Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:27])(=[O:26])[NH:18]2)=[C:9]1[CH3:28])(C)(C)C.Cl[CH2:31][C:32]1[C:33]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[N:34][O:35][C:36]=1[CH3:37]>>[CH3:28][C:9]1[N:8]([CH2:7][C:6]([OH:5])=[O:29])[C:16]2[C:11]([C:10]=1[CH:17]1[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:27])(=[O:26])[N:18]1[CH2:31][C:32]1[C:33]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[N:34][O:35][C:36]=1[CH3:37])=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: Cc1onc(-c2ccccc2)c1CCl
Reactant: Cc1c(C2NS(=O)(=O)c3ccccc32)c2ccccc2n1CC(=O)OC(C)(C)C
Product: Cc1onc(-c2ccccc2)c1CN1C(c2c(C)n(CC(=O)O)c3ccccc23)c2ccccc2S1(=O)=O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 3, step c) and 4-chloromethyl-5-methyl-3-phenyl-isoxazole. MS: ESI (negative): 526 (M−H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]([CH2:18][C:19](O)=[O:20])[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:36]([NH:38][CH2:39][CH3:40])[CH3:37]>O1CCCC1>[CH2:36]([N:38]([CH2:39][CH3:40])[C:19](=[O:20])[CH2:18][N:17]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[N:10]=[C:9]1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:22])([F:23])[F:1])=[CH:8][CH:7]=1)[CH3:37]
Reactant: CCNCC
Reactant: O=C(O)Cn1c(-c2ccc(C(F)(F)F)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCN(CC)C(=O)Cn1c(-c2ccc(C(F)(F)F)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.5 %

Procedure:
A suspension of 2-(4-trifluoromethylphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (10.0 g, 0.0312 mole), 1,1'-carbonyldiimidazole (6.1 g, 0.0374 mole), and dry tetrahydrofuran (250 ml) was stirred at room temperature for 3 hr with a stream of nitrogen bubbling through it. An additional 6.1 g (0.0374 mole) of 1,1'-carbonyldiimidazole was added, and the suspension was stirred at room temperature under nitrogen overnight. The suspension was heated at 50° C. for 2 hours and then treated with diethylamine (7.07 g, 0.097 mole) in dry tetrahydrofuran (10 ml). The reaction mixture was heated at 50° C. for 5 hr and allowed to stand at room temperature over the weekend. The solvent was evaporated under reduced pressure, the resulting solid was triturated in water (200 ml) and filtered. The solid was dissolved in hot isopropyl alcohol, treated with charcoal and filtered while hot. Upon cooling, a solid precipitated. The solid was filtered and rinsed with isopropyl ether to give 6.4 g (55%) of white solid, mp. 140.5°-142.5° C.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[C:6]([C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:1]([NH:5][C:18](=[O:19])[C:17]1[CH:16]=[CH:15][C:14]([C:6](=[O:13])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:22][CH:21]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: O=C(Cl)c1ccc(C(=O)c2ccccc2)cc1
Reactant: CC(C)CN
Product: CC(C)CNC(=O)c1ccc(C(=O)c2ccccc2)cc1

Procedure:
N-iso-butylamine was reacted with p-benzoylbenzoic acid chloride to provide N-iso-butyl-p-benzoyl benzamide. At a 4% by weight loading in the test solution described in Example 1, a cure rate of 7.5 - 10 ft./min./lamp was observed for several samples.
Reaction SMILES: C(OC[C@@H](OC(C)(C)C)C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(N1CCOCC1)C=C2)(=[O:6])C(C)(C)C.[C:39]([O:43][C@@H:44]([C:47]1[C:48]([C:66]2[CH:71]=[CH:70][C:69]([Cl:72])=[CH:68][CH:67]=2)=[C:49]2[C:54](=[CH:55][C:56]=1[CH3:57])[N:53]=[C:52]([CH2:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[CH:51]=[CH:50]2)[CH2:45][OH:46])([CH3:42])([CH3:41])[CH3:40]>>[C:39]([O:43][C@@H:44]([C:47]1[C:48]([C:66]2[CH:71]=[CH:70][C:69]([Cl:72])=[CH:68][CH:67]=2)=[C:49]2[C:54](=[CH:55][C:56]=1[CH3:57])[N:53]=[C:52]([CH2:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[CH:51]=[CH:50]2)[C:45]([OH:6])=[O:46])([CH3:42])([CH3:40])[CH3:41]
Reactant: Cc1cc2nc(CCc3ccccc3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Reactant: Cc1cc2nc(N3CCOCC3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Product: Cc1cc2nc(CCc3ccccc3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-phenethylquinolin-6-yl)acetic acid (4.8 mg) was prepared in a similar manner as compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)acetic acid of Example 29 except using (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-phenethylquinolin-6-yl)ethanol instead of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-morpholinoquinolin-6-yl)ethanol. 1H-NMR 400 MHz (CD3OD) δ 8.21 (d, J=8 Hz, 1 H), 7.93 (s, 1 H), 7.7-7.6 (m, 4 H), 7.37 (d, J=8 Hz, 1 H), 7.3-7.15 (m, 5 H), 5.24 (s, 1 H), 3.46 (d, J=7.6 Hz, 2 H), 3.18 (d, J=7.6 Hz, 2 H), 2.76 (s, 3 H), 0.96 (s, 9 H); LCMS-ESI+ (m/z): [M+H]+ calcd for C30H31ClNO3: 488.2. Found: 488.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Li]CCCC.[C:17](=[O:19])=[O:18].O>C1COCC1>[F:11][C:9]1[CH:10]=[C:2]([C:17]([OH:19])=[O:18])[CH:3]=[C:4]2[C:8]=1[NH:7][CH:6]=[CH:5]2
Reactant: O=C=O
Reactant: Fc1cc(Br)cc2cc[nH]c12
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(F)c2[nH]ccc2c1
Reaction time: 4 h

Procedure:
To a solution of 5-bromo-7-fluoroindole 70f (1.71 mmol, 365 mg) in THF at −60° C. was added n-BuLi (1.6 M solution in hexanes, 5.2 mmol, 3.2 mL). The solution was kept at −60° C. for 4 h and was then poured onto an excess of freshly crushed dry ice. Water was added and the mixture was acidified to pH=4. The organic phase was concentrated and the residue was purified by flash column chromatography (silica gel, 35% EtOAc/hexanes) to give compound 70h.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([CH2:14][CH2:15][OH:16])(=[O:13])=[O:12])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([CH2:14][CH2:15][OH:16])(=[O:13])=[O:12])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CS(=O)(=O)CCO)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(CS(=O)(=O)CCO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.7 %

Procedure:
A suspension of 2-{[(4-Nitrophenyl)methyl]sulfonyl}ethanol (Intermediate 148, 7.64 g, 46.3 mmol theoretical) and 10 wt % Pd/C (788 mg) in MeOH was stirred under an atmosphere of H2 at room temperature for 2 h, then filtered through a pad of celite. The filtrate was concentrated in vacuo, and the orange residue was recrystallized from MeOH/Et2O to give the desired product as light yellow crystals (3.65 g, 17.0 mmol, 37% over 3 steps). MS: M(C9H13NO3S)=215.27, (M+H)+=216.0.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:26])=[CH:4][C:5]2[C:6]([CH:25]=1)=[N:7][C:8]1[N:9]([CH2:21][O:22][CH2:23][CH3:24])[CH:10]=[C:11]([C:16]([O:18]CC)=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2>O.C(O)C.[OH-].[K+]>[Cl:1][C:2]1[C:3]([F:26])=[CH:4][C:5]2[C:6]([CH:25]=1)=[N:7][C:8]1[N:9]([CH2:21][O:22][CH2:23][CH3:24])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2
Reactant: CCOCn1cc(C(=O)OCC)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Temperature: 20 °C
Yield: 72 %

Procedure:
A suspension of 6 g of 8-chloro-3-ethoxycarbonyl-1-ethoxymethyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine in 120 cm3 of water, 120 cm3 of ethanol and 47.5 cm3 of 2N aqueous potassium hydroxide solution is heated, with stirring, at a temperature close to 75° C. for 2 hours and a half. A small amount of insoluble matter is removed by filtering at the same temperature. After cooling to about 20° C., 6 cm3 of acetic acid are added to the filtrate. The precipitate obtained is drained, washed with 3 times 20 cm3 of water and recrystallized from 60 cm3 of dimethylformamide. 4 g of 8-chloro-1-ethoxymethyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid which decomposes at 285° C.
Reaction SMILES: [N:1]([C:4](=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][Cl:18])=[C:11]([O:19][CH3:20])[CH:10]=1)[C:5]([O-:7])=[O:6])=[N+]=[N-].[C:21]1(C)C(C)=CC=CC=1>>[Cl:18][CH2:17][CH2:16][O:15][C:12]1[CH:13]=[C:14]2[C:9]([CH:8]=[C:4]([C:5]([O:7][CH3:21])=[O:6])[NH:1]2)=[CH:10][C:11]=1[O:19][CH3:20]
Reactant: COc1cc(C=C(N=[N+]=[N-])C(=O)[O-])ccc1OCCCl
Reactant: Cc1ccccc1C
Product: COC(=O)c1cc2cc(OC)c(OCCCl)cc2[nH]1
Yield: 52 %

Procedure:
A warmed (40° C.) solution of the above azidocinnamate (5.08 g, 16.3 mmol) in xylenes (140 mL) was added to boiling xylenes (60 mL) over 1 h. After a further 15 min at reflux, most of the xylene was removed by distillation. The precipitate that formed in the cooled residue was isolated by filtration, washed with CHCl3 and hexanes, and crystallized from MeOH to give methyl 6-(2-chloroethoxy)-5-methoxyindole-2-carboxylate (2.423 g, 52%) as fluffy white needles, mp 164-166° C. (sublimes 110° C.). 1H NMR [(CD3)2SO] δ 11.65 (br s, 1 H, NH), 7.13 (s, 1 H, H-4), 7.03 (d, J=1.6 Hz, 1 H, H-3), 6.91 (s, 1 H, H-7), 4.24 (t, J=5.2 H, 2 H, OCH2), 3.98 (t, J=5.2 H, 2 H, CH2Cl), 3.84 3.78 (2×s, 3 H each, OCH3); 13C NMR δ 161.5 (CO2), 147.8, 145.8, 132.4, 125.5, 120.3 (C-2, 3a, 5, 6, 7a), 107.8 (C-3), 103.0 (C-4), 96.3 (C-7), 68.9 (OCH2), 55.7 (OCH3), 51.4 (CO2CH3), 42.9 (CH2Cl).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[N:4]([Si](C(C)C)(C(C)C)C(C)C)[CH:3]=1.[CH3:33][O:34][CH:35]([CH3:40])[CH2:36][CH2:37][CH:38]=[O:39]>>[CH3:33][O:34][CH:35]([CH3:40])[CH2:36][CH2:37][C:38]([C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[NH:4][CH:3]=1)=[O:39]
Reactant: COc1cc(-c2cnc3c(n2)c(I)cn3[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC
Reactant: COC(C)CCC=O
Product: COc1cc(-c2cnc3[nH]cc(C(=O)CCC(C)OC)c3n2)cc(OC)c1OC

Procedure:
4-Methoxy-1-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-pentan-1-one was prepared starting from 7-iodo-5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine and 4-methoxy-pentanal (Berichte der Deutschen Chemischen Gesellschaft [Abteilung] B: Abhandlungen (1919), 52B 1800-12) following general procedures as described in these Examples 66, to afford a brown solid. MP 150-151° C., M+H=400.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2(O)[CH2:11][O:10][CH2:9]2)[CH:5]=[C:4]([F:13])[C:3]=1[C:14]1[S:15][CH:16]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[N:18]=1.COCCN(S(F)(F)[F:33])CCOC>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([C:8]2([F:33])[CH2:11][O:10][CH2:9]2)[CH:5]=[C:4]([F:13])[C:3]=1[C:14]1[S:15][CH:16]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[N:18]=1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: COC(=O)c1csc(-c2c(F)cc(C3(O)COC3)cc2F)n1
Solvent: ClCCl
Product: COC(=O)c1csc(-c2c(F)cc(C3(F)COC3)cc2F)n1
Temperature: 25 °C

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with 3-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol (see US2012/225062) gave the title compound, after adding the following fluorination step prior to ester hydrolysis: A solution of methyl 2-(2,6-difluoro-4-(3-hydroxyoxetan-3-yl)phenyl)thiazole-4-carboxylate (50 mg) in dichloromethane (5 mL) was cooled to −78° C., then deoxo-fluor (1.5 equiv., 50 wt % solution in toluene) was added. The mixture was allowed to slowly warm to rt over 30 minutes. The reaction was then quenched by the addition of sat. NaHCO3(aq), then the mixture was diluted with EtOAc and washed with brine. The organic extracts were dried (Na2SO4) and concentrated in vacuo. Purification by CombiFlash (0 to 100% EtOAc in heptane) provided methyl 2-(2,6-difluoro-4-(3-fluorooxetan-3-yl)phenyl)thiazole-4-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:25](I)[CH3:26]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:25][CH3:26])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)cc(NC2CCCC2)c1C
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCN(c1cc(Cl)cc(C(=O)OC)c1C)C1CCCC1
Temperature: 80 °C
Yield: 14.7 %

Procedure:
To a stirred solution of methyl 5-chloro-3-(cyclopentylamino)-2-methylbenzoate (0.62 g, 2.32 mmol) in dry DMF (10 mL), cesium carbonate (3.78 g, 11.6 mmol) and ethyl iodide (5.43 g, 34.8 mmol) were added and the resulting reaction mass was heated at 80° C. for 18 h. On completion, reaction mixture was cooled to room temperature and filtered. The residue was washed with ethyl acetate and filtrate concentrated and purified by column chromatography to afford desired methyl 5-chloro-3-(cyclopentyl(ethyl)amino)-2-methylbenzoate (0.101 g, 15%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:15][CH2:14]2)=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CN(C=O)C>[CH3:24][C:22]([O:21][C:20]([NH:19][CH:16]1[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][NH:10][C:3]2[C:2]([NH:1][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:7][CH:6]=[C:5]([O:8][CH3:9])[N:4]=2)[CH2:18][CH2:17]1)=[O:26])([CH3:23])[CH3:25]
Reactant: COc1ccc(N)c(NCCN2CCC(NC(=O)OC(C)(C)C)CC2)n1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1ccc(OC)nc1NCCN1CCC(NC(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
A mixture of 1,1-dimethylethyl [1-(2-{[3-amino-6-(methyloxy)-2-pyridinyl]amino}ethyl)-4-piperidinyl]carbamate (2.8 g, 7.6 mmol), ethyl bromoacetate (0.85 ml, 1.3 g, 7.6 mmol) and potassium carbonate (2 g, 15.2 mmol) in acetonitrile (40 ml) and DMF (20 ml) was stirred under argon overnight. The mixture was filtered, washing with acetonitrile, and evaporated. The residue was dissolved in the minimum volume of DCM (20 ml) and washed with water (20 ml). The organic extract was added to a silica column which was then eluted with 0-100% ethyl acetate in hexane affording a brown oil (1.3 g, 38%).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:16]=[C:17]2[C:28]([CH3:29])=[N:27][N:26]([CH3:30])[C:18]2=[N:19][C:20]=1[NH:21][CH2:22][CH:23]1[CH2:25][CH2:24]1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.C(N(CC)CC)C.[CH:47]1([C:50](Cl)=[O:51])[CH2:49][CH2:48]1>C1COCC1.C(OCC)(=O)C>[F:38][C:2]([F:1])([F:39])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:16]=[C:17]2[C:28]([CH3:29])=[N:27][N:26]([CH3:30])[C:18]2=[N:19][C:20]=1[N:21]([CH2:22][CH:23]1[CH2:24][CH2:25]1)[C:50]([CH:47]1[CH2:49][CH2:48]1)=[O:51])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1nn(C)c2nc(NCC3CC3)c(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)cc12
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nn(C)c2nc(N(CC3CC3)C(=O)C3CC3)c(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)cc12
Temperature: 25 °C
Yield: 52.6 %

Procedure:
A mixture of (5-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-cyclopropylmethyl-amine (0.25 g, 0.45 mmol), triethylamine (0.13 g, 1.3 mmol), and cyclopropanecarbonyl chloride (0.28 g, 2.7 mmol) in THF (5 mL) was prepared in 10 mL reaction vessel and irradiated with 250 Watt microwave power, under 250 psi at 80° C. for 2 h. The vessel was cooled to RT and the reaction mixture was diluted with ethyl acetate (100 mL). The ethyl acetate layer was washed with water (3×100 mL), the organic layer was separated out, dried over sodium sulfate, and concentrated. The resulting oil was purified by column chromatography using silica gel (230-400 mesh) and eluting the column with 1% methanol in dichloromethane afforded a colorless solid (0.147 g, yield: 52.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH2:8]Cl)=[CH:4][CH:3]=1.[C:12]([N:15]1[C:28]2[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=2)[C:17]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:16]1)(=[O:14])[CH3:13].C(N(C(C)C)CC)(C)C.C(OCC)(=O)C.CCCCCC.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:12]([N:15]1[C:28]2[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=2)[C:17]2([CH2:22][CH2:21][N:20]([CH2:8]/[CH:7]=[CH:6]/[C:5]3[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:19][CH2:18]2)[CH2:16]1)(=[O:14])[CH3:13]
Reactant: ClCC=Cc1ccc(Cl)cc1
Reactant: CC(=O)N1CC2(CCNCC2)c2cc(Cl)ccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)N1CC2(CCN(C/C=C/c3ccc(Cl)cc3)CC2)c2cc(Cl)ccc21
Temperature: 50 °C
Yield: 61.3 %

Procedure:
A solution of 4-chlorocinnamyl chloride (4.0 g) in chloroform (120 ml) was added slowly to a stirred mixture of 1-acetyl-5-chlorospiro[indoline-3,4′-piperidine] (5.3 g) and diisopropylethylamine (6.7 ml) in chloroform (120 ml) under an atmosphere of nitrogen at room. The reaction was heated to 50° C. for 30 h. The reaction mixture was concentrated in vacuo to yield a red oil. Flash chromatography [SiO2; ethyl acetate-hexane-triethylamine (50:50:1)] yielded 5.1 g (68%) of the desired compound. 1H NMR (400 MHz, CDCl3) δ 5:1 mixture of rotamers. Major rotamer 1.70 (d, J=12 Hz, 2H), 2.0 (td, J=12 & 2 Hz), 2.08 (t, J=12 Hz, 2H), 2.25 (s, 3H), 3.03 (d, J=12 Hz, 2H), 3.20 (d, J=7 Hz, 2H), 3.96 (s, 2H), 6.28 (dt, J=12 & 5 Hz, 1H), 6.50 (d, J=12 Hz, 1H), 7.13 (d, J=1 Hz, 1H), 7.18 (dd, J=7 & 1 Hz, 1H), 7.3 (m, 4H), 8.15 (d, J=7 Hz, 1H). Minor rotamer (partial data) 2.42 (s, 3H), 4.00 (s, 2H). MS (ES+) 415/417/419 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:44])[CH2:15][NH:16][C:17]([C:19]2[CH:43]=[CH:42][C:22]3[N:23]([CH3:41])[C:24]([NH:26][C:27]4[S:28][C:29]5[CH:35]=[C:34]([O:36][C:37]([F:40])([F:39])[F:38])[CH:33]=[CH:32][C:30]=5[N:31]=4)=[N:25][C:21]=3[CH:20]=2)=[O:18])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:45]>>[ClH:45].[ClH:45].[O:44]=[C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH2:15][NH:16][C:17]([C:19]1[CH:43]=[CH:42][C:22]2[N:23]([CH3:41])[C:24]([NH:26][C:27]3[S:28][C:29]4[CH:35]=[C:34]([O:36][C:37]([F:40])([F:39])[F:38])[CH:33]=[CH:32][C:30]=4[N:31]=3)=[N:25][C:21]=2[CH:20]=1)=[O:18]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)N3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Agent: Cl
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)N3CCNCC3)ccc21

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide dihydrochloride (42 mg) was prepared by following General Procedure L using 4-(2-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]amino}-acetyl)-piperazine-1-carboxylic acid tert-butyl ester (63 mg), and hydrochloric acid (0.25 ml, 4.0 N solution dioxane). LC/MS: m/z 535. 1H NMR (DMSO-d6, 400 MHz): δ 9.55 (br, 1H), 9.48 (br, 1H), 8.64 (t, 1H), 8.13 (s, 1H), 7.98 (s, 1H), 7.84 (d, 1H), 7.66 (d, 1H), 7.57 (d, 1H), 7.40 (d, 1H), 4.21 (d, 2H), 3.79 (m, 2H), 3.73 (m, 2H), 3.71 (s, 3H), 3.16 (m, 2H), and 3.07 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([Cl:15])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH3:2].[N+:17]([O-])([O-:19])=[O:18].[Na+]>S(=O)(=O)(O)O>[CH2:1]([O:3][C:4](=[O:16])[NH:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([Cl:15])(=[O:13])=[O:14])=[CH:10][C:11]=1[N+:17]([O-:19])=[O:18])[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)Nc1ccc(S(=O)(=O)Cl)cc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 82.1 %

Procedure:
To a stirred suspension of (4-chlorosulfonyl-phenyl)-carbamic acid ethyl ester (5 g, Reference Example 64) in concentrated sulfuric acid (25 ml) at 0° C., was added dropwise a suspension of sodium nitrate (1.61 g) in concentrated sulfuric acid and the reaction stirred for 3 hours. The reaction mixture was then poured onto ice, the resultant precipitate collected by filtration and dried in vacuo to give (4-chlorosulfonyl-2-nitro-phenyl)-carbamic acid ethyl ester (4.80 g) as a yellow solid. LC-MS (METHOD B): RT=3.32 minutes, 307.08 (M−H)−.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C@@H:9]([NH:33]C(OC(C)(C)C)=O)[C:10](=[O:32])[NH:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH2:24][CH3:25])[CH:18]=2)[N:14]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:13]=1)(C)(C)C.[ClH:42]>O1CCOCC1>[ClH:42].[ClH:42].[NH2:33][C@H:9]([CH2:8][NH2:7])[C:10]([NH:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH2:24][CH3:25])[CH:18]=2)[N:14]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:13]=1)=[O:32]
Reactant: CCCc1cccc(-c2cc(NC(=O)[C@@H](CNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)nn2-c2ccccc2)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCCc1cccc(-c2cc(NC(=O)[C@H](N)CN)nn2-c2ccccc2)c1
Reaction time: 2 h

Procedure:
To a solution of [(R)-2-tert-butoxycarbonylamino-2-[1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-ylcarbamoyl]ethyl]carbamic acid tert-butyl ester (328 mg) in 1,4-dioxane (3 ml) was added a 4M solution of hydrogen chloride in 1,4-dioxane (3 ml) at room temperature, and the mixture was stirred for 2 hours. This reaction solution was concentrated, and then n-hexane (4 ml) was added thereto, and the mixture was stirred. The insoluble substance was collected by filtration, washed with n-hexane, and dried under reduced pressure to give the titled compound (181 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12].[N:21]1([CH2:27][CH2:28]O)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.FC1C=CC(OC2C=CC(S(N3CCC4C(=CC=C(OCCCN5CCN(C)CC5)C=4)C3C(OC)=O)(=O)=O)=CC=2)=CC=1>>[CH3:20][C:17]1[CH:16]=[CH:15][C:14]([S:11]([NH:10][CH2:9][CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[O:1][CH2:28][CH2:27][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:13])=[O:12])=[CH:19][CH:18]=1
Reactant: OCCN1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)NCCc2ccccc2O)cc1
Agent: COC(=O)C1c2ccc(OCCCN3CCN(C)CC3)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Product: Cc1ccc(S(=O)(=O)NCCc2ccccc2OCCN2CCCCC2)cc1
Yield: 69 %

Procedure:
N-[2-(2-Hydroxyphenyl)ethyl]-4-methylbenzenesulfonamide is reacted with 2-piperidin-1-ylethanol by the method described under 3C. Yield 69%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([OH:18])([CH3:17])[C:13]([F:16])([F:15])[F:14])[CH:6]=[CH:5]2.[H-].[Na+].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C1COCC1>[CH3:21][S:22]([O:18][C:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[N:8]=1)([CH3:17])[C:13]([F:15])([F:14])[F:16])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)(c1ccc2cc(Br)ccc2n1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(OS(C)(=O)=O)(c1ccc2cc(Br)ccc2n1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 6-Bromo-quinolin-2-yl-1,1,1-trifluoropropan-2-ol (5.06 g, 15.8 mmol) in THF (50 ml) was added sodium hydride (1.26 g, 31.6 mmol) portionwise at 0° C. and the mixture was stirred at room temperature for 2 hour. A solution of methanesulfonyl chloride (3.62 g, 31.6 mmol) in THF (10 ml) was added there at 0°. Then the reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched with saturated sodium bicarbonate aqueous solution, and the product was extracted with ethyl acetate which was dried over sodium sulfate. Then, filtration, evaporation, purification through silica gel column chromatography eluting with hexane/ethyl acetate (15:1 to 5:1) furnished the title compound (6.29 g, 84% yield) as a white solid. 1H NMR (300 MHz, CDCl3) ppm 2.45 (3H, s), 3.24 (3H, s), 7.81-7.86 (2H, m), 7.96-8.05 (2H, m), 8.17 (1H, d, J=8.8 Hz). MS (ESI): m/z 397, 399 (M+H)+.