL) is added to a mixture of 3-amino benzoic acid ethyl ester (17.21 g, 104 mmol) and cyanamide (50% in water, 12.1 mL, 156 mmol) in 50 mL of ethanol. The reaction mixture is heated for 24 hours under reflux. It is then cooled to room temperature and filtered. The solid is washed with water, ether and dried to give 3-ethoxycarbonyl-phenyl-guanidine nitrite as a gray solid; ESI-MS (m/z): 208.1 (M+-HNO3+H).
Reaction SMILES: [CH2:1]([S:8][C:9]1([CH2:19][NH:20][C:21]([C:23]2[NH:24][C:25]3[C:30]([CH:31]=2)=[CH:29][CH:28]=[CH:27][C:26]=3[N:32]([CH3:41])[S:33]([C:36]2[S:37][CH:38]=[CH:39][CH:40]=2)(=[O:35])=[O:34])=[O:22])[CH2:18][CH2:17][C:12]2(OCC[O:13]2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>O>[CH2:1]([S:8][C:9]1([CH2:19][NH:20][C:21]([C:23]2[NH:24][C:25]3[C:30]([CH:31]=2)=[CH:29][CH:28]=[CH:27][C:26]=3[N:32]([CH3:41])[S:33]([C:36]2[S:37][CH:38]=[CH:39][CH:40]=2)(=[O:35])=[O:34])=[O:22])[CH2:18][CH2:17][C:12](=[O:13])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(c1cccc2cc(C(=O)NCC3(SCc4ccccc4)CCC4(CC3)OCCO4)[nH]c12)S(=O)(=O)c1cccs1
Solvent: O
Solvent: CC(=O)O
Product: CN(c1cccc2cc(C(=O)NCC3(SCc4ccccc4)CCC(=O)CC3)[nH]c12)S(=O)(=O)c1cccs1
Yield: 70.4 %

Procedure:
A mixture of N-{[8-(benzylthio)-1,4-dioxaspiro[4.5]dec-8-yl]methyl}-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (1.21 g) and acetic acid (15 mL) was added at 80° C. for 24 hr, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4), and concentrated. The residue was subjected to basic silica gel column chromatography to give the title compound (0.79 g, yield 71%) as a colorless amorphous solid from a fraction eluted with tetrahydrofuran-methanol (1:1, volume ratio). MS: 568(MH+).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]2[NH:7][C:8]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[N:9][C:5]=2[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:25][Si:26]([CH2:29][CH2:30][O:31][CH2:32]Cl)([CH3:28])[CH3:27]>CN(C)C=O>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:16]=[CH:15][C:6]2[N:7]([CH2:32][O:31][CH2:30][CH2:29][Si:26]([CH3:28])([CH3:27])[CH3:25])[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[N:9][C:5]=2[CH:4]=1.[F:18][C:2]([F:1])([F:17])[C:3]1[CH:16]=[CH:15][C:6]2[N:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[N:9]([CH2:32][O:31][CH2:30][CH2:29][Si:26]([CH3:28])([CH3:27])[CH3:25])[C:5]=2[CH:4]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: OCCCCc1nc2cc(C(F)(F)F)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(CCCCO)nc2cc(C(F)(F)F)ccc21
Product: C[Si](C)(C)CCOCn1c(CCCCO)nc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.3 %
Yield: 15.4 %

Procedure:
4-(5-Trifluoromethyl-1H-benzoimidazol-2-yl)-butan-1-ol (2.2 g, 0 mmol) was dissolved in N,N-dimethylformamide (25 ml). Potassium carbonate (1.47 g, 10.65 mmol) was added, and the reaction stirred at RT for 1 h. SEM-Cl (1.66 ml, 9.37 mmol) was added dropwise, and the reaction stirred at RT for 3 h. An additional amount of SEM-Cl (0.50 ml, 2.81 mmol) was added dropwise, and the reaction stirred for a further 1 h. The reaction mixture was filtered, then concentrated under reduced pressure. The residue was redissolved in EtOAc (30 ml), and washed with water (3×30 ml, some NaCl added to aid separation). The organic layer was then dried (MgSO4) and concentrated to afford a red oil. The crude material was purified by biotage FCC, eluting with 18-100% EtOAc in heptane to afford 511.1 mg (15.4%) of 4-[5-Trifluoromethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-butan-1-ol (regioisomer 1) and 738.6 mg (22.3%) of 4-[6-Trifluoromethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-butan-1-ol (regioisomer 2) as yellow oils. Regioisomers was arbitrarily assigned.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[F:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[C@H:21]1[CH2:27][N:26]2[C:28]([C:31]3([C:34]([F:37])([F:36])[F:35])[CH2:33][CH2:32]3)=[N:29][N:30]=[C:25]2[C@H:24]([NH2:38])[CH2:23][CH2:22]1.[CH3:39][N:40]1[C:44]2=[N:45][CH:46]=[CH:47][CH:48]=[C:43]2[N:42]([CH:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)[C:41]1=[O:55]>O1CCCC1>[F:13][C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[C@H:21]1[CH2:27][N:26]2[C:28]([C:31]3([C:34]([F:37])([F:35])[F:36])[CH2:32][CH2:33]3)=[N:29][N:30]=[C:25]2[C@H:24]([NH:38][C:1]([N:52]2[CH2:53][CH2:54][CH:49]([N:42]3[C:43]4[C:44](=[N:45][CH:46]=[CH:47][CH:48]=4)[N:40]([CH3:39])[C:41]3=[O:55])[CH2:50][CH2:51]2)=[O:2])[CH2:23][CH2:22]1
Reactant: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c1nnc2C1(C(F)(F)F)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cn1c(=O)n(C2CCNCC2)c2cccnc21
Solvent: C1CCOC1
Product: Cn1c(=O)n(C2CCN(C(=O)N[C@@H]3CC[C@@H](c4cccc(F)c4F)Cn4c3nnc4C3(C(F)(F)F)CC3)CC2)c2cccnc21
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
1,1′-Carbonyldiimidazole (24.0 mg, 0.15 mmol) was added to a solution of (6S,9R)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl)cyclopropyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-amine (28 mg, 0.075 mmol) and in tetrahydrofuran (1.0 mL) at 0° C. After 30 min, additional 1,1′-carbonyldiimidazole (11.0 mg, 0.068 mmol) was added. After 30 min, 3-methyl-1-piperidin-4-yl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (26 mg, 0.113 mmol) was added and the mixture was heated to 60° C. After 1 h, additional 3-methyl-1-piperidin-4-yl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (23 mg, 0.099 mmol) was added. After 1 h, the reaction mixture was concentrated. Purification by reverse phase HPLC (100% water→100% acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (33 mg). MS 631.2566 (M+1).
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].Br[CH2:15][C:16]([C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=1[O:26][CH3:27])=O>>[CH3:27][O:26][C:19]1[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:18]=1[C:16]1[N:1]=[C:2]([C:3]2[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=2[CH3:8])[S:13][CH:15]=1
Reactant: COc1ccc(OC)c(C(=O)CBr)c1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Product: COC(=S)c1cc(-c2nc(-c3cc(OC)ccc3OC)cs2)c(C)s1
Yield: 46.4 %

Procedure:
132 mg (0.534 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was reacted with 2-bromo-2′,5′-dimethoxy acetophenone (0.587 mmol; 152 mg) in a manner similar to Example 22, step (a) to afford 97 mg (45% yield) of methyl 4-[4-(2,5-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.
Reaction SMILES: C(C1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1)#N.[OH-:10].[K+].[CH2:12]([OH:15])[CH2:13]O>O>[OH:9][C:4]1[N:5]=[CH:6][CH:7]=[CH:8][C:13]=1[C:12]([OH:15])=[O:10]
Reactant: [OH-]
Reactant: OCCO
Reactant: N#Cc1ccc[nH]c1=O
Agent: [K+]
Solvent: O
Product: O=C(O)c1cccnc1O
Temperature: 0 °C

Procedure:
Prepare a solution containing 6 g of 3-cyano-2-pyridone, 7.5 g of potassium hydroxide pellets (85%), 8 ml. of ethylene glycol and 1.5 ml. of water. Heat the solution to 150°-160° C for 15 minutes and pour the reaction mixture into ice water. Acidify the aqueous solution to a pH of about 3. The 2-hydroxy-nicotinic acid precipitates, is collected by filtration and dried yielding the product of this step, m.p. 258°-260° C.