Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[CH:20]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([C:25]([N:13]2[CH2:14][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=3)[CH2:10][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12]2)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(Cl)C1CCCC1
Reactant: CCOC(=O)C1CNCC(c2ccc(CC)cc2)C1
Product: CCOC(=O)C1CC(c2ccc(CC)cc2)CN(C(=O)C2CCCC2)C1

Procedure:
5.2 g (14.0 mmol) of ethyl 5-(4-ethylphenyl)piperidine-3-carboxylate and 2.1 g (2.1 mmol, 1.2 eq.) of cyclopentanecarbonyl chloride were reacted according to General Method 3A. Yield: 4.8 g (96% of theory)
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[CH3:17][C:18]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][C:19]=1[NH2:28]>>[CH3:17][C:18]1[C:23]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:21]=[CH:20][C:19]=1[NH:28][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3
Reactant: Cc1c(N)cccc1C(F)(F)F
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Product: Cc1c(Nc2ccc3c(=O)[nH]c4ncccc4c3c2)cccc1C(F)(F)F
Yield: 28.3 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 231 using 6 (50 mg, 0.22 mmol) and 2-methyl-3-trifluoromethyl-phenylamine (0.03 mL, 0.33 mmol) to provide 237 (23 mg, 28% yield) as a brown solid. LC-MS (M+H=370, obsd.=370).
Reaction SMILES: [CH2:1]([NH:15][CH:16]1[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[C@H:19]([OH:20])[C@H:17]1[OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:27](Cl)(=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]>>[CH:16]1([N:15]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:27](=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[C@H:19]([OH:20])[C@H:17]1[OH:18]
Reactant: CCCCCCCCCCCCCCNC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCCCCCCCC(=O)N(CCCCCCCCCCCCCC)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
Preparation in analogy to Example 11 from N-tetradecylglucopyranosylamine and stearoyl chloride.
Reaction SMILES: CS(C)=O.[C:5](Cl)(=[O:9])[C:6](Cl)=O.[OH:11][CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([OH:23])=O)[CH2:17][CH2:16]1.Cl>ClCCl.C(N(CC)CC)C>[O:11]=[CH:12][CH2:13][CH2:14][CH:15]1[CH2:16][CH2:17][N:18]([C:21]([O:9][CH2:5][C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:23])[CH2:19][CH2:20]1
Reactant: O=C(O)N1CCC(CCCO)CC1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=CCCC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: -60 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
0.81 ml of dimethylsulphoxide in solution in 10 ml of dichloromethane (DCM) is cooled to −50° C. and 0.42 ml (4.8 mM) of oxalyl chloride in solution in 1.5 ml of DCM are added. The mixture is agitated for 10 minutes at −60° C. are then, at this temperature, 1.21 g (4.4 mM) of the benzyl ester of 4-(3-hydroxypropyl)piperidinecarboxylic acid in solution in 6 ml of DCM are added dropwise. The reaction mixture is agitated for 30 minutes at −50° C. and 3 ml of triethylamine are then added dropwise and the temperature is allowed to rise up to ambient temperature in 2 hours. The mixture is hydrolysed on 25 ml of N hydrochloric acid and extracted with DCM. The organic phase is washed with water, dried over magnesium sulphate and concentrated under reduced pressure. The crude product is purified by silica gel chromatography in eluting with the aid of a cyclohexane/ethyl acetate mixture (75/25; v/v). The product sought after is thus obtained as a yellow oil (yield=83%).
Reaction SMILES: N=C=N.[C:4]1([CH3:21])[CH:9]=[CH:8][C:7]([S:10]([NH:13][C@H:14]([C:18]([OH:20])=O)[CH:15]([CH3:17])[CH3:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1.[NH2:22][CH:23]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH:24]([OH:41])[CH:25]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:37]([O:36][C:34]([NH:33][CH:25]([CH:24]([OH:41])[CH:23]([NH:22][C:18](=[O:20])[C@H:14]([CH:15]([CH3:16])[CH3:17])[NH:13][S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH3:21])=[CH:9][CH:8]=1)(=[O:11])=[O:12])[CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: Cc1ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)C(N)Cc1ccccc1
Agent: N=C=N
Product: Cc1ccc(S(=O)(=O)N[C@H](C(=O)NC(Cc2ccccc2)C(O)C(Cc2ccccc2)NC(=O)OC(C)(C)C)C(C)C)cc1

Procedure:
According to the carbodiimide coupling procedure of Example 55, N-(p-toluenesulfonyl)valine was coupled to the resultant compound of Example 11 to give the desired compound.
Reaction SMILES: [CH2:1]([C:3]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[N:5][C:4]=1[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH3:2].[H-].[Na+].[CH3:23]I.[Cl-:25].[NH4+]>CN(C)C=O>[ClH:25].[ClH:25].[CH2:1]([C:3]1[N:7]([CH3:23])[C:6]([C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)=[N:5][C:4]=1[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH3:2]
Reactant: [Cl-]
Reactant: CCc1[nH]c(-c2ccc(F)cc2)nc1-c1cccnc1
Reactant: CI
Agent: [H-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1c(-c2cccnc2)nc(-c2ccc(F)cc2)n1C
Product: Cl
Reaction time: 0.25 h

Procedure:
To a solution of 5-ethyl-2-(4-fluorophenyl)-4-(3-pyridyl)-imidazole (481 mg) in N,N-dimethylformamide (7 ml) was added sodium hydride (79 mg, 60% mineral oil) under ice-acetone cooling, and the mixture was stirred for 15 minutes. To the mixture was added methyl iodide (307 mg) and the mixture was stirred at room temperature for one hour. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel flush column chromatography (solvent: chloroform:methanol=95:5), and treated with hydrogen chloride-methanol solution to obtain 5-ethyl-2-(4-fluoro-phenyl)-1-methyl-4-(3-pyridyl)imidazole dihydrochloride (285 mg).
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].[N+:5](/[CH:8]=[CH:9]/[C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)([O-:7])=[O:6].CC(O)C.CCCCCC>C(Cl)(Cl)Cl>[O:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[C@H:9]([CH2:8][N+:5]([O-:7])=[O:6])[C@H:2]([CH3:3])[CH:1]=[O:4]
Reactant: O=[N+]([O-])/C=C/c1ccco1
Reactant: CCC=O
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Solvent: CC(C)O
Product: C[C@H](C=O)[C@@H](C[N+](=O)[O-])c1ccco1

Procedure:
The title compound was prepared from propionaldehyde and (E)-2-(2-nitro-vinyl)furan according to the general procedure. Both enantiomeric excess and diastereomeric ratio were determined by HPLC with an AD-H column at 220 nm (2-propanol:hexane=0.8:99.2), 1.0 mL/min; major enantiomer tmajor=30.44 min, minor enantiomer tminor=26.29 min. [α]D20=−20 (c=2.0, CHCl3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(O[CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)(=O)=O)=CC=1.Cl>CC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:4][C:3]=1[NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CCCC2)cc1
Reactant: O=C(Nc1cc(O)c(Cl)cc1F)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(Nc1cc(OC2CCCC2)c(Cl)cc1F)OCc1ccccc1
Yield: 99 %

Procedure:
Then, benzyl N-(2-fluoro-4-chloro-5-hydroxyphenyl)carbamate (12.2 g, 41.3 mmol), potassium carbonate (5.97 g, 432.1 mmol), cyclopentyl p-toluenesulfonate (11.2 g, 46.4 mmol) and acetone (150 ml) as a solvent were charged into a 500 cc round-bottom flask and heated for 9 hours while refluxing. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid. After thoroughly stirring, the precipitated benzyl N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)carbamate as a pale yellow solid (14.9 g, 40.9 mmol, 99% yield) was isolated by filtration and well dried.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][N:12]=2)[CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3].[H][H]>CO.[Pd]>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)CN1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)CN1CCN(c2ccc(N)cn2)CC1
Yield: 95.1 %

Procedure:
A mixture of 2.48 g 1-isobutyl-4-(5-nitro-pyridin-2-yl)-piperazine (intermediate 7) and 0.8 g Pd/C (10%) in 30 ml methanol was treated with 1 bar hydrogen at room temperature for 2 h. After filtration the mixture was evaporated to dryness to yield 2.09 g (95%) of the title compound as colorless solid. (m/e): 235.0 (MH+; 100%).
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=1)=[O:4].[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:15][C:11]1[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:14])([CH3:13])[CH3:1])=[N:7][C:8]([CH3:12])=[CH:9][CH:10]=1.[Br:15][CH2:12][C:8]1[N:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:14])([CH3:13])[CH3:1])[CH:11]=[CH:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(NC(=O)C(C)(C)C)n1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)Nc1cccc(CBr)n1
Product: Cc1ccc(Br)c(NC(=O)C(C)(C)C)n1
Reaction time: 2 h
Yield: 33 %
Yield: 47 %

Procedure:
Carbontetrachloride (CCl4, 300 mL) and the product of Example 1 (50.6 g, 0.26 mol) were added to a 1 L flask equipped with a N2 inlet The solution was stirred until all solid dissolved. N-bromo-succinimide (NBS, 46.8 g, 0.26 mol) was then added to the reaction flask, followed by 2,2'-azobisisobutyronitrile (AIBN, 0.02 g). The reaction was heated to reflux for 6 h with a 500 watt reflector spot lamp. An additional 0.5 eq (23.4 g) of NBS was added to the reaction, and refluxing was continued for 2 h. After cooling the reaction to room temperature, it was filtered and all solvent was removed under reduced pressure. Flash chromatography (15/85 EtOAc/Hex) provided 31.6 g (47%) of title product and 22.2 g (33%) of the title material of Example 2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[OH-].[K+].F[B-](F)(F)F.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]#[N:26])=[CH:21][CH:20]=1)([O-:18])=[O:17].C(O)(=O)C>O>[Cl:1][C:2]1[C:7]([N:26]=[N:25][C:22]2[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:24][CH:23]=2)=[N:6][CH:5]=[C:4]([OH:8])[CH:3]=1
Reactant: Oc1cncc(Cl)c1
Reactant: N#[N+]c1ccc([N+](=O)[O-])cc1
Agent: F[B-](F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(N=Nc2ncc(O)cc2Cl)cc1
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To a solution of 5-chloro-3-pyridinol (20.0 g, 0.154 mol, Aldrich) and KOH (13.0 g, 0.232 mol) in 300 mL of water at 0° C. was added p-nitrobenzenediazonium tetrafluoroborate (36.6 g, 0.154 mol, Aldrich). After 1 hour, 50 mL of glacial acetic acid was added, and the bright red precipitate was filtered and air-dried. Chromatography (silica gel; CH2Cl2 /MeOH, 95:5-90:10) afforded the title compound as a bright red solid (28.8 g, 67%): 1H NMR (DMSO-d6, 300 MHz) δ 7.14 (d, J=2.4 Hz, 1H), 7.89 (d, J=2.4 Hz, 1H), 8.00 (m, 2H), 8.39 (m, 2H); MS (CI/NH3) m/z: 279, 281 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:40])[N:14]([CH2:26][C:27]([NH:29][CH:30]([CH:37]([CH3:39])[CH3:38])[CH:31]([OH:36])[C:32]([F:35])([F:34])[F:33])=[O:28])[C:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.ClCCl>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:40])[N:14]([CH2:26][C:27]([NH:29][CH:30]([CH:37]([CH3:38])[CH3:39])[C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])=[O:28])[C:15]([CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(NC(=O)Cn1c(CCc2ccccc2)ccc(NC(=O)OCc2ccccc2)c1=O)C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)C(NC(=O)Cn1c(CCc2ccccc2)ccc(NC(=O)OCc2ccccc2)c1=O)C(=O)C(F)(F)F

Procedure:
Using a similar procedure to that described in Example 1, using ethyl acetate:dichloromethane (5:95) as the chromatography solvent, 2-(3-benzyloxycarbonylamino-2-oxo-6-phenethyl-1,2-dihydro-1-pyridyl)-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)acetamide was oxidized to afford the title product; HPLC: tR =6.16, FR=2.0, column A, water:acetonitrile (2:3); MS: m/z=558(M+1). Analysis for C29H30F3N3O5 :
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][S:12][CH2:13][C:14]#[N:15])=[CH:9][C:4]=2[O:3][CH2:2]1.C([Li])CCC.[C:21](=[O:23])=[O:22].O>CCOCC.CCCCCC>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][S:12][CH:13]([C:14]#[N:15])[C:21]([OH:23])=[O:22])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: N#CCSCCc1ccc2c(c1)OCO2
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: N#CC(SCCc1ccc2c(c1)OCO2)C(=O)O
Temperature: -50 °C
Reaction time: 2 h
Yield: 11.7 %

Procedure:
5.0 g of [{2-(1,3-benzodioxol-5-yl)ethyl}thio]-acetonitrile was dissolved in 50 ml of anhydrous ether. 22 ml of a 1.6 M solution of n-butyllithium in hexane was added to the solution at -78° C. The mixture was stirred at -50° C. for 2 h. It was cooled again to -78° C. and 10 g of dry ice was added thereto. The temperature of the mixture was elevated to room temperature. Water was added to the reaction mixture. After extraction with chloroform, the extract was dried over magnesium sulfate and concentrated. The residue was purified according to silica gel column chromatography (chloroform) and recrystallized from ethyl acetate/hexane to obtain 0.70 g of the intended compound in the form of colorless needles.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.[O:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH:39]=O>>[CH:29]([N:25]1[C:24]([C:18]2[S:19][C:20]3[CH2:21][CH2:22][O:23][C:14]4[CH:13]=[C:12]([CH:10]5[CH2:11][N:8]([CH2:39][C:35]6[O:34][CH:38]=[CH:37][N:36]=6)[CH2:9]5)[CH:33]=[CH:32][C:15]=4[C:16]=3[N:17]=2)=[N:28][CH:27]=[N:26]1)([CH3:31])[CH3:30]
Reactant: O=Cc1ncco1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(Cc4ncco4)C3)ccc1-2
Yield: 44 %

Procedure:
Following the procedure for 423, a suspension of 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 and oxazole-2-carbaldehyde were reacted. The crude product was purified by flash chromatography (SiO2, 0-6% 2N NH3/MeOH in DCM) to give an oil. The oil was triturated with ether, the resulting solid filtered off and washed with ether to give 481 as a cream solid (81 mg, 44%). LCMS: RT=3.21 min, [M+H]+=449. 1H NMR δ (ppm) (CDCl3): 8.30 (1H, d, J=8.18 Hz), 7.89 (1H, s), 7.62 (1H, d, J=0.84 Hz), 7.08 (1H, dd, J=8.21, 1.86 Hz), 7.06 (1H, d, J=0.83 Hz), 6.96 (1H, d, J=1.83 Hz), 5.93-5.84 (1H, m), 4.38 (2H, t, J=5.06 Hz), 3.87 (2H, t, J=7.32 Hz), 3.80 (2H, s), 3.78-3.69 (1H, m), 3.41-3.34 (4H, m), 1.60 (6H, d, J=6.63 Hz)
Reaction SMILES: C1C=CC2N(O)N=[N:7]C=2C=1.Cl.CN1CCOCC1.[NH:19]1[C:27]2[C:22](=[CH:23][C:24]([CH2:28][NH2:29])=[CH:25][CH:26]=2)[CH:21]=[CH:20]1.[CH2:30]([N:34]1[CH2:38][CH2:37][CH2:36][C@@H:35]1[CH2:39][NH:40][C:41]1[C:42](=[O:52])[N:43]([CH2:48][C:49](O)=[O:50])[C:44]([CH3:47])=[CH:45][N:46]=1)[CH:31]([CH3:33])[CH3:32]>CN(C)C=O>[NH3:7].[NH:19]1[C:27]2[C:22](=[CH:23][C:24]([CH2:28][NH:29][C:49](=[O:50])[CH2:48][N:43]3[C:44]([CH3:47])=[CH:45][N:46]=[C:41]([NH:40][CH2:39][C@H:35]4[CH2:36][CH2:37][CH2:38][N:34]4[CH2:30][CH:31]([CH3:32])[CH3:33])[C:42]3=[O:52])=[CH:25][CH:26]=2)[CH:21]=[CH:20]1
Reactant: On1nnc2ccccc21
Reactant: NCc1ccc2[nH]ccc2c1
Reactant: Cc1cnc(NC[C@H]2CCCN2CC(C)C)c(=O)n1CC(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cnc(NC[C@H]2CCCN2CC(C)C)c(=O)n1CC(=O)NCc1ccc2[nH]ccc2c1
Product: N
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.6 %

Procedure:
HOBT (24 mg, 0.18 mmol), WSCDl.HCl (29 mg, 0.15 mmol), N-methylmorpholine (39 ml, 0.36 mmol) and 1H-indol-5-ylmethylamine (preparation 8) (19 mg, 0.13 mmol) were added to a solution of 2-[3-({[(2R)-1-isobutylpyrrolidinyl]methyl}amino)-6-methyl-2-oxo-1(2H)-pyrazinyl]acetic acid (preparation 62) (38 mg, 0.12 mmol) in N,N-dimethylformamide (2 ml), and the reaction was stirred at room temperature overnight. The mixture was evaporated under reduced pressure and the residue purified by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (95:5:0.5) as eluant. The product was repurified using a Biotage™ (KP-Sil™ 60 Å silica gel) cartridge and dichloromethane:methanol:0.88 ammonia (95:5:0.5) as eluant to afford the title compound, (16 mg, 30%).
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)([CH3:10])[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[SH2:24]>CN(C)C=O>[C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)([CH3:10])[C:8]([NH2:9])=[S:24])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C#N)(c1ccccc1)c1ccccn1
Reactant: S
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C(N)=S)(c1ccccc1)c1ccccn1

Procedure:
With continuous stirring, subject a mixture containing 6 g. of α-phenyl-α-(2-pyridyl) propionitrile and 5 ml. of triethylamine in 60 ml. of dimethylformamide to a stream of hydrogen sulfide for 24 hours. Pour the resulting solution into 200 ml. of ice water, filter, wash and dry the solids which are formed. Recrystallize the solids from acetonitrile to obtain the intermediate α-phenyl-α-(2-pyridyl) thiopropionamide, m.p. 186°-188° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:10]([CH2:24][CH2:25][C:26]2[CH:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=2)[C:11]([C@@H:13]([O:20]C(=O)C)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])[CH:6]=[CH:7][C:8]=1[CH3:9].O.[OH-].[Li+]>O1CCCC1.O>[OH:20][C@@H:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:11]([N:10]([C:5]1[CH:6]=[CH:7][C:8]([CH3:9])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:24][CH2:25][C:26]1[CH:27]=[N:28][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:31]=1)=[O:12]
Reactant: COc1cc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)[C@@H](OC(C)=O)c2ccccc2)ccc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)[C@@H](O)c2ccccc2)ccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 9.1 %

Procedure:
To a solution of acetic acid (S)-{(3-methoxy-4-methyl-phenyl)-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-carbamoyl}-phenyl-methyl ester (155 mg, 0.32 mmol) in tetrahydrofuran (2.0 mL) were added 1.0 mL water and 20.0 mg (0.84 mmol) lithium hydroxide monohydrate. The mixture was stirred at room temperature for 2 h. The mixture was diluted with water and extracted 3 times with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude oil was purified with flash column chromatography on silica eluting with a gradient formed from heptane and ethylacetate to provide 13 mg (9%) of the title compound as a colourless oil. MS(m/e): 445.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C(O)C.O.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>[O:30]1[CH2:31][CH2:32][N:27]([C:24]2[CH:25]=[CH:26][C:21]([C:2]3[CH:3]=[CH:4][C:5]4[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=4[CH:18]=3)=[CH:22][CH:23]=2)[CH2:28][CH2:29]1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
Reactant: [O-]B([O-])Oc1ccc(N2CCOCC2)cc1
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+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COC(=O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
Under argon atmosphere, a mixture of methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.7 g), 4-morpholinophenyl borate (481 mg) and potassium carbonate (0.59 g) in toluene/ethanol/water (20/2/2 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (0.12 g), and the mixture was refluxed for 20 hours and cooled. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and precipitated solid was recrystallized from ethyl acetate/hexane to give yellow crystals of methyl 7-(4-morpholinophenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (617.6 mg).
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH2:15].[OH-:16].[Na+]>[O-2].[O-2].[O-2].[Ni+3].[Ni+3]>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[C:11]([C:12]([OH:14])=[O:13])[C:2]=1[C:1]([OH:16])=[O:15]
Reactant: Cc1nc2ccccc2cc1C(=O)O
Reactant: [OH-]
Reactant: O
Agent: [Ni+3]
Agent: [Na+]
Agent: [O-2]
Product: O=C(O)c1cc2ccccc2nc1C(=O)O

Procedure:
Three grams of 2-methylquinoline-3-carboxylic acid (0.012 mol of 3.5 hydrate) is dissolved in 100 ml 15% sodium hydroxide solution and an additional 100 ml H2O is added. The mixture becomes homogeneous. At room temperature is added, all at once, 12.0 g nickel peroxide, (0.044 mol, 3.6 eq, 20% excess) and the mixture is stirred magnetically for 12 hours. The insolubles are removed by vacuum filtration and washed with water. The filtrate is acidified to pH 2 and a solid fluffy precipitate forms. It is filtered and dried to give 2.48 g of quinoline-2,3-dicarboxylic acid which is hydrated with 1.3 moles H2O/mole compound as determined by NMR. Additional product is isolated from the aqueous filtrate by concentration and filtration. This brings the total actual product yield to 2.88 g of product having a melting point of 271°-277° C. Product yield is essentially quantitative.