Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:21]3[CH:20]=[CH:19][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3ccc4ccccc4c3)cccc2c1N
Yield: 84.2 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.33 mmol) and 2-naphthalene boronic acid (167 mg, 0.97 mmol) were reacted to afford the title compound (99 mg, 86.9% yield) as a pale-yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.58 (br, 1H), 8.11 (s, 1H), 7.83-7.99 (m, 6H), 7.76 (dd, J=8.0 Hz, J′=7.1 Hz, 1H), 7.46-7.55 (m, 2H), 3.46 (q, J=6.7 Hz, 2H), 1.66 (m, J=7.2 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H) MS APCI, m/z=357 (M+H) HPLC 2.11 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd].[C]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][CH:13]([OH:16])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(N2CCC(O)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(N2CCC(O)CC2)cc1
Yield: 92.5 %

Procedure:
1.0 g (4.5 mmol) of 1-(4-nitrophenyl)-4-hydroxypiperidine are hydrogenated in a conventional manner with Pd/carbon in methanol. 0.8 g of 1-(4-aminophenyl)-4-hydroxypiperidine is obtained. Melting point 176° C.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:18]1[N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:21]2[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:20]=2[N:19]=1)[CH2:9][O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:11]([O:10][CH2:9][C@H:8]([NH2:7])[C:18]1[N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:21]2[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:20]=2[N:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)c1nc2ccc(F)cc2n1-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](COCc1ccccc1)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.5 %

Procedure:
To a solution of [(R)-2-benzyloxy-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester (0.797 g, 1.7 mmol) in DCM (9 mL) was added TFA (5 mL) and the mixture was stirred at RT for 2 h. The volatiles were removed under reduced pressure and the resulting residue partitioned between DCM and a saturated aqueous solution of NaHCO3. The two phase system was stirred for 10 min, then the organic fraction was dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford the title compound (298 mg, 49%). LCMS (Method J): RT 2.02 min [M+H]+ 362.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:24]=[CH:23][C:19]3[O:20][CH2:21][O:22][C:18]=3[CH:17]=2)[C:7]=1[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:5])[CH3:2].[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:36]3[CH:37]=[CH:38][C:33]([C:32]([F:43])([F:42])[F:31])=[CH:34][CH:35]=3)[CH:13]=2)[N:8]([C:16]2[CH:24]=[CH:23][C:19]3[O:20][CH2:21][O:22][C:18]=3[CH:17]=2)[C:7]=1[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc2c(c1)OCO2
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cc3)ccc2n1-c1ccc2c(c1)OCO2

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 1-(benzo[1,3]dioxol-5-yl)-2-ethoxycarbonylmethyl-5-hydroxyindole-3-carboxylic acid ethyl ester (189 mg, 0.46 mmol, see step (b) Example 6) and 4-trifluoromethylphenylboronic acid (129 mg, 0.68 mmol). Yield 175 mg, 68%.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].Cl[CH2:14][CH2:15][CH2:16][O:17][CH3:18].[I-].[Na+].Cl>CS(C)=O>[OH:1][C:2]1[C:9]([O:10][CH2:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COCCCCl
Reactant: O=Cc1cccc(O)c1O
Agent: Cl
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Product: COCCCOc1cccc(C=O)c1O
Reaction time: 1 h

Procedure:
A solution of 5.00 g of 2,3-dihydroxybenzaldehyde in 10 ml of dimethyl sulphoxide is added dropwise at room temperature to the suspension of 3.77 g of sodium hydride dispersion (55%) in 28 ml of dimethyl sulphoxide. The reaction mixture is stirred over 1 hour and then admixed with a solution of 3.81 g of 1-chloro-3-methoxypropane in 2 ml of dimethyl sulphoxide. After 2 hours, 0.50 g of sodium iodide is added. After 16 hours, the reaction mixture is poured onto water, acidified to pH 2 with 4N HCl and extracted with dichloromethane (7×). The combined organic phases are washed with 0.5N HCl (2×), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=023 (95:5 dichloromethane-methanol); Rt=3.60.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[CH3:17])[C:11]([OH:13])=[O:12])=[C:5]([CH3:7])[N:6]=1.IC1NC([CH:24]2C[CH2:27][O:26][CH2:25]2)=NC=1C.IC1NC(C)=NC=1C>>[CH3:17][C:16]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[C:4]1[NH:3][C:2]([CH:1]2[CH2:24][CH2:25][O:26][CH2:27]2)=[N:6][C:5]=1[CH3:7]
Reactant: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Reactant: Cc1nc(C2CCOC2)[nH]c1I
Agent: Cc1nc(C)c(I)[nH]1
Product: Cc1ccc(C(=O)O)cc1-c1[nH]c(C2CCOC2)nc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.7, except 5-iodo-4-methyl-2-(tetrahydrofuran-3-yl)-1H-imidazole (compound 171.1) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:20][C:21]1[CH:33]=[CH:32][C:31]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:34])[C:23]=2[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:8][NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:20][C:21]1[CH:33]=[CH:32][C:31]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:34])[C:23]=2[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2-c2ccc(O)cc21
Reactant: O=C(CCCCCCCBr)NOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCCCCCCOc1ccc2c(c1)C(=O)c1ccccc1-2)NOCc1ccccc1

Procedure:
In a manner analogous to that of example 1(b), 8-bromo-octanoic acid benzyloxy-amide (example 1(a); 0.3 g, 1.3 mmol) was reacted with 2-hydroxy-fluoren-9-one (0.30 g, 1.5 mmol) in the presence of potassium carbonate (0.21 g, 1.5 mmol) and dimethyl formamide (10 ml) to give 8-(9-oxo-9H-fluoren-2-yloxy)-octanoic acid benzyloxyamide as an almost colorless wax (yield 0.43 g, 63%; purified by column chromatography using silica gel and ethyl acetate: heptane=1:1 as eluent). MS (M−H+)=442.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:8][O:9][C:10]=2[C:11]([F:14])([F:13])[F:12])[N:3]=[CH:2]1.[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)=[N:8][O:9][C:10]=3[C:11]([F:14])([F:12])[F:13])[N:3]=[CH:2]2)=[CH:24][CH:23]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: FC(F)(F)c1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: Fc1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Yield: 52 %

Procedure:
As described for Example 1j, 4-(1H-imidazol-4-yl)-3-phenyl-5-trifluoromethyl-isoxazole (100 mg, 0.36 mmol) was converted, using 4-fluorophenylboronic acid instead of phenylboronic acid, to the title compound (70 mg, 52%) which was obtained as a white solid. MS: m/e=374.2 [M+H]+.
Reaction SMILES: Br[CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[N:20])[CH:14]=1)[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[F:21][C:22]1[CH:23]=[C:24]([C@H:29]([CH:34]2[CH2:37][NH:36][CH2:35]2)[C:30]([F:33])([CH3:32])[CH3:31])[CH:25]=[C:26]([F:28])[CH:27]=1>>[C:19]([C:15]1[CH:14]=[C:13]([C@@H:2]([N:36]2[CH2:37][CH:34]([C@@H:29]([C:24]3[CH:23]=[C:22]([F:21])[CH:27]=[C:26]([F:28])[CH:25]=3)[C:30]([F:33])([CH3:31])[CH3:32])[CH2:35]2)[C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=2)[CH:18]=[CH:17][CH:16]=1)#[N:20]
Reactant: COC(=O)c1ccc(C(Br)c2cccc(C#N)c2)cc1
Reactant: CC(C)(F)[C@H](c1cc(F)cc(F)c1)C1CNC1
Product: COC(=O)c1ccc([C@@H](c2cccc(C#N)c2)N2CC([C@@H](c3cc(F)cc(F)c3)C(C)(C)F)C2)cc1

Procedure:
The title compound was prepared methyl 4-[bromo(3-cyanophenyl)methyl]benzoate and 3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidine (Step 1, Preparation 15) by the procedure described in Step 2 of Preparation 15. The product was purified by chromatography on an AD column using 30% isopropanol-heptane to afford the title compound; 1H-NMR(CDCl3) δ 1.25 (t, J=22 Hz, 6H), 2.33 (t, J=6.5 Hz, 1H), 2.83-2.89 (m, 2H), 3.05-3.22 (m, 2H), 3.65 (m, 1H), 3.92 (s, 3H), 4.34 (s, 1H), 6.68-6.71 (m, 3H), 7.21-7.8 (m, 8H); Mass Spectrum: m/e=493 (M+1).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([O:18]CC)=O)[CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21]1([Mg]Br)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>O1CCCC1.CCOCC>[CH:21]1([C:16]([CH:13]2[CH2:12][CH2:11][N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])[CH2:15][CH2:14]2)=[O:18])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Br[Mg]C1CCCCC1
Reactant: CCOC(=O)C1CCN(S(=O)(=O)c2ccccc2)CC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(C1CCCCC1)C1CCN(S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.8 %

Procedure:
To a solution of 25.1 g (0.085 mole) of 1-(phenylsulfonyl) -4-piperidine-carboxylic acid, ethyl ester in 500 ml of dry tetrahydrofuran cooled to 0° C. and under an atmosphere of nitrogen, was added 95 ml of a 2 molar solution(0.19 mole) of cyclohexylmagnesium bromide in ether. The mixture was stirred for 2 hr at ambient temperature and then was quenched on an icy solution of ammonium chloride. The mixture was extracted with methylene chloride. The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo to give a semisolid material. This was recrystallized from ethanol to give 8.50 g (29.8% yield) of title compound as a white, crystalline solid, m.p. 141°-143° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH:11]([O:14][CH2:15][CH2:16][NH2:17])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O>[CH:11]([O:14][CH2:15][CH2:16][NH:17][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)OCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(C)OCCNc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Yield: 80.9 %

Procedure:
2 g of para-fluoronitrobenzene was added to a solution of 20 ml of N-methylpyrrolidinone (NMP), 1.75 g of 2-aminoethyl isopropyl ether and 2.35 g of K2CO3. The reaction medium was heated at 60° C. for 8 hours and, after cooling to room temperature, was poured into a water+ice mixture. A yellow precipitate formed and was filtered off. The precipitate was reslurried in water and then dried over P2O5.2.57 g of N-(2-isopropoxyethyl)-4-nitro-1-aminobenzene (7) were obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]3[N-:14][N:15]=[N:16][N:17]=3)[C:11](=[O:12])[N:6]2[CH:5]=[CH:4][CH:3]=1.[K+].C(O)(=O)C>O.C1COCC1>[CH3:1][C:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]3[NH:14][N:15]=[N:16][N:17]=3)[C:11](=[O:12])[N:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccn2c(=O)c(-c3nnn[n-]3)cnc12
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cccn2c(=O)c(-c3nnn[nH]3)cnc12
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
The free acid was prepared from pemirolast potassium (15.8 g; Chemtronica AB) by dissolution in a mixture of water (100 mL) and THF (80 mL) at room temperature and acidification with acetic acid (1 eq.; 17.5 g; 20% aq.). Firstly, ca. 1 mL of acetic acid was added and the obtained thin slurry was equilibrated for about 30 minutes. Thereafter the rest of the acetic acid was added slowly. The resultant thick slurry was diluted with water (50 mL) and equilibrated for 2 hours and then filtered and washed with water. The resultant solid was dried at 40° C. and under reduced pressure for 5-10 hours to yield 7.5 g of sub-title compound.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:20])=[CH:15][N:14]=3)[CH:11]=2)[N:6]([C:27](=[O:29])[CH3:28])[C@@H:5]([CH3:30])[CH2:4]1.Br[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][N:33]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([NH:2][C@H:3]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:13]4[CH:18]=[CH:17][C:16]([C:19]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)=[O:20])=[CH:15][N:14]=4)[CH:11]=3)[N:6]([C:27](=[O:29])[CH3:28])[C@@H:5]([CH3:30])[CH2:4]2)=[N:33][CH:34]=1
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCOCC4)cn3)cc2[C@H](N)C[C@@H]1C
Reactant: Clc1ccc(Br)nc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCOCC4)cn3)cc2[C@H](Nc2ccc(Cl)cn2)C[C@@H]1C
Temperature: 120 °C
Yield: 29 %

Procedure:
1-((2S,4R)-4-amino-2-methyl-6-(5-(morpholine-4-carbonyl)pyridin-2-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone hydrochloride (for a preparation see Intermediate 65) (100 mg, 0.232 mmol), 2-bromo-5-chloropyridine (89 mg, 0.464 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (18.3 mg, 0.046 mmol), tris(dibenzylideneacetone)dipalladium(0) (21.3 mg, 0.023 mmol) and sodium tert-butoxide (44.6 mg, 0.464 mmol) were combined in 1,4-dioxane (2 mL) and the mixture degassed over a period of 15 mins, before being heated under microwave irradiation to 120° C. for 25 mins. A further portion of 2-bromo-5-chloropyridine (89 mg, 0.464 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (18.3 mg, 0.046 mmol), tris(dibenzylideneacetone)dipalladium(0) (21.3 mg, 0.023 mmol), sodium tert-butoxide (44.6 mg, 0.464 mmol) and 1,4-dioxane (1 mL) were added and the mixture degassed over a period of 15 mins, before being heated under microwave irradiation to 120° C. for 25 mins. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate (50 mL) and DCM (3×50 mL). The organics were combined, dried by passing through a hydrophobic frit and concentrated in vacuo to give a residue which was purified by MDAP (HpH) to give 1-((2S,4R)-4-((5-chloropyridin-2-yl)amino)-2-methyl-6-(5-(morpholine-4-carbonyl)pyridin-2-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone (34 mg, 0.067 mmol, 29% yield) LCMS: (Formate, 2 min), Rt=0.83 mins, MH+506.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][C:11](O)=[O:12])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.[Pd]>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][OH:12])[CH3:2]
Reactant: CCc1ccccc1C=CC(=O)O
Agent: [Pd]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCc1ccccc1CCCO
Temperature: 0 °C
Reaction time: 14 h

Procedure:
3-(2-Ethyl-phenyl)-acrylic acid (17.00 g, 96.60 mmol) in THF was mixed with Pd/C (1.50 g) and hydrogenated at 50 psi for 6 hours. The resulting mixture was filtered through a pad of celite and the filtrate was concentrated. The residue was dissolved in THF and cooled to 0° C. LAH (100.00 mL, 1.0 M in THF, 0.10 mol) was added and the reaction mixture was stirred for 14 hours. The resulting mixture was quenched with NaOH and extracted with Et2O (3×250 mL). The combined organic extracts were washed with H2O (3×150 mL) and brine (1×150 mL), then dried over MgSO4 and concentrated to give the title alcohol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[N:17]=[CH:16][C:15]2[C:18]([CH3:26])([CH3:25])[C:19](=[O:24])[N:20]([CH:21]3[CH2:23][CH2:22]3)[C:14]=2[CH:13]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:11][C:12]1[N:17]=[CH:16][C:15]2[C:18]([CH3:26])([CH3:25])[C:19](=[O:24])[N:20]([CH:21]3[CH2:22][CH2:23]3)[C:14]=2[CH:13]=1)=[O:7]
Reactant: CC1(C)C(=O)N(C2CC2)c2cc(N)ncc21
Reactant: O=C(O)c1ccnc(Cl)c1
Product: CC1(C)C(=O)N(C2CC2)c2cc(NC(=O)c3ccnc(Cl)c3)ncc21

Procedure:
Prepared in analogy to example 26 from 2-chloroisonicotinic acid and 6-amino-1-cyclopropyl-3,3-dimethyl-1H-pyrrolo[3,2-c]pyridin-2(3H)-one (example 79c). The title compound was obtained as light yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14](=O)[CH3:15])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:23][S@@:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22])[CH3:15])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: CC(=O)c1ccc(OCC(F)(F)F)c(Cl)c1
Reactant: CC(C)(C)[S@](N)=O
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(OCC(F)(F)F)c(Cl)c1
Yield: 58 %

Procedure:
The title compound is prepared in 58% yield (940 mg, clear colorless oil) from 1-(3-chloro-4-(2,2,2-trifluoroethoxy)phenyl)ethanone (390 mg, 1.6 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[S:10])[NH2:9])=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:14][C:15](=O)[C:16]([OH:18])=[O:17].Cl>O.CO>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:10][CH:14]=[C:15]([C:16]([OH:18])=[O:17])[N:9]=2)=[CH:4][CH:3]=1
Reactant: NC(=S)c1ccc(O)cc1
Reactant: O=C(O)C(=O)CBr
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1csc(-c2ccc(O)cc2)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4-Hydroxybenzenecarbothioamide (1.53 g, 10 mmol) and potassium hydroxide (1.50 g, 26.8 mmol) were dissolved in a mixture of 60 ml of water and 15 ml of methanol. A solution of bromopyruvic acid (1.67 g, 10 mmol) in 10 ml of methanol was added dropwise at room temperature. The resulting mixture was heated to reflux for 1.5 h, cooled to room temperature, poured into 100 ml of water and adjusted with 0.2N HCl solution to pH2. The mixture was placed in a refrigerator for 15 h. The title compound was obtained by filtration as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:13]([O:20][CH3:21])(=[O:19])[CH2:14][C:15]([O:17][CH3:18])=[O:16]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]([CH2:7][N+:8]([O-:10])=[O:9])[CH:14]([C:13]([O:20][CH3:21])=[O:19])[C:15]([O:17][CH3:18])=[O:16])=[CH:4][CH:3]=1
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])C=Cc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: COC(=O)C(C(=O)OC)C(C[N+](=O)[O-])c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 48 h

Procedure:
[(S,S)-N-(pentamethylbenzenesulfonyl)-1,2-diphenyl-ethylenediamine](hexamethylbenzene)ruthenium (13.7 mg, 0.02 mmol, S/C=50), 4-chloro-β-nitrostyrene (1.0 mmol), dimethyl malonate (114 μl, 1.0 mmol) and toluene (1 ml) were added into Schlenk (20 ml) under an argon atmosphere, and stirred at −20° C. for 48 hours. The reaction solution was purified by flash column chromatography (hexane/acetone=80/20, SiO2), showing that the isolation yield of the product was 24%. The optical purity was measured by HPLC (CHIRALPACK AD manufactured by Daicel Co., Ltd., hexane:2-propanol=90:10, flow rate 0.5 ml/min, detection by 210 nm), resulting to 95% ee.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[C:17](O)(=O)[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:14][C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[N:16][N:15]=1
Reactant: O=C(O)c1ccncc1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccncc2)o1
Yield: 20 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using isonicotinic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane:methanol=40:50:10:0 to 0:90:0:10, 57 mg, 20%) which was obtained as a white foam. MS: m/e=305.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH:11]1([C:14]2[CH:15]=[C:16]([CH3:26])[C:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[N:18][CH:19]=2)[CH2:13][CH2:12]1>>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([N:23]2[CH2:24][CH2:25][N:20]([C:17]3[C:16]([CH3:26])=[CH:15][C:14]([CH:11]4[CH2:12][CH2:13]4)=[CH:19][N:18]=3)[CH2:21][CH2:22]2)=[O:10])=[N:6][CH:7]=1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: O=C(O)c1cnc(Br)cn1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2cnc(Br)cn2)CC1
Yield: 65.6 %

Procedure:
Using 5-bromopyrazine-2-carboxylic acid (1 g) and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (1.07 g) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Preparation Example 118, the title compound (1.3 g) was obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:13]([O:15]CC3C=CC=CC=3)=[O:14])[C:8](=[O:27])[C:7]3=[CH:28][N:29]([S:30]([C:33]4[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[C:5]([C:6]=23)=[N:4][CH:3]=1.[CH3:40][Al](C)C>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.O1CCOCC1>[CH3:25][C:23]([CH3:24])([CH3:26])[C@@H:12]([N:9]1[C:8](=[O:27])[C:7]2=[CH:28][N:29]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:31])=[O:32])[C:5]3[C:6]2=[C:11]([C:2]([CH3:40])=[CH:3][N:4]=3)[CH2:10]1)[C:13]([OH:15])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)n2cc3c4c(c(Cl)cnc42)CN([C@@H](C(=O)OCc2ccccc2)C(C)(C)C)C3=O)cc1
Reactant: C[Al](C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc3c4c(c(C)cnc42)CN([C@@H](C(=O)O)C(C)(C)C)C3=O)cc1
Temperature: 120 °C
Yield: 439.1 %

Procedure:
(R)-Benzyl 2-(6-chloro-3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3,3-dimethylbutanoate (10 mg, 0.018 mmol), Pd(Ph3P)4 (10 mg, 0.009 mmol), and dioxane (1 mL) were combined in a 2 mL microwave vial. The mixture was purged with nitrogen, and trimethylaluminum (2.0M/toluene, 0.053 mL, 0.11 mmol) was added. The vial was sealed and the reaction mixture was heated in a Biotage Initiator™ microwave for 1 h at 120° C. The reaction was repeated three times with an increased amount of (R)-benzyl 2-(6-chloro-3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3,3-dimethylbutanoate (30 mg) in each reaction. The reaction mixtures were combined and the resulting mixture was concentrated and purified by preparative HPLC (30-70% AcCN/H2O with 0.035% TFA) to afford the title compound as a yellow oil (36 mg, 44%). 1H NMR (500 MHz, CD3OD) δ 1.21 (s, 9H), 2.30 (s, 3H), 2.36 (s, 3H), 4.94 (s, 1H), 5.07 (d, J=18.6 Hz, 1H), 5.21 (d, J=19.0 Hz, 1H), 7.36 (d, J=8.3 Hz, 2H), 8.04 (d, J=4.9 Hz, 2H), 8.10 (s, 1H), 8.22 (s, 1H). [M+H] calc'd for C23H25N3O5S, 456; found, 456