Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:41])[N:24]([CH:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[CH2:25][CH2:26][CH2:27][NH:28][S:29]([C:32]([F:35])([F:34])[F:33])(=[O:31])=[O:30])[CH:20]=[C:19]([Cl:42])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>ClCCl>[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[Cl:42][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:18]=1)[C:23]([N:24]([CH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1)[CH2:25][CH2:26][CH2:27][NH:28][S:29]([C:32]([F:33])([F:35])[F:34])(=[O:30])=[O:31])=[O:41]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCNS(=O)(=O)C(F)(F)F)C2CCCC2)c1)c1ccncc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cc(Cl)cc(OCCNc2ccncc2)c1)N(CCCNS(=O)(=O)C(F)(F)F)C1CCCC1

Procedure:
A solution of (2-{3-chloro-5-[cyclopentyl-(3-trifluoromethanesulfonylamino-propyl)-carbamoyl]-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester (0.0118 g) in dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 19 h and then concentrated under reduced pressure. The title compound was obtained as a pale brown gum (0.010 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:8]=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[Li]CCCC.CCCCCC.[I:22]I>C1COCC1>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([I:22])=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Clc1nccn2cncc12
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Clc1nccn2c(I)ncc12
Temperature: 30 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 8-chloro-imidazo[1,5-a]pyrazine (200.00 mg, 1.30 mmol) in THF (10.0 mL) was slowly added n-BuLi in hexane (2.5 M, 0.62 mL, 1.55 mmol) at −78° C. under nitrogen. The resulting mixture was stirred at the same temperature for 15 min. Then to this mixture a solution of iodine (429.7 mg, 1.693 mol) in 3 mL of THF was slowly added. The mixture was allowed to warm up to 30° C. in 1 hour. Reaction was quenched by 2 mL saturated aq. solution of NH4Cl. The reaction mixture was extracted with DCM. The solvent was removed under reduced pressure and the residue was used in next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J=5.05 Hz, 1H), 7.71 (dd, J=5.05, 1.01 Hz, 1H), 7.94 (d, J=1.01 Hz, 1H). MS (ES+): m/z 279.86/281.90 [MH+]; HPLC: tR=2.70 min (OpenLynx, polar—5 min).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28].[F:31][CH:32]([F:64])[O:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[N:39]([CH3:43])[N:38]=[C:37]2[C:44]1[N:45]=[C:46]2[C:52]([C:53](O)=[O:54])=[CH:51][N:50]([CH2:56][O:57][CH2:58][CH2:59][Si:60]([CH3:63])([CH3:62])[CH3:61])[C:47]2=[N:48][CH:49]=1>CN(C=O)C>[F:64][CH:32]([F:31])[O:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[N:39]([CH3:43])[N:38]=[C:37]2[C:44]1[N:45]=[C:46]2[C:52]([C:53]([NH:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])=[O:54])=[CH:51][N:50]([CH2:56][O:57][CH2:58][CH2:59][Si:60]([CH3:62])([CH3:61])[CH3:63])[C:47]2=[N:48][CH:49]=1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Reactant: CC(C)(N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)CO)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
In a 16×100 mm screw cap test tube were added HATU (28.0 mg, 73.5 μmol.20) and 2-amino-2-methylpropan-1-ol (21.8 mg, 245 μmol) then 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (30 mg, 61.3 μmol) dissolved in DMF (2.00 mL) was added to give a light yellow solution. The reaction mixture stirred at 25° C. overnight. TLC and LCMS showed incomplete reaction added 2-amino-2-methylpropan-1-ol (21.8 mg, 245 μmol) and HATU (28.0 mg, 73.5 μmol) and the reaction continued at 25° C. for 3 h. Solvents evaporated and residue purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 50% EtOAc in hexanes over 30 min to yield 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (34.4 mg, 61.3 μmol, 100%) as an off-white solid. 1H NMR (CDCl3) δ: 9.22 (s, 1H), 8.35 (s, 1H), 8.31 (s, 1H), 8.24 (d, J=2.3 Hz, 1H), 7.43-7.52 (m, 1H), 7.34 (dd, J=8.9, 2.1 Hz, 1H), 6.53 (t, J=75.0 Hz, 1H), 5.72 (s, 2H), 4.21 (s, 3H), 3.79 (s, 2H), 3.53-3.64 (m, 2H), 1.55 (s, 6H), 0.85-1.07 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH:4]=1)#[CH:2].Cl[CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH3:17].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.O>[CH2:13]([N:14]1[CH2:15][CH2:16][CH2:17][C:1]([C:3]2[CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH:4]=2)=[CH:2]1)[CH2:12][CH3:11]
Reactant: C#CC1=CC(=O)CCC1
Reactant: CCCNCCCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CCCN1C=C(C2=CC(=O)CCC2)CCC1

Procedure:
3-Ethynyl-cyclohex-2-enone (3.20 g, 26.8 mmol) (from a) above) and (3-Chloro-propyl)-propyl-amine (4.50 g, 33.2 mmol) were mixed in acetonitril (50 mL). Cs2CO3 (100 mg) and KI (200 mg) were added and the mixture was refluxed under N2 for 10 h. After cooling the mixture was diluted with water (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine, dried (MgSO4) and evaporated. The resulting dark oil was purified by column chromatography (silica, ethyl acetate) to give a yellow red oil. Yield 5.1 g, 23.3 mmol (87%). IR (neat) 2932, 2871, 1589, 1538, 1157 cm−; 1H-NMR (CDCl3) δ6.84 (s, 1H), 5.69 (s, 1H), 3.04-3.12 (m, 4H), 2.44 (t, 2H), 2.33 (t,2H), 2.18 (t, 2H), 1.83-2.03 (m, 4H), 1.49-1.64 (m, 2H), 0.87 (t, 3H) ppm; 13C-NMR (CDCl3) δ197.0, 158.5, 140.1, 112.1, 102.4, 56.6, 44.3, 35.6, 23.6, 21.4, 20.2, 20.1, 19.7, 9.6 ppm; MS (CI) m/z 220 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH:7]=[CH:8][C:9]([CH3:12])(O)[CH3:10])=[CH:3][CH2:4][OH:5].[OH:13]C/C=C(/C)\CCC=C(C)C>>[OH:5][CH2:4][CH:3]1[O:13][C:2]1([CH3:1])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:12])[CH3:10]
Reactant: CC(C)=CCC/C(C)=C\CO
Reactant: CC(=CCO)CC=CC(C)(C)O
Product: CC(C)=CCCC1(C)OC1CO

Procedure:
Ohloff prepared the intermediate 3,7-dimethyl-octa-2,5-dien-1,7-diol from nerol by its photosensitized air oxidation followed by reduction and cyclisation with an acid to obtain racemic nerol oxide [G. Ohloff, K. H. Schulte-Elite & B. Willhalm Helv. Chim. Acta. 47, 602, 1964]. In another publication nerol was first subjected to epoxidation at C6–C7 double bond and the epoxy derivative so obtained was heated in dimethyl amine at 150° to give 3,7-dimethyl-6-dimethyl amino-2-octen-1,7-diol which on oxidation with hydrogen peroxide and pyrolysis at 180° C. gave a diol intermediate that on acid catalysed cyclisation led to the formation of nerol oxide [G. Ohloff & B. Lienhard Helv. Chim. Acta. 48, 182, 1965].
Reaction SMILES: [C:1](O)(=O)/C=C\C(O)=O.[C:9]([O:16][CH3:17])(=[O:15])/[CH:10]=[CH:11]\[C:12]([O-:14])=[O:13].O>CO>[C:12]([O:14][CH3:1])(=[O:13])/[CH:11]=[CH:10]\[C:9]([O:16][CH3:17])=[O:15]
Reactant: O=C(O)/C=C\C(=O)O
Reactant: COC(=O)/C=C\C(=O)[O-]
Solvent: CO
Solvent: O
Product: COC(=O)/C=C\C(=O)OC

Procedure:
This example relates to FIG. 1. In this example a 95 wt % solution of aqueous maleic acid is provided as described in Example 1. The aqueous maleic acid is fed to the mono-ester reactor column (9). Recycled methanol from the refining section (line 16a) is fed to the bottom of the column 9. More than 80% of the maleic acid is converted to mono-methyl maleate from the bottom product line (line 17) contains less than 10 mole % water. Mainly water and methanol and a small amount of maleic acid in the overhead (line 14) are fed to the methanol column (line 25). The bottom product from column (9) is fed to a reaction column (19) to react the mono-methyl maleate with methanol to produce di-methyl maleate. 300 mols per hour of methanol (line 24) are fed to the bottom of the reaction column (19). Essentially water free, fully converted di-methyl maleate is fed (line 26) to hydrogenation in reactor (20). Recycle methanol from the refining section is fed to the top of the reaction column as wash (line 16b) to minimise the di-methyl maleate and maleic acid in the overhead of the column. Methanol and water from the overhead (line 31) of the reaction column is fed to the methanol column (25) where the methanol is separated and recycled to the reaction column (line 24). Water and a small amount of recovered maleic acid and di-methyl maleate from the bottom of the methanol column are recycled to the absorber (2) in line 3.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]([C:11]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]2[C:12]=1[C:13]([C:22]#[N:23])=[CH:14][NH:15]2)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:24][NH:25]CCC(C1C=C2C(=CC=1)NC=C2C#N)C1C=CC=CC=1>>[CH3:21][O:20][C:18]1[CH:17]=[C:16]2[C:12]([C:13]([C:22]#[N:23])=[CH:14][NH:15]2)=[C:11]([CH:4]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:3][CH2:2][NH:25][CH3:24])[CH:19]=1
Reactant: COc1cc(C(CCO)c2ccccc2)c2c(C#N)c[nH]c2c1
Reactant: CNCCC(c1ccccc1)c1ccc2[nH]cc(C#N)c2c1
Product: CNCCC(c1ccccc1)c1cc(OC)cc2[nH]cc(C#N)c12

Procedure:
6-Methoxy-4-(3-methylamino-1-phenyl-propyl)-1H-indole-3-carbonitrile CXXXII (90 mg) was prepared from 4-(3-hydroxy-1-phenyl-propyl)-6-methoxy-1H-indole-3-carbonitrile using the procedure described above for preparation of 5-(3-Methylamino-1-phenyl-propyl)-1H-indole-3-carbonitrile LXVI. MS (M+H)=320.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][NH:16][CH:17]=3)[N:10]3[CH:18]=[CH:19][N:20]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1.[CH2:21]1[C:24]2([CH2:27][C:26](=[CH:28][C:29]#[N:30])[CH2:25]2)[CH2:23][O:22]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([C:26]4([CH2:28][C:29]#[N:30])[CH2:27][C:24]5([CH2:23][O:22][CH2:21]5)[CH2:25]4)[CH:17]=3)[N:10]3[CH:18]=[CH:19][N:20]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1
Reactant: N#CC=C1CC2(COC2)C1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cn[nH]c3)n2)cn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CC5(COC5)C4)c3)n2)cn1
Temperature: 50 °C
Reaction time: 24 h
Yield: 73.1 %

Procedure:
A mixture of 7-(1-methyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (25 mg; 0.094 mmol), 2-(2-oxaspiro[3.3]heptan-6-ylidene)acetonitrile (19 mg; 0.14 mmol) and DBU (7.2 mg; 0.047 mmol) in acetonitrile (1 mL) was stirred in a sealed vial at 50° C. for 24 hours. The solvent was removed under reduced pressure and the material was purified by silica gel chromatography, eluting with (6% ammonium hydroxide in methanol)/methylene chloride (1:25 to 1:15 gradient) to provide pure desired product as a white solid (27.5 mg). MS (apci) m/z=401.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:18])=O.CN(C)C=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:4]=1[C:5]([Cl:18])=[O:6]
Reactant: COc1cc(OC)c(C(=O)O)cc1OC
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc(OC)c(C(=O)Cl)cc1OC
Temperature: 80 °C
Reaction time: 1 h

Procedure:
2,4,5-Trimethoxybenzoic acid (500 g) was suspended in dried toluene (2 l) and to the suspension, thionyl chloride (206 ml) and N,N-dimethylformamide (1.0 ml) were added at room temperature, and the mixture was stirred at 80° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. To the resultant residue, n-hexane was added and through co-boiling the mixture, 2,4,5-trimethoxybenzoyl chloride was obtained. To the resultant compound, 2-amino-4-methoxycarbonyl-1,3-thiazole (372.7 g) and 1,2-dichloroethane (4.5 l) were added and the mixture was refluxed for 6 hours. After completion of reaction, the reaction mixture was allowed to cool. Crystals so precipitated were collected by filtration, washed with 1,2-dichloroethane, and air-dried. The crystals were suspended in water (8 l) and to the suspension, ice (2 kg) was added. While cooling, a solution of sodium hydroxide (94 g) in water (850 ml) was added thereto to thereby adjust the pH of the suspension at about 7.5. Subsequently, the mixture was stirred for 3 hours at room temperature. Crystals so precipitated were collected by filtration, washed with water, and air-dried to thereby obtain the title compound (702.7 g).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:33]=[CH:32][C:12]2[N:13]([CH3:31])[C:14]([NH:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[N:15][C:11]=2[CH:10]=1)=[O:8].Cl.[CH3:35][N:36]([CH3:41])[CH2:37][C:38](O)=[O:39].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:35][N:36]([CH3:41])[CH2:37][C:38]([NH:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:33]=[CH:32][C:12]2[N:13]([CH3:31])[C:14]([NH:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([O:26][C:27]([F:28])([F:29])[F:30])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[N:15][C:11]=2[CH:10]=1)=[O:8])=[O:39]
Reactant: CN(C)CC(=O)O
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCN)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)NCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 101 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(2-dimethylamino-acetylamino)-ethyl]-amide (62 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-amino-ethyl)-amide dihydrochloride (60 mg), N,N-dimethylglycine hydrochloride (18 mg), HBTU (57 mg), and DIEA (33 uL). LC/MS: m/z 536.8. 1H NMR (DMSO-d6, 400 MHz): δ 12.37 (bs, 1H), 8.48 (s, 1H), 8.08 (s, 1H), 8.04 (s, 1H), 7.94 (s, 1H), 7.80-7.65 (m, 2H), 7.49 (d, 1H), 7.37 (d, 1H), 3.76-3.46 (m, 5H), 2.97 (s, 2H), 2.89 (s, 2H), 2.25 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25](O)=[O:26])[C:13]2=[O:31])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[CH3:44][S:45]([NH2:48])(=[O:47])=[O:46]>CN(C1C=CN=CC=1)C.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([NH:48][S:45]([CH3:44])(=[O:47])=[O:46])=[O:26])[C:13]2=[O:31])[CH:9]([CH3:10])[CH3:11])=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: CC(C)C(=C1C(=O)N(Cc2cccc(C(=O)O)c2)c2ccccc21)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)C(=C1C(=O)N(Cc2cccc(C(=O)NS(C)(=O)=O)c2)c2ccccc21)c1ccc(Cl)cc1
Reaction time: 72 h
Yield: 38.5 %

Procedure:
A mixture of 3-{3-[1-(4-chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoic acid (0.22 g, 0.51 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.20 g, 1.02 mmol), methylsulfonamide (97 mg, 1.02 mmol), DMAP (12.2 mg, 0.10 mmol) in dichloromethane (20 ml) was stirred for 72 hours. The organic solution washed with brine (10 ml) then dried over sodium sulfate. After removal of solvent, the residue was dissolved in 2 ml DMF for prepared HPLC to give the product N-(3-{3-[1-(4-chloro-phenyl)-2-methyl-propylidene]-2-oxo-2,3-dihydro-indol-1-ylmethyl}-benzoyl)-methanesulfonamide (100 mg, 38%) as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21 (d, J=6.82 Hz, 6H) 3.50 (s, 3H) 5.00-5.12 (m, 1H) 5.17 (s, 2H) 5.52 (s, 1H) 5.84 (d, J=7.83 Hz, 1H) 6.75 (t, J=7.83 Hz, 1H) 6.85 (d, J=7.83 Hz, 1H) 7.17 (t, J=7.20 Hz, 1H) 7.28 (d, J=8.59 Hz, 2H) 7.60 (t, J=7.71 Hz, 1H) 7.65 (d, J=8.34 Hz, 2H) 7.70 (d, J=7.83 Hz, 1H) 7.94 (d, J=7.83 Hz, 1H) 8.02 (s, 1H). MS calcd. for C27H25ClN2O4S 508.5, obsd. (ESI+) [(M+H)+] 509.2.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([C:26]([F:29])([F:28])[F:27])=[N:19]3)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:31][C:32]#[N:33]>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([C:26]([F:29])([F:27])[F:28])=[N:19]3)[CH2:11][CH2:12][N:13]1[CH2:31][C:32]#[N:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCCl
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)c2ccc(C(F)(F)F)nc12
Product: COc1ccc(N2CCN(CC#N)[C@@H](Cc3ccccc3)C2)c2ccc(C(F)(F)F)nc12
Yield: 21 %

Procedure:
Prepared using the same procedure described in Example 405 from 5-((S)-3-benzyl-piperazin-1-yl)-8-methoxy-2-trifluoromethyl-quinoline and chloroacetonitrile to afford the title compound as a yellow solid (26 mg, 21%). LC/MS (Method B) 4.10 min, [M+1]+ 441.
Reaction SMILES: [NH2:1][C:2]1[C:8]([OH:9])=[CH:7][C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[OH:4].[C:13](OCC)(OCC)(OCC)[CH3:14]>C1(C)C=CC=CC=1.C1COCC1>[N+:10]([C:6]1[CH:5]=[C:3]([OH:4])[C:2]2[N:1]=[C:13]([CH3:14])[O:9][C:8]=2[CH:7]=1)([O-:12])=[O:11]
Reactant: CCOC(C)(OCC)OCC
Reactant: Nc1c(O)cc([N+](=O)[O-])cc1O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1nc2c(O)cc([N+](=O)[O-])cc2o1
Yield: 39.4 %

Procedure:
To a stirred solution of the 2-amino-5-nitroresorcinol (2.9 g, 0.017 mole) in toluene (50 ml) and THF (5 ml) was added triethyl orthoacetate (4.1 g, 0.0255 mole). This mixture was heated to reflux for one hour. Upon cooling, the product crystallized out of solution and was collected and dried to yield a tan solid (1.3 g, 39.4 percent). TLC showed the product to be pure.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:7]1[CH:28]=[CH:27][C:10]([CH2:11][N:12]([CH2:19][CH2:20][C:21]2[S:22][CH:23]=[C:24]([CH3:26])[N:25]=2)C(=O)C(F)(F)F)=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].O>C(O)C>[C:3]([C:7]1[CH:28]=[CH:27][C:10]([CH2:11][NH:12][CH2:19][CH2:20][C:21]2[S:22][CH:23]=[C:24]([CH3:26])[N:25]=2)=[CH:9][CH:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: Cc1csc(CCN(Cc2ccc(C(C)(C)C)cc2)C(=O)C(F)(F)F)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1csc(CCNCc2ccc(C(C)(C)C)cc2)n1
Reaction time: 3 h

Procedure:
102 mg of sodium borohydride (2.7 mmol) were added to a solution of 260 mg of N-(4-tert-butyl-benzyl)-2,2,2-trifluoro-N-[2-(4-methyl-thiazol-2-yl)-ethyl]-acetamide (0.68 mmol) in ethanol at ambient temperature and the reaction mixture was stirred for 3 h. Then water was added and the mixture was extracted three times with EtOAc. The combined organic extracts were washed with brine, dried with magnesium sulfate, filtered and the solvent was evaporated. The remaining 195 mg (100%) of (4-tert-butyl-benzyl)-[2-(4-methyl-thiazol-2-yl)-ethyl]-amine were used in the following coupling step without further purification. 1H NMR (CDCl3, 300 MHz): δ 1.31 (s, 9H), 2.41 (s, 3H), 3.06 (m, 2H), 3.17 (m, 2H), 3.81 (s, 2H), 6.72 (s, 1H), 7.25 (d, J=8 Hz, 2H), 7.34 (d, J=8 Hz, 2H); MS (ISP) 289.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17](=[O:31])[C:18]([N:20]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:21][CH2:22][CH2:23][CH2:24][C:25]#[CH:26])=[O:19])[CH:9]2[C:12]([O:14]CC)=[O:13])=[CH:4][C:3]=1[O:32][CH3:33].[OH-].[K+].Cl>O1CCOCC1.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17](=[O:31])[C:18]([N:20]([C:27]([CH3:29])([CH3:30])[CH3:28])[CH2:21][CH2:22][CH2:23][CH2:24][C:25]#[CH:26])=[O:19])[CH:9]2[C:12]([OH:14])=[O:13])=[CH:4][C:3]=1[O:32][CH3:33]
Reactant: C#CCCCCN(C(=O)C(=O)N1CCc2cc(OC)c(Br)cc2C1C(=O)OCC)C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C#CCCCCN(C(=O)C(=O)N1CCc2cc(OC)c(Br)cc2C1C(=O)O)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
A solution of 480 mg of 19b in 10 ml of dioxane was mixed with 200 mg of KOH in 2 ml of water. The mixture was stirred at rt for 3 h and then diluted with 40 ml of water and acidified to pH 3 with 0.5 N HCl. The product was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated, to provide 420 mg of 19c as white amorphous material; MS-ESI: [M+1] 495.19 and 493.18. NMR (CDCl3) δ 1.43 (m, 2, CH2), 1.53 (s, 9, tertC4H9), 1.68-1.90 (bm, 2, CH2), 1.92 (t, 1, CH), 2.16 (m, 2, CH2), 2.80-3.00 (bm, 2, CH2), 3.22-3.45 (bm, 2, CH2), 3.68 (m, 2, CH2), 3.88 (s, 3, OCH3), 5.74 (s, 1, CH), 6.65 (s, 1, ArH), 7.73 (s, 1, ArH).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH:6]=[CH:7][CH2:8][NH:9][CH2:10][CH2:11][NH:12][S:13]([C:16]2[C:17]3[CH:18]=[CH:19][N:20]=[CH:21][C:22]=3[CH:23]=[CH:24][CH:25]=2)(=[O:15])=[O:14])=[CH:4][CH:3]=1.[CH2:28](O)[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:28]([N:12]([CH2:11][CH2:10][NH:9][CH2:8][CH:7]=[CH:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:27][CH:26]=1)[S:13]([C:16]1[C:17]2[CH:18]=[CH:19][N:20]=[CH:21][C:22]=2[CH:23]=[CH:24][CH:25]=1)(=[O:14])=[O:15])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1
Reactant: O=S(=O)(NCCNCC=Cc1ccc(Cl)cc1)c1cccc2cnccc12
Reactant: COc1ccc(CO)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN(CCNCC=Cc2ccc(Cl)cc2)S(=O)(=O)c2cccc3cnccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.3 %

Procedure:
0.4 g of the crystals obtained in Example 172, 0.276 g of anisyl alcohol and 0.524 g of triphenylphosphine were dissolved in 10 ml of tetrahydrofuran, and to the solution was added dropwise a solution of 0.404 g of diisopropyl azodicarboxylate in 2 ml of tetrahydrofuran with stirring under ice cooling. The reaction mixture was warmed to a room temperature and was allowed to stand overnight and then evaporated under a reduced pressure to remove the solvent. The resulting residue was dissolved in 30 ml of ethyl acetate, and the mixture was extracted twice with 30 ml of 1N hydrochloric acid. The extract was alkalized with sodium bicarbonate and extracted twice with 30 ml of ethyl acetate. The ethyl acetate solution was washed with water, dried over magnesium sulfate and evaporated under a reduced pressure to remove the solvent. The resulting residue was applied to a silica gel column and eluted with 1% methanol in chloroform, to obtain 0.22 g of the title compound as a colorless oil.