Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][C:12]3[N:13]=[CH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][C:18]([C:22](O)=[O:23])=[CH:17][C:16]=4[CH3:25])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH2:57]([NH2:64])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>CC(N(C)C)=O>[CH2:57]([NH:64][C:22]([C:18]1[CH:19]=[C:20]2[C:15](=[C:16]([CH3:25])[CH:17]=1)[CH:14]=[N:13][C:12]([NH:11][CH:8]1[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]1)=[CH:21]2)=[O:23])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1
Reactant: NCc1ccccc1
Reactant: Cc1cc(C(=O)O)cc2cc(NC3CCC4(CC3)OCCO4)ncc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)NCc2ccccc2)cc2cc(NC3CCC4(CC3)OCCO4)ncc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
3-(1,4-Dioxa-spiro[4.5]dec-8-ylamino)-8-methyl-isoquinoline-6-carboxylic acid (100.0 mg, 0.29 mmol) in 5 ml DMA was treated with a HATU (240.0 mg, 0.63 mmol) and triethylamine (192.0 mg, 1.89 mmol) for 1 hour at room temperature. After 1 hour, benzylamine (74.5 mg, 0.69 mmol) was added and the mixture was heated to 50° C. for 2 hours. The reaction was completed by LC/MS monitoring. The solvent DMA was evaporated under vacuum, and the crude was dissolved in CH2Cl2 and washed with NaHCO3 aqueous (10%) to remove the by-products from HATU. The crude residue was purified by a silica gel column to give 119.0 mg (94.4%). 1H NMR (400 MHz, CHLOROFORM-d) ppm 1.59-1.75 (m, 2H), 1.78-1.95 (m, 4H), 2.01-2.12 (m, 2H), 2.64 (s, 3H), 3.39-3.55 (m, J=4.28 Hz, 1H), 3.91-4.04 (m, 4H), 4.69 (d, J=5.54 Hz, 2H, 6.62 (s, 1H), 6.94 (s, 1H), 7.34-7.46 (m, 5H), 7.87 (s, 1H), 8.85 (s, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH:7]=[N:8][N:9]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4].[OH-].[Na+].Cl>O.CO>[F:20][C:17]1[CH:16]=[CH:15][C:14]([N:9]2[C:10]3[CH:11]=[CH:12][CH:13]=[C:5]([C:3]([OH:4])=[O:2])[C:6]=3[CH:7]=[N:8]2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1cccc2c1cnn2-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid methyl ester (2.0 g, 7.4 mmol) in water (20 mL) and methanol (20 mL) is added a solution of 2N sodium hydroxide (10 mL). The solution is warmed at reflux for 1 hour. The solution is cooled to room temperature and acidified to pH 3-4 with 1N aqueous HCl. The mixture is filtered, and the resulting solid is washed with MeOH (30 mL) and dried to afford 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Br:10]Br>>[F:1][C:2]1[CH:7]=[C:6]([Br:10])[CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: BrBr
Reactant: COc1ccccc1F
Product: COc1ccc(Br)cc1F

Procedure:
The procedure for synthesis is briefly explained below. First, 2-fluoroanisole [1] is reacted with bromine to give 2-fluoro-4-bromoanisole [2], which is subsequently reacted with magnesium to give a compound [3] of Grignard reagent type. This compound is condensed with 2-fluoro-4-bromoanisole [2] in the presence of a palladium chloride catalyst to give 3,3'-difluoro-4,4'-dimethoxybiphenyl [4]. In this way, the biphenyl skeleton is formed. Then, the both terminals of 3,3'-difluoro- 4,4,-dimethoxybiphenyl [4] are demethylated by boron tribromide to give 3,3'-difluoro-4,4'-dimethoxybiphenyl [4]. One of the two hydroxyl groups in the compound [5] is blocked by acylation with acetic acid chloride to give a compound [6]. The remaining hydroxyl group in the compound [6] is alkylated with a halogenated alkyl having a specific chain length (p=6 to 15) to give a compound [7]. Finally, the compound [7] undergoes hydrolysis by an alkali catalyst (sodium hydroxide) to remove the acyl group. Thus there is obtained an unblocked compound [8], which is ready for coupling with a cyclohexane ring through an ester linkage.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:17])[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH:10]=[CH:9]2.[CH3:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH3:18][N:19]([CH2:2][CH:3]([OH:17])[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH:10]=[CH:9]2)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CNCc1ccccc1
Reactant: O=c1ccc2cc(OCC(O)CCl)ccc2[nH]1
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)CC(O)COc1ccc2[nH]c(=O)ccc2c1
Reaction time: 5 h
Yield: 37.1 %

Procedure:
A solution of 6-(3-chloro-2-hydroxypropoxy)carbostyril (5.05 g) and N-methylbenzylamine (6.0 g) in dimethylformamide (50 ml) is heated with stirring at 50°-60° C. for 5 hours. The solvent is distilled off under reduced pressure and the resulting residue is purified by silica gel column chromatography (solvent; methanol:chloroform =1:100-1:25) and recrystallized from ethanol to give 6-[3-(N-methyl-N-benzylamino)-2-hydroxypropoxy]carbostyril (2.5 g), as white powder, m.p. 129°-132° C.
Reaction SMILES: Cl.Cl.[CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][N:13]([CH3:23])[CH2:14][C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH2:16])[CH2:8][CH2:7]1)([CH3:5])[CH3:4].[Cl:24][C:25]1[C:33]2[C:28](=[CH:29][C:30]([C:34](O)=[O:35])=[CH:31][CH:32]=2)[NH:27][CH:26]=1>>[Cl:24][C:25]1[C:33]2[C:28](=[CH:29][C:30]([C:34]([NH:16][C@H:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:14][N:13]([CH2:12][CH:9]3[CH2:8][CH2:7][N:6]([CH:3]([CH3:5])[CH3:4])[CH2:11][CH2:10]3)[CH3:23])=[O:35])=[CH:31][CH:32]=2)[NH:27][CH:26]=1
Reactant: O=C(O)c1ccc2c(Cl)c[nH]c2c1
Reactant: CC(C)N1CCC(CN(C)C[C@H](N)c2ccccc2)CC1
Agent: Cl
Product: CC(C)N1CCC(CN(C)C[C@H](NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccccc2)CC1

Procedure:
Using coupling method A, crude (R)-N2-(1-isopropyl-piperidin-4-ylmethyl)-N2-methyl-1-phenylethane-1,2-diamine dihydrochloride (500 mg, 1.4 mmol) and 3-chloroindole-6-carboxylic acid (325 mg, 1.7 mmol) afforded, after purification (SiO2: 0 to 30% isopropylamine in 1:1 hexane:EtOAc), 115 mg (18%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([I:13])=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:14])[C:3]=1[C:15](=O)[CH3:16].[OH:18][C:19]1[CH:28]=[C:27]([OH:29])[CH:26]=[CH:25][C:20]=1[C:21]([NH:23][NH2:24])=[O:22]>CS(C)=O>[CH3:14][C:4]1[C:3](=[C:15]([NH:24][NH:23][C:21](=[O:22])[C:20]2[CH:25]=[CH:26][C:27]([OH:29])=[CH:28][C:19]=2[OH:18])[CH3:16])[C:2](=[O:1])[N:6]([C:7]2[CH:12]=[CH:11][C:10]([I:13])=[CH:9][CH:8]=2)[N:5]=1
Reactant: NNC(=O)c1ccc(O)cc1O
Reactant: CC(=O)c1c(C)nn(-c2ccc(I)cc2)c1O
Solvent: CS(C)=O
Product: CC1=NN(c2ccc(I)cc2)C(=O)C1=C(C)NNC(=O)c1ccc(O)cc1O
Temperature: 85 °C
Yield: 94.1 %

Procedure:
1.03 g (3 mmol) of 1-(5-hydroxy-1-(4-iodophenyl)-3-methyl-1H-pyrazol-4-yl)-ethanone and 505 mg (3 mmol) of 2,4-dihydroxybenzoic hydrazide were dissolved in 50 ml of DMSO and heated at 85° C. for 9 hours with stirring. After cooling and evaporation of the solvent, the crude product was recrystallized from chloroform/ether to give 1.39 g of the desired product as a pale brown solid (yield 94%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[CH3:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.CO.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH3:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][NH:1][CH2:2][CH2:3][OH:4])=[CH:9][CH:8]=1
Reactant: NCCO
Reactant: COc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(CNCCO)cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A 1 L round bottom flask is charged with 2-aminoethanol (29 g, 213 mmol), 4-methoxybenzaldehyde (39 g, 639 mmol), methanol (250 mL) and acetic acid (75 mL) under a nitrogen atmosphere. The contents were cooled to 0° C. and sodium triacetoxyborohydride (50 g, 234 mmol) was added over a 20 minute period. The reaction mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure and partitioned between water (500 mL) and ethyl acetate (500 mL). The ethyl acetate layer was washed with 3N HCl (400 mL). The HCl layer is separated, cooled to 0° C., made basic using 6N NaOH and extracted with dichloromethane (2×100 mL). The dichloromethane layer was dried over sodium sulfate and concentrated under reduced pressure to yield the title compound a as an oil (20 g). 1H-NMR of the oil was consistent with the desired structure.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:20]([NH:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[O:21])[C:13](=[O:19])[C:14]3([CH3:18])[CH3:17])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>>[C:1]1([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:20]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21])[C:13](=[O:19])[C:14]3([CH3:17])[CH3:18])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(-c3ccccc3)cc2C(C)(C)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2ccc(-c3ccccc3)cc21
Yield: 95.6 %

Procedure:
1,1-Dimethylethyl N-((7-phenyl-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (169 mg, 401 μmol) was stirred in TFA (1 mL, 13462 μmol) at room temperature for 20 minutes. The reaction mixture was partitioned between water and EtOAc. The organic layer was separated, dried (MgSO4), and concentrated in vacuo to give the desired product as a yellow solid (140 mg). MS (m/z)=366.2 (M+H)+. Calculated for C21H19NO5 365.13.
Reaction SMILES: C[O:2][CH:3]=[CH:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][C:11](=[O:15])[NH:12]2)=[CH:7][CH:6]=1.Cl.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[O:15]=[C:11]1[CH2:10][CH2:9][C:8]2[C:13](=[CH:14][C:5]([CH2:4][CH:3]=[O:2])=[CH:6][CH:7]=2)[NH:12]1
Reactant: COC=Cc1ccc2c(c1)NC(=O)CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=CCc1ccc2c(c1)NC(=O)CC2
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a THF (11.8 mL) solution of the compound (590 mg) obtained in Step 50-1, concentrated HCl (8.9 mL) was added under ice cooling and the mixture was stirred at the same temperature for one hour. To the reaction mixture, a saturated K2CO3 was added and the solution was extracted with CHCl3. The organic layer was dried over MgSO4 and concentrated under reduced pressure to obtain (2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)acetaldehyde (0.51 g, colorless amorphous).
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[O:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[SH:30].N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3](=[O:21])[C:2]=1[S:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[O:23][CH3:22]
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Br
Reactant: COc1ccccc1S
Solvent: ClCCl
Solvent: C1CCNCC1
Product: COc1ccccc1SC1=C(O)CC(c2ccccc2)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared as described in General Method 6 from 1.5 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in example AAA), 1.6 mmol of 2-methoxybenzenethiol, and 1.6 mmol of piperidine in 25 mL of dichloromethane. The product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform, to give the title compound (m.p. 170-172° C. dec.). 1H NMR (DMSO-d6) δ 3.76 (bs, 5 H), 5.44 (dd, 1 H), 6.26 (t, 1 H), 6.85 (m, 1 H), 6.91 (t, 1 H), 7.34-7.50 (m, 10 H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([F:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[CH3:13][C:14]([S@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15].O>C1COCC1>[Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([F:11])=[C:6]([C:8](=[N:19][S@@:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18])[CH3:9])[CH:7]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cc(Br)c(F)cc1F
Solvent: C1CCOC1
Solvent: O
Product: CC(=N[S@](=O)C(C)(C)C)c1cc(Br)c(F)cc1F
Temperature: 70 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
To a solution of 1-(5-bromo-2,4-difluoro-phenyl)-ethanone (19 g, 64.7 mmoles, 1 equiv.) and (R)-2-methyl-propane-2-sulfinic acid amide (10.2 g, 84.1 mmoles, 0.76 equiv) in THF (0.3 M, 215 mL) is added Ti(OEt)4 (29.5 g, 129 mmoles, 2.0 equiv) in a single portion at ambient temperature. The reaction is heated to 70° C. and allowed to stir 18 h. The reaction is cooled to ambient temperature, and poured into water. The resulting suspension is filtered through a pad of diatomaceous earth and washed with ethyl acetate. The filtrate is collected and extracted with ethyl acetate. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue is purified by silica gel chromatography, eluting with a linear gradient of hexane to hexane:ethyl acetate (3:1) over 20 minutes to give the title compound (81% yield): MS (m/z): 338, 340 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:15](=O)[CH3:16])[CH:7]=[N:8][C:9]=2[O:10][CH2:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.[CH3:18][C:19]([S@:22]([NH2:24])=[O:23])([CH3:21])[CH3:20]>>[CH:1]1([C:4]2[CH:5]=[C:6]([CH:15]([NH:24][S@@:22]([C:19]([CH3:21])([CH3:20])[CH3:18])=[O:23])[CH3:16])[CH:7]=[N:8][C:9]=2[O:10][CH2:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cnc(OCC(F)F)c(C2CC2)c1
Product: CC(N[S@](=O)C(C)(C)C)c1cnc(OCC(F)F)c(C2CC2)c1
Yield: 73 %

Procedure:
The title compound is prepared in 73% yield (0.21 g, colorless oil) from 1-(5-cyclopropyl-6-(2,2-difluoroethoxy)pyridin-3-yl)ethanone (0.20 g, 0.82 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [OH:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>CN(C=O)C>[OH:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([O:5][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)=[O:4]
Reactant: CC(C)[C@H](O)C(=O)O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)[C@@H](O)C(C)C)cc1
Temperature: 0 °C

Procedure:
The title compound was prepared by reacting 14.652 g of (S)-2-hydroxy-3-methylbutyric acid with 21.21 g cesium carbonate and 20.396 of para-methoxybenzyl chloride in 300 mL of DMF at room temperature for 40 hours. The reaction mixture was poured into 400 mL of ice water, extracted with 5×150 mL ether, and the combined ether solution was washed with 5×100 mL water and 100 mL saturated brine. After drying over Na2SO4 and filtration, the filtrate was concentrated under reduced pressure to give 30.62 g of crude product, which was purified by flash chromatography on silica gel with 10˜30% ethyl acetate in hexanes to afford 29.12 g title compound as a colorless oil (99%). RF: 0.58 (30% EtOAc in hexane). 1H NMR (500 MHz, CDCl3): δ7.30˜7.33 (m, 2H), 6.90˜6.93 (m, 2H), 5.20 (AB d, 11.9 Hz, 1H), 5.15 (AB d, 11.9 Hz, 1H), 4.07 (d, 3.4 Hz, 1H), 3.83 (s, 3H), 2.68 (br s, 1H), 2.04˜2.13 (m, 1H), 1.01 (d, 7.0 Hz, 3H), 0.83 (d, 6.9 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:13][CH:14]=O)=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[O:16]1[C:20]2([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[O:16]1[C:20]2([CH2:25][CH2:24][N:23]([CH2:14][CH2:13][C:4]3[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[C:10]4[C:5]=3[CH:6]=[CH:7][CH:8]=[N:9]4)[CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: COc1ccc2ncccc2c1CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc2ncccc2c1CCN1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
0.72 g of (6-methoxyquinolin-5-yl)acetaldehyde and 0.75 g of 1,4-dioxa-8-azaspiro[4.5]decane were dissolved in 30 ml of methylene chloride. Then, 0.50 ml of acetic acid and 0.89 g of sodium triacetoxyborohydride were added to the reaction solution, and the obtained mixture was then stirred at room temperature overnight. Thereafter, a saturated sodium bicarbonate aqueous solution was added to the reaction solution, followed by extraction with methylene chloride. The extract was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate), so as to obtain 1.01 g of the subject compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH2:12])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][O:14][C:15]([C:17]1[S:18][C:19]([C:22](O)=[O:23])=[CH:20][CH:21]=1)=[O:16]>>[CH3:13][O:14][C:15]([C:17]1[S:18][C:19]([C:22](=[O:23])[NH:12][CH:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH3:11])=[CH:20][CH:21]=1)=[O:16]
Reactant: CC(N)c1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1ccc(C(=O)O)s1
Product: COC(=O)c1ccc(C(=O)NC(C)c2ccc([N+](=O)[O-])cc2)s1

Procedure:
The title compound was prepared in an analogous manner to that described in example 1, step 3 from 1-(4-nitro-phenyl)-ethylamine and thiophene-2,5-dicarboxylic acid monomethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](Cl)=[C:9]([NH2:12])[C:8]([F:13])=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:6]=1)=[O:4].[CH3:21][Sn](C)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH3:21])=[C:9]([NH2:12])[C:8]([F:13])=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:6]=1)=[O:4]
Reactant: C[Sn](C)(C)C
Reactant: COC(=O)c1nc(-c2ccc(Cl)cc2)c(F)c(N)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: COC(=O)c1nc(-c2ccc(Cl)cc2)c(F)c(N)c1C
Temperature: 130 °C
Yield: 38.2 %

Procedure:
4-Amino-3-chloro-6-(4-chlorophenyl)-5-fluoropyridine-2-carboxylic acid methyl ester (0.400 g, 1.269 mmol), tetramethylstannane (3.41 g, 19.04 mmol), and bis(triphenylphosphine)palladium(II) dichloride (0.089 g, 0.127 mmol) were combined and heated to 130° C. for 25 min in a CEM microwave reactor. The cooled reaction mixture was concentrated onto silica gel and purified by flash chromatography on silica gel (ethyl acetate/hexane gradient) to yield the title compound (0.143 g, 38.2% yield): 1H NMR (CDCl3) δ 7.88 (m, 2H), 7.41 (m, 2H), 4.41 (br s, 2H), 3.96 (s, 3H), 2.36 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([S:12](Cl)(=[O:14])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1.[CH3:27][NH:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1>>[CH3:27][N:28]([CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)[S:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:2](=[O:1])[N:3]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:4][CH2:5]2)[CH2:7][CH2:8]1)(=[O:14])=[O:13]
Reactant: CNCCc1ccccn1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)Cl)CC2
Product: CN(CCc1ccccn1)S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
This material was prepared in analogy to example 285 step B) from 1-Oxo-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-8-sulfonyl chloride and methyl-(2-pyridin-2-yl-ethyl)-amine. The reaction was subjected to work-up and purification after stirring for 2 h at room temperature. MS (ESI): 513.5 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[N:10][N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[C:24]([NH2:27])(=[O:26])[CH3:25].[H-].[Na+]>CN(C)C=O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:9]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:27][C:24](=[O:26])[CH3:25])[N:7]=3)=[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][N:11]3[N:10]=2)=[CH:18][CH:19]=1
Reactant: CC(N)=O
Reactant: Fc1ccc(-c2nn3c(c2-c2ccnc(Cl)n2)CCCC3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1nccc(-c2c(-c3ccc(F)cc3)nn3c2CCCC3)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3-(2-chloro-4-pyrimidinyl)-2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (i.e. the product of Step B) (0.10 g, 0.27 mmol), acetamide (0.08 g, 1.3 mmol), molecular sieves (4 Å, 3.0 g) in 4 mL of N,N-dimethylformamide was stirred at room temperature for 15 minutes. Sodium hydride (55% dispersion, 0.06 g, 1.3 mmol) was added, and the reaction mixture was heated at 100° C. overnight. The reaction mixture was then filtered though a pad of Celite® diatomaceous filter aid, and then concentrated under reduced pressure. The crude oil was purified by medium-pressure liquid chromatography on silica gel using 0-100% of ethyl acetate in hexanes as eluant to give 55 mg of the title compound, a compound of the present invention, as an oil.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:18])[C@H:8]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27]>C(#N)C>[C:2]([O:6][C:7](=[O:18])[C@H:8]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[NH:9][CH2:27][CH:26]=[CH2:25])([CH3:4])([CH3:5])[CH3:3]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCN[C@@H](CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
L-aspartic acid di-tert-butyl ester hydrochloride (1.0 g, 3.5 mmol) was dissolved in acetonitrile (7 ml), potassium carbonate (0.98 g, 7.1 mmol) and allyl bromide (0.29 mL, 3.4 mmol) were added, and the mixture was stirred at room temperature overnight. The insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5) to give N-allyl-L-aspartic acid di-tert-butyl ester (0.50 g, 1.8 mmol).
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:22][CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[CH2:1]([C:5]1[C:9]([CH2:10][NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH:22][CH:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:18])=[CH:14][N:13]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: NC1CCOCC1
Reactant: CCCCc1noc(C)c1CNc1ccc(C(=O)O)cn1
Product: CCCCc1noc(C)c1CNc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 86 %

Procedure:
As described for example 19b, 6-[(3-butyl-5-methyl-isoxazol-4-ylmethyl)-amino]-nicotinic acid (70 mg, 0.24 mmol) instead of 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid, was converted, using 4-aminotetrahydropyran instead of rac-2,2,2-trifluoro-1-(methyl)ethylamine, to the title compound (77 mg, 86%) which was obtained as an off white foam after purification by chromatography (silica, heptane:ethyl acetate=1:0 to 2:1). MS: m/e=373.3 [M+H]+.