Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:25]2[CH:30]=[CH:29][C:28]([C:31](=[O:37])[N:32]([CH2:34][CH2:35][OH:36])[CH3:33])=[CH:27][CH:26]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[OH:36][CH2:35][CH2:34][N:32]([CH3:33])[C:31](=[O:37])[C:28]1[CH:27]=[CH:26][C:25]([C:14](=[C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)=[CH:30][CH:29]=1
Reactant: CN(CCO)C(=O)c1ccc(C(=C2CCN(C(=O)OC(C)(C)C)CC2)c2cccc3cccnc23)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CN(CCO)C(=O)c1ccc(C(=C2CCNCC2)c2cccc3cccnc23)cc1
Reaction time: 2 h
Yield: 99.1 %

Procedure:
Compound 1B (4.7 g, 9.3 mmol) was treated with 4N HCl in dioxane (30 mL). 10 min. later, the mixture was decanted, and the solid was stirred in ether (40 mL) for 2 h. The ether was then decanted and the remaining yellow solid dried under high vacuum to yield 3.7 g 1C (100%). 1H NMR (300.132 MHz, DMSO, 90° C.) δ 8.98 (s, 1H), 8.47 (d, J=8.1 Hz, 1H), 7.96 (d, J=6.6 Hz, 1H), 7.69-7.57 (m, 3H), 7.38 (d, J=8.0 Hz, 2H), 7.29 (d, J=8.3 Hz, 2H), 3.53 (t, J=5.8 Hz, 2H), 3.36 (t, J=5.7 Hz, 2H), 3.23 (t, J=6.0 Hz, 2H), 3.07 (t, J=6.0 Hz, 2H), 2.92 (s, 3H), 2.63 (t, J=6.0 Hz, 2H), 2.15 (t, J=6.0 Hz, 2H). TOF MS ES+ 402.17.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:8]=1)[NH2:5].[CH3:18][O:19][CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:5][S:22]([CH2:21][CH2:20][O:19][CH3:18])(=[O:24])=[O:23])[CH:6]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:8]=1
Reactant: CC1(C)OB(c2cc(N)cc(F)c2)OC1(C)C
Reactant: COCCS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COCCS(=O)(=O)Nc1cc(F)cc(B2OC(C)(C)C(C)(C)O2)c1
Temperature: 45 °C
Reaction time: 3 h
Yield: 17 %

Procedure:
3-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (250 mg, 1.05 mmol) was treated with 2-methoxyethanesulfonyl chloride (326 mg, 2.06 mmol) and 1 ml pyridine as a solvent according to the method described in Preparation 15b but stirring at 45° C. during 3 h. The residue was purified using SP1® Purification System (0% to 100% hexane-ethyl acetate) to obtain 80 mg (17% yield, 81% purity) of the title compound.
Reaction SMILES: [CH3:1][CH:2](C)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=[O:4].NC1C=CC(C2CCN(C(OC(C)(C)C)=O)CC2)=CC=1.C(Cl)(=O)CC>>[NH:15]1[CH2:16][CH2:17][CH:12]([C:9]2[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH2:2][CH3:1])=[CH:7][CH:8]=2)[CH2:13][CH2:14]1
Reactant: CC(C)C(=O)Nc1ccc(C2CCNCC2)cc1
Agent: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Agent: CCC(=O)Cl
Product: CCC(=O)Nc1ccc(C2CCNCC2)cc1

Procedure:
Prepared by the procedure for 2-methyl-N-[4-(4-piperidinyl)phenyl]propanamide using tert-butyl 4-(4-aminophenyl)-1-piperidinecarboxylate and propanoyl chloride: ESMS m/e: 233.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:7][CH2:6][CH2:5][NH:4][C:3]1=[O:8].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.O>[CH2:10]([N:7]1[CH2:6][CH2:5][NH:4][C:3](=[O:8])[C:2]1([CH3:9])[CH3:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)NCCNC1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)C(=O)NCCN1Cc1ccccc1
Temperature: 12.5 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 3,3-dimethylpiperazin-2-one (prepared according to procedure reported in WO200516900 A1, 6.0 g, 46.8 mmol) in N,N-dimethylformamide (10 ml) was added benzyl bromide (6.68 ml, 56.2 mmol) at 0° C., followed by addition of triethylamine (19.57 ml, 140 mmol). Reaction was stirred for 3 h at 0-25° C. The progress of reaction was monitored by TLC. After completion of reaction, the reaction mixture was diluted with ethyl acetate (100 ml) and water (100 ml). Aqueous layer was extracted with ethyl acetate (50 ml×6). The combined organic phase was washed with brine (50 mL) and dried over sodium sulphate and concentrated under reduced pressure till dryness. Crude compound was adsorbed on 100-200 mesh silica gel and purified by using flash column chromatography method using 5% methanol in dichloromethane as eluent. Title compound was eluted at 5% methanol in dichloromethane (6.2 g, 60.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:9][C:10]([NH:12][CH2:13][C:14]([O:16]CC)=[O:15])=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C.Cl>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[CH:9][C:10]([NH:12][CH2:13][C:14]([OH:16])=[O:15])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CNC(=O)C=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CNC(=O)C=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
A mixture of 1.0 g. of ethyl N-[3,3-bis(p-chlorophenyl)acryloyl]glycinate, 106 mg. of sodium hydroxide, 18 ml. of ethanol, and 2 ml. of water is stirred under reflux for one hour, allowed to cool, diluted with 80 ml. of water, and acidified with 20 ml. of 1N hydrochloric acid. The solid is collected, dried in vacuo at 50° C., and then stirred with 50 ml. of dichloromethane and 50 ml. of water. The solid which fails to dissolve is collected and dried at 50° C., giving 150 mg. of the desired product as a white solid, m.p. 166°-168° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[OH:14].[CH2:15]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([O-])=O)=[CH:25][CH:24]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>O>[CH2:15]([C:23]1[CH:31]=[CH:30][C:26]([C:27]2[O:14][C:3]3[CH:4]=[CH:5][C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:7][C:2]=3[N:1]=2)=[CH:25][CH:24]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCc1ccc(O)c(N)c1
Reactant: CCCCCCCCc1ccc(C(=O)[O-])cc1
Solvent: O
Product: CCCCCCCCc1ccc(-c2nc3cc(CCCCCC)ccc3o2)cc1
Temperature: 250 °C
Reaction time: 3.5 h
Yield: 28 %

Procedure:
In a 50 ml-round-bottomed flask, 19 g of polyphosphoric acid, 0.30 g (1.55 mM) of 2-amino-4-hexylphenol and 0.37 g (1.58 mM) of 4-octylbenzoate acid were placed, followed by stirring for 3.5 hours at about 250° C. After the reaction, the reaction mixture was poured into water to precipitate a crystal. The crystal was recovered by filtration and was washed with 10% K2CO3. The crystal was dissolved in ethyl acetate and washed with water, followed by drying with anhydrous sodium sulfate and distilling-off of the solvent. The resultant residue was purified by silica gel column chromatography (eluent: toluene/hexane=1/2) to obtain 0.17 g of 2-(4-octylphenyl)-5-hexylbenzoxazole (yield: 28.0%). ##STR72##
Reaction SMILES: N[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][CH3:11].Cl.N([O-])=O.[Na+].[I-:17].[K+]>O>[CH2:10]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[I:17])[C:6]#[N:7])[CH3:11]
Reactant: CCc1cc(C#N)ccc1N
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: CCc1cc(C#N)ccc1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
To 4-amino-3-ethylbenzonitrile (2.50 g, 17.1 mmol) stirred in water (14 mL) at 0° C. was added concentrated hydrochloric acid (7.80 mL, 257 mmol) dropwise followed by a solution of sodium nitrite (1.24 g, 18.0 mmol) in water (3.43 mL) dropwise. The resultant mixture was stirred for 15 minutes and then added over 15 minutes to a solution of potassium iodide (2.98 g, 18.0 mmol) in water (6.0 mL) at 0° C. The mixture was stirred at room temperature for 2 h. The mixture was extracted with ethyl acetate (3×100 mL) and the combined organic fractions washed with brine (100 mL), dried (phase separator) and concentrated in vacuo to give the title compound as a brown solid (4.21 g, 16.4 mmol). δH (methanol-d4, 400 MHz): 8.02 (1H, d), 7.61 (1H, d), 7.24 (1H, dd), 2.80 (2H, q), 1.21 (3H, t).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11](O)=[O:12])[C:2]=1[C:14](O)=[O:15].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:12][CH2:11][C:3]1[C:2]([CH2:14][OH:15])=[CH:1][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1
Reactant: O=C(O)c1cc2ccccc2cc1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc2ccccc2cc1CO
Reaction time: 3 h
Yield: 84.8 %

Procedure:
A solution of 2,3-naphthalenedicarboxylic acid (4.6 g, 0.023 mole) in dry THF (135 mL, warmed to 50° C. to maintain solution) is added dropwise over 15 minutes to a 1.15M lithium aluminum hydride solution in THF (45 mL, 0.052 mole). The solution is stirred 3 hours after which TLC indicated consumption of diacid and formation of a new major product. The reaction is quenched carefully with THF-water, then 2N hydrochloric acid (40 mL) is added, and the resulting mixture is extracted 3 times with ether. The combined ether extracts are washed with water (2 times), with saturated sodium bicarbonate solution (1 time), with water, and are dried (sodium sulfate), filtered, and concentrated to give a tan solid (3.67 g). The solid is recrystallized from ethyl acetate giving the title compound (2.91 g) as a light tan crystalline material, mp 161°-162° C. (lit. ref mp 160° C.).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]2[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=O.C(OC(C1C2C=C(OC)C=CC=2OC=1C1C=CC(F)=CC=1)=O)C.CI.C(=O)([O-])[O-].[K+].[K+].[C:54](#[N:56])C>>[CH3:54][NH:56][C:3]([C:5]1[C:9]2[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[O:2]
Reactant: COC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OC)cc12
Reactant: CC#N
Agent: CCOC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OC)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
Preparation of compound 12(b)(i) and compound 12(b)(ii) (2-(4-fluoro-phenyl)-5-methoxy-benzofuran-3-carboxylic acid methyl ester and 2-(4-fluoro-phenyl)-5-methoxy-benzofuran-3-carboxylic acid ethyl ester). Methyl iodide (0.43 mL, 6.99 mmol) was added to a mixture of the compounds 12(a)(i) and 12(a)(ii) (1.00 g, 3.49 mmol), potassium carbonate (milled, 1.21 g, 8.73 mmol) and anhydrous acetonitrile (15 mL) under an argon atmosphere. The reaction mixture was heated to reflux under argon for 18 hours, and then cooled to room temperature and stirred for 24 hours. The mixture was diluted with acetonitrile (10 mL) and filtered, followed by evaporation of the solvent. The crude solid was diluted with 60:40 ethyl acetate/hexanes, refiltered, and purified by HPLC (silica gel, ethyl acetate/hexanes) to provide 0.85 g (78%) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:9]([OH:10])=[C:8]([F:11])[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([CH3:18])[C:3]=1[C:4]#[N:5].C(N(CC)CC)C.[C:26]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][CH2:28][CH:27]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(#N)C>[C:26]1([C:31]([O:10][C:9]2[C:8]([F:11])=[C:7]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:6]([CH3:18])=[C:3]([C:4]#[N:5])[C:2]=2[NH2:1])=[O:32])[CH2:30][CH2:29][CH2:28][CH:27]=1
Reactant: O=C(Cl)C1=CCCC1
Reactant: Cc1c(C#N)c(N)c(O)c(F)c1-c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(C#N)c(N)c(OC(=O)C2=CCCC2)c(F)c1-c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
Under nitrogen atmosphere, 2-amino-5-phenyl-4-fluoro-3-hydroxy-6-methylbenzonitrile (I-41) (200 mg, 0.83 mmol) was dissolved in acetonitrile (10 ml), and cooled to 0° C. Triethylamine (195 μl, 1.4 mmol) and cyclopentenecarbonyl chloride (162 mg, 1.24 mmol) were dropwise added to the solution, followed by stirring at room temperature for 1 hour. 10% citric acid was added to the reaction liquid, and the solvent was evaporated away under reduced pressure. Ethyl acetate was added to the resulting residue, followed by washing with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was subjected to preparative silica gel column chromatography, and the eluate with ethyl acetate/hexane (1:3, v/v) gave the entitled compound (180 mg, 77%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][N:8]3[C:15](=[O:16])[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:13][C:12]([C:23]([N:25]4[CH2:28][CH:27]([O:29][CH3:30])[CH2:26]4)=[O:24])=[C:9]32)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].Cl>CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][NH:7][N:8]3[C:15](=[O:16])[C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:13][C:12]([C:23]([N:25]4[CH2:26][CH:27]([O:29][CH3:30])[CH2:28]4)=[O:24])=[C:9]32)=[CH:4][CH:3]=1
Reactant: COC1CN(C(=O)c2cc(-c3ccccc3)c(=O)n3ncc4ccc(Cl)cc4c23)C1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC1CN(C(=O)c2cc(-c3ccccc3)c(=O)n3c2-c2cc(Cl)ccc2CN3)C1
Temperature: 0 °C

Procedure:
1.26 g of 1-[(10-chloro-4-oxo-3-phenyl-4H-pyrido[2,1-a]phthalazin-1-yl)carbonyl]-3-methoxyazetidine and 0.75 g of sodium cyanoborohydride in 30 ml of methanol are treated dropwise at room temperature under argon with saturated methanolic hydrochloric acid. The reaction is completed after a short time. The mixture is poured into 70 ml of ice-water and the yellowish crystals are removed by filtration. The crystals are washed three times with 2 ml of water each time and dried at 60° in vacuo. After recrystallization of the crude product from ethyl acetate/acetone (1:1), there is obtained 1-[(10-chloro-6,7-dihydro-4-oxo-3-phenyl-4H-pyrido[2,1-a]phthalazin-1-yl)carbonyl]-3-methoxyazetidine as yellowish crystals of m.p. 238°-239°.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccc(Cl)cc1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(Cl)cc2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-chlorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.21 (2H, s), 6.72 (1H, d, J=2.0 Hz), 7.26 (1H, s), 7.37-7.47 (4H, m), 7.56 (1H, d, J=2.0 Hz), 8.03 (1H, s), 8.69 (1H, d, J=4.8 Hz) [M+H] Calc'd for C16H11ClN4O, 311; Found, 311.
Reaction SMILES: BrCC1C=CSN=1.C(N)CN.[S:12]1[CH:16]=[CH:15][C:14]([CH2:17][NH:18][CH2:19][CH2:20][NH2:21])=[N:13]1.[CH3:22][N:23]=[C:24]=[S:25]>>[CH3:22][NH:23][C:24]([NH:21][CH2:20][CH2:19][NH:18][CH2:17][C:14]1[CH:15]=[CH:16][S:12][N:13]=1)=[S:25]
Reactant: NCCNCc1ccsn1
Reactant: CN=C=S
Agent: BrCc1ccsn1
Solvent: NCCN
Product: CNC(=S)NCCNCc1ccsn1

Procedure:
Reaction of 3-bromomethylisothiazole with ethylenediamine by the procedure of Example 34 and reaction of the resulting N-(3-isothiazolylmethyl)ethylenediamine with methyl isothiocyanate by the procedure of Example 3(b) and then chromatographing gives N-methyl-N'[2-(3-isothiazolylmethylamino)ethyl]thiourea. This intermediate is reacted with lead cyanamide by the procedure of Example 3(b) to give N-cyano-N'-[2-(3-isothiazolylmethylamino)ethyl]-N"-methylguanidine. Hydrolysis of the last prepared compound by the procedure of Example 3(e) gives N-[2-(3-isothiazolylmethylamino)ethyl]-N'-methylguanidine dihydrochloride.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=[O:7].[H][H]>[Ni].C1(C)C=CC=CC=1>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:12])[F:13])[CH:10]=1)[CH2:6][OH:7]
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: Cc1ccccc1
Product: OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 82.5 %

Procedure:
37 g of 3,5-bis(trifluoromethyl)benzaldehyde and 4 g of Raney nickel together with 150 ml of toluene were placed in a reaction vessel at room temperature. The vessel was pressurized with 30 bar of hydrogen gas and the mixture was hydrogenated at 50° C. for 7.5 hours while stirring. The mixture was subsequently cooled to room temperature, depressurized and the catalyst was filtered off. The filtrate was evaporated and the crude product obtained in this way was distilled at 17 mbar. 3,5-bis(trifluoro-methyl)benzyl alcohol having a boiling point of 97° C. was obtained in a yield of 31.5 g and a purity of 97.7%. This corresponds to a yield of 82.5% of theory.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)#[N:2].[Cl:14][C:15]([Cl:19])([Cl:18])[S:16]Cl.C(N(CC)CC)C>C(Cl)Cl>[C:1]([CH2:3][N:4]([S:16][C:15]([Cl:19])([Cl:18])[Cl:14])[C:5](=[O:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)#[N:2]
Reactant: N#CCNC(=O)Cc1ccccc1
Reactant: ClSC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CCN(SC(Cl)(Cl)Cl)C(=O)Cc1ccccc1
Yield: 88.3 %

Procedure:
To a stirred mixture of 4.9 g (0.028 mole) N-cyanomethyl phenylacetamide (the product of Example 6) and 5.7 g (0.031 mole) trichloromethylsulfenyl chloride in ml methylene chloride which had been cooled in an ice bath, 3.5 g (0.035 mole) triethylamine in 25 ml methylene chloride were dropped in over 20 minutes. The reaction mixture was washed three times with 75 ml portions of water, dried over magnesium sulfate and stripped to give 8.0 g of a dark brown oil, which failed to crystallize.
Reaction SMILES: [CH3:1][CH:2]([CH2:28][CH3:29])[CH:3]([C:8]1[C:9]([CH3:27])=[N:10][C:11]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)[C:4]([O:6]C)=[O:5].[OH-].[Na+]>CO>[CH3:1][CH:2]([CH2:28][CH3:29])[CH:3]([C:8]1[C:9]([CH3:27])=[N:10][C:11]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)[C:4]([OH:6])=[O:5]
Reactant: CCC(C)C(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(C)C(C(=O)O)c1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Yield: 74.1 %

Procedure:
This compound was prepared according to general method D from methyl 3-methyl-2-(4-methyl-2-(piperidin-1-yl)-6-p-tolylpyrimidin-5-yl)pentanoate (0.039 g; 0.099 mmol), sodium hydroxide 10N (0.100 mL; 0.1 mmol) in methanol (1 mL) to afford 0.028 g (73%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6]([OH:16])[CH:5]=1.C([O-])([O-])=O.[K+].[K+].[CH2:24](I)[CH3:25]>CN(C=O)C.Cl>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6]([O:16][CH2:24][CH3:25])[CH:5]=1
Reactant: COC(=O)c1cc(O)cc(N2CCCC2=O)c1
Reactant: CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)OC)cc(N2CCCC2=O)c1
Temperature: 50 °C
Yield: 95 %

Procedure:
To 3-hydroxy-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (D37) (0.80 g, 3.4 mmol, 1 equiv) dissolved in DMF (10 ml) was added K2CO3 (0.94 g, 6.8 mmol, 2 equiv) and ethyl iodide (1.1 g, 6.8 mmol, 2 equiv). The resulting mixture was heated at 50° C. for 4 h, cooled to room temperature, diluted with 2N aqueous HCl solution (50 ml) and extracted with Et2O (50 ml). The organic phase was then washed with water (50 ml), dried over MgSO4 and concentrated in vacuo to give of 3-ethoxy-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (B11) (0.85 g, 95%) as a brown oil which slowly solidified to a tan solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]([NH:21][C:22]2[CH:23]=[C:24]([C:28]([NH:30][CH2:31][C:32]([NH:34][CH:35]([C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)[CH2:36][C:37]([O:39]CC)=[O:38])=[O:33])=[O:29])[CH:25]=[CH:26][CH:27]=2)=[O:20])(=[O:17])=[O:16])=[CH:11][CH:10]=1.[OH-].[Li+].FC(F)(F)C(O)=O>O.C(#N)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C:9]1[CH:10]=[CH:11][C:12]([S:15]([NH:18][C:19]([NH:21][C:22]2[CH:23]=[C:24]([C:28]([NH:30][CH2:31][C:32]([NH:34][CH:35]([C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)[CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[O:29])[CH:25]=[CH:26][CH:27]=2)=[O:20])(=[O:16])=[O:17])=[CH:13][CH:14]=1
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(NC(=O)NS(=O)(=O)c2ccc(C)cc2)c1)c1cccnc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)NC(=O)Nc2cccc(C(=O)NCC(=O)NC(CC(=O)O)c3cccnc3)c2)cc1
Temperature: 25 °C
Yield: 563.7 %

Procedure:
The compound of Example 111 (500 mg, 0.095 mmol) was dissolved in water/acetonitrile (1:1), followed by the addition of lithium hydroxide (100 mg, 0.4 mmol). The reaction mixture was stirred at 25° C., and monitored by HPLC. After complete hydrolysis (1-2 hours) trifluoroacetic acid was added until pH=2. The product was purified by reverse phase chromatography (water/acetonitrile) and lyophilized to result in a white solid (350 mg). MS and 1H-NMR were consistent with the proposed structure.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C[Al](C)C.C([O:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:23]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[N:24][O:25][C:26]=2[CH2:27][OH:28])=[CH:16][N:15]=1)=O)C>O1CCOCC1>[CH:1]([NH:4][C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:23]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)=[N:24][O:25][C:26]=2[CH2:27][OH:28])=[CH:16][N:15]=1)=[O:11])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1
Reactant: CC(C)N
Agent: C[Al](C)C
Solvent: C1COCCO1
Product: CC(C)NC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1
Reaction time: 0.5 h
Yield: 22.1 %

Procedure:
To a stirred solution of isopropylamine (47.8 mg, 0.8 mmol) in dioxane (3.75 mL) was added dropwise a trimethylaluminium (603 μL, 2 M solution in toluene, 1.21 mmol) and the resulting solution stirred under argon for 30 min. A solution of 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-pyridine-2-carboxylic acid ethyl ester (75 mg, 0.2 mmol) in dioxane (3.75 mL) was then added and the resulting solution stirred under argon for a further 1 h at 50° C. The reaction mixture was cooled and concentrated in vacuo. Purification by chromatography (silica, 0 to 10% methanol in dichloromethane) gave the title compound (17 mg, 21%) as a colourless gum. MS: m/e=386.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH2:6][C:5]2=[O:17].CO.[B-](F)(F)(F)[F:21].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH:6]([F:21])[C:5]2=[O:17]
Reactant: F[B-](F)(F)F
Reactant: O=C1CC2(CCCOC2)Oc2ccc(Br)cc21
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CO
Product: O=C1c2cc(Br)ccc2OC2(CCCOC2)C1F
Yield: 10 %

Procedure:
To a solution of 6-bromo-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (2 g, 6.8 mmol) in MeOH Selectfluor™ (2.5 g, 7.1 mmol) was added. The suspension was refluxed overnight. Then the solvent was removed in vacuo. CH2Cl2 was added to the resulting residue and insoluble material filtered off. The filtrate was washed with H2O, dried and concentrate in vacuo. The crude product was purified by column chromatography to give 6-bromo-3-fluoro-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (220 mg, 10%). 1H-NMR (CDCl3): 1.72-2.21 (m, 4H), 3.44 (m, 1H), 3.63 (m, 1H), 3.73 (m, 1H), 3.92 (m, 1H), 4.91 (m, 1H), 6.94 (m, 1H), 7.56 (m, 1H), 7.90 (m, 1H).