Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:21]2=[CH:22][CH:23]=[N:24][CH:25]=[C:20]2[C:5]2[C:6]([OH:19])=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([O:19][C:6]1[C:5]2[C:20]3[C:21]([C:2]([CH3:1])([CH3:26])[O:3][C:4]=2[CH:9]=[C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])[CH:7]=1)=[CH:22][CH:23]=[N:24][CH:25]=3)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Solvent: c1ccncc1
Product: CCCCCC(C)C(C)c1cc(OC(C)=O)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
A mixture of 3.53 g. (0.01 mole) of 5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-5H-[1]benzopyrano[3,4-d]pyridine, 1.22 g. (0.012 mole) of acetic anhydride, and 5 ml. of pyridine was stirred at room temperature for 24 hours. The reaction mixture was evaporated in vacuo, and the residue was taken up in ether. The ether solution was washed with water, dried with anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by chromatography on a Florosil® activated aluminum magnesium silicate 22 mm×30 inch column with chloroform to give the pure product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:35]=[CH:34][C:12]([O:13][CH2:14][CH2:15][C:16]2[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=2)[O:19][CH2:20][C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([O:25]C)=[O:24])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][C:16]2[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=2)[O:19][CH2:20][C:21]2[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=2[C:23]([OH:25])=[O:24])=[CH:34][CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccccc1COc1cccc(CCOc2ccc(OCc3ccccc3)cc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1COc1cccc(CCOc2ccc(OCc3ccccc3)cc2)c1
Yield: 97.2 %

Procedure:
Methyl 2-[(3-{2-[4-(benzyloxy)phenoxy]ethyl}phenoxy)methyl]benzoate (20 mg, 0.043 mmol) was dissolved in a mixture of THF/H2O (7/1, 3 ml) and LiOH (4.1 mg, 0.17 mmol) was added. The reaction was performed in a single node microwave oven (7 min, 150° C.). The mixture was acidified (HCl, 1 ml, 1M) and the water phase washed with two portions of EtOAc (3×5 ml). After removing the solvent by evaporation the crude was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min)). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). Removing the solvent by evaporation gave 19 mg of 2-[(3-{2-[4-(benzyloxy)phenoxy]ethyl}phenoxy)methyl]benzoic acid (yield 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[S-:18][C:19]#[N:20].[NH4+].BrBr>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][C:9]=2[S:18][C:19]#[N:20])=[CH:6][CH:7]=1
Reactant: N#C[S-]
Reactant: CCOC(=O)c1ccc(-c2ccc(Cl)cc2)[nH]1
Agent: BrBr
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(SC#N)c(-c2ccc(Cl)cc2)[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.9 %

Procedure:
A solution of ethyl 5-(p-chlorophenyl)pyrrole-2-carboxylate (0.95 g, 3.8 mmol) in acetic acid (20 mL) is treated with ammonium thiocyanate (1.75 g, 22.8 mmol), stirred at room temperature for five minutes, cooled to 15° C., treated with a solution of bromine (0.91 g, 5.7 mmol) in acetic acid (10 mL) and stirred at room temperature for several hours. The reaction mixture is filtered to remove solids and the filtrate is poured into water and stirred. The aqueous mixture is filtered to obtain an off-white solid. Flash chromatography of the solid using a 1:10 ethyl acetate/hexanes solution gives the title product as a white solid (0.99 g, mp 138°-141° C.) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[N:10][N:9]=1.[CH3:13][C:14](O)([CH3:16])[CH3:15].OS(O)(=O)=O>FC(F)(F)C(O)=O>[C:14]([N:9]1[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])=[N:12][N:11]=[N:10]1)([CH3:16])([CH3:15])[CH3:13]
Reactant: CC(C)(C)O
Reactant: Brc1ccccc1-c1nnn[nH]1
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)n1nnnc1-c1ccccc1Br
Reaction time: 18 h
Yield: 67.1 %

Procedure:
To a solution of 5-(2-bromophenyl)-1H-tetrazole (7.9 g, 0.035 mol) in trifluoroacetic acid (35 mL) was added tBuOH (5.2 g, 0.070 mol) and H2SO4 (1.0 mL, 0.0175 mol). After 18 h, the solution was concentrated and the residue was taken up in EtOAc. The mixture was washed with water, 2.5 N NaOH, water, dried (MgSO4), and concentrated. Purification by flash chromatography (20% EtOAc/hexane) gave 6.6 g (67%) of product as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10](Cl)(=[O:12])=[O:11])[S:7][C:6]=2[CH:14]=1.Cl.[NH2:16][C@H:17]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]#[CH:24])[C:18]1=[O:25]>>[O:25]=[C:18]1[C@@H:17]([NH:16][S:10]([C:8]2[S:7][C:6]3[CH:14]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[CH:9]=2)(=[O:12])=[O:11])[CH2:21][CH2:20][N:19]1[CH2:22][C:23]#[CH:24]
Reactant: C#CCN1CC[C@H](N)C1=O
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Agent: Cl
Product: C#CCN1CC[C@H](NS(=O)(=O)c2cc3ccc(Cl)cc3s2)C1=O

Procedure:
The title compound is prepared as described in EXAMPLE 1, Part K using 6-chloro-benzo[b]thiophene-2-sulfonyl chloride and 3-(S)-amino-1-prop-2-ynyl-pyrrolidin-2-one hydrochloride as starting material. The crude product is isolated as a beige foam and used in the subsequent step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:11])=[O:10])=[C:4]([CH:22]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[OH:23])[CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:39][C:40]([NH2:42])=[O:41]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:11])=[O:10])[CH2:39][C:40]([NH2:42])=[O:41])=[C:4]([CH:22]([OH:23])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)[CH:3]=1
Reactant: NC(=O)CBr
Reactant: COc1cccc(C(O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(OC)c(OC)c2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cccc(C(O)c2cc(Cl)ccc2N(CC(N)=O)S(=O)(=O)c2ccc(OC)c(OC)c2)c1
Reaction time: 48 h
Yield: 50.9 %

Procedure:
To 0.7 g of N-{4-chloro-2-[(3-methoxyphenyl)(hydroxy)methyl]phenyl}-3,4-dimethoxybenzenesulfonamide dissolved in 5 ml of THF are added, at room temperature, 0.2 g of potassium tert-butoxide and 0.25 g of 2-bromoacetamide. After 48 hours at 20° C., the reaction medium is concentrated, taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with dichloromethane to give 0.4 g of the expected product.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH2:21]([NH:23][CH2:24][CH2:25][O:26][CH3:27])[CH3:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:21]([N:23]([CH2:24][CH2:25][O:26][CH3:27])[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[CH3:22]
Reactant: CCNCCOC
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CCOC)C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with N-ethyl-2-methoxyethanamine (34322-82-2) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=370.6 [MH+].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:23]3[O:22][C:21]([C:24]([O-])=[O:25])=[CH:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.[Li+].[O:28]1[C:32]2[CH:33]=[CH:34][C:35]([CH2:37][NH2:38])=[CH:36][C:31]=2[O:30][CH2:29]1>>[O:28]1[C:32]2[CH:33]=[CH:34][C:35]([CH2:37][NH:38][C:24]([C:21]3[O:22][C:23]4[C:15]([N:12]5[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][C:2]6[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=6)[CH2:10][CH2:11]5)=[CH:16][CH:17]=[CH:18][C:19]=4[CH:20]=3)=[O:25])=[CH:36][C:31]=2[O:30][CH2:29]1
Reactant: O=C([O-])c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1
Reactant: NCc1ccc2c(c1)OCO2
Agent: [Li+]
Product: O=C(NCc1ccc2c(c1)OCO2)c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1

Procedure:
The compound was prepared according to the procedure disclosed in Example 1 starting from lithium 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (80 mg, 0.21 mmol) and benzo[d][1,3]dioxol-5-ylmethaneamine (41 mg, 0.27 mmol). Yield: 78 mg (72%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:14][CH:13]([C:15](O)=[O:16])[CH:12]([C:18](=[O:30])[NH:19][C:20]3([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:22][CH:21]3[CH:23]=[CH2:24])[CH2:11]2)[CH:6]=[C:5]([O:31][CH3:32])[N:4]=1.[CH3:33][NH:34][CH:35]=[CH:36][CH2:37][CH2:38][CH2:39][CH3:40].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:28]([O:27][C:25]([C:20]1([NH:19][C:18]([CH:12]2[CH2:11][CH:10]([O:9][C:7]3[CH:6]=[C:5]([O:31][CH3:32])[N:4]=[C:3]([O:2][CH3:1])[N:8]=3)[CH2:14][CH:13]2[C:15](=[O:16])[N:34]([CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=[CH2:40])[CH3:33])=[O:30])[CH2:22][CH:21]1[CH:23]=[CH2:24])=[O:26])[CH3:29]
Reactant: CCCCC=CNC
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(OC)nc(OC)n2)CC1C(=O)O)C(=O)OCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCCN(C)C(=O)C1CC(Oc2cc(OC)nc(OC)n2)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Yield: 67.9 %

Procedure:
The acid 18d (1.2 g, 2 mmol) was reacted with N-methylhexeneamine (0.34 g, 3.0 mmol), DIEA (1.29 g, 10.0 mmol) and HATU (1.1 g, 3 mmol) in dry DMF (30 ml) according to the procedure described in Example 13 step c. Purification by column chromatography on silica gel gave the title compound (0.74 g, 74%), (M+H)+545.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]([OH:18])=O)=[CH:15][C:10]=2[N:9]=[CH:8]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:42][O:43][NH:44][CH3:45]>C(Cl)Cl.O>[CH3:42][O:43][N:44]([CH3:45])[C:16]([C:14]1[CH:13]=[CH:12][C:11]2[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[CH:8]=[N:9][C:10]=2[CH:15]=1)=[O:18]
Reactant: O=C(O)c1ccc2c(c1)ncn2C1CCCCO1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc2c(c1)ncn2C1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To the solution of 166 (170 mg, 0.69 mmol) in DCM (5 mL) was added EDC.HCl (190 mg, 1 mmol), HOBt (160 mg, 1 mmol), TEA (0.3 mL) and N-methoxymethanamine hydrochloride (100 mg, 1 mmol). The mixture was stirred at RT overnight. The mixture was poured into water, extracted with EtOAc, washed sequentially with H2O and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography affording 140 mg (85%) of 1-(tetrahydro-pyran-2-yl)-1H-benzoimidazole-5-carboxylic acid methoxy-methyl-amide (168) as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[CH:4][C:3]=1[CH3:12].[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[F:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([NH:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])cc1F
Reaction time: 38 h
Yield: 64 %

Procedure:
1,4-Difluoro-2-methyl-5-nitrobenzene (1.5 mol, 260 mg) in dimethylformamide (10 mL) was treated under argon at room temperature with 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (1.5 mmol, 300.5 mg, 1 eq) and diisopropylethylamine (1.5 mmol, 260 μL, 1 eq) then stirred at 70 (→80) ° C. for 38 h. The mixture was concentrated under vacuum, treated with water and extracted twice with ether. Organics were combined, dried on MgSO4 and concentrated under vacuum to give a red-brown residue which was chromatographed (0-25% ethyl acetate/petrol ether 6 CV) to give the title compound as a red solid (0.96 mmol, 340 mg, 64% yield). M+H=298.07, main fragment (molecule has lost its tert-butyl group).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:21][CH3:22])[C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[O:7][C:8]1[CH:9]=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=1.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH3:22][O:21][CH:3]([O:2][CH3:1])[C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[O:7][C:8]1[CH:9]=[C:10]([NH:14][S:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:31])=[O:30])[CH:11]=[CH:12][CH:13]=1
Reactant: COC(OC)c1cc(Oc2cccc(N)c2)ccc1[N+](=O)[O-]
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: C1CCOC1
Product: COC(OC)c1cc(Oc2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of 3-(3-dimethoxymethyl-4-nitro-phenoxy)phenylamine (0.013 mol) in THF (100 mL) and TEA (200 mL) was stirred at room temperature and a mixture of benzenesulfonyl chloride (0.013 mol) in THF (50 mL) was added dropwise, then the reaction mixture was stirred overnight at room temperature and again overnight at 60° C. The solvent was evaporated and the residue was stirred in H2O. After extraction with CH2Cl2, the organic layer was separated, dried, filtered off and the solvent was evaporated. The residue was purified by Biotage column chromatography (eluent: CH2Cl2 100%). The purest product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][N:7]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: COc1cccc(CBr)c1
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Oc2cc(C)cc(C)c2)n(Cc2cccc(OC)c2)c(=O)[nH]c1=O
Yield: 56 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 3-methoxybenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (213 mg, yield: 56.0%).
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH3:10])[NH:4][C:3]=1[CH:11]=[O:12].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1>>[CH3:33][O:32][C:30](=[O:31])[C:29]1[CH:34]=[CH:35][C:26]([CH2:25][N:4]2[C:3]([CH:11]=[O:12])=[C:2]([Br:1])[N:6]=[C:5]2[CH2:7][CH2:8][CH2:9][CH3:10])=[CH:27][CH:28]=1
Reactant: CCCCc1nc(Br)c(C=O)[nH]1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1nc(Br)c(C=O)n1Cc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.9 %

Procedure:
5-Bromo-2-butyl-3H-imidazole-4-carbaldehyde (38 g, 160 mmol) was dissolved in DMF (400 mL, 5 mol). Potassium carbonate (27 g, 200 mmol) was added followed by methyl 4-bromomethylbenzoate (38 g, 160 mmol) and the solution was stirred at room temperature overnight. The mixture was then concentrated and purified by silica gel chromatography (0-50% EtOAc:hexanes) to yield intermediate (9a) (32.2 g, 62.2 mmol). MS m/z: [M+H+] calcd for C17H19N2O3Br, 379.3. found 379.1. 1H-NMR (400 Mz, CD3OD) δ (ppm): 0.82 (t, 3H, J=5 Hz), 1.28 (m, 2H), 1.54 (q, 2H, J=5 Hz), 2.70 (t, 2H, J=5 Hz), 5.69 (s, 2H), 7.15 (d, 2H, J=5 Hz), 7.96 (d, 2H, J=5 Hz), 9.66 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:27])[CH2:9][N:10]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:34][C:35]1[CH:36]=[C:37]([C:42]([O:44][CH3:45])=[O:43])[CH:38]=[N:39][C:40]=1Cl>CS(C)=O>[C:13]([O:12][C:11]([N:10]([CH2:9][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[OH:27])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:40]2[C:35]([Cl:34])=[CH:36][C:37]([C:42]([O:44][CH3:45])=[O:43])=[CH:38][N:39]=2)=[CH:22][CH:21]=1)=[O:17])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(O)cc1)C[C@H](O)c1cccc(Cl)c1
Reactant: COC(=O)c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1cnc(Oc2ccc(CCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.6 %

Procedure:
To a solution of tert-butyl [(2R)-2-(3-chlorophenyl)-2-hydroxyethyl][2-(4-hydroxyphenyl)ethyl]carbamate (600 mg) and potassium carbonate (254 mg) in dimethylsulfoxide (6.0 ml) was added methyl 5,6-dichloro-3-pyridinecarboxylate (347 mg), and the mixture was stirred at room temperature for 12 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give methyl 6-[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenoxy]-5-chloronicotinate (770 mg).
Reaction SMILES: [CH2:1]([C:4]1C=C2C(=CC=1O)NC(=O)CC2)[CH:2]=C.[CH2:16]([C:19]1[C:20]([OH:30])=[CH:21][CH:22]=[C:23]2[C:28]=1[NH:27][C:26](=[O:29])[CH2:25][CH2:24]2)[CH:17]=[CH2:18].C(Br)C=C>CO.[OH-].[K+]>[CH2:16]([C:19]1[C:20]([O:30][CH2:4][CH:1]=[CH2:2])=[CH:21][CH:22]=[C:23]2[C:28]=1[NH:27][C:26](=[O:29])[CH2:25][CH2:24]2)[CH:17]=[CH2:18]
Reactant: C=CCc1cc2c(cc1O)NC(=O)CC2
Reactant: C=CCc1c(O)ccc2c1NC(=O)CC2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C=CCBr
Product: C=CCOc1ccc2c(c1CC=C)NC(=O)CC2
Yield: 60 %

Procedure:
6.1 Grams of the mixture of 6-allyl-3,4-dihydro-7-hydroxy-2(1H)-quinolinone and 8-allyl-3,4-dihydro-7-hydroxy-2(1H)-quinolinone obtained in Example 8 was dissolved in 200 ml of methanol containing 1.8 g of potassium hydroxide. Under stirring, 3 ml of allyl bromide was added thereto at room temperature. The reaction mixture was stirred at room temperature for 4 hours, and further stirred at 60° C. for 1 hour. After the reaction was finished, the reaction mixture was concentrated under reduced pressure, next 200 ml of water was added and stirred vigorously, then extracted with 500 ml of ethyl acetate. The extract was washed with water and an aqueous solution saturated with sodium chloride, and dried with anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration, and the filtrate was concentrated to dryness. This mixture was subjected to purification by means of a flush column chromatography by using methylene chloride-methanol (100:1). The first eluted portion was collected and concentrated under reduced pressure, there was obtained 4.4 g (60%) of 8-allyl-7-allyloxy-3,4-dihydro-2(1H)-quinolinone. Colorless needle-like crystals (recrystallized from ethyl acetate-n-hexane). Melting point: 119°-121° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:26])=[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13]OS(C)(=O)=O)=[O:5])[CH3:2].[NH2:27][CH2:28][CH:29]([OH:37])[CH2:30][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>ClCCl.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:26])=[C:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13][NH:27][CH2:28][CH:29]([OH:37])[CH2:30][N:31]1[CH2:32][CH2:33][O:34][CH2:35][CH2:36]1)=[O:5])[CH3:2]
Reactant: NCC(O)CN1CCOCC1
Reactant: CCOC(=O)c1c(CCCOS(C)(=O)=O)[nH]c(C(=O)OC(C)(C)C)c1C
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1c(CCCNCC(O)CN2CCOCC2)[nH]c(C(=O)OC(C)(C)C)c1C
Temperature: 45 °C
Yield: 45.6 %

Procedure:
5-(3-methanesulfonyloxy-propyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1g (1.13 g, 2.9 mmol) was dissolved in 5.6 ml of dichloromethane under stirring, and 1-amino-3-morpholin-4-yl-propan-2-ol 53c (0.93 g, 5.8 mmol) was added to the solution at room temperature. Upon completion of the addition, the reaction mixture was stirred at room temperature overnight and heated for 14 hours at 45° C. in an oil bath. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was added with saturated brine (15 ml), exacted with dichloromethane (20 ml×3). The combined organic extracts were concentrated under reduced pressure, purified by silica gel column chromatography to obtain the title compound 5-[3-(2-hydroxy-3-morpholin-4-yl-propylamino)-propyl]-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 53d (600 mg, yield 72.5%) as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[F:15][CH:16]([F:29])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH2:26])=[CH:21][C:20]=1[O:27][CH3:28]>>[Cl:13][C:12]1[C:3]2[CH2:2][N:26]([CH2:25][C:22]3[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH:16]([F:29])[F:15])=[C:20]([O:27][CH3:28])[CH:21]=3)[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: COc1cc(CN)ccc1OCC(F)F
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: COc1cc(CN2Cc3c(ccnc3Cl)C2=O)ccc1OCC(F)F
Yield: 35 %

Procedure:
The title compound is prepared in 35% yield (74 mg, white solid) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and (4-(2,2-difluoroethoxy)-3-methoxyphenyl)methanamine hydrochloride (144 mg, 0.57 mmol, Amine-32) in a similar manner to Intermediate-2.
Reaction SMILES: [CH:1]1([C:6]#[N:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:18](=[N:20]/[S@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])\[CH3:19]>C1COCC1>[C:6]([C:1]1([C@H:18]([NH:20][S@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[CH3:19])[CH2:5][CH2:4][CH2:3][CH2:2]1)#[N:7]
Reactant: C/C=N/[S@@](=O)C(C)(C)C
Reactant: N#CC1CCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](N[S@@](=O)C(C)(C)C)C1(C#N)CCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
In a flask, cyclopentanecarbonitrile (3.53 g, 37.1 mmol) was dissolved in THF (40 mL) and cooled at −78° C. LiHMDS (1.0 M in THF, 41 mL, 41 mmol) was added and the mixture stirred for 30 min at −78° C. A solution of (S)-2-methyl-propane-2-sulfinic acid (E)-ethylideneamide (crude from step 1, 1.82 g, 12.4 mmol) in THF (10 mL) was slowly added. The mixture was stirred at −78° C. for 2 h then allowed to warm to room temperature overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4 and concentrated. The residue was purified by SiO2 chromatography (50-100% EtOAc/heptane) to afford 1.96 g (65%) of (S)-2-methyl-propane-2-sulfinic acid [(R)-1-(1-cyano-cyclopentyl)-ethyl]-amide as a white solid.