Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]12[C:11]3[CH:12]=[CH:13][C:14]([S:16][C:17]4[S:18][C:19]5[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=5[N:21]=4)=[CH:15][C:10]=3[CH2:9][CH2:8][C@H:7]1[NH:6][C:5](=[O:26])[CH2:4][CH2:3]2.[CH3:27]I>>[CH3:27][N:6]1[C@H:7]2[C@@:2]([CH3:1])([C:11]3[CH:12]=[CH:13][C:14]([S:16][C:17]4[S:18][C:19]5[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=5[N:21]=4)=[CH:15][C:10]=3[CH2:9][CH2:8]2)[CH2:3][CH2:4][C:5]1=[O:26]
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(Sc3nc4ccccc4s3)ccc12
Reactant: CI
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc5ccccc5s4)cc3CC[C@@H]12

Procedure:
A 170 mg portion of (4aR)-(10bR)-10b-methyl-8-(2-benzothiazolylthio)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one was alkylated with methyl iodide substantially according to the process of Example 95 to obtain 84 mg of the desired product. mp 188°-189° FDMS: m/e=394.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5](=O)[CH:6]([O:9][CH3:10])[O:7][CH3:8].O.[NH2:14]N>CO>[CH3:8][O:7][CH:6]([O:9][CH3:10])[C:5]1[CH:4]=[CH:3][NH:2][N:14]=1
Reactant: NN
Reactant: COC(OC)C(=O)C=CN(C)C
Solvent: CO
Solvent: O
Product: COC(OC)c1cc[nH]n1
Reaction time: 8 h

Procedure:
A mixture of 5 g of 4-dimethylamino-1,1-dimethoxy-3-butene-2-one, 1.7 ml of hydrazine monohydrate and 15 ml of methanol was stirred for 8 hours under heat refluxing. The reaction mixture was concentrated under reduced pressure to obtain 4.07 g of 3-(dimethoxymethyl)-1H-pyrazole of the formula:
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:20]([O:24][C:25]([C@@H:27]1[CH2:31][C@@H:30]([OH:32])[CH2:29][C@H:28]1[C:33](=[O:45])[NH:34][C@:35]1([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:37][C@H:36]1[CH:38]=[CH2:39])=[O:26])([CH3:23])([CH3:22])[CH3:21].[F:46][C:47]1[CH:48]=[C:49]([C:53]2[N:62]=[C:61](O)[C:60]3[C:55](=[C:56]([CH3:66])[C:57]([O:64][CH3:65])=[CH:58][CH:59]=3)[N:54]=2)[CH:50]=[CH:51][CH:52]=1.N#N.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CN(C=O)C.C1COCC1>[C:20]([O:24][C:25]([CH:27]1[CH2:31][CH:30]([O:32][C:61]2[C:60]3[C:55](=[C:56]([CH3:66])[C:57]([O:64][CH3:65])=[CH:58][CH:59]=3)[N:54]=[C:53]([C:49]3[CH:50]=[CH:51][CH:52]=[C:47]([F:46])[CH:48]=3)[N:62]=2)[CH2:29][CH:28]1[C:33](=[O:45])[NH:34][C:35]1([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:37][CH:36]1[CH:38]=[CH2:39])=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@H](O)C[C@H]1C(=O)OC(C)(C)C)C(=O)OCC
Reactant: COc1ccc2c(O)nc(-c3cccc(F)c3)nc2c1C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=CC1CC1(NC(=O)C1CC(Oc2nc(-c3cccc(F)c3)nc3c(C)c(OC)ccc23)CC1C(=O)OC(C)(C)C)C(=O)OCC
Reaction time: 18 h
Yield: 94.3 %

Procedure:
PPh3 (787 mg, 3.0 mmol) was added to a stirred solution of the alcohol 15 (550 mg, 1.5 mmol) and the quinazolinol 127 (430 mg, 1.5 mmol) in a mixture of dry THF (40 mL) and dry DMF 10 mL. The reaction mixture was put under inert atmosphere (N2) at room temperature and DIAD (591 μL, 3.0 mmol) was added. The reaction mixture was stirred for 18 h whereafter the solvents were evaporated. The residue was dissolved in CHCl3 and washed with brine in a separatory funnel. The organic phase was dried with Na2SO4, evaporated on silica and purified by flash chromatography (heptane:ethyl acetate 2:1 to 1:1) which gave the title compound as a white-beige solid (896 mg, 94%), LRMS (M+H) 634.
Reaction SMILES: [CH2:1]([P:5]([CH2:8][CH:9]([C:22]([O:24]CC1C=CC=CC=1)=[O:23])[CH2:10][CH2:11][C:12]([O:14]CC1C=CC=CC=1)=[O:13])(=[O:7])[OH:6])[CH2:2][CH2:3][CH3:4]>O>[CH2:1]([P:5]([CH2:8][CH:9]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:22]([OH:24])=[O:23])([OH:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCP(=O)(O)CC(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Solvent: O
Product: CCCCP(=O)(O)CC(CCC(=O)O)C(=O)O
Yield: 43.3 %

Procedure:
Butyl[2,4-di(benzyloxycarbonyl)butyl]phosphinic acid (2.9 g, 6.5 mmol) in 30 mL of water containing 0.32 g 10% Pd/C was hydrogenated on a Parr hydrogenator at 40 psi for 4.5 hours. The mixture was filtered through a pad of Celite and evaporated under high vacuum to give 2-[(butylhydroxyphosphinyl)methyl]pentanedioic acid (4, R=n-butyl) (0.75 g, 43w) as a clear and colorless viscous oil.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[C:28]([CH2:30][C:31](O)=[O:32])#[N:29]>>[C:28]([CH2:30][C:31]([NH:27][C@H:24]1[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]2[CH2:17][CH2:18][N:13]([C:9]3[N:10]=[CH:11][CH:12]=[C:7]4[CH2:6][CH2:5][O:4][C:8]=34)[CH2:14][CH2:15]2)[CH2:22][CH2:23]1)=[O:32])#[N:29]
Reactant: N#CCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: N#CCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (41 mg, 65%), MS (ISP) m/z=398.3 [(M+H)+], mp 215.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (70.4 mg, 0.16 mmol) 2-cyano-acetic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C@@:8]2([CH3:25])[N:14](CC3C=CC(OC)=CC=3)[C:13](=[O:24])[CH2:12][CH2:11][O:10][CH2:9]2)[CH:7]=1.C1(OC)C=CC=CC=1.FC(F)(F)S(O)(=O)=O.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C@@:8]2([CH3:25])[NH:14][C:13](=[O:24])[CH2:12][CH2:11][O:10][CH2:9]2)[CH:7]=1
Reactant: COc1ccc(CN2C(=O)CCOC[C@@]2(C)c2cc(Br)ccc2F)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@]1(c2cc(Br)ccc2F)COCCC(=O)N1
Temperature: 73 °C
Yield: 3.4 %

Procedure:
A solution of (R)-3-(5-bromo-2-fluoro-phenyl)-4-(4-methoxy-benzyl)-3-methyl-[1,4]oxazepan-5-one (2.278 g, 5.39 mmol) and anisole (10.7 g, 98.7 mmol) in trifluoroacetic acid (28 ml) was treated dropwise within 6 minutes at room temperature with trifluoromethanesulfonic acid (9.47, 61.9 mmol). After complete addition, the reaction mixture was heated at 73° C. for 24 hours. Following TLC no starting material in a complex mixture of products. For the workup, the cold mixture was poured carefully under stirring into a mixture of saturated sodium hydrogen carbonate solution (200 ml) and ice. The extraction with ethyl acetate (500 ml) and re-extraction of the separated aqueous layer with ethyl acetate (250 ml) was followed by washing the combined organic layers with saturated sodium hydrogen carbonate solution (200 ml) and brine (200 ml). The organic phase was dried over sodium sulfate, then evaporated at reduced pressure. Chromatography on silica gel using a gradient of heptane and ethyl acetate=100/0 to 20/10 as the eluent yielded a product containing fraction of 628 mg which was engaged in the next step without further purification and characterisation. For characterisation of the title compound another fraction of 104 mg was again purified by chromatography on Silicycle-Si-amine column using a gradient of heptane and ethyl acetate=100/0 to 20/10 as the eluent yielding the pure (R)-3-(5-bromo-2-fluoro-phenyl)-3-methyl-[1,4]oxazepan-5-one (intermediate C11A) as a beige foam (56 mg). MS (ISP): m/z=302.2, 304.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1COCC1>[C:8]([C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])#[N:9]
Reactant: N#CCc1ccccc1
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
To a solution of benzyl cyanide (11.7 g, 100 mmol) in anhydrous THF (100 mL) was added slowly the solution of LiHMDS in THF (1 M, 200 mL, 200 mmol) at −78° C. in a dry-ice/acetone bath. After addition, the mixture was warmed to rt, stirred for 1 h, cooled to −78° C., and added ethyl bromoacetate (32.9 g, 198 mmol) dropwise. After addition, the reaction mixture was stirred at rt overnight. When TLC showed that the benzyl cyanaide was consumed, the reaction mixture was quenched with satd aq NH4Cl (150 mL), and extracted with EtOAc (3×150 mL). The combined organic layers were washed with satd aq NaHCO3 (150 mL) and brine (150 mL), dried over Na2SO4, and concentrated to give the crude final product, which was purified by chromatography on a silica gel column eluted with PE/EtOAc=50:1-10:1 to give diethyl 3-cyano-3-phenylpentanedioate (10.6 g, yield 37%) as brown oil. 1H NMR (CDCl3 400 MHz): δ 7.45 (d, 2H), 7.37 (t, 2H), 7.28 (t, 1H), 4.06 (q, 4H), 3.2 (m, 4H), 1.12 (t, 6H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[CH:16]=[N:15][C:14](Br)=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)[N:12]=1)=[O:10].Cl.[CH:30]1([NH:33][CH3:34])[CH2:32][CH2:31]1.C(N(C(C)C)C(C)C)C>CS(C)=O>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C:11]1[CH:16]=[N:15][C:14]([N:33]([CH:30]2[CH2:32][CH2:31]2)[CH3:34])=[C:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)[N:12]=1)=[O:10]
Reactant: CNC1CC1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(Br)c(-c2ccc(OC(F)(F)F)cc2)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CN(c1ncc(C(=O)N[C@@H]2CCCC[C@H]2O)nc1-c1ccc(OC(F)(F)F)cc1)C1CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.8 %

Procedure:
To a solution of 0.052 g of 5-bromo-6-(4-trifluoromethoxy-phenyl)-pyrazine-2-carboxylic acid ((1R,2R)-2-hydroxy-cyclohexyl)-amide in 2 ml dimethylsulfoxide was added at room temperature 0.024 g of cyclopropyl-methyl-amine hydrochloride and 0.04 ml N-ethyldiisopropylamine. The mixture was stirred at room temperature for 72 hours. The reaction mixture was partitioned between 10% aqueous citric acid and ethyl acetate. The phases were separated and the organic layer washed with 10% aqueous sodium bicarbonate and brine, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel to yield 0.033 g (61% yield) of the title compound as colorless oil. MS (ISP) (M+H+)=451.1.
Reaction SMILES: CON(C)[C:4](=[O:30])[CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[N:20]([CH3:29])[S:21]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)(=[O:23])=[O:22])=[N:8][CH2:7]1.O1CCC[CH2:33]1.C[Mg]Br.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH3:29][N:20]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[NH:12][C:11]([C:9]1[S:10][CH:6]([CH2:5][C:4](=[O:30])[CH3:33])[CH2:7][N:8]=1)=[CH:19]2)[S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:23])=[O:22]
Reactant: C1CCOC1
Reactant: CON(C)C(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Agent: C[Mg]Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: CC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Temperature: 10 °C
Reaction time: 5 h
Yield: 67 %

Procedure:
N-Methoxy-N-methyl-2-(2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetamide (0.20 g) was dissolved in absolute tetrahydrofuran (20 mL), and a 12% methylmagnesium bromide tetrahydrofuran solution (1.4 mL) was added under ice-cooling. The mixture was stirred at 10° C. for 5 hr under ice-cooling, acidified with aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=35:65-50:50), and the obtained colorless oil was crystallized from ethyl acetate-hexane-to give the title compound (121 mg, yield: 67%) as colorless crystals. MS:434(MH+). melting point 123-124° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:14](=O)[CH2:15][CH3:16])=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6](O)=[O:7].O.[NH2:19][NH2:20]>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:5]2[C:4]=1[C:14]([CH2:15][CH3:16])=[N:19][NH:20][C:6]2=[O:7]
Reactant: NN
Reactant: CCC(=O)c1c(OC)cc(OC)cc1C(=O)O
Solvent: O
Product: CCc1n[nH]c(=O)c2cc(OC)cc(OC)c12

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting unpurified 3,5-dimethoxy-2-propionylbenzoic acid with hydrazine hydrate.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([CH2:18][C:19]2[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=2[Cl:26])=[N:8][N:7]=1.O>CN(C=O)C>[Cl:25][C:24]1[CH:23]=[N:22][CH:21]=[C:20]([Cl:26])[C:19]=1[CH2:18][C:9]1[C:10]2[C:15](=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:6]2=[N:7][N:8]=[N:3][N:2]2[N:1]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nn3nnnc3c2c1
Temperature: 80 °C
Reaction time: 7 h
Yield: 78.5 %

Procedure:
NaN3 was added to a solution under N2 of 4-chloro-1-(3,5-dichloro-pyridin4-ylmethyl)-6-methoxy-phthalazine (1 g, 2.82 mmoles), obtained as described in example 13, in anhydrous DMF (20 ml) and the mixture was heated at 80° C. overnight, then at 120° C. for 7 hours, then poured into water (10 volumes) and extracted 3 times with CH2Cl2, dried and concentrated under vacuum to give a solid which was purified by flash chromatography (eluent:60:80 petrolatum/ethyl acetate 6:4). The eluate was crystallised from acetonitrile (75 ml) to give 0.36 g of the title compound (yield: 78.5%). m. p.: 275-276° C.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)CCC.[Cl:19][C:20]1[C:24](Cl)=[N:23][S:22][N:21]=1>C1(C)C=CC=CC=1.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>[Cl:19][C:20]1[C:24]([C:6]2[O:7][CH:8]=[CH:9][CH:10]=2)=[N:23][S:22][N:21]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: Clc1nsnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Clc1nsnc1-c1ccco1
Yield: 60 %

Procedure:
0.85 g (0.00238 mol) of 2-(tributylstannyl)furan and 0.12 g (0.0001 mol) of tetrakis(triphenylphosphine)palladium(0) were added to a solution of 0.33 g (0.00213 mol) of 3,4-dichloro-1,2,5-thiadiazole in 4 mL of toluene under nitrogen and heated at reflux. After 3 and 6 h respectively, 0.04 g (2 times 3.5×10−5 mol) of tetrakis(triphenylphosphine)palladium(0) were added. After 24 h of reflux (quantitative HPLC: 60% of product formed, all the stannane was consumed), the reaction medium was diluted with 5 mL of ethyl acetate and vigorously stirred with 10 mL of a 1M aqueous solution of KF for 2 h. After filtration through celite, the aqueous phase was re-extracted with ethyl acetate, the combined organic phases were dried over magnesium sulfate and concentrated.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3]O.[CH3:6][C:7]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:8]=1[NH2:9].[I-].[K+].ClCCl>O>[CH3:6][C:7]1[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][C:8]=1[NH:9][CH2:1][CH:2]([CH3:5])[CH3:3]
Reactant: CC(C)CO
Reactant: Cc1ccc(C(F)(F)F)cc1N
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C(F)(F)F)cc1NCC(C)C
Yield: 36.7 %

Procedure:
2-methyl-1-propanol (0.556 mL, 6.00 mmol), 2-methyl-5-(trifluoromethyl)aniline (525 mg, 3 mmol), potassium iodide (996 mg, 6.00 mmol) and [Cp*IrCl2]2 (33.1 mg, 0.030 mmol) were dissolved in water (2 mL). The resulting mixture was irradiated under microwaves (CEM microwave) at 170° C. for 1 hour. To the reaction mixture was added dichloromethane (5 mL) and the crude material was purified by mass directed autoprep (250 mg scale ×3, Method C, formic acid modifier). Relevant fractions were combined and evaporated to give 2-methyl-N-(2-methylpropyl)-5-(trifluoromethyl)aniline (260 mg, 1.102 mmol, 36.7% yield) as a dark yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:11]([CH3:22])[C:12](=[O:21])[C:13]([CH3:20])=[CH:14][C:15]=1[C:16]([O:18]C)=[O:17].C1COCC1.[Li+].[OH-]>O>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:11]([CH3:22])[C:12](=[O:21])[C:13]([CH3:20])=[CH:14][C:15]=1[C:16]([OH:18])=[O:17]
Reactant: COC(=O)c1cc(C)c(=O)n(C)c1Nc1ccc(I)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)c(Nc2ccc(I)cc2F)n(C)c1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 78.4 %

Procedure:
A 100 mL round-bottom flask was charged with methyl 2-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylate (2.38 g, 6.72 mmol) and THF (80 mL). To the mixture was added LiOH (20 mmol) previously dissolved in 30 mL of H2O and the reaction was stirred at room temperature for 72 hours. The organic solvent was removed under reduced pressure and the resulting aqueous layer was acidified with 1N aq. HCl. The precipitate was filtered and dried under vacuum to afford the title compound as a white solid (2.12 g, 92%).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[C:11]([Cl:19])[CH:10]=1)(=O)=O.[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>>[Cl:19][C:11]1[CH:10]=[C:9]([CH2:8][CH2:7][CH2:6][N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)[CH:14]=[CH:13][C:12]=1[O:15][CH2:16][O:17][CH3:18]
Reactant: c1c[nH]cn1
Reactant: COCOc1ccc(CCCOS(C)(=O)=O)cc1Cl
Product: COCOc1ccc(CCCn2ccnc2)cc1Cl
Yield: 65 %

Procedure:
In substantially the same manner as in Reference Example 88, 3-(3-chloro-4-methoxymethoxyphenyl)propyl methanesulfonate was reacted with imidazole to obtain 1-[3-(3-chloro-4-methoxymethoxyphenyl)propyl]imidazole as an oil. The yield was 65%.
Reaction SMILES: [Br:1][C:2](=[CH2:6])[CH2:3][CH2:4][OH:5].Cl[Si:8]([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1C=CN=C1>CN(C)C1C=CN=CC=1>[Br:1][C:2](=[CH2:6])[CH2:3][CH2:4][O:5][Si:8]([C:21]([CH3:24])([CH3:23])[CH3:22])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C=C(Br)CCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Product: C=C(Br)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C

Procedure:
The title compound was prepared in 8.7 g yield as a colourless oil, following an analogous procedure to that reported in WO2005058884, starting from 3-bromo-3-buten-1-ol (4 g), chloro(1,1-dimethylethyl)diphenylsilane (8.27 ml), imidazole (2.34 g) and N,N-dimethyl-4-pyridineamine (0.025 g).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[NH2:19][CH2:20][C:21]1([OH:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[OH:27][C:21]1([CH2:20][NH:19][C:10]([C:7]2[CH:6]=[C:5]([O:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)[C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:9][N:8]=2)=[O:12])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NCC1(O)CCCCC1
Reactant: O=C(O)c1cc(OCC2CC2)c(C2CC2)cn1
Agent: Cl
Product: O=C(NCC1(O)CCCCC1)c1cc(OCC2CC2)c(C2CC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 54, using 5-Cyclopropyl-4-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42c) and 1-(aminomethyl)cyclohexanol hydrochloride (CAN 19968-85-5) as starting materials and isolated (70.5 mg, 58%) as a white solid; MS (ESI, m/z): 345.1 (M+H+).
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:26])([F:25])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:15]2=[O:24])=[CH:10][CH:9]=1.[C:27]1([CH:33]([CH2:37][CH3:38])[C:34](Cl)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:27]1([CH:33]([CH2:37][CH3:38])[C:34]([N:21]2[CH2:20][CH2:19][C:16]3([C:15](=[O:24])[N:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][C:6]([F:5])([F:25])[F:26])=[CH:9][CH:10]=4)[CH2:18][CH2:17]3)[CH2:23][CH2:22]2)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCC(C(=O)Cl)c1ccccc1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Solvent: CC(=O)O
Product: CCC(C(=O)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O)c1ccccc1

Procedure:
The title compound was prepared in analogy to example 7 step A from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (described in example 180 step C) and 2-phenyl-butyryl chloride. Off-white solid. MS (ESI): 461.4 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH3:11][C:12]([N+:15]([O-])=[O:16])([CH3:14])[CH3:13].C(O)(=O)C>C(O)C.[Zn]>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[N+:15]([C:12]([CH3:14])([CH3:13])[CH3:11])[O-:16]
Reactant: COc1ccccc1C=O
Reactant: CC(C)(C)[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccccc1C=[N+]([O-])C(C)(C)C
Temperature: 5 °C

Procedure:
To a suspension of 2-methoxybenzaldehyde (622.4 mg, 4.57 mmol), 1,1-dimethylnitroethane (942.7 mg, 9.14 mmol) and zinc (896.3 mg, 13.7 mmol) in ethanol (15 ml) was added acetic acid (944.8 mg, 15.7 mmol) dropwise at 5° C. while stirring. The mixture was stirred at room temperature for one day. After the mixture was cooled to 5° C., zinc acetate was filtered off and the filtrate was concentrated and purified by silica gel chromatography (hexane/ethyl acetate=2/1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[C:4]([Cl:10])[N:3]=1.N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].O>CN(C=O)C>[Si:16]([O:9][CH2:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([Cl:10])=[CH:5][CH:6]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: OCc1ccc(Cl)nc1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a solution of (2,6-dichloropyridin-3-yl)methanol (from Step A above, 6.3 g) in DMF was added imidazole (3.06 g) and t-butyldimethylsilyl chloride (6.02 g) at 0° C. The mixture was warmed to room temperature and stirred for 1 h before poured into water. The solution was extracted with ethyl acetate. The organic layer was washed with water (5×), brine, dried over MgSO4 and concentrated. The residue was purified by silica gel (hexanes/ethyl acetate) to give the title compound (8.7 g).
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5]Br.[CH3:7][O:8][C:9](=[O:20])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([F:19])[CH:12]=1>O1CCCC1>[CH3:7][O:8][C:9]([C:10]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([F:19])[CH:12]=2)[CH2:5][CH2:4]1)=[O:20]
Reactant: BrCCBr
Reactant: COC(=O)Cc1ccc(C#N)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1(c2ccc(C#N)c(F)c2)CC1
Temperature: 75 °C

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.360 g) was suspended in anhydrous tetrahydrofuran (60 mL) under nitrogen. 1,2-Dibromoethane (2.0 mL) was added to the suspension, followed by (4-cyano-3-fluoro-phenyl)-acetic acid methyl ester (0.499 g). After the rate of gas evolution slowed, the reaction mixture was transferred to an oil bath and heated to 75° C. for 15 min. The reaction mixture was allowed to cool to ambient temperature and quenched with excess saturated ammonium chloride. The organic layer was separated and the remaining aqueous layer extracted with ethyl acetate (5×60 mL). The combined organics were dried with magnesium sulfate, filtered, and concentrated in vacuo. The crude product (0.637 g) was purified by silica gel chromatography (ethyl acetate:hexanes=2:3) yielding the title compound (0.500 g).