Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[S:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[CH2:17][CH2:18][CH2:19][C:20](=O)[CH3:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCCl>[CH3:17][C:18]12[CH2:19][CH2:20][CH2:21][N:1]1[C:2]1[N:3]=[C:4]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[S:5][C:6]=1[C:7](=[O:8])[NH:9]2
Reactant: NC(=O)c1sc(N2CCOCC2)nc1N
Reactant: CC(=O)CCCCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCCl
Solvent: O
Product: CC12CCCN1c1nc(N3CCOCC3)sc1C(=O)N2
Yield: 10 %

Procedure:
A stirred solution of 4-amino-2-(morpholin-4-yl)-1,3-thiazole-5-carboxamide (0.22 g, 0.99 mmol), 5-chloro-2-pentanone (0.5 mL, excess) and p-toluenesulfonic acid monohydrate (cat. amount) in DCE (4 mL) was heated to 100° C. in a sealed tube, under microwave irradiation, for 1 h. The reaction mixture was then concentrated in vacuo and purification by preparative HPLC gave the title compound (0.03 g, 10%) as an off-white solid. δH (DMSO-d6) 7.29 (1H, s), 3.73-3.64 (4H, m), 3.57-3.39 (6H, m), 2.08-1.96 (2H, m), 1.93-1.83 (2H, m), 1.36 (3H, s). LCMS (ES+) 295.2 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]1[CH:12]([CH:25]([OH:30])[CH2:26][N+:27]([O-])=O)[CH:13]([NH:21][C:22]([CH3:24])=[O:23])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(O)(=O)C>CO.[Pd]>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]1[CH:12]([CH:25]([OH:30])[CH2:26][NH2:27])[CH:13]([NH:21][C:22]([CH3:24])=[O:23])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(=O)NC(C(=O)OC(C)(C)C)C(C(O)C[N+](=O)[O-])N1CCc2ccccc2C1=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)NC(C(=O)OC(C)(C)C)C(C(O)CN)N1CCc2ccccc2C1=O
Reaction time: 4 h

Procedure:
A mixture of 3-(1,2,3,4-tetrahydro-1-oxo-isoquinoline-2-yl)-acetamino-4-hydroxy-5-nitro-pentanoic acid, tert-butyl ester (2.55 g, 6.05 mMol) and 10% Pd on charcoal (1.5 g) in 100 mL of methanol containing 5 mL of 10% aqueous acetic acid was hydrogenated at room temperature for 4 hours. Filtration and evaporation of the solvent under reduced pressure gave of 3-(1,2,3,4-tetrahydro-1-oxo-isoquinoline-2-yl)-acetamino-5-amino-4-hydroxy-pentanoic acid, tert-butyl ester hydroacetate (2.7 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][CH:24]=1)[CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=O)[CH2:15][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C.[CH:40]1([NH2:46])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>C(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:24]=[CH:23][CH:22]=[C:11]([CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([C:19](=[O:21])[NH:46][CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)[CH2:17][CH2:18]2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CN2CCC(C(=O)O)CC2)c1
Reactant: NC1CCCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1cccc(CN2CCC(C(=O)NC3CCCCC3)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.4 %

Procedure:
A suspension of crude 1-(3-tert-butoxycarbonylamino-benzyl)-piperidine-4-carboxylic acid (6.7 g, 20 mmol) in DCM (250 mL) and DMF (0.2 mL) is treated with oxalyl chloride (25 mmol, 2.21 mL) dropwise at 0° C. during 20 min. under nitrogen. The reaction mixture is stirred at RT for 2 h. Then the solvent is evaporated under reduced pressure and dried under high vacuum. The crude acid chloride is dissolved in DCM (250 mL) and treated with DIPEA (20 mmol, 3.42 mL) and cooled down to 0° C. A solution of cyclohexylamine (2.18 g, 22 mmol) in DCM (20 mL) is added dropwise over 15 min. and the resulting mixture is stirred for 2 h. at RT. The reaction mixture is washed twice with aq. sat. NaHCO3 (100 mL) and dried over MgSO4. After evaporation of the solvent, the crude residue is purified by flash chromatography on silica gel using a mixture of DCM/MeOH 9:1. After concentration of the product containing fractions, the title compound (2.44 g, 29%) is obtained as a beige powder: LC-MS A: tR=0.66 min; [M+H]+=416.2.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1.[Br:19]Br>C(Cl)(Cl)(Cl)Cl.[Fe]>[Br:19][C:14]1[C:5]([CH2:4][CH2:3][CH2:2][OH:1])=[CH:6][C:7]2[C:8]([CH3:18])([CH3:17])[CH2:9][CH2:10][C:11]([CH3:16])([CH3:15])[C:12]=2[CH:13]=1
Reactant: CC1(C)CCC(C)(C)c2cc(CCCO)ccc21
Reactant: BrBr
Agent: [Fe]
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)CCC(C)(C)c2cc(CCCO)c(Br)cc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
To a solution of 12.3 g (49.8 mmol) of 2-(3-hydroxypropyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene in 100 mL of carbon tetrachloride at 0° C. was added a trace of iron powder followed by a solution of 8.76 g (54.8 mmol) of bromine in 80 mL of carbon tetrachloride. After 4.5 hours at 0° C. the reaction mixture was warmed to room temperature. After 3 hours at room temperature, the reaction mixture was poured into ice water and the mixture was extracted with dichloromethane. The organic fraction was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (30% ethyl acetate/hexane) to give 10.2 g (63%) of 2-bromo-3-(3-hydroxypropyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene. (M+=324).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:35]2[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=2)[CH2:38]Cl)[CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)[CH2:38][C:37]2[CH:40]=[CH:41][CH:42]=[C:35]([C:27]3[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:25]([O:24][CH3:23])[CH:26]=3)[CH:36]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: COc1cc(-c2cccc(CCl)c2)cc(OC)c1OC
Product: COc1cc(-c2cccc(CN(c3ccc(SC)cc3)C3CCN(C(=O)OC(C)(C)C)CC3)c2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-[[4-(methylthio)phenyl]amino]piperidine (645 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (586 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([C:19]3[C:28]4[C:23](=[CH:24][C:25]([OH:29])=[CH:26][CH:27]=4)[CH:22]=[CH:21][C:20]=3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[F:37])=[O:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([BH-](CC)CC)C.[Li+].C(=O)(O)[O-].[Na+].C(Cl)(Cl)Cl.C(O)(C)C>C1COCC1>[N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([OH:18])[C:19]3[C:20]([C:30]4[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=4[F:37])=[CH:21][CH:22]=[C:23]4[C:28]=3[CH:27]=[CH:26][C:25]([OH:29])=[CH:24]4)=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc(OCCN2CCCCCC2)cc1)c1c(-c2cc(F)ccc2F)ccc2cc(O)ccc12
Agent: CC[BH-](CC)CC
Agent: O=C([O-])O
Agent: [Li+]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Oc1ccc2c(C(O)c3ccc(OCCN4CCCCCC4)cc3)c(-c3cc(F)ccc3F)ccc2c1
Reaction time: 1 h

Procedure:
Dissolve [4-(2-azepan-1-yl-ethoxy)-phenyl]-[2-(2,5-difluorophenyl)-6-hydroxynaphthalen-1-yl]-methanone (770 mg, 1.54 mmol) in 10 mL THF and add 5.0 mL (5.0 mmol) of lithium triethylborohydride (1.0 M solution in THF). After one hour at room temp, add another 4.0 mL of the lithium triethylborohydride gently warm the solution with a heat gun. After ½ hour the reaction is complete. Quench the reaction with water and pour into a two phase system of saturated sodium bicarbonate and a 3/1 mixture of chloroform/isopropanol. Separate the phases, dry the organic layer with 3 Å sieves and evaporate to give the title compound to be taken on to the next step without purification.
Reaction SMILES: FC1C=C(C=CC=1OC)C(CCC(O)=O)=O.N1CCC[C@H]1C(O)=O.[F:25][C:26]1[CH:27]=[C:28]([CH:43]=[CH:44][C:45]=1[O:46][CH3:47])[C:29]([CH2:31][CH2:32][C:33]([N:35]1[CH2:42][CH2:41][CH2:40][C@H:36]1[C:37]([OH:39])=[O:38])=[O:34])=[O:30].[C:48]([O-:51])(=[S:50])[CH3:49].[K+]>C(O)C.O>[C:48]([S:50][CH:31]([C:29](=[O:30])[C:28]1[CH:43]=[CH:44][C:45]([O:46][CH3:47])=[C:26]([F:25])[CH:27]=1)[CH2:32][C:33]([N:35]1[CH2:42][CH2:41][CH2:40][C@H:36]1[C:37]([OH:39])=[O:38])=[O:34])(=[O:51])[CH3:49]
Reactant: CC([O-])=S
Reactant: COc1ccc(C(=O)CCC(=O)N2CCC[C@H]2C(=O)O)cc1F
Agent: COc1ccc(C(=O)CCC(=O)O)cc1F
Agent: O=C(O)[C@@H]1CCCN1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(=O)C(CC(=O)N2CCC[C@H]2C(=O)O)SC(C)=O)cc1F

Procedure:
As described in Example 15, the preceding compound is converted to 3-(3-fluoro-4-methoxybenzoyl)propionic acid, hydroxysuccinimide ester and coupled to L-proline as in Example 16. The 1-[3-(3-fluoro-4-methoxybenzoyl)propionyl]-L-proline m.p. 180°-182° C. is brominated as in Example 20 and the product reacted with potassium thioacetate in ethanol-water as in Example 21 to give the product of the Example as a glass.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([F:19])=[CH:12][C:13]=2[O:15][CH2:16][CH2:17]Cl)[C:8]([S:20]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[N:7]1.[CH3:36][NH2:37].Cl.CCOCC>CS(C)=O.O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([F:19])=[CH:12][C:13]=2[O:15][CH2:16][CH2:17][NH:37][CH3:36])[C:8]([S:20]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)(=[O:21])=[O:22])=[N:7]1
Reactant: O=S(=O)(c1cccc2ccccc12)c1nn(Cc2cccc(Cl)c2)c2c(OCCCl)cc(F)cc12
Reactant: CN
Agent: Cl
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: O
Product: CNCCOc1cc(F)cc2c(S(=O)(=O)c3cccc4ccccc34)nn(Cc3cccc(Cl)c3)c12
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of 1-(3-chloro-benzyl)-7-(2-chloro-ethoxy)-5-fluoro-3-(naphthalene-1-sulfonyl)-1H-indazole (0.075 g, 0.14 mmoles) and methylamine (0.56 mmoles) in DMSO (1 mL) was stirred under nitrogen at 100° C. for 4 hours. Mixture was cooled to room temperature, diluted with water, extracted with EtOAc, washed with water (2×), brine (1×), dried over Na2SO4, and concentrated under vacuum. Compound was purified by flash chromatography using as eluent 5% CH3OH/EtOAc. The purified compound was dissolved in methanol, 1M HCl in ether (0.1 mL, 0.1 mmoles) was added, and compound was dried to afford the title compound as the HCl salt.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[Li+].CC([N-]C(C)C)C.[CH3:17][C:18]([CH3:20])=[O:19]>C1COCC1.C1COCC1.CCCCCCC.C(C1C=CC=CC=1)C>[Br:1][C:2]1[CH:7]=[C:6]([C:18]([OH:19])([CH3:20])[CH3:17])[C:5]([F:8])=[CH:4][N:3]=1
Reactant: CC(C)=O
Reactant: Fc1ccc(Br)nc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Product: CC(C)(O)c1cc(Br)ncc1F
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-5-fluoro-pyridine (CAS 41404-58-4, 25.0 g, 139 mmol) in THF (300 ml) was added dropwise LDA (100 ml of a 2M soln. in THF/heptane/ethylbenzene, 200 mmol) at −78° C. under a N2 atmosphere. Stirring was continued for 1 h at −78° C., then acetone (20.44 ml, 16.17 g, 278 mmol) was added dropwise and stirring was continued at −78° C. for another 1 h. The reaction mixture was quenched with aq. 1M NH4Cl soln. and diluted with EtOAc. The phases were separated and the aq. phase was twice reextracted with EtOAc. The combined org. phases were washed with brine, dried over Na2SO4, filtered, concentrated. Flash chromatography on silica gel (gradient cyclohexane:EtOAc 100:0 to 90:10) followed by crystallization from pentane yielded the title compound as a colourless solid. HPLC RtH4=0.81 min; ESIMS: 234, 236 [(M+H)+]; 1H NMR (400 MHz, DMSO-d6): δ 8.32 (br s, 1H), 7.71 (d, 1H), 5.57 (s, 1H), 4.90 (t, 1H), 3.65-3.57 (m, 1H), 3.53-3.44 (m, 1H), 1.39 (s, 3H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[NH:16][C:17](=[O:21])[CH2:18][CH2:19][CH3:20])(=O)=O.C(N(CC)CC)C.[C:31]1([C:37]#[CH:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[Cl-].[NH4+]>C(#N)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.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.[Cu](I)I>[N+:13]([C:10]1[CH:11]=[CH:12][C:7]([C:38]#[C:37][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:8]([NH:16][C:17](=[O:21])[CH2:18][CH2:19][CH3:20])[CH:9]=1)([O-:15])=[O:14]
Reactant: CCCC(=O)Nc1cc([N+](=O)[O-])ccc1OS(=O)(=O)C(F)(F)F
Reactant: C#Cc1ccccc1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCC(=O)Nc1cc([N+](=O)[O-])ccc1C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
To a solution of 2-butyramido-4-nitrophenyl trifluoromethanesulfonate (860 mg, 2.42 mmol) in dry acetonitrile (30 mL) under nitrogen was added tetrabutylammonium iodide (1.34 g, 3.62 mmol), tetrakis(triphenylphosphine)palladium(0) (280 mg, 0.24 mmol) and copper iodide (140 mg, 0.72 mmol). Triethylamine (6 mL) was then added, followed by phenyl acetylene (530 μL, 4.83 mmol). The resulting solution was stirred at room temperature for 2 h. Ammonium chloride was then added to quench the reaction, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting using a gradient (hexanes to ethyl acetate) to afford 580 mg (78%) of the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:11][C:10]([CH:20]([CH3:22])[CH3:21])=[N:9]2)=[CH:4][C:3]=1[N+:23]([O-:25])=[O:24].[Li+].[OH-].OO.[O-:30]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1.O.C(O)(=O)C>[OH:30][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:11][C:10]([CH:20]([CH3:22])[CH3:21])=[N:9]2)=[CH:4][C:3]=1[N+:23]([O-:25])=[O:24]
Reactant: O=S([O-])([O-])=S
Reactant: CC(C)c1cc(C(=O)OC(C)(C)C)n(-c2ccc(F)c([N+](=O)[O-])c2)n1
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)c1cc(C(=O)OC(C)(C)C)n(-c2ccc(O)c([N+](=O)[O-])c2)n1
Temperature: 60 °C
Yield: 37 %

Procedure:
To a solution of tert-butyl 1-(4-fluoro-3-nitrophenyl)-3-isopropyl-1H-pyrazole-5-carboxylate (0.74 g, 2.1 mmol) in THF/water (12 mL) was added LiOH (300 mg, 13 mmol) and H2O2 (30% wt, 0.96 mL). The reaction mixture was heated overnight at 60° C. Na2S2O3 solution was added until the peroxide test (starch-iodide paper) was negative. Acetic acid was added until the pH was 4-5. The solution was extracted with EtOAc and the organic layer was washed with brine, dried (MgSO4), concentrated in vacuo and purified by silica gel column chromatography (EtOAc/hexanes) to obtain tert-butyl 1-(4-hydroxy-3-nitrophenyl)-3-isopropyl-1H-pyrazole-5-carboxylate (0.27 g, 37% yield). MS (ESI) m/z: 348.3 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)[CH3:2].[CH:15]([C:18]1[CH:19]=[CH:20][C:21]([O:27][CH3:28])=[C:22](B(O)O)[CH:23]=1)([CH3:17])[CH3:16]>>[CH2:1]([O:3][C:4](=[O:14])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([C:22]2[CH:23]=[C:18]([CH:15]([CH3:17])[CH3:16])[CH:19]=[CH:20][C:21]=2[O:27][CH3:28])=[CH:9][CH:8]=1)[CH3:2]
Reactant: COc1ccc(C(C)C)cc1B(O)O
Reactant: CCOC(=O)/C=C/c1ccc(Br)cc1
Product: CCOC(=O)/C=C/c1ccc(-c2cc(C(C)C)ccc2OC)cc1

Procedure:
(E)-3-(4-Bromo-phenyl)-acrylic acid ethyl ester (450 mg, 2.0 mmol) was reacted with 5-isopropyl-2-methoxy-benzene boronic acid (776 mg, 4.0 mmol) by a procedure described in example 52 a, to give (E)-3-(5′-Isopropyl-2′-methoxy-biphenyl-4-yl)-acrylic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18](O)=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH2:45][CH2:46][NH2:47])[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH2:45][CH2:46][NH:47][C:18]([C:14]2[CH2:15][CH2:16][O:17][C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=4)=[CH:21][C:12]=3[CH:13]=2)=[O:19])[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)NCCC2CCN(C(=O)OC(C)(C)C)CC2)CCO3)cc1
Yield: 66.8 %

Procedure:
To 7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxylic acid (1402 mg, 5.00 mmol) dissolved in DMF (30 ml) were added at 0° C. 1-hydroxybenzotriazole (743 mg, 5.50 mmol), 2-[1-(tert-butoxycarbonyl)piperidin-4-yl]ethylamine (1256 mg, 5.50 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1438 mg, 7.50 mmol), and the resulting mixture was stirred at room temperature for 8 hours. The reaction mixture was concentrated, ethyl acetate (120 ml) was added to the residue and the resulting mixture was washed successively with water (30 ml), an aqueous saturated solution of sodium bicarbonate (20 ml×3) and an aqueous saturated solution of sodium chloride (20 ml). The organic layer was dried with anhydrous magnesium sulfate and was then concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel, ethyl acetate/hexane=1/2→1/1). The objective fractions were concentrated under reduced pressure and were mixed with diisopropyl ether to collect an insoluble material by filtration. The insoluble material was washed with diisopropyl ether and was dried under reduced pressure to obtain N-[2-[1-(tert-butoxycarbonyl)piperidin-4-yl]ethyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (1.64 g, 3.34 mmol, 67%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[OH:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[N:14]1.C(N(CC)CC)C>C1C=CC=CC=1.O>[CH2:5]([O:4][C:2]([O:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[N:14]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: c1ccccc1
Product: O=C(OCc1ccccc1)On1nnc2ccccc21
Reaction time: 3 h
Yield: 90.2 %

Procedure:
Benzyl chloroformate (8.5 g.) was added dropwise under ice-cooling to a solution of 1-hydroxy-1H-benzotriazole (6.8 g.) and triethylamine (7.0 ml.) in a mixture of benzene (100 ml.) and water (50 ml.), and the mixture was stirred for 3 hours at the same temperature. The reaction mixture was filtered and the precipitated crystals were washed with water and dried. The benzene layer was washed with water, dried and concentrated. The residue and the crystals obtained above were mixed and recrystallized from a mixed solvent of benzene and petroleum ether to give 1-benzyloxycarbonyloxy-1H-benzotriazole (12.1 g.), mp 130° to 131° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12]Cl)=[CH:8][C:7]=1[CH3:14].[N-:16]=[N+:17]=[N-:18].[Na+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:16]=[N+:17]=[N-:18])=[CH:8][C:7]=1[CH3:14]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)CCc1ccc(CCl)cc1C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1ccc(CN=[N+]=[N-])cc1C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
To a solution of 3-(4-Chloromethyl-2-methyl-phenyl)-propionic acid methyl ester (0.52 g, 2.31 mmol) in DMF (7 mL) is added sodium azide (0.25 g, 3.84 mmol). The mixture is stirred overnight. Water is added, and the mixture is extracted with EtOAc. The organics are dried with Na2SO4 and concentrated to yield the title compound (0.49 g, 91%). The material is used without further purification.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH2:6]([O:8][C:9]1[N:14]=[C:13]([CH2:15][Cl:16])[CH:12]=[C:11]([OH:17])[N:10]=1)[CH3:7].O.[OH-].[Na+]>C(Cl)Cl>[CH2:6]([O:8][C:9]1[N:14]=[C:13]([CH2:15][Cl:16])[C:12]([Cl:4])=[C:11]([OH:17])[N:10]=1)[CH3:7]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOc1nc(O)cc(CCl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOc1nc(O)c(Cl)c(CCl)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.8 ml (0.035 mol) of sulphuryl chloride are added dropwise to a solution of 6 g (0.032 mol) of 2-ethoxy-4-chloromethyl-6-hydroxy-pyrimidine in 90 ml of methylene chloride and the mixture is subsequently stirred at room temperature for 4 hours. The mixture is then treated with 100 ml of water and adjusted to pH 7 with 30% sodium hydroxide solution. The organic phase is separated and the combined organic phases are extracted with water, dried over anhydrous sodium sulphate and evaporated. There is obtained crystalline 2-ethoxy-5-chloro-4-chloromethyl-6-hydroxy-pyrimidine, 1H-NMR (CDCl3): 1.45 (t, OCH2CH3), 4.54 (q, OCH2CH3), 4.54 (s, CH2Cl), 9.80 (broad signal, OH).
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[C:11]([C:18]([NH:20][NH2:21])=[O:19])=[CH:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=1.CN([CH:25]=[O:26])C>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:18]2[O:19][C:25](=[O:26])[NH:21][N:20]=2)=[CH:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=1
Reactant: Cn1cc(C(=O)NN)c(Nc2ccc(I)cc2F)cc1=O
Reactant: CN(C)C=O
Product: Cn1cc(-c2n[nH]c(=O)o2)c(Nc2ccc(I)cc2F)cc1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-(2-Fluoro-4-iodo-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid hydrazide was dissolved in DMF (20 mL) and treated with the 1,1′-carbonydiimidazole (2.90 g, 17.92 mmol). The mixture was stirred at room temperature for 24 hours. The solid was precipitate out. This material was isolated by filtration, washed well with water and hexanes, then dried to afford 4-(2-Fluoro-4-iodo-phenylamino)-1-methyl-5-(5-oxo-4,5-dihydro-[1,3,4]oxadiazol-2-yl)-1H-pyridin-2-one as an off white solid (5.0 g, 71%). (APCI+) calcd for C14H10FIN4O3 428.16 (M+1), found 428.9. Anal. Calcd for C14H10FIN4O3: C, 39.27; H, 2.35; N, 13.09. Found: C, 39.55; H, 2.88; N, 13.12.
Reaction SMILES: Cl[C:2]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:16][C:5]([C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[OH:15])=[O:7])=[CH:4][N:3]=1.[C:25]([CH:27]1[CH2:29][CH2:28]1)#[CH:26]>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]2[C:2]([C:26]#[C:25][CH:27]3[CH2:29][CH2:28]3)=[N:3][CH:4]=[C:5]([CH:16]=2)[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[OH:15])=[O:7])=[CH:19][CH:20]=1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Reactant: C#CC1CC1
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(C#CC2CC2)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 112, using 6-chloro-5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide and ethynylcyclopropane as starting materials to yield the product as an off-white solid, MS (ISP) 395.3, 397.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:11])[CH:3]=1.[CH3:12][OH:13].C(N(CC)CC)C>>[CH3:12][O:13][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[F:11]
Reactant: O=C(Cl)c1ccc(Br)cc1F
Reactant: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Bromo-2-fluorobenzoyl chloride (45.0 g, 0.190 mol) was slowly added to a solution of methanol (31 mL, 0.76 mol) and triethylamine (53 mL, 0.38 mol) at 0° C. and the mixture was stirred at room temperature overnight. The MeOH was removed under vacuum and the residue was dissolved in CH2Cl2 (500 mL). The organic layer was washed with water, dried (Na2SO4), and concentrated to give a white solid.