Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]([F:20])[F:19])[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].[N+:26]([CH3:29])([O-:28])=[O:27]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:29]/[N+:26]([O-:28])=[O:27])[CH:14]=[CH:15][C:16]=1[O:17][CH:18]([F:20])[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OC(F)F)c(OCc2ccccc2)c1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(OC(F)F)c(OCc2ccccc2)c1
Temperature: 130 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
3-(Benzyloxy)-4-(difluoromethoxy)benzaldehyde described in Production Example 19-2 (3.94 g, 14.2 mmol) was dissolved in acetic acid (11 mL), then ammonium acetate (1.27 g, 16.4 mmol) and nitromethane (1.9 mL, 35.1 mmol) were added under nitrogen atmosphere at room temperature, and the mixture was heated and stirred at 130° C. for 2 hours. The mixture was cooled to room temperature and then heated and stirred at 130° C. again for 1 hour. The precipitate was collected by filteration and washed with a liquid mixture of acetic acid and ethanol to obtain the title compound (2.36 g, 52%). The filtrate was dissolved in dichloromethane and the resultant was purified with silica gel column chromatography (n-heptane:ethyl acetate=19:1-4:1), and then the target fraction was concentrated under vacuum. The precipitate was washed with ethanol to obtain the title compound (406 mg, 8.9%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C1(S(O[CH2:15][C:16]#[N:17])(=O)=O)C=CC=CC=1.[C:18]1([CH3:26])[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[CH:19]=1>>[CH3:26][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[C:19]=1[CH2:15][C:16]#[N:17]
Reactant: N#CCOS(=O)(=O)c1ccccc1
Reactant: Cc1cc(C)cc(C)c1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(C)c(CC#N)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
8.0 g (0.06 mol) of aluminum chloride are first introduced into 40 ml of mesitylene at 0° C. 4.1 g (0.02 mol) of phenylsulfonyloxyacetonitrile are then added, and the reaction mixture is stirred at room temperature overnight. The crude product obtained after hydrolysis is chromatographed on silica gel using dichloromethane. 2.3 g (72.3% of theory) of 2,4,6-trimethylbenzyl cyanide are isolated.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([NH2:13])=[S:12].[CH3:14][I:15]>CO>[I-:15].[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([S:12][CH3:14])=[NH2+:13]
Reactant: NC(=S)Nc1nc2ccccc2[nH]1
Reactant: CI
Solvent: CO
Product: CSC(=[NH2+])Nc1nc2ccccc2[nH]1
Product: [I-]

Procedure:
To 0.27 g (1.40 mmol) N-1H-benzimidazole-2-ylthiourea were added 0.115 ml (1.83 mmol) methyl iodide dissolved in 4 ml of methanol. It was heated for 30 minutes at reflux. After completion of the reaction, the solvent was removed under vacuum and 0.47 g 1H-benzimidazole-2-ylamino)(methylthio)methane iminium iodide was used without further purification for the following reaction.
Reaction SMILES: [NH2:1][C@H:2]([C:13](O)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.S(C)C>C1COCC1>[NH2:1][C@@H:2]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)[CH2:13][OH:14]
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Solvent: C1CCOC1
Solvent: CSC
Product: N[C@H](CO)Cc1c[nH]c2ccccc12
Temperature: 70 °C
Yield: 92 %

Procedure:
To a stirred solution of (S)-tryptophan (4.0 g, 20.0 mmol) in THF (100 mL) at 0° C. was slowly added BH3.Me2S complex (5.9 mL, 10M solution in THF, 59.0 mmol). The reaction mixture was heated to 70° C. for 16 h and, after cooling, the excess borane was quenched by the addition of MeOH (10 mL) at 0° C. The reaction mixture was then concentrated in vacuo and the resultant white solid was dissolved in EtOAc (100 mL) and washed with aqueous NaOH solution (20% w/v, 2×70 mL). The organic fraction was then extracted into aqueous 2M HCl (2×100 mL). The combined acidic aqueous fractions were basified to pH 14 (addition of solid NaOH) and were re-extracted with EtOAc (2×150 mL). The combined organic fractions were washed with brine (70 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound (3.5 g, 92%) as a white solid that was used without further purification. δH (CD3OD) 7.46 (1H, d, J 7.9 Hz), 7.21 (1H, d, J 8.0 Hz), 6.96 (3H, m), 3.79 (1H, dd, J 11.3 Hz and J 3.6 Hz), 3.54 (1H, dd, J 11.2 Hz and J 6.2 Hz), 3.05 (1H, m), 2.80 (1H, m), 2.61 (1H, m). Exchangeable protons were not observed.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH:10]([CH2:14][CH2:15][CH3:16])[C:11]([O-:13])=[O:12].N1C(C)=CC=[CH:19][C:18]=1C>C(#N)C>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH2:16][CH2:15][CH2:14][CH2:10][C:11]([O:13][CH2:18][CH3:19])=[O:12]
Reactant: CNc1ccccc1
Reactant: CCCC(Br)C(=O)[O-]
Reactant: Cc1cccc(C)n1
Solvent: CC#N
Product: CCOC(=O)CCCCN(C)c1ccccc1

Procedure:
5.52 ml (48 mmol) of N-Methyl aniline, 8 ml Bromovalerate (50.2 mmol) and 2,6-lutidine (5.82 ml, 50.2 mmol) were taken in 100 ml acetonitrile and the reaction was refluxed for 24 hour under stirring. Acetonitrile was removed under vacuum and residues were dissolved in ether. The organic phase was washed with water. After drying over magnesium sulfate and filtering, the solvent was removed to give a brown liquid. The residue was purified by flash chromatography on silica gel using a 10% ethyl acetate in hexane as eluent gave 10.1 g light yellow oil as product. MW C14H21NO2 235.32 g/mol (yields 90%).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[C:3](=[O:8])[NH:2]2.N1C=CC=CC=1.[C:15]1([CH2:21][C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>C(#N)C>[C:15]1([CH2:21][C:22]([C:1]23[CH2:7][CH:4]([CH:5]=[CH:6]2)[C:3](=[O:8])[NH:2]3)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1NC2C=CC1C2
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CC#N
Solvent: O
Solvent: c1ccncc1
Product: O=C1NC2(C(=O)Cc3ccccc3)C=CC1C2
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 112.6 %

Procedure:
33.4 g of (±)-2-azabicyclo[2.2.1]hept-5-en-3-one were dissolved in acetonitrile (240 ml) and pyridine (48.3 ml) under nitrogen. At 12° C., 68.6 g of phenylacetyl chloride were added dropwise over the course of 30 minutes. The mixture was then stirred at room temperature for 3.5 hours. 240 ml of water were added to the mixture. The acetonitrile was evaporated off in vacuo, and the aqueous phase was extracted 3 times with ethyl acetate (150 ml). The combined org. phases were washed with 1N HCl (150 ml), saturated NaCl (150 ml) and water (150 ml), dried with magnesium sulphate and completely evaporated. The crude product was filtered through silica gel (hexane:ethyl acetate =1:1). 78.34 g of the crude product were obtained as a yellow oil.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:6]=[C:7]([CH:22]=[CH:23][CH:24]=1)[CH2:8][CH:9]([CH:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[OH:14])C(O)=O)([F:4])[CH3:3].C([N:27]([CH2:30]C)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:39])C=CC=CC=1>O1CCCC1>[F:4][C:2]([C:5]1[CH:6]=[C:7]([CH:22]=[CH:23][CH:24]=1)[CH2:8][CH:9]1[CH:13]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[O:14][C:30](=[O:39])[NH:27]1)([F:1])[CH3:3]
Reactant: CCN(CC)CC
Reactant: CC(F)(F)c1cccc(CC(C(=O)O)C(O)c2ccc(F)cc2)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(F)(F)c1cccc(CC2NC(=O)OC2c2ccc(F)cc2)c1
Yield: 87.5 %

Procedure:
To a solution of (2RS,3RS)-2-[3-(1,1-difluoroethyl)benzyl]-3-(4-fluorophenyl)-3-hydroxypropionic acid (4.22 g, 13.6 mmol) in tetrahydrofuran (130 ml) were added triethylamine (2.85 ml, 20.4 mmol) and diphenylphosphoryl azide (3.23 ml, 14.96 mmol), and the mixture was heated under reflux for 5 hrs. The solvent was evaporated, and the residue was diluted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to give [4RS,5SR]-4-(3-[1,1-difluoroethyl)benzyl]-5-(4-fluorophenyl)-1,3-oxazolidin-2-one (3.99 g, 95%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:4][CH:3]=1.[CH3:28][O:29][CH2:30][C:31](Cl)=[O:32]>C1COCC1>[CH3:28][O:29][CH2:30][C:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:6][CH:7]=1)=[O:32]
Reactant: COCC(=O)Cl
Reactant: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1
Solvent: C1CCOC1
Product: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(NC(=O)COC)cc2)c2ccccc2N1

Procedure:
The title compound was synthesized using (Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one and methoxy acetyl chloride in THF according to the procedure described in the synthesis of Example 26. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.69 (t, J=7.33 Hz, 3H) 1.26-1.36 (m, J=7.38, 7.38, 7.38, 7.38, 7.38 Hz, 2H) 2.23 (t, J=7.33 Hz, 2H) 3.40 (s, 3H) 4.06 (s, 2H) 6.76 (s, 1H) 7.64 (t, J=7.71 Hz, 1H) 7.70 (d, J=8.34 Hz, 2H) 7.87 (t, J=7.71 Hz, 1H) 7.91-7.96 (m, 1H) 7.98 (d, J=8.59 Hz, 2H) 8.15 (d, J=8.34 Hz, 1H) 10.18 (s, 1H); ESI-MS: m/z calc'd for C24H24N4O3S 448.54. found 449.2 (M+H)+.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[S:2].C(N(C(C)C)CC)(C)C.Cl.[F:23][C:24]([F:28])([F:27])[CH2:25][NH2:26].[NH2:29][CH:30]([CH2:48][S:49]([CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)(=[O:51])=[O:50])[C:31]([NH:33][CH:34]([CH:37]([C:39]1[O:40][C:41]2[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=2[N:43]=1)[OH:38])[CH2:35][CH3:36])=[O:32]>C(Cl)Cl.CCOC(C)=O>[O:40]1[C:41]2[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=2[N:43]=[C:39]1[CH:37]([OH:38])[CH:34]([NH:33][C:31](=[O:32])[CH:30]([NH:29][C:1]([NH:26][CH2:25][C:24]([F:28])([F:27])[F:23])=[S:2])[CH2:48][S:49]([CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)(=[O:50])=[O:51])[CH2:35][CH3:36]
Reactant: NCC(F)(F)F
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CCC(NC(=O)C(N)CS(=O)(=O)Cc1ccccc1)C(O)c1nc2ccccc2o1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(NC(=O)C(CS(=O)(=O)Cc1ccccc1)NC(=S)NCC(F)(F)F)C(O)c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,1′-Thiocarbonyldiimidazole (0.980 g, 5.50 mmol, 1.2 equiv.) was dissolved in CH2Cl2 (200 mL), followed by addition of diisopropylethylamine (3.2 mL), and trifluoroethylamine hydrochloride (0.620 g, 4.58 mmol, 1.0 equiv.). The solution was stirred for 1 h at ambient temp, then 2-amino-N-[1-(benzoxazol-2-ylhydroxymethyl)-propyl]-3-phenylmethanesulfonylpropionamide was added in one portion. After stirring overnight, the reaction mixture was diluted with EtOAc (150 mL), washed with saturated bicarb, brine, dried over MgSO4. Purification with flash chromatography (50% ETOAc/hexanes as eluent) afforded N-[1-(benzoxazol-2-ylhydroxymethyl)-propyl]-3-phenylmethanesulfonyl-2-[3-(2,2,2-trifluoroethyl)thioureido]propionamide (0.720 g) as a mixture of diasteomers.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:11][C@H:10]([CH2:12][P:13]([O:18][CH2:19][CH3:20])(=[O:17])[O:14][CH2:15][CH3:16])[C@@H:9]([N:21]=[N+]=[N-])[C@@H:8]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:7]1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:3])[CH3:2].[BH4-].[Na+].[CH3:42][C:43](OC(C)=O)=[O:44]>CO.C1(C)C=CC=CC=1.Cl[Ni]Cl>[C:1]([O:4][CH2:5][C@H:6]1[O:11][C@H:10]([CH2:12][P:13]([O:18][CH2:19][CH3:20])(=[O:17])[O:14][CH2:15][CH3:16])[C@@H:9]([NH:21][C:43](=[O:44])[CH3:42])[C@@H:8]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:7]1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=[O:3])[CH3:2]
Reactant: CCOP(=O)(C[C@H]1O[C@H](COC(C)=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1N=[N+]=[N-])OCC
Reactant: CC(=O)OC(C)=O
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOP(=O)(C[C@H]1O[C@H](COC(C)=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1NC(C)=O)OCC
Yield: 76 %

Procedure:
To a stirred solution of 4 (2.50 g, 4.45 mmol) in MeOH (125 mL) a catalytic amount of NiCl2×6H2O was added followed by portions of NaBH4 (in total 0.34 g, 8.9 mmol) every 10 min until no starting material was observed on TLC (system). Ac2O (3 mL) was added after 50 min and the reaction mixture was diluted with toluene, filtered through a plug of silica and concentrated. The residue was purified by silica gel chromatography to give 5 (1.95 g, 3.4 mmol, 76%). 13C-NMR (CDCl3) 170.4, 169.7, 137.3, 137.0 remaining aromatic C 128.5-127.7, 75.3, 72.6, 72.4, 72.1, 72.0, 67.1, 61.91, 61.8, 61.8, 61.3, 61.2, 48.8, 48.6, 28.5 (d, J=142 Hz), 23.0, 20.6, 16.3, 16.2, 16.1; 31P-NMR (CDCl3) 29.5.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1)[NH2:15]>CN1CCCC1=O.C(OCC)(=O)C>[ClH:1].[Cl:11][C:12]1[CH:13]=[C:14]([NH:15][C:2]2[C:3]3[NH:10][CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cl
Product: Fc1cccc(COc2ccc(Nc3ncnc4cc[nH]c34)cc2Cl)c1
Temperature: 140 °C
Yield: 79.7 %

Procedure:
4-Chloro-5H-pyrrolo[3,2-d]pyrimidine (770 mg) and 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (2.52 g) were dissolved in 1-methyl-2-pyrrolidone (10 mL), and the mixture was stirred with heating at 140° C. for 2.5 hrs. After cooling to room temperature, the mixture was diluted with ethyl acetate (300 mL), and stirred at room temperature for 1 hr. The precipitated powder was collected by filtration, washed with ethyl acetate (30 mL), and dried under reduced pressure to give the title compound (1.62 g).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[CH:19][CH:18]=[C:17]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+].CO.C(Cl)(Cl)Cl>CCO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[CH:19][CH:18]=[C:17]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:16]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(-c2ccc(-c3ccccc3)nc2-c2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: CO
Product: COc1ccc(-c2ccc(-c3ccccc3)nc2-c2ccc(O)cc2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
The 2-(4-benzyloxyphenyl)-3-(4-methoxyphenyl)-6-phenylpyridine (3.5 g, 7.9 mmol) and ammonium formate (2.5 g, 40 mmol) were stirred in 150 mL of EtOH, then 5% Pd/ C (1.4 g, 0.6 mmol Pd) was added and the reaction mixture was stirred at 60 ° C. for 1 h. The TLC (MeOH/ CHCl3, 1:9) indicated a small amount of the starting material remained, so more ammonium formate (0.3 g, 5 mmol) was added and reaction mixture stirred at 60° C. for 0.5 h, which consumed the remaining starting material. After cooling, the reaction mixture was filtered and the filter pad washed with 50 mL of EtOH, then 50 mL of EtOAc. The filtrates were combined and concentrated, then redissolved in 150 mL of EtOAc, washed with brine, dried (Na2SO4), concentrated, and the residue triturated with Et2O/ pet. ether to give 2.5 g (90% yield) of white solid: mp 200°-202° C.; 1H NMR (CDCl3) d 3.85 (s, 3H, OCH3), 5.07 (s, 1H, ArOH), 6.71-6.90 (m, 4H, ArH), 7.17-7.20 (d, 2H, J=8 Hz, ArH), 7.38-7.54 (m, 5H, ArH), 7.75 (s, 2H, ArH), 8.13-8.16 (d, 2H, J=9 Hz, ArH); MS(FD) 354(M+). Anal. Calcd for C24H19 NO2 : C, 81.56; H, 5.42; N, 3.96. Found: C, 81.50; H, 5.61; N, 3.99.
Reaction SMILES: [CH:1]1([C@H:4]([O:6][C:7](=[O:31])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]([CH:27]4[CH2:30][CH2:29][CH2:28]4)[C:17]4[C:22]([C:23]=3[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([OH:26])[CH:18]=4)=[CH:11][CH:10]=2)[CH3:5])[CH2:3][CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:39]1[N:44]=[CH:43][CH:42]=[CH:41][N:40]=1.O>CN(C=O)C>[CH:1]1([C@H:4]([O:6][C:7](=[O:31])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]([CH:27]4[CH2:28][CH2:29][CH2:30]4)[C:17]4[C:22]([C:23]=3[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([O:26][C:39]3[N:44]=[CH:43][CH:42]=[CH:41][N:40]=3)[CH:18]=4)=[CH:11][CH:10]=2)[CH3:5])[CH2:3][CH2:2]1
Reactant: C[C@@H](OC(=O)Nc1ccc(-c2c(C#N)c3ccc(O)cc3n2C2CCC2)cc1)C1CC1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](OC(=O)Nc1ccc(-c2c(C#N)c3ccc(Oc4ncccn4)cc3n2C2CCC2)cc1)C1CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
A mixture of (R)-[4-(3-cyano-1-cyclobutyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (0.083 g, 0.2 mmol), Cs2CO3 (0.163 g, 0.5 mmol), 2-chloropyrimidine (0.046 g, 0.4 mmol) in DMF (2.0 mL) was stirred at 70° C. for 2 h. After cooling to room temperature, the mixture was poured into water (15 mL) and the precipitate was collected via filtration and washed with water, purified on silica gel (CH2Cl2/EtOAc, 9.5:0.5) to provide (R)-{4-[3-cyano-1-cyclobutyl-6-(pyrimidin-2-yloxy)-1H-indol-2-yl]-phenyl}carbamic acid 1-cyclopropyl-ethyl ester (0.073 g, 74%).
Reaction SMILES: [CH3:1][C:2]1[N:11]2[C:5]([CH:6]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10]2)=[N:4][C:3]=1[C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.[CH:40]([N:43]=[C:44]=[S:45])([CH3:42])[CH3:41]>C(#N)C>[CH:40]([NH:43][C:44]([NH:30][C:27]1[CH:28]=[CH:29][C:24]([C:3]2[N:4]=[C:5]3[N:11]([CH2:10][CH2:9][C:8]4[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=4[CH:6]3[O:16][CH:17]3[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]3)[C:2]=2[CH3:1])=[CH:25][CH:26]=1)=[S:45])([CH3:42])[CH3:41]
Reactant: Cc1c(-c2ccc(N)cc2)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Reactant: CC(C)N=C=S
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1c(-c2ccc(NC(=S)NC(C)C)cc2)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Temperature: 80 °C

Procedure:
To a solution of 4-[1-methyl-4-(1-methyl piperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenylamine (example 173) (50 mg, 0.124 mmole) in ACN (1 mL) are added DIEA (65 μL, 0.372 mmole) and isopropylisothiocyanate (18.8 mg, 0.182 mmole). The reaction mixture is heated overnight at 80° C. Solvent is removed under reduced pressure. The residue is purified by silica gel chromatography eluting with (CH2Cl2:MeOH:NH4OH) from (98:2:02) to (96.5:3.5:0.35) to give 1-isopropyl-3-{4-[1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diazabenzo[f]azulen-2-yl]-phenyl}-thiourea. [M+H]+=504.37.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[CH2:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([OH:17])=[CH:9][CH:8]=1)[CH3:2].[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:30][C:31]([CH3:37])=[C:32]([CH2:34][CH2:35]O)[N:33]=2)=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:18][CH2:19][CH3:20])[CH2:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([O:17][CH2:35][CH2:34][C:32]2[N:33]=[C:29]([C:26]3[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=3)[O:30][C:31]=2[CH3:37])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c2c1CCCC2)OCC
Reactant: Cc1oc(-c2ccc(F)cc2)nc1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccc(F)cc3)oc2C)c2c1CCCC2)OCC

Procedure:
In analogy to the procedure described in example 17 a], [rac]-2-ethoxy-3-(4-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid ethyl ester (example 108 b]) was reacted with 2-[2-(4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethanol [J. Med. Chem. (1998), 41(25), 5037-5054] in the presence of triphenylphosphine and DEAD (diethyl azodicarboxylate) to yield [rac]-2-ethoxy-3-(4-{2-[2-(4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 91 e] to yield [rac]-2-ethoxy-3-(4-{2-[2-(4-fluoro-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-5,6,7,8-tetrahydro-naphthalen-1-yl)-propionic acid as colorless solid.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]=1[C:18]([OH:20])=O.CI.CN([CH:26]=[O:27])C>>[CH3:1][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]=1[C:18]([O:27][CH3:26])=[O:20]
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Reactant: O=C(O)c1c(O)ccc2ccccc12
Agent: [K+]
Solvent: CI
Product: COC(=O)c1c(OC)ccc2ccccc12
Temperature: 80 °C

Procedure:
Potassium carbonate (111 g, 803 mmol) was added to a mixture of 2-hydroxy-l-naphthoic acid (50.0 g, 266 mmol) and methyl iodide (189 g, 1330 mmol) in DMF (500 mL). The resulting mixture was heated at 80° C. overnight, then was partitioned between ether and water. The organic was washed with dilute aqueous HCl, dried (MgSO4), and concentrated to afford methyl 2-methoxynaphthoate as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[CH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.Cl[Pd]Cl>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]2[CH:14]=[CH:13][N:12]=[C:11]([O:10][CH3:9])[CH:16]=2)=[N:3][CH:4]=1
Reactant: Clc1ccc(Br)nc1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc(-c2ccc(Cl)cn2)ccn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 34.6 %

Procedure:
2-Bromo-5-chloropyridine (2.04 g, 10.6 mmol), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.50 g, 10.6 mmol), K2CO3 (4.38 g, 31.8 mmol) and PdCl2 (dppf) (0.40 g, 0.53 mmol) were stirred in DMSO (20 mL). The reaction mixture was degassed, then back-filled with N2. The reaction mixture was stirred at 80° C. in a pre-heated oil bath for 2 hours. After cooling, the reaction was quenched with water and extracted with CH2Cl2. The organic layer was washed with H2O and 5% LiCl, dried with Na2SO4, filtered and concentrated. Flash chromatography (silica gel, hexanes/EtOAc), 100:0 to 50:50) afforded the title compound (810 mg, 34%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.67 (d, J=2.0 Hz, 1H), 8.27 (d, J=5.3 Hz, 1H), 7.79-7.75 (dd, J=8.8, 2.3 Hz, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.46-7.44 (dd, J=5.3, 1.5 Hz, 1H), 7.30 (s, 1H), 3.99 (s, 3H).
Reaction SMILES: CC(C)([O-])C.[K+].[N+:7]([CH:9]([CH2:14][CH3:15])[C:10]([O:12][CH3:13])=[O:11])#[C-:8].Br[CH2:17][C:18]1[S:19][CH:20]=[CH:21][CH:22]=1.C(O)(=O)C>O1CCCC1>[N+:7]([C:9]([CH2:17][C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)([CH2:14][CH3:15])[C:10]([O:12][CH3:13])=[O:11])#[C-:8]
Reactant: [C-]#[N+]C(CC)C(=O)OC
Reactant: BrCc1cccs1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: [C-]#[N+]C(CC)(Cc1cccs1)C(=O)OC
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
A suspension of potassium tert.-butoxide (5.5 g) in tetrahydrofuran (50 ml) is cooled to -30° C., and a solution of methyl 2-isocyanobutyrate (5.5 g) in tetrahydrofuran (10 ml) is added dropwise to the suspension at -30° C. The mixture is stirred at the same temperature for 30 minutes and a solution of 2-bromomethylthiophene (6.9 g) in tetrahydrafuran (10 ml) is added dropwise to the mixture. The mixture is stirred at room temperature for 4 hours, adjusted to pH 7 with acetic acid and then concentrated under reduced pressure to remove solvent. The residue is dissolved in a mixture of ethyl acetate and water and the organic layer is collected therefrom. The organic layer is washed with an aqueous saturated sodium chloride solution, dried and concentrated to remove solvent. The residue is distilled under reduced pressure, whereby methyl 2-isocyano-2-(2-thienylmethyl)butyrate (7.7 g) is obtained as pale yellow oil.