Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[N:11]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[C:20]([O:19][C:17]([N:11]1[CH2:16][CH2:15][N:14]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[CH3:10])[CH2:13][CH2:12]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc(C#N)ccc1Br
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(C#N)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 86.9 %

Procedure:
Part 4: To a nitrogen flushed flask containing PdCl2dppf (65.8 mg, 0.081 mmol), dppf (44.6 mg, 0.081 mmol) and 4-bromo-3-methylbenzonitrile (631 mg, 3.22 mmol) in THF (5 mL) at −78° C. was added tert-butyl 1-piperazinecarboxylate (500 mg, 2.68 mmol) as a solid. The resultant mixture was heated to 100° C. and vigorously stirred overnight under nitrogen. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with 0 to 30% ethyl acetate in hexane) to afford 4-(4-cyano-2-methyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (702 mg, 86.9%). MS (ESI): 302.0 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[C:11](=[O:12])[CH:10]=[CH:9][C:8](=[O:13])[C:6]=2[N:7]=1)[CH3:2].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[NH:14]([C:9]1[C:8](=[O:13])[C:6]2[N:7]=[C:3]([CH2:1][CH3:2])[O:4][C:5]=2[C:11](=[O:12])[CH:10]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCc1nc2c(o1)C(=O)C=CC2=O
Reactant: Nc1ccccc1
Solvent: CCO
Product: CCc1nc2c(o1)C(=O)C=C(Nc1ccccc1)C2=O
Reaction time: 1 h

Procedure:
A mixture of 2-ethyl-1,3-benzoxazole-4,7-dione (1 eq) and aniline (1.1 eq.) in ethanol is kept under string for 1 hour. The reaction medium turns to dark violet. After concentration, the residue is purified by medium pressure chromatography on silica in order to produce a violet-coloured powder. Melting point: 200° C.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[N:8][C:9](OC)=[CH:10][CH:11]=2)[N:6]([CH2:15][C:16]([OH:18])=[O:17])[CH:5]=1)(=[O:3])[CH3:2].[NH:19]1C2=NC(C#N)=CC=C2C=[CH:20]1>>[C:1]([C:4]1[C:12]2[C:7](=[N:8][C:9]([C:20]#[N:19])=[CH:10][CH:11]=2)[N:6]([CH2:15][C:16]([OH:18])=[O:17])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(C(C)=O)cn(CC(=O)O)c2n1
Reactant: N#Cc1ccc2cc[nH]c2n1
Product: CC(=O)c1cn(CC(=O)O)c2nc(C#N)ccc12

Procedure:
was prepared using similar procedures as described for the synthesis of (3-acetyl-6-methoxy-pyrrolo[2,3-b]pyridin-1-yl)-acetic acid in Scheme A15 from 1H-pyrrolo[2,3-b]pyridine-6-carbonitrile. MS (UPLC/MS): 244.1 [M+H]+, 242.1 [M−H]−; tR (HPLC conditions f): 1.42 min.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[C:18]([Mg]Br)#[C:19][CH3:20]>C1COCC1.C(Cl)Cl>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:14])([C:18]#[C:19][CH3:20])[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:15]=1
Reactant: CC#C[Mg]Br
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC#CC(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (535 mg) in THF (10 mL) at −78° C. was added 1-propynyl magnesium bromide (8 mL of 0.5 M in THF) dropwise. The resulting mixture was then stirred at 0° C. for 3 hr. The reaction was quenched with H2O and 1 N HCl, extracted with EtOAc, dried over Na2SO4, filtered, and concentrated to yield a residue. The residue was purified by flash chromatography with Biotage 40s+ column and elution with 10%-40% EtOAc/hexanes to yield a yellow solid. The yellow solid was dissolved in a minimal amount of CH2Cl2 and triturated with hexanes to yield the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[N:10][C:11](=[S:13])[N:12]=2)=[CH:4][CH:3]=1.[O-]CC.[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][C:11]([SH:13])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2=NC(=S)N=C2c2ccncc2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CO
Product: Fc1ccc(-c2[nH]c(S)nc2-c2ccncc2)cc1
Reaction time: 0.17 h

Procedure:
Under an atmosphere of argon, 5-(4-fluorophenyl)-4-(4-pyridinyl)imidazole-2-thione (0.001 mol/0.271 g) was dissolved in 20 ml of absolute methanol. Sodium ethoxide (0.0012 mol/0.065 g) was then added and the mixture was stirred for 10 min. The bromoaliphatic compound (0.0011 mol) in question, dissolved in 10 ml of absolute methanol, was added dropwise to the initial charge. The mixture was then heated under reflux for 4 h and subsequently stirred at room temperature for 2 h. After neutralization with HCl 10% to pH 7, the liquid was removed under reduced pressure and the residue was worked up by column chromatography (mobile phase: CH2Cl2/EtOH 9:1; silica gel).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26]2.N1CCCCC1>C(O)C>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[C:26]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C=C2C(=O)Nc3ccc(F)cc32)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.1 %

Procedure:
A stirred solution of 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (52 mg, 0.15 mmol), 5-fluoro-1,3-dihydro-indol-2-one (25 mg, 0.4 mmol) in 0.4 ml of ethanol was added dropwise with anhydrous piperidine (0.04 ml). The mixture was stirred at room temperature overnight. The precipitate was filtered under reduced pressure. The resulting solid was washed with anhydrous ethanol (0.2 ml×5), purified by silica gel column chromatography with dichloromethane:methanol (10:1) as eluents to give 2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-morpholin-4-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (30 mg, 38%) as a yellow solid.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Br[CH2:41][C:42]([N:44]1[C:49]([CH3:51])([CH3:50])[CH2:48][CH2:47][CH2:46][C:45]1([CH3:53])[CH3:52])=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:41][CH2:42][N:44]2[C:49]([CH3:51])([CH3:50])[CH2:48][CH2:47][CH2:46][C:45]2([CH3:53])[CH3:52])=[CH:36][CH:37]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC1(C)CCCC(C)(C)N1C(=O)CBr
Product: CCN(Cc1ccc(OCCN2C(C)(C)CCCC2(C)C)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(O)ccc2C1
Yield: 11.2 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 2-bromo-1-(2,2,6,6-tetramethylpiperidin-1-yl)ethanone (18 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.4 mg) was obtained.
Reaction SMILES: [CH:1]1([C:6](=[NH:8])[NH2:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:9][C:10]([F:20])([F:19])[C:11](=O)[CH2:12][C:13](OCC)=[O:14].C[O-].[Na+]>C(O)C>[CH:1]1([C:6]2[N:7]=[C:13]([OH:14])[CH:12]=[C:11]([C:10]([F:20])([F:19])[F:9])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N=C(N)C1CCCC1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: Oc1cc(C(F)(F)F)nc(C2CCCC2)n1
Temperature: 85 °C
Reaction time: 16 h
Yield: 35.6 %

Procedure:
To a solution of cyclopentanecarboximidamide (3.0 g, 27.1 mmol) in ethanol (100 mL) was added ethyl 4,4,4-trifluoro-3-oxobutanoate (5.0 g, 27.1 mmol) and sodium methoxide (1.76 g, 32.5 mmol). The mixture was stirred at 85° C. for 16 h. After this time, the mixture was concentrated, diluted with ethanol (10 mL), and the suspension was chilled to 0° C. HCl (2M, 50 mL) was added and the suspension was filtered and washed with water. The solid was dried under heat and vacuum to afford the title compound (2.24 g, 36%) as a white solid. MW=232.20. 1H NMR (DMSO-d6, 500 MHz) δ 12.96 (s, 1H), 6.67 (s, 1H), 3.03 (quin, J=8.2 Hz, 1H), 2.00-1.92 (m, 2H), 1.83-1.67 (m, 4H), 1.64-1.53 (m, 2H); APCI MS m/z 233 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH2:20])=[N:8][C:6]=2[N:7]=1.[CH2:21]([N:24]=[C:25]=[O:26])[CH2:22][CH3:23]>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH:20][C:25]([NH:24][CH2:21][CH2:22][CH3:23])=[O:26])=[N:8][C:6]=2[N:7]=1
Reactant: CCCN=C=O
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Product: CCCNC(=O)Nc1nc2nc(N)ncc2cc1-c1c(Cl)cccc1Cl

Procedure:
The title compound was prepared as described in Example 2 by reacting 1.0 g of 2,7-diamino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidine from Example 1 and 0.339 g of n-propyl isocyanate. The product was purified by radial chromatography eluting with a gradient of 10-100% ethyl acetate/Hexane. MS(CI).
Reaction SMILES: [NH:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([O:10][CH3:11])=[O:9])[NH2:2].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[CH:12](=[N:2]/[NH:1][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([O:10][CH3:11])=[O:9])\[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)c1sccc1NN
Solvent: CCO
Product: COC(=O)c1sccc1N/N=C/c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 104.8 %

Procedure:
A solution of methyl 3-hydrazinothiophene-2-carboxylate (Maybridge technical grade, 2.0 g, 0.11 mol) in ethanol (250 mL) at 25° C. was reacted with a solution of benzaldehyde (12.32 g, 0.11 mol) in ethanol (100 mL). The mixture was stirred at 25° C. for 1.5 hours and concentrated to yield 30 g of a white solid. HPLC/MS show a single peak with retention time of 2.35 min. and a M+1 peak of 261. 1H NMR (300 MHz, CDCl3) δ ppm 3.85 (s, 3 H) 7.35 (m, 4 H) 7.64 (dd, J=8.09, 1.47 Hz, 2 H) 7.77 (s, 1 H) 10.10 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:81]C(=O)OCC)[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]3[CH2:23][CH:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:21]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH:20]([O:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH3:80])[CH2:19]3)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C(O)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH2:81])[C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH:18]3[CH2:19][CH:20]([O:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH3:80])[CH:21]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:23]3)=[CH:14][CH:15]=2)=[CH:5][CH:4]=1
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(COc2ccc(C(NC(=O)OCC)c3ccc(OC)cc3)cc2)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCOC1CC(COc2ccc(C(N)c3ccc(OC)cc3)cc2)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Temperature: 100 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To crude crystals (127 mg) of ethyl {(4-methoxy-phenyl)-[4-(3,4,5-tris-octadecyloxy-cyclohexylmethoxy)-phenyl]-methyl}-carbamate were added toluene (2 mL), ethanol (2 mL), and sodium hydroxide (21 mg, 525 μmol), and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, toluene (2 mL) was added, and washed with water (4 mL×3 times) to allow partitioning. The organic layer was evaporated, and the residue was crystallized from acetonitrile (5 mL) to give {(4-methoxy-phenyl)-[4-(3,4,5-tris-octadecyloxy-cyclohexylmethoxy)-phenyl]-methyl}-amine (123 mg, 100% vs —OH form).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][CH2:27][C:28]1([NH2:32])[CH2:31][CH2:30][CH2:29]1>>[NH2:32][C:28]1([CH2:27][NH:26][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=[C:4]([N:13]3[CH2:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]3)[CH:3]=2)[CH2:31][CH2:30][CH2:29]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NCC1(N)CCC1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(N)CCC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 1-(aminomethyl)cyclobutanamine. MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (m, J=2.0 Hz, 1 H), 7.86 (d, J=1.8 Hz, 1 H), 7.70 (s, 1 H), 7.61 (t, J=3.6 Hz, 1 H), 7.45 (m, J=3.0 Hz, 2 H), 7.30 (m, J=2.5 Hz, 1 H), 6.13 (s, 1 H), 5.18 (s, 2 H), 4.53 (br. s., 2 H), 3.59 (t, J=2.3 Hz, 2 H), 3.46 (s, 2 H), 2.43 (s, 3 H), 2.28-2.22 (m, J=6.3 Hz, 2 H), 2.12-2.03 (m, J=9.2 Hz, 2 H), 1.97-1.82 (m, J=14.7 Hz, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[C:24]([F:26])[CH:25]=3)[NH:22][C:21]([CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])=[CH:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].Cl>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[C:24]([F:26])[CH:25]=3)[NH:22][C:21]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)CCc1cc2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cc(F)c2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(C)Oc1ccc(-c2nc(-c3cc(F)c4[nH]c(CCC(=O)O)cc4c3)no2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.4 %

Procedure:
To a suspension of ethyl 3-[5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-7-fluoro-1H-indol-2-yl]propanoate (D164) (240 mg) in isopropanol (15 mL) was added 20% sodium hydroxide (509 mg) solution, then the reaction mixture was stirred at room temperature overnight. The mixture was acidified with HCl (2 M) to pH 4. The solvent of the reaction was removed by evaporation. The residue was dissolved in DMF (5 mL), the precipitation was filtered then the filtrate was purified by Mass Directed Auto Prep to afford 3-[5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-7-fluoro-1H-indol-2-yl]propanoic acid (E112) (75.3 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.30 (6H, d), 2.65 (2H, t), 2.93 (2H, t), 4.8 (1H, m), 6.38 (1H, s), 7.36 (1H, d), 7.44 (1H, d), 8.01 (1H, s), 8.05 (1H, d), 8.11 (1H, s), 11.76 (1H, s), 12.20 (1H, s); δF (DMSO-d6, 376 MHz): −132.6; MS (ES): C22H19ClFN3O4 requires 443; found 444.2 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1)#[N:2].S(Cl)([Cl:14])=O>ClCCl>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:14])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1ccc(C(=O)O)cc1
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-cyanobenzoic acid (5 g, 33.98 mmol, 1.00 equiv) in dichloromethane (50 mL) was added thionyl chloride (25 mL) dropwise with stirring. The resulting solution was refluxed for 4 h. The reaction mixture was cooled to room temperature and concentrated under vacuum to give 3 g of crude 4-cyanobenzoyl chloride as a brown solid. The crude was used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[F:22][C:23]([F:29])([F:28])[CH2:24][CH:25]1[CH2:27][O:26]1>>[F:22][C:23]([F:29])([F:28])[CH2:24][CH:25]([OH:26])[CH2:27][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: FC(F)(F)CC1CO1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CC(O)CC(F)(F)F)CC1)O2

Procedure:
Compound 160 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-(2,2,2-trifluoroethyl)oxirane and conditions outlined in procedure X. M.p.=145-148° C.; 400 MHz 1H NMR (CDCl3) δ: 8.05 (d, 1H), 7.75 (d, 1H), 7.65 (t, 1H), 7.5 (t, 1H), 4.05 (m, 1H), 3.5 (s, 1H), 2.95 (m, 3H), 2.85-2.7 (m, 2H), 2.6-2.3 (m, 4H), 2.2-2.1 (m, 3H), 2.0-1.9 (m, 2H); LCMS: 428 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([NH:12][CH3:13])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.Cl.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:22]=1.CN(C1C=CC=CN=1)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]([CH3:13])[S:27]([C:23]2[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=2)(=[O:29])=[O:28])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CNc1cc(C(=O)OC)cc(Cl)n1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)nc(N(C)S(=O)(=O)c2cccnc2)c1
Temperature: 50 °C
Reaction time: 36 h
Yield: 91.6 %

Procedure:
To a solution of methyl 2-chloro-6-(methylamino)isonicotinate (2.00 g, 9.97 mmol) in 3:1 CH2Cl2:pyridine (100 mL total) was added 3-pyridine sulfonyl chloride hydrochloride (6.40 g, 29.9 mmol) and dimethylaminopyridine (0.609 g, 4.98 mmol). Reaction heated to reflux at 50° C. After 36 h, reaction cooled to rt. Reaction diluted with CH2Cl2 (200 mL) and washed with 1N HCl (150 mL) solution. The aqueous solution was extracted with CH2Cl2 (100 mL×2). The combined organics were washed with brine (100 mL), dried over Mg2SO4, filtered, and concentrated in vacuo. Purification by normal-phase chromatography (20->40% EtOAc/hexanes) yielded 3.12 g (92%) of methyl 2-chloro-6-[methyl(pyridin-3-ylsulfonyl)amino]isonicotinate as a yellow residue. 1H NMR (CDCl3, 400 MHz) 8.95 (d, J=0.64 Hz, 1H); 8.82 (m, 1H); 8.03 (m, 2H); 7.67 (m, 1H); 7.45 (m, 1H); 3.99 (s, 3H); 3.39 (s, 3H); LC/MS [M+H]+=341.9.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:8]=2)[CH:6]=1.[C:27]([NH:31][S:32]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)(=[O:34])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][S:32]([C:35]1[CH:40]=[CH:39][C:38]([C:2]2[N:3]=[CH:4][N:5]([C:7]3[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][CH:18]=4)[N:8]=3)[CH:6]=2)=[CH:37][CH:36]=1)(=[O:34])=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)cc1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)cc1

Procedure:
N-tert-Butyl-4-{1-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide was prepared from 2-(4-iodo-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.68) (0.48 g, 1.0 mmol) and commercially available 4-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as a light brown solid (0.043 g) which was subsequently deprotected.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[N:21]=[C:22]([C:34](=[O:36])[CH3:35])[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:24]=1[CH3:25])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[OH:18][CH2:19][C:20]1[N:21]=[C:22]([C:34](=[O:36])[CH3:35])[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:31])[CH3:33])[C:24]=1[CH3:25]
Reactant: CC(=O)c1nc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(C)n1COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1nc(CO)c(C)n1COCC[Si](C)(C)C
Reaction time: 1 h

Procedure:
The compound (11.7 g) obtained in (1) was dissolved in THF (100 mL), followed by addition of TBAF (1.0 M THF solution, 24.7 mL) under stirring, and the stirring was continued for 1 hour. The reaction solution was diluted with water, followed by extraction with ethyl acetate. The combined extract was washed with saturated brine, dried over anhydrous sodium sulfate, and subsequently the solvent was distilled off under reduced pressure. The resulting residue was purified by flash chromatography (ethyl acetate/hexane=10%→100%) using amino column (product name: Hi-Flash Column 3 L, manufactured by Yamazen Corporation) to afford the title compound (5.41 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[F:24][C:25]([F:30])([F:29])[CH:26]([OH:28])[CH3:27]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:28][CH:26]([CH3:27])[C:25]([F:30])([F:29])[F:24])=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Reactant: CC(O)C(F)(F)F
Product: CCOC(=O)c1c(OC(C)C(F)(F)F)nc2ccc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 37 step A from 2,6-dichloro-4-phenyl-quinoline-3-carboxylic acid ethyl ester (prepared as described in example 11 step B, 100 mg, 0.29 mmol) and 1,1,1-trifluoro-propan-2-ol (40 mg, 0.35 mmol). Pale yellow solid (76 mg, 62%). LC-MS: 424 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5](N)=[CH:4][C:3]=1[O:9][CH3:10].[OH:11]S(O)(=O)=O.N([O-])=O.[Na+]>O>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([OH:11])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: O=S(=O)(O)O
Reactant: COc1cc(N)ccc1C
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc(O)ccc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
To a suspension of 4-methyl-3-(methyloxy)aniline (Intermediate 17, 1.86 g) in water (100 mL)/H2SO4 (30 mL, 563 mmol) at 0° C. a solution of sodium nitrite (1.029 g, 14.91 mmol) in water (10 mL) was slowly added and the reaction mixture was stirred for 30 minutes at 0° C. The reaction mixture was slowly added to a solution of H2SO4 98% (20 mL) in Water (80 mL) pre-heated at 90° C. and stirred at this temperature for 1 h. After cooling the mixture was extracted with Et2O (2×200 mL), the organic layer was dried on sodium sulphate, filtered and evaporated to afford the title compound (1.86 g) as a red/brown oil.