Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[C:18]([N:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH:30]3[CH2:32][CH2:31]3)[CH2:22][CH2:21]2)=[O:19])[C:8]([Cl:33])=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[CH3:68][O:69][C:70](=[O:73])[CH2:71][NH2:72]>CN(C)C=O>[CH3:68][O:69][C:70](=[O:73])[CH2:71][NH:72][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([Cl:33])[C:9]([O:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[C:18]([N:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH:30]3[CH2:31][CH2:32]3)[CH2:22][CH2:21]2)=[O:19])=[CH:10][C:2]=1[Cl:1]
Reactant: O=C(O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Reactant: COC(=O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 82 %

Procedure:
To a solution of 0.18 g (0.37 mmol) 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid in 2 mL N,N-dimethylformamide were added 0.148 g (0.39 mmol) 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, commercially available, CAS RN 148893-10-1) and 0.25 mL (1.49 mmol) N,N-diisopropylethylamine. To the light brown solution 0.049 g (0.39 mmol) glycine methyl ester hydrochloride (commercially available, CAS RN 5680-79-5) was added and the solution was stirred at room temperature for 2.5 hours. The solution was poured on water and extracted three times with ethyl acetate. The combined organic layers were washed twice with water and brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The resulting powder was purified by silica gel chromatography using a MPLC system (10 g silica gel column, CombiFlash Companion, Isco Inc.) with a gradient of n-heptane:ethyl acetate (100:0 to 0:100) to yield 0.169 g (82%) of the desired compound as a light brown solid. MS (ESI): m/z=555.12 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[N:16][N:17]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[C:18]=3[CH:19]=[CH:20][CH:21]=2)=[O:12])[CH:6]=[CH:5][N:4]=1.Cl.[NH+]1C=CC=CC=1>C(OCC)(=O)C.O>[O:2]=[C:3]1[CH:8]=[C:7]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[N:16][N:17]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[C:18]=3[CH:19]=[CH:20][CH:21]=2)=[O:12])[CH:6]=[CH:5][NH:4]1
Reactant: COc1cc(CNC(=O)c2cccc3c2cnn3-c2ccc(F)cc2)ccn1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NCc1cc[nH]c(=O)c1)c1cccc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(4-Fluoro-phenyl)-1H-indazole-4-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide (38 mg, 0.10 mmol) and pyridinium hydrochloride (117 mg, 1.01 mmol) were heated to 125° C. in a sealed tube. After 10 minutes, the mixture was cooled to room temperature and diluted with ethyl acetate (3 mL) and water (3 mL). The organic layer was washed with water (3×3 mL) and concentrated at 45° C. under a stream of nitrogen. The residue was dissolved in CH2Cl2 (3 mL) and concentrated (repeated 3 times). The solid was triturated with ether (3 mL), filtered and air dried to afford the title compound as a white solid.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([NH:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]3[C:13]=2[C:14]2[CH:28]=[C:27]([CH3:29])[CH:26]=[N:25][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[CH:30]1([C:33](Cl)=[O:34])[CH2:32][CH2:31]1>C1COCC1>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([N:21]([CH3:22])[C:33]([CH:30]3[CH2:32][CH2:31]3)=[O:34])[C:18]([O:23][CH3:24])=[C:17]3[C:13]=2[C:14]2[CH:28]=[C:27]([CH3:29])[CH:26]=[N:25][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1cccc(-c2cc(NC)c(OC)c3[nH]c4ncc(C)cc4c23)c1
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1cccc(-c2cc(N(C)C(=O)C3CC3)c(OC)c3[nH]c4ncc(C)cc4c23)c1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
To a solution of Compound 252 (150 mg, 0.37 mmol) in dry THF (3 mL) was added cyclopropylcarbonyl chloride (34 μL, 0.37 mmol) at 0° C. Slowly the temperature was raised to room temperature and stirred for an additional hour. Reaction was quenched with aqueous NaHCO3 solution and extracted with EtOAc, washed with brine, dried over Na2SO4 and finally purified preparative HPLC to provide Compound 253 (132 mg, 75%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.63 (br. d, J=8.1 Hz, 2H) 0.80 (br. s., 2H) 1.18 (t, J=7.45 Hz, 3H) 1.48 (td, J=8.02, 3.92 Hz, 1H) 2.27 (s, 3H) 3.26 (s, 3H) 3.41 (q, J=7.45 Hz, 2H) 3.98 (s, 3H) 7.17 (s, 1H) 7.54 (s, 1H) 7.88 (t, J=7.71 Hz, 1H) 8.04 (d, J=8.08 Hz, 2H) 8.14 (s, 1H) 8.31 (d, J=1.26 Hz, 1H) 12.31 (s, 1H); [M+H] calc'd for C26H28N3O4S, 478.2; found, 478.3.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].C([Li])CCC.CCCCCC.[CH3:20][C:21]1[CH:22]=[C:23]([O:26][C:27]=1[CH3:28])[CH:24]=[O:25].O>O1CCCC1>[CH3:20][C:21]1[CH:22]=[C:23]([CH:24]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[CH3:8])[OH:25])[O:26][C:27]=1[CH3:28]
Reactant: Cc1cc(C=O)oc1C
Reactant: Cc1ccncc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: Cc1ccncc1C(O)c1cc(C)c(C)o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 28.4 %

Procedure:
3-Bromo-4-methylpyridine (500 mg) was dissolved in tetrahydrofuran (15 ml) under an argon atmosphere to prepare a solution. A 1.6 M n-butyllithium/hexane solution (2 ml) was added dropwise to the solution at −78° C., and the mixture was then stirred at −78° C. for 30 min. A solution of 4,5-dimethylfurfural (350 mg) in tetrahydrofuran (2 ml) was added dropwise thereto, and the temperature of the reaction solution was raised to room temperature while stirring. Water was added to the reaction solution to stop the reaction, and the solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-ethyl acetate to give (4,5-dimethylfuran-2-yl)-(4-methylpyridin-3-yl)-methanol (174 mg, yield 28%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5](/[C:8](=[N:11]/[S:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])/[CH2:9][CH3:10])=[CH:4][CH:3]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[BH4-].[Li+]>C1COCC1>[Br:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]([NH:11][S:12]([C:14]([CH3:15])([CH3:17])[CH3:16])=[O:13])[CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: CC/C(=N\S(=O)C(C)(C)C)c1ccc(Br)nc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@H](NS(=O)C(C)(C)C)c1ccc(Br)nc1
Reaction time: 6 h

Procedure:
To a chilled (−78° C.) solution of 2-methyl-propane-2-sulfinic acid [1-(6-bromo-pyridin-3-yl)-prop-(E)-ylidene]-amide (10.4 g, 32.78 mmol) in THF (150 mL) was added a 1 M solution of L-Selectride (33.0 mL, 33.0 mmol) in THF. The reaction was monitored by TLC (ethyl acetate-ether 3:7) indicating a single diastereomer (when compared to a mixture of diastereomers prepared by a reduction of 2-methyl-propane-2-sulfinic acid [1-(6-bromo-pyridin-3-yl)-prop-(E)-ylidene]-amide with lithium borohydride in THF). After 6 hours, the mixture was quenched with saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (2×50 mL), brine (50 mL), dried over magnesium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography eluting with ether-dichloromethane (0:100, then 5:95, then 1:9, then 2:8). The material from the chromatography was triturated with ether to afford in two crops material which by 1H NMR is consistent with a single diastereomer however an impurity is present by TLC (ethyl acetate-ether 3:7). This material and the filtrate was purified by silica gel chromatography separately using ethyl acetate-dichloromethane (0:100, then 4:96, then 8:98, then 12:88, then 2:8, then 3:7, then 4:6). The material from the two purifications was combined and crystallized from dichloromethane-hexanes-ether to afford in 3 crops 2-methyl-propane-2-sulfinic acid [(S)-1-(6-bromo-pyridin-3-yl)-propyl]-amide.
Reaction SMILES: C(O[C:4](=[O:26])[C:5]([N:7]([C:14]1[C:19]([CH:20]([CH3:22])[CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=1[CH:23]([CH3:25])[CH3:24])C1C=CC=CC=1)=[O:6])C.[NH2:27][C:28]1[CH:33]=[CH:32][C:31](C)=[CH:30][C:29]=1[OH:35].[CH2:36](N(CC)CC)C>C1(C)C=CC=CC=1>[CH:20]([C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:23]([CH3:24])[CH3:25])[C:14]=1[NH:7][C:5](=[O:6])[C:4]([NH:27][C:28]1[CH:33]=[C:32]([CH3:36])[CH:31]=[CH:30][C:29]=1[OH:35])=[O:26])([CH3:21])[CH3:22]
Reactant: CCN(CC)CC
Reactant: Cc1ccc(N)c(O)c1
Reactant: CCOC(=O)C(=O)N(c1ccccc1)c1c(C(C)C)cccc1C(C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(O)c(NC(=O)C(=O)Nc2c(C(C)C)cccc2C(C)C)c1
Yield: 89.7 %

Procedure:
N-(2,6-Diisopropylphenyl)-oxanilic acid ethyl ester (5.14 g, 18.5 mmol, 1.0 eq) and 2-amino-5-methylphenol (2.28 g, 18.5 mmol, 1 eq) were dissolved in toluene (50 ml), forming a suspension. To this suspension was then added triethylamine (2.6 ml, 18.5 mmol, 1 eq). The suspension was then heated to reflux, causing the solids to dissolve. After heating at reflux overnight, the product precipitated. At this point, ethyl acetate was added until the precipitate redissolved. The solution was then washed with 2 M HCl solution (2×100 ml). The aqueous layer was then washed with ethyl acetate, and the combined organic layers were washed with brine (100 ml), and dried over MgSO4. The solvent was then removed under reduced pressure, leaving a yellowish solid. The yellowish solid was then recrystallized from toluene, producing a product, white crystalline solid (5.90 g, 16.6 mmol, 90% yield). 1H NMR (300 MHz, CDCl3) δ 9.58 (s, 1H), 8.81 (s, 1H), 7.92 (s, 1H), 7.37 (t, J=7.8 Hz 1H), 7.27 (d, J=0.9 Hz, 1H), 7.23 (d, J=7.8 Hz, 2H), 6.97 (dd, J=8.1, 2.1 Hz, 1H), 6.90 (d, J=8.1 Hz, 1H), 3.02 (septet, J 6.6, 2H), 2.29 (s, 3H), 1.22 (d, J=7.2, 12H); 13C NMR (75 MHz, CDCl3) δ 158.8, 158.2, 146.0, 130.7, 129.4, 128.7, 124.0, 123.8, 122.6, 119.1, 29.2, 23.9, 20.7. Anal. Calcd for C21H26N2O3: C, 71.16; H, 7.39; N, 7.90. Found: C, 70.85; H, 7.68; N, 7.73.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:15]2[N:14]=[C:13]([CH3:16])[N:12]([CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C:11]=2[C:10](=[O:25])[NH:9][C:8]1=[O:26].[H-].[Na+].[C:29]([O:32][C@@H:33]([CH3:39])[CH2:34][CH2:35][CH2:36][CH2:37]Br)(=[O:31])[CH3:30].C(OCC)(=O)C>CS(C)=O>[C:29]([O:32][C@@H:33]([CH3:39])[CH2:34][CH2:35][CH2:36][CH2:37][N:9]1[C:10](=[O:25])[C:11]2[N:12]([CH2:17][O:18][C:19](=[O:24])[C:20]([CH3:22])([CH3:23])[CH3:21])[C:13]([CH3:16])=[N:14][C:15]=2[N:7]([CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[C:8]1=[O:26])(=[O:31])[CH3:30]
Reactant: Cc1nc2c(c(=O)[nH]c(=O)n2Cc2ccco2)n1COC(=O)C(C)(C)C
Reactant: CC(=O)O[C@@H](C)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(=O)O[C@@H](C)CCCCn1c(=O)c2c(nc(C)n2COC(=O)C(C)(C)C)n(Cc2ccco2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.5 %

Procedure:
To a stirring solution of 3-(2-Furylmethyl)-7-pivaloyloxymethyl-8-methylxanthine (0.65 g, 1.8 mmol) in dimethyl sulfoxide (20 ml) was added sodium hydride in one portion. After 30 minutes, (S)-5-acetoxy-1-bromohexane (0.48 g, 2.16 mmol) was added neat. After stirring at ambient temperature for 20 hours, the reaction was quenched by addition of water (70 ml) and then extracted with ethyl acetate (3×35 ml). The combined extracts were washed with saturated aqueous sodium chloride solution (30 ml), dried over sodium sulfate and concentrated to give a yellow oil. Flash chromatography on silica gel eluting with ethyl acetate gave (S)-1-(5-Acetoxyhexyl)-3-(2-furylmethyl)-7-pivaloyloxymethyl-8-methylxanthine (0.43 g) as a yellow oil. The product oil was dissolved in methanol (20 ml) and treated with a sodium methoxide solution (25 wt. % in MeOH, 0.98 ml, 4.3 mmol). After stirring at ambient temperature for 48 hours, the solution was diluted with ethyl acetate (40 ml) and quenched with water (20 ml). The organic phase was washed with saturated aqueous sodium chloride solution (20 ml), dried over sodium sulfate and concentrated to give a yellow solid. Column chromatography on silica gel eluting with 10% methane ethyl acetate gave (S)-3-(2-furylmethyl)1-(5-hydroxyhexyl)-8-methylxanthine CT2412S (80 mg) as a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[OH-].[Na+].[OH:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.[CH3:17][N:18]=[C:19]=[O:20]>>[CH3:17][NH:18][C:19]([N:2]1[CH2:3][CH2:4][S:5][CH:13]1[C:12]1[CH:15]=[CH:16][C:9]([OH:8])=[CH:10][CH:11]=1)=[O:20]
Reactant: NCCS
Reactant: CN=C=O
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CNC(=O)N1CCSC1c1ccc(O)cc1
Yield: 68 %

Procedure:
5.68 g of cysteamine hydrochloride, 2 g of sodium hydroxide, 6.1 g of 4-hydroxybenzaldehyde and 3.5 g of methyl isocyanate are treated in the same manner as described in paragraph 2. 8.1 g of N-methyl-2-(4-hydroxyphenyl)thiazolidine-3-carboxamide are obtained. Yield: 68.1%.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH3:9])=[O:7])=[CH:4][C:3]=1[C:19]1[CH:20]=[N:21][C:22]([C:26]#[N:27])=[CH:23][C:24]=1[CH3:25].[C:28]([O-:31])([O-])=O.[K+].[K+].[C:34](OCC)(=O)[CH3:35]>CN(C=O)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:34][CH2:35][CH2:28][OH:31])[CH3:9])=[O:7])=[CH:4][C:3]=1[C:19]1[CH:20]=[N:21][C:22]([C:26]#[N:27])=[CH:23][C:24]=1[CH3:25]
Reactant: O=C([O-])[O-]
Reactant: CCOC(C)=O
Reactant: Cc1cc(C#N)ncc1-c1cc(C(=O)N(C)c2ccccc2O)ccc1Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C#N)ncc1-c1cc(C(=O)N(C)c2ccccc2OCCCO)ccc1Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 4-chloro-3-(6-cyano-4-methyl-pyridin-3-yl)-N-(2-hydroxy-phenyl)-N-methyl-benzamide 8-1 (50 mg, 0.13 mmol), 4-bromopropanol (18 μL, 0.2 mmol) and K2CO3 (55 mg, 0.40 mmol) in DMF (0.4 mL) was stirred at room temperature for 14 hrs. Ethyl acetate was added and the combined organic layers were washed with water, dried over Na2SO4, then purified by silica gel column chromatography eluting with ethyl acetate/hexane (2/3) up to 100% EtOAc to yield 4-chloro-3-(6-cyano-4-methyl-pyridin-3-yl)-N-[2-(3-hydroxy-propoxy)-phenyl]-N-methyl-benzamide (30 mg). Example 1. MS [M+H]+: 436.1; tR=2.19 min. (method 1)
Reaction SMILES: [C:1]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][C:19](O)=[O:20])=[CH:15][CH:14]=[C:13]([Cl:22])[CH:12]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(C#N)(=O)(OCC)O[CH2:25]C.C([N:35]([CH2:38][CH3:39])[CH2:36][CH3:37])C.O>CN(C=O)C>[C:1]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][C:19]([N:35]1[CH2:36][CH2:37][CH2:25][CH2:39][CH2:38]1)=[O:20])=[CH:15][CH:14]=[C:13]([Cl:22])[CH:12]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(=O)(C#N)OCC
Reactant: CCN(CC)CC
Reactant: O=C(O)Cc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccccc1)c1[nH]c2cc(Cl)ccc2c1CC(=O)N1CCCCC1
Yield: 8.2 %

Procedure:
A solution of (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid (Example 2, 200 mg, 0.64 mmol), diethyl phosphorocyanidate (DEPC, 0.12 ml, 0.76 mmol) and triethylamine (0.11 ml, 0.76 mmol) in DMF (3.0 ml) was stirred at room temperature for 5 min. The mixture was then poured into water (20 ml) and the orange precipitates were collected by filtration to give 20 mg (11%) of the title compound as orange solids.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C@@H:23]3[C@@H:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][C:26]4([CH2:28][CH2:27]4)[CH2:25][NH:24]3)=[O:22])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C=O.[C:40](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(OCC)(=O)C>[CH3:40][N:24]1[C@H:23]([C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]([CH3:1])[CH:11]=3)=[CH:15][CH:16]=2)=[O:22])[C@@H:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][C:26]2([CH2:27][CH2:28]2)[CH2:25]1
Reactant: Cc1cc(COc2ccc(NC(=O)[C@H]3NCC4(CC4)C[C@@H]3C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(COc2ccc(NC(=O)[C@@H]3[C@@H](C(=O)OC(C)(C)C)CC4(CC4)CN3C)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
To a solution of tert-butyl (6S,7S)-6-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}amino)carbonyl]-5-azaspiro[2.5]octane-7-carboxylate (140 mg, 0.27 mmol) in methanol (3.0 mL) was added formaldehyde (37% solution in water, 0.5 mL) and sodium triacetoxyborohydride (0.25 g, 1.2 mmol). The mixture was then stirred at room temperature for 2 h. The reaction was diluted with ethyl acetate, washed with saturated NaHCO3, water and brine. Dried and concentrated. tert-butyl (6S,7S)-5-methyl-6-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}amino)carbonyl]-5-azaspiro[2.5]octane-7-carboxylate (105.0 mg) was obtained by column using CH2Cl2/Methanol (10%). ESI (M+H)+ 516.5.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:7]=[C:8]([Br:12])[CH:9]=[CH:10][CH:11]=1.[C:13]([N:16]1[CH2:24][CH2:23][CH:19]([C:20](Cl)=[O:21])[CH2:18][CH2:17]1)(=[O:15])[CH3:14]>>[Br:12][C:8]1[CH:9]=[CH:10][C:11]([C:20]([CH:19]2[CH2:18][CH2:17][N:16]([C:13](=[O:15])[CH3:14])[CH2:24][CH2:23]2)=[O:21])=[C:6]([F:5])[CH:7]=1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: Fc1cccc(Br)c1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)N1CCC(C(=O)c2ccc(Br)cc2F)CC1
Yield: 19 %

Procedure:
To a stirred suspension of 21.1 g of aluminum chloride and 63 ml of 3-fluorobromobenzene was added, portionwise, 16.0 g of 1-acetylisonipecotoyl chloride. The reaction mixture was stirred under reflux for 4 hrs. Most of the supernatant 3-fluorobromobenzene was decanted and ice water was added. The aqueous mixture was extracted with dichloromethane and the extract was washed with water, dried over anhydrous magnesium sulfate and the solvent concentrated to give an oil. The oil was triturated with ether and a solid separated out. Recrystallization of the solid from cyclohexane gave 4.9 g (19%) of product. Recrystallization from cyclohexane yielded the analytical sample, mp 111°-113° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[C@H:4]([CH3:12])[CH2:3]1.C(N(CC)CC)C.[CH3:21][N:22]1[CH:26]=[C:25]([C:27](Cl)=[O:28])[C:24]([C:30]([F:33])([F:32])[F:31])=[N:23]1>CN(C)C1C=CN=CC=1.C1COCC1>[CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH:11][C:27]([C:25]3[C:24]([C:30]([F:33])([F:32])[F:31])=[N:23][N:22]([CH3:21])[CH:26]=3)=[O:28])[CH:7]=[CH:8][CH:9]=2)[C@H:4]([CH3:12])[CH2:3]1
Reactant: Cn1cc(C(=O)Cl)c(C(F)(F)F)n1
Reactant: C[C@@H]1CC(C)(C)c2cccc(N)c21
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H]1CC(C)(C)c2cccc(NC(=O)c3cn(C)nc3C(F)(F)F)c21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.5 %

Procedure:
Into a solution composed of 0.15 g of (R)-1,1,3-trimethyl-4-aminoindane (optical purity: 99% ee), 0.13 g of triethylamine, 5 mg of 4-dimethylaminopyridine and 1 mL of THF, a solution of 0.18 g of 1-methyl-3-trifluoromethylpyrazole-4-carbonyl chloride in THF was dropped under ice cool. The mixture was stirred at room temperature for 15 minutes, then, to the reaction mixture was added ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution and saturated saline sequentially, then, dried over magnesium sulfate and concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography to obtain 0.18 g of (R)-(−)-N-(1,1,3-trimethylindan-4-yl)-1-methyl-3-trifluoromethylpyrazole-4-carboxamide (hereinafter, referred to as present carboxamide compound (1)) (optical purity: 99% ee).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[O-:12].[K+].Cl[CH2:15][C:16]([C:18]1[CH:23]=[C:22]([CH:24]([CH3:26])[CH3:25])[C:21]([OH:27])=[C:20]([CH:28]([CH3:30])[CH3:29])[CH:19]=1)=[O:17].C(N(CC)CC)C.Cl>O.CN(C)C=O>[OH:27][C:21]1[C:22]([CH:24]([CH3:26])[CH3:25])=[CH:23][C:18]([C:16](=[O:17])[CH2:15][O:12][N:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]2=[O:1])=[CH:19][C:20]=1[CH:28]([CH3:30])[CH3:29]
Reactant: O=C1c2ccccc2C(=O)N1[O-]
Reactant: CC(C)c1cc(C(=O)CCl)cc(C(C)C)c1O
Agent: Cl
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1cc(C(=O)CON2C(=O)c3ccccc3C2=O)cc(C(C)C)c1O
Yield: 44 %

Procedure:
A mixture of 3.03 g (15 mmol) of potassium 1,3-dioxo-1,3-dihydro-isoindol-2-olate [prepared according to P. Consonni, D Favara, A. Omodei-Salé, G. Bartolini, A. Ricci, J. Chem. Soc., Perkin Trans. 2, 1983, 967-973], 3.82 g (15 mmol) of 2-chloro-1-(4-hydroxy-3,5-di-iso-propyl-phenyl)-ethanone, 2.3 ml of triethylamine and 100 ml of dimethylformamide is stirred at room temperature and under nitrogen atmosphere for 1.5 hours. Then the mixture is poured onto 500 ml of water containing 9 ml of 2N HCl and is extracted with ethyl acetate. The collected organic phases are washed with water, dried and evaporated. The resulting crude product is recrystallized from ethyl acetate and hexane to give 2.52 g of compound 114, m.p. 136-139°.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.O.C[CH2:12][O:13]CC.[CH3:16]O>Cl[Ti](Cl)(Cl)Cl>[I:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([O:13][CH3:12])[O:7][CH3:16])=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=Cc1ccc(I)cc1
Reactant: CCOCC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Product: COC(OC)c1ccc(I)cc1
Reaction time: 0.25 h
Yield: 96 %

Procedure:
A solution of 4-iodobenzaldehyde (10.0 g, 43.1 mmol) in MeOH (150 mL) was treated with TiCl4 (80 μL, 430 μmol) under argon for 15 min. TEA (0.2 mL) was added. After 15 min, water and Et2O were added. The organic layer was collected, dried (Na2SO4), filtered, and concentrated to give a pale yellow oil (11.5 g, 96%): 1H NMR δ 3.30 (s, 6H), 5.34 (s, 1H), 7.19 (d, J=8.4 Hz, 2H), 7.70 (d, J=8.4 Hz, 2H); 13C NMR δ 52.4, 94.3, 102.1, 128.6, 137.1, 137.6.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[C:10]([C:14]([NH:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:15])[NH:11]2)=[C:7]([CH3:23])[CH:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>C(#N)C.O>[CH:17]1([NH:16][C:14]([C:10]2[NH:11][C:12]3[C:8]([CH:9]=2)=[C:7]([CH3:23])[CH:6]=[C:5]([O:4][CH2:3][CH2:2][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:13]=3)=[O:15])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cc1cc(OCCBr)cc2[nH]c(C(=O)NC3CCCCC3)cc12
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(OCCN2CCOCC2)cc2[nH]c(C(=O)NC3CCCCC3)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.8 %

Procedure:
To a stirred solution of 6-(2-bromoethoxy)-N-cyclohexyl-4-methyl-1H-indole-2-carboxamide (I-9A-c: 0.1 g, 0.26 mmol) in acetonitrile (5 mL) at 0° C. was added Cs2CO3 (172.7 mg, 0.53 mmol) followed by morpholine (46.12 mg, 0.53 mmol) dropwise. The resulting reaction mixture was stirred at room temperature for 16 h, diluted with water (10 mL) and extracted with ethyl acetate (2×20 mL). The combined ethyl acetate layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to afford 70 mg (70%) of N-cyclohexyl-4-methyl-6-(2-morpholinoethoxy)-1H-indole-2-carboxamide (9A) as a white solid.