Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[N:12]1.[C:20]([NH2:24])(=[O:23])[CH:21]=[CH2:22]>N1C=CC=CC=1.CO.C(=O)(O)[O-].[Na+]>[N:11]1([CH2:10][C:2]2[N:1]([CH2:22][CH2:21][C:20]([NH2:24])=[O:23])[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[N:12]1
Reactant: c1ccc2[nH]c(Cn3nnc4ccccc43)nc2c1
Reactant: C=CC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: NC(=O)CCn1c(Cn2nnc3ccccc32)nc2ccccc21
Yield: 33.3 %

Procedure:
1-(1H-Benzimidazol-2-ylmethyl)-1H-benzotriazole (300 mg, 1.20 mmol) and acrylamide (86 mg, 1.20 mmol) were dissolved in pyridine (5 mL). Triton B (40% by weight in methanol, 0.010 mL, 0.024 mmol) was added at room temperature. The temperature was slowly raised to reflux. The reaction mixture was stirred at reflux overnight under nitrogen. The solvent was stripped under reduced pressure. The residue was taken up in aqueous saturated sodium bicarbonate solution and extracted with EtOAc (4×100 mL). The combined organic extracts were dried over magnesium sulfate, filtered and evaporated. The residue was purified by chromatography (EtOAc/MeOH 12:1 to 4:1) to give 128 mg (33%) of the title compound as a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C@H:4]([NH:12][S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[NH:22]([C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[CH2:23][C:24](O)=[O:25].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:8]([O:7][C:5](=[O:6])[C@@H:4]([NH:12][S:13]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)(=[O:15])=[O:14])[CH2:3][NH:2][C:24](=[O:25])[CH2:23][NH:22][C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)CNC(=O)OCc1ccccc1)NS(=O)(=O)c1ccccc1
Reaction time: 8 h

Procedure:
Amine 1-5 (0.42 g, 1.25 mmol), Cbz—Gly—OH (288 mg, 1.38 mmol), NMM (0.55 mL, 5.0 mmol) and BOP (829 mg, 1.88 mmol) were combined in 6 mL DMF. After stirring overnight the solvent was evaporated, the residue was taken up in EtOAc, the organic solution was washed with water (2×), 5% KHSO4, sat. NaHCO3 and brine, dried (MgSO4), filtered and concentrated. Flash chromatography (silica, 60% EtOAc/hexane) provided 5-6 as a white glass.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH3:21])=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:12])[N:3]=2)[CH3:21])=[CH:16][CH:15]=1
Reactant: CNc1ccc(F)cc1
Reactant: Cc1nc(Cl)c2ccccc2n1
Product: Cc1nc(N(C)c2ccc(F)cc2)c2ccccc2n1

Procedure:
The title compound was prepared from 4-chloro-2-methyl-quinazoline (178.6 mg, 1.0 mmol) and (4-fluoro-phenyl)-methyl-amine (125 mg, 2.52 mmol) by a procedure similar to Example 28 (46.8%). 1H NMR (CDCl3): 7.76 (dd, J=0.9 Hz, J=8.3 Hz, 1H), 7.58-7.52 (m,1H), 7.16-7.00 (m, 6H), 3.60 (s, 3H), 2.73 (s, 3H),
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26]C)[CH2:6][N:7]1[CH:11]=[CH:10][N:9]([CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)[C:8]1=[S:22].B(Br)(Br)Br.O>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[OH:26])[CH2:6][N:7]1[CH:11]=[CH:10][N:9]([CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)[C:8]1=[S:22]
Reactant: COc1ccc(Cn2ccn(C3CCc4ccccc4C3)c2=S)cc1OC
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(Cn2ccn(C3CCc4ccccc4C3)c2=S)cc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 0.1 %

Procedure:
A solution of 3-(3,4-dimethoxybenzyl)-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione (900 mg, 2.37 mol), prepared as in Example 15, in methylene chloride was cooled to 0° C. under nitrogen and then boron tribromide (1M, 7.1 mL, 7.1 mmol) in an additional 10 mL of methylene chloride was added dropwise. The mixture was allowed to cool to room temperature, stirred for 16 hours and then slowly added to water. The organic layer was separated, washed with brine, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography on silica gel eluting with methylene chloride/methanol (96:4) and then crystallized from methanol/ethanol/hexane to give 3-(3,4-dihydroxybenzyl)-1-(1,2,3,4-tetrahydronaphthalen-2-yl)-1,3-dihydroimidazole-2-thione (520 mg), m.p. 173°-174° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:15][CH3:16])[CH:8]=2)[N:3]=1>[Pd].CO.O1CCCC1>[NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:15][CH3:16])[CH:8]=2)[N:3]=1
Reactant: COc1ccc2nc(N)c([N+](=O)[O-])cc2c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2nc(N)c(N)cc2c1
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
10 mg of palladium on charcoal (10% Pd) are added to a solution of 0.64 g of 2-amino-3-nitro-6-methoxyquinoline (compound B3) in 40 ml of methanol/tetrahydrofurane 1:1. After hydration for 0.5 h, the catalyst is filtered off and the filtrate is concentrated in vacuo. 0.38 g of the title compound are obtained as light yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[C:18]([C@@H:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[C:34]([C:35]([F:38])([F:36])[F:37])=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:24][CH:23]=1)([OH:20])=[O:19]
Reactant: N[C@@H](Cc1ccc(Oc2ncccc2C(F)(F)F)cc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(Oc2ncccc2C(F)(F)F)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 109c, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(3-trifluoromethyl-pyridin-2-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) in DMSO to provide the title compound in good yield.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]([OH:5])[CH3:4].[H-].[Na+].Cl[C:11]1[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[N:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(P(N(C)C)(N(C)C)=O)C>[F:1][C:2]([F:7])([F:6])[CH:3]([CH3:4])[O:5][C:11]1[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[N:15][CH:16]=1
Reactant: N#Cc1ccc(Cl)cn1
Reactant: CC(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(Oc1ccc(C#N)nc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 90.1 %

Procedure:
Add 1,1,1-trifluoro-2-propanol (971 mg, 8.5 mmol) slowly to a slurry of sodium hydride (205 mg, 60% mineral oil, washed with hexane) in HMPA (8 mL) under nitrogen at 0° C. Allow the slurry to warm to ambient temperature and stir for 5 min. Add 5-chloro-pyridine-2-carbonitrile (590 mg, 4.2 mmol), then heat the mixture at 90° C. for 4 h. Adjust the mixture to pH 9 with sodium carbonate then extract with diethyl ether (2×50 mL). Dry the combined organic extracts over Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (95/5 to 80/20) to obtain the desired intermediate (818 mg, 89%). GC-MS m/z: 216 (M+).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N+:33]([C:36]1[C:41]2[O:42][CH2:43][O:44][C:40]=2[C:39]([C:45](O)=[O:46])=[CH:38][CH:37]=1)([O-:35])=[O:34].C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:8][N:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:45]([C:39]2[C:40]3[O:44][CH2:43][O:42][C:41]=3[C:36]([N+:33]([O-:35])=[O:34])=[CH:37][CH:38]=2)=[O:46])[CH2:3][CH2:4]1
Reactant: CN1CCC(N)CC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c2c1OCO2
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: CN1CCC(NC(=O)c2ccc([N+](=O)[O-])c3c2OCO3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.8 %

Procedure:
4-Amino-1-methylpiperidine (Fluorochem; 325 mg, 2.84 mmol), HATU (1.09 g, 2.84 mmol) and 7-nitrobenzo[1,3]dioxole-4-carboxylic acid (WO 2003082827; 400 mg, 1.89 mmol) were stirred in DMF (5 mL) and diisopropylethylamine (0.99 ml, 5.68 mmol) added. The mixture was stirred for 2 hours at room temperature. The reaction mixture was loaded on to an SCX column, which was subsequently washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and the solid suspended in methanol and filtered off to yield the title compound as a yellow solid (295 mg, 51%).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][C:7]1([C:13]#[N:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl.[C:19]([C:21]1[CH:34]=[CH:33][C:24]([CH2:25][N:26]2[C:30]([CH2:31]Cl)=[CH:29][N:28]=[CH:27]2)=[CH:23][CH:22]=1)#[N:20].C(N(C(C)C)CC)(C)C>C(#N)C>[C:19]([C:21]1[CH:22]=[CH:23][C:24]([CH2:25][N:26]2[C:30]([CH2:31][N:10]3[CH2:11][CH2:12][C:7]([CH2:6][C:5]4[CH:15]=[CH:16][CH:17]=[C:3]([CH3:2])[CH:4]=4)([C:13]#[N:14])[CH2:8][CH2:9]3)=[CH:29][N:28]=[CH:27]2)=[CH:33][CH:34]=1)#[N:20]
Reactant: N#Cc1ccc(Cn2cncc2CCl)cc1
Reactant: Cc1cccc(CC2(C#N)CCNCC2)c1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(CC2(C#N)CCN(Cc3cncn3Cc3ccc(C#N)cc3)CC2)c1

Procedure:
A solution of 4-(3-methylbenzyl)piperidine-4-carbonitrile hydrochloride salt (129 mg, 0.51 mmol), 1-(4-cyanobenzyl)-5-chloro-methylimidazole hydrochloride salt (135 mg, 0.51 mmol; Example 52, Step D), and diisopropylethylamine (440 mL, 2.5 mmol) in anhydrous acetonitrile (5 mL) was heated under reflux overnight. The resultant mixture was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with a 85:15 v/v mixture of chloroform saturated with ammonia gas and hexane. After collection and concentration of appropriate fractions, the residue was triturated with a mixture of ethyl acetate and diethyl ether. The white solid precipitated was filtered to provide the title compound.
Reaction SMILES: C([N:8]1[CH:12]=[N:11][C:10]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[N:15]([CH:29]3[CH2:31][CH2:30]3)[C:14]=2[C:32]([N:34]2[CH2:39][CH2:38][CH:37]([N:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[CH2:36][CH2:35]2)=[O:33])=[N:9]1)C1C=CC=CC=1.[H][H]>[Pd].CO.Cl>[CH:29]1([N:15]2[C:14]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([N:40]4[CH2:41][CH2:42][CH2:43][CH2:44]4)[CH2:38][CH2:39]3)=[O:33])=[C:13]([C:10]3[N:11]=[CH:12][NH:8][N:9]=3)[N:17]=[C:16]2[C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25]([F:27])([F:26])[F:28])=[CH:22][CH:23]=2)[CH2:31][CH2:30]1
Reactant: [H][H]
Reactant: O=C(c1c(-c2ncn(Cc3ccccc3)n2)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1)N1CCC(N2CCCC2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=C(c1c(-c2nc[nH]n2)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1)N1CCC(N2CCCC2)CC1
Yield: 77.6 %

Procedure:
A solution of 0.07 g (0.1 mmol) of [5-(1-benzyl-1H-[1,2,4]triazol-3-yl)-3-cyclopropyl-2-(4-trifluoromethoxy-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (intermediate 12) and a generous spatula of 10% palladium on activated charcoal in 1 ml of MeOH made acidic by addition of a few drops of 25% HCl was stirred under one atmosphere of hydrogen for 16 h. Then, the mixture was filtered over Hyflo, concentrated and the residue taken up in CH2Cl2. The organic phase was washed with saturated sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. Purification by flash column chromatography [CH2Cl2/MeOH 9:1 to 8:2] afforded 0.04 g (64%) of the title compound as a colorless amorphous solid. MS: 516.2 (MH+).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[O:15][CH:14]=[N:13][CH:12]=3)[NH:10][C:4]=2[CH:3]=1.[Cl:16]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([Cl:16])=[C:9]([C:11]3[O:15][CH:14]=[N:13][CH:12]=3)[NH:10][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Brc1cc2[nH]c(-c3cnco3)cc2cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1c(-c2cnco2)[nH]c2cc(Br)ncc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.1 %

Procedure:
5-(6-Bromo-1H-pyrrolo[3,2-c]pyridin-2-yl)oxazole (Preparation 139, 80 mg 0.303 mmole) was dissolved in DMF (0.8 mL) and N-chlorosuccinimide (40.4 mg 0.303 mmole) was added. The reaction was stirred at room temperature for 48 hours. The reaction was diluted with ethyl acetate (20 mL) and washed with water (3×7 mL) and brine. The combined aqueous layers were back-washed with ethyl acetate. The organic layers were dried (MgSO4) and concentrated in vacuo to afford the title compound (86 mg). 1H-NMR (d6-acetone, 500 MHz): 7.66 (d, J=0.95 Hz, 1H), 7.84 (s, 1H), 8.40 (s, 1H), 8.66 (d, J=0.63 Hz, 1H), 11.62 (br s, 1H, NH).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2]1.[C:12]([OH:17])(=[O:16])[C:13]([CH3:15])=[CH2:14].C(N(CC)CC)C>C(Cl)Cl>[C:12]([O:17][CH2:2][CH:3]([OH:1])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: c1ccc(OCC2CO2)cc1
Reactant: C=C(C)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OCC(O)COc1ccccc1
Temperature: 60 °C
Yield: 85 %

Procedure:
In a two neck flask equipped with a condenser under nitrogen atmosphere were placed 15.017 g (0.1 mol) of 1,2-epoxy-3-phenoxypropane, 9.039 g (0.105 mol) of methacrylic acid, 1.35 g (0.013 mol) of triethylamine and 30 mg of BHT. The reaction mixture was stirred at 60° C. 1H NMR showed reaction completion at 24 hours. Reaction mixtures was dissolved in methylene chloride and extracted with saturated solution of sodium hydroxide (NaOH) 3×25 ml, diluted solution of acid chloride (HCl) 2×25 ml, 2×25 ml of saturated solution of sodium bicarbonate (NaHCO3) and finally with brine 1×25 ml. Organic layer was dried over sodium sulfate (Na2SO4), filtered and vacuum dried. 20.14 grams (yield: 85%) of low viscosity (η=0.0891 Pa*s) amber material was obtained.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([N:13]2[CH2:17][CH2:16][CH:15]([NH:18]C(=O)OC(C)(C)C)[CH2:14]2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].[NH:26]([C:28](OCC)=[O:29])[NH2:27]>CN1C(=O)CCC1.CO>[NH2:18][CH:15]1[CH2:16][CH2:17][N:13]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:12]=[C:3]([C:1]3[NH:2][C:28](=[O:29])[NH:26][N:27]=3)[N:4]=2)[CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2nc(C#N)cc3ccccc23)C1
Reactant: CCOC(=O)NN
Solvent: CO
Solvent: CN1CCCC1=O
Product: NC1CCN(c2nc(-c3n[nH]c(=O)[nH]3)cc3ccccc23)C1
Temperature: 175 °C
Yield: 17 %

Procedure:
To a crude reaction mixture containing tert-butyl (1-(3-cyanoisoquinolin-1-yl)pyrrolidin-3-yl)carbamate (786 mg) was added ethyl hydrazinecarboxylate (242 mg, 2.323 mmol) in NMP (5 mL). The resulting suspension was heated at 175° C. overnight and was subsequently cooled, diluted with MeOH, and filtered. The crude product was purified using mass-triggered HPLC eluting with a gradient of 20-45% ACN in water (acid mode). The product-containing fractions were concentrated to give the title compound (117 mg, 17.0% over 2 steps). ESI-MS m/z [M+H]+ 297.5.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[N+:12]([O-])=O.[C:16](OC(=O)C)(=[O:18])[CH3:17].O>[Pd].C(O)(=O)C>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[NH:12][C:16](=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)Cc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)Cc1ccc(Cl)cc1NC(C)=O
Reaction time: 2 h

Procedure:
An argon filled flask was charged with (4-Chloro-2-nitro-phenyl)-acetic acid methyl ester (40 g, 175 mmol), 10% Pd/C (2.5 g), acetic anhydride (64 mL, 677 mmol), water (9 mL) and acetic acid (150 mL). The flask was vacuum flushed with hydrogen gas at 30 PSI and shook vigorously. After 2 hours, more 10% Pd/C (2 g) was added, and the reaction was complete after a total of 4 hours reaction time. The 10% Pd/C was removed by filtration, and the solvent was removed by rotary evaporation.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[C:5]([N:26]3C(=O)C4=CC=CC=C4C3=O)[CH:6]=[C:7]([O:24][CH3:25])[C:8]=2[O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:3]=1.O.NN>C(O)C>[NH2:26][C:5]1[CH:6]=[C:7]([O:24][CH3:25])[C:8]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)=[C:9]2[C:4]=1[N:3]=[C:2]([Cl:1])[CH:11]=[C:10]2[CH3:12]
Reactant: COc1cc(N2C(=O)c3ccccc3C2=O)c2nc(Cl)cc(C)c2c1Oc1cccc(C(F)(F)F)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1cc(N)c2nc(Cl)cc(C)c2c1Oc1cccc(C(F)(F)F)c1
Reaction time: 3 h

Procedure:
A suspension of 2-chloro-6-methoxy-4-methyl-8-phthalimido-5-(3-trifluoromethylphenoxy)quinoline (23.2 g, 45.2 mmol) in ethanol (900 mL) was treated with excess hydrazine hydrate (75%, 16.75 mL) and the mixture was refluxed with mechanical stirring for 3 hours. After cooling, the solids were collected and washed with CH2Cl2. The combined filtrate and washings were evaporated in vacuo to a small volume and dissolved in CH2Cl2 ( 500 mL). The solution was extracted with 20% KOH (3×200 mL), and with brine, dried (K2CO3) and evaporated in vacuo to an amber gum. Recrystallization from cyclohexane-ligroin (5:2, 500 mL) with charcoaling gave 15.4 g (89%) of 1st crop title compound, mp 133°-135° C. Further recrystallization did not change the melting point.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][O:15]2)=[CH:4][C:5]2[S:9][C:8]([NH2:10])=[N:7][C:6]=2[CH:11]=1.[CH2:19]([N:21]=[C:22]=[O:23])[CH3:20]>O1CCOCC1>[Br:1][C:2]1[C:3]([O:12][CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][O:15]2)=[CH:4][C:5]2[S:9][C:8]([NH:10][C:22]([NH:21][CH2:19][CH3:20])=[O:23])=[N:7][C:6]=2[CH:11]=1
Reactant: CCN=C=O
Reactant: Nc1nc2cc(Br)c(OCC3CCCO3)cc2s1
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(Br)c(OCC3CCCO3)cc2s1
Temperature: 80 °C
Reaction time: 5 h
Yield: 82.4 %

Procedure:
To a solution of iii (1.0 g, 3.03 mmol) in 1,4-dioxane (10 mL) was added ethyl isocynate (1.23 mL, 15.19 mmol) at RT. The mixture was stirred at 80° C. for 5 h. The reaction mixture was evaporated in vacuo, H2O (50 mL) added to and the mixture stirred at 70° C. for 4 h. The residue was filtered and dried under vacuum to obtain iv (1.0 g, 83%). 1HNMR (DMSO-d6, 400 MHz): δ 10.69 (br s, 1H), 7.80 (s, 1H), 7.68 (s, 1H), 6.65 (m, 1H), 4.21 (m, 1H), 4.04 (m, 2H), 3.83 (m, 1H), 3.70 (m, 1H), 3.16 (m, 2H), 2.0 (m, 2H), 1.82 (m, 2H) and 1.09 (t, J=7.20 Hz, 3H). MS: 400 [M+H]+.
Reaction SMILES: C1(N2CCC3(CCNC3)C2)CC1.C(O)(C(F)(F)F)=O.[F:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[C@H:34]([NH:38]C(=O)OC(C)(C)C)[CH2:33][CH2:32][CH2:31]3)[CH2:23][CH2:22]1>C(Cl)Cl>[F:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[C@H:34]([NH2:38])[CH2:33][CH2:32][CH2:31]3)[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCc2cc(CN3CCC(F)CC3)ccc21
Agent: C1CC2(CCN(C3CC3)C2)CN1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CCCc2cc(CN3CCC(F)CC3)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of (R)-(5-(tert-butoxycarbonylamino)-5,6,7,8-tetrahydronaphthalen-2-yl)methyl methanesulfonate (2.0 g, 5.633 mmol, 1.0 eq.), 4-fluoropiperidine.HCl (0.78 g, 5.633 mmol, 1.0 eq.) and K2CO3 (2.33 g, 16.9 mmol, 3.0 eq.) in THF (25 ml) was heated at reflux for 16 h. After completion of the reaction (monitored by TLC), the solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (150 ml), washed with water (100 ml) and brine (100 ml), and dried over Na2SO4. The solvent was evaporated under reduced pressure to give the crude product which was purified by column chromatography (silica gel; 40% ethyl acetate/hexanes) to yield the title compound as a light yellow solid. Yield: 60% (1.22 g, 3.37 mmol) 2. TFA (1 ml) was added to a solution of (R)-tert-butyl 6-((4-fluoropiperidin-1-yl)methyl)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate (325 mg, 0.898 mmol, 1.0 eq.) in DCM (4 ml) at 0° C. and the resulting reaction mixture was stirred at 25° C. for 4 h. The solvent was evaporated under reduced pressure and the residue was azeotroped with toluene to yield the desired product which was employed in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.ClC(N(C)C)=C(C)C.N1C=CC=CC=1.[NH2:32][C:33]1[CH:34]=[C:35]([CH:47]=[CH:48][C:49]=1[Cl:50])[CH2:36][C:37]1([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39][CH2:38]1>ClCCl>[Cl:50][C:49]1[CH:48]=[CH:47][C:35]([CH2:36][C:37]2([C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[CH2:39][CH2:38]2)=[CH:34][C:33]=1[NH:32][C:9](=[O:11])[C@H:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14]
Reactant: CC(C)(C)OC(=O)C1(Cc2ccc(Cl)c(N)c2)CC1
Reactant: C[C@H]([C@H](C(=O)O)c1ccc(Cl)cc1)C(F)(F)F
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@H]([C@H](C(=O)Nc1cc(CC2(C(=O)OC(C)(C)C)CC2)ccc1Cl)c1ccc(Cl)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
368 mg (1.38 mmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid were dissolved in 15 ml of dichloromethane, 246 mg (1.84 mmol) of 1-chloro-N,N,2-trimethylprop-1-en-1-amine were added and the mixture was then stirred at room temperature for 30 min. 279 μl (3.45 mmol) of pyridine and 324 mg (1.15 mmol) of tert-butyl 1-(3-amino-4-chlorobenzyl)-cyclopropanecarboxylate were then added, and the reaction mixture was stirred at room temperature for another 1 h. The reaction mixture was then concentrated under reduced pressure and the crude product obtained was purified by preparative RP-HPLC (mobile phase acetonitrile/water). This gave 540 mg of the target compound (88% of theory).
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+](C)C.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:33]2[C:43](=[O:44])[CH2:42][C:36]3([CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH2:35][C:34]=2[OH:45])[NH:19][C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)=[O:21])=[CH:14][CH:13]=1)#[N:11].C(N(CC)C(C)C)(C)C>ClCCl>[C:10]([C:12]1[CH:13]=[CH:14][C:15]([CH:18]([C:33]2[C:34](=[O:45])[CH2:35][C:36]3([CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)[CH2:42][C:43]=2[O:44][CH3:6])[NH:19][C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)=[O:21])=[CH:16][CH:17]=1)#[N:11]
Reactant: C[O+](C)C
Reactant: N#Cc1ccc(C(NC(=O)Nc2cccc(C(F)(F)F)c2)C2=C(O)CC3(CCOCC3)CC2=O)cc1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC1=C(C(NC(=O)Nc2cccc(C(F)(F)F)c2)c2ccc(C#N)cc2)C(=O)CC2(CCOCC2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trimethyloxonium tetrafluoroborate (320 mg, 2.16 mmol) is added to a solution of 1-((4-cyanophenyl)(8-hydroxy-10-oxo-3-oxaspiro[5.5]undec-8-en-9-yl)methyl)-3-(3-(trifluoromethyl)phenyl)urea (intermediate 10, 712 mg, 1.43 mmol) and N,N-diisopropylethylamine (490 μL, 2.81 mmol) in dichloromethane (20 mL). The mixture is stirred at room temperature for 30 min and washed with water. The organic layer is concentrated under reduced pressure, and the residue is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 380 mg; ESI mass spectrum [M+H]+=514, Retention time HPLC: 1.18 min (V012_S01).