Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:13](N1C=CN=C1)(N1C=CN=C1)=[S:14]>C(Cl)Cl>[Cl:12][C:5]1[CH:4]=[CH:3][C:2]([N:1]=[C:13]=[S:14])=[CH:7][C:6]=1[C:8]([F:9])([F:10])[F:11]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: ClCCl
Product: FC(F)(F)c1cc(N=C=S)ccc1Cl
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a 0° C. solution of 5-amino-2-chlorobenzotrifluoride (0.932 g, 4.76 mmol) in 30 mL CH2Cl2 was added 1,1′-thiocarbonyldiimidazole (0.976 g, 1.15 mmol). The reaction was warmed to RT and stirred for 45 min. The reaction was stirred for an additional 1 h, during which additional 1,1′-thiocarbonyldiimidazole (0.50 g and 0.20 g) was added at 30 min intervals. The reaction was concentrated down to a small volume and purified by short column silica gel chromatography using EtOAc:hexanes (15:75), to obtain the title compound.
Reaction SMILES: C[O:2][P:3]([O:6][CH3:7])[O:4][CH3:5].Cl[CH2:9][C:10]([O:12][CH3:13])=[O:11]>>[CH3:13][O:12][C:10](=[O:11])[CH2:9][P:3]([O:6][CH3:7])([O:4][CH3:5])=[O:2]
Reactant: COP(OC)OC
Reactant: COC(=O)CCl
Product: COC(=O)CP(=O)(OC)OC
Yield: 75.4 %

Procedure:
682 g (5.5 M) of trimethylphosphite have been slowly added (21/2 h) to 272 g (2.5 M) of methyl chloroacetate preliminarly heated to 118°. The temperature of the reaction mixture rose at the end of the addition to 125° and was kept at this value for 2 h, whereupon 962 g of raw material was isolated on distillation. A further distillation allowed the obtainment of 344 g (yield 75%) of methyl-dimethylphosphonoacetate having b.p. 125°/8 Torr.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]4[C:31](I)=[CH:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:23]4=[N:24][C:25]=3[CH:26]3[CH2:28][CH2:27]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:40][C:41]1[CH:42]=[C:43]([CH:61]=[C:62]([F:64])[CH:63]=1)[CH2:44][N:45]1[C:49]([CH3:50])=[C:48](B2OC(C)(C)C(C)(C)O2)[C:47]([CH3:60])=[N:46]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]4[C:31]([C:48]5[C:47]([CH3:60])=[N:46][N:45]([CH2:44][C:43]6[CH:61]=[C:62]([F:64])[CH:63]=[C:41]([F:40])[CH:42]=6)[C:49]=5[CH3:50])=[CH:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:23]4=[N:24][C:25]=3[CH:26]3[CH2:28][CH2:27]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nn(Cc2cc(F)cc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cc4c(I)cn(C(=O)OC(C)(C)C)c4nc3C3CC3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1nn(Cc2cc(F)cc(F)c2)c(C)c1-c1cn(C(=O)OC(C)(C)C)c2nc(C3CC3)c(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc12
Yield: 45.1 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 5-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)-6-cyclopropyl-3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (intermediate 57) (120 mg, 0.186 mmol) was coupled with 1-(3,5-difluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 24) (97.24 mg, 0.27 mmol) in sodium carbonate (59.1 mg, 0.483 mmol), Pd(PPh3)2Cl2 (6.5 mg, 0.009 mmol), 1,2-dimethoxyethane/water (15/2 ml) to afford 62 mg (45% yield) of titled compound. MS: m/z=739.2 (M+1).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[NH:10]N.O=[C:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(O)C>C(O)(=O)C>[Br:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]2[C:4]=1[NH:10][C:13]1[CH:14]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:15][CH2:16][CH2:17][C:18]2=1
Reactant: CCOC(=O)CC1CCCCC1=O
Reactant: NNc1ccc(F)cc1Br
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)CC1CCCc2c1[nH]c1c(Br)cc(F)cc21
Yield: 29.5 %

Procedure:
To a suspension of 7.24 g of (2-bromo-4-fluorophenyl)hydrazine hydrochloric acid salt in 100 mL of acetic acid, 5.5 g of ethyl 2-(2-oxocyclohexyl)-acetate was added. The resulting mixture was heated to reflux for 1 h. Then 10 mL of ethanol was added and the reaction mixture was heated at reflux overnight. The solvent was evaporated and the residue was diluted with EtOAc and washed with saturated aqueous NaHCO3 solution, water, and brine successively. The organic layer was separated and dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was purified by flash chromatography over silica gel (5% EtOAc/hexane) to afford 3.12 g of desired compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])[CH2:3]1>C(#N)C>[OH:1][CH:2]1[CH2:3][C:4]([CH3:11])([CH3:10])[N:5]([CH2:7][C:2]#[C:3][CH2:4][N:5]2[C:6]([CH3:9])([CH3:8])[CH2:7][CH:2]([OH:1])[CH2:3][C:4]2([CH3:11])[CH3:10])[C:6]([CH3:9])([CH3:8])[CH2:7]1
Reactant: CC1(C)CC(O)CC(C)(C)N1
Solvent: CC#N
Product: CC1(C)CC(O)CC(C)(C)N1CC#CCN1C(C)(C)CC(O)CC1(C)C
Yield: 45.8 %

Procedure:
) A solution of 12.6 g (42.2 mmol) of N-n-butyl-N-[ 1-(2-hydroxyethyl)-2,2,6,6-tetramethylpiperidin-4-yl]acetamide [Example 1bη2] in 180 ml of 2N hydrochloric acid is refluxed for 48 hours. The reaction mixture is then cooled 0°-5 C. and, after addition of 40 ml of 30% sodium hydroxide solution, extracted twice with toluene. The organic phases are washed with water, combined, dried over sodium sulfate, and concentrated on a vacuum rotary evaporator. Chromatography of the residue on silica gel with the solvent system ethyl acetate/ethanol/triethylamine=50:2:1 yields 8.1 g (68%) of 2-(4-n-butylamino-2,2,6,6-tetramethylpiperidin-1-yl) ethanol (208) as a white powder of m.p. 106°-111° C. Analysis: calcd: C 70.26%; H 12.58%; N 10.92%. found: C 70.42%; H 12.85%; N 11.00%. ##STR65## τ) 833 g (5.30 mol) of 4-hydroxy-2,2,6,6-tetramethylpiperidine and 418 g (1.05 mol) of 2-butyne-1,4-diol-ditosylate [C.A. Registry No. 6337-59-3] in 3.6 1 of acetonitrile are placed, under argon, in a round-bottomed flask equipped with magnetic stirrer and condenser. The reaction mixture is refluxed overnight, then cooled, poured on ice and extracted repeatedly with ethyl acetate. The organic phases are combined, dried over sodium sulfate and concentrated on a vacuum rotary evaporator. Crystallisation of the residue from ethanol yields 295 g (76%) of 1,4-bis(4-hydroxy-2,2,6,6-tetramethylpiperidin-1-yl)-but-2-yne (209), m.p. 203.4° C., in the form of white crystals. Analysis: calcd: C 72.48%; H 11.06%; N 7.68%. found: C 72.52%; H 11.12%; N 7.75%. ##STR66## κ) The HALS diol (210) is known and described in U.S. Pat. No. 4,569,997 (Ciba-Geigy, Example 1, column 14). ##STR67## λ)1.) 9.15 g (50 mmol) of adipyl dichloride are added dropwise at 0°-5° C., under nitrogen, to a stirred solution of 22.2 g (105 mmol) of 4-n-butylamino-2,2,6,6-tetramethylpiperidine IEP-A-302 020, Example 1, page 41 in 70 ml of triethylamine and 150 ml of toluene. After c. 30 minutes the reaction mixture is heated to c. 100° C. and stirred for 90 minutes at this temperature. The resultant dense suspension is thereafter cooled to room temperature, filtered to remove the salts, and the filtrate is concentrated on a vacuum rotary evaporator. Chromatography of the residue on silica gel with the solvent system ethyl acetate/ethanol/triethylamine=20:1:1 and crystallisation of the pure fractions from hexane yields 17.15 g (64%) of N,N'-di-n-butyl-N,N'-bis-(2,2,6,6-tetramethyl-4-piperidinyl)hexane diamide as a white powder; m.p. 134°-144° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=3)[N:17]=[C:16](Cl)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[CH2:30][CH3:31].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=3)[N:17]=[C:16]([N:35]3[CH2:36][CH2:37][N:32]([CH2:29][CH2:30][CH3:31])[CH2:33][CH2:34]3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(-c3ccc(F)c(Cl)c3)nc(Cl)n2)CC1
Reactant: CCCN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCCN1CCN(c2nc(-c3ccc(F)c(Cl)c3)cc(N3CCN(C(=O)OC(C)(C)C)CC3)n2)CC1

Procedure:
Heat a solution of 4-[2-chloro-6-(3-chloro-4-fluoro-phenyl)-pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (2.5 g, 5.9 mmol), N-propylpiperazine (5.9 mmol) and DIEA (11.7 mmol) in DMA at 100° C. for 16 h. Cool, partition between 10% NaOH and EtOAc and wash the organic layer with additional NaOH solution (3×). Dry the organic layer (Na2SO4) and concentrate under reduced pressure to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5]Cl.[Mg].[CH3:12][C:13]([CH3:15])=[O:14].Cl>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][C:13]([CH3:15])([OH:14])[CH3:12])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CC(C)=O
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)(O)Cc1ccc(Cl)c(Cl)c1
Yield: 56.2 %

Procedure:
A solution of 3,4-dichlorobenzylchloride (49.2 g, 0.254 mole) in dry ether (125 ml) was added dropwise during one hour to magnesium (6.08 g, 0.250 mole) in a three-necked flask equipped with stirrer and reflux condenser. Refluxing was continued until all the magnesium was dissolved and the solution was then cooled. Acetone (15.0 g, 0.258 mole) was added dropwise and the solution heated to reflux for three hours. After cooling the reaction mixture was poured out on ice (125 ml) and concentrated hydrochloric acid (23 ml). The phases were separated and the organic layer was washed with water, dried (Na2SO4) and evaporated in vacuum. The residual oil was distilled affording 1-(3,4-dichlorophenyl)-2-methyl-2-propanol (bp. 81°-83° C./0.2 mm Hg; 31.3 g, 57% yield). After several recrystallizations from petroleum ether the compound melted at 40°-41° C. The substituted propanol above (21.9 g, 0.100 mole) was mixed with dimethylaniline (12.4 g, 0.102 mole) and ether (50 ml). The solution was cooled and α-bromopropionyl bromide (21.4 g, 0.099 mole) was added dropwise during 40 minutes. Stirring at room temperature for 48 hours gave a crystalline precipitate of dimethylaniline hydrobromide, which was filtered off and washed with ether. The etheral solutions were combined and evaporated in vacuo. The residual oil was distilled affording 2-bromopropanoic acid 1-(3,4-dichlorophenyl)-2-methyl-2-propylester (bp. 135°-143° C./0.2 mm Hg; 19.2 g, 55% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([C:17]#[C:18][CH3:19])=[O:16].[C:20]([Mg]Br)#[C:21][CH3:22]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([C:20]#[C:21][CH3:22])([C:17]#[C:18][CH3:19])[OH:16]
Reactant: CC#C[Mg]Br
Reactant: CC#CC(=O)c1cc(-c2cccc(Cl)c2)ccc1N
Product: CC#CC(O)(C#CC)c1cc(-c2cccc(Cl)c2)ccc1N

Procedure:
Following the procedure of Example 41, (4-amino-3′-chloro-biphenyl-3-yl)-propynyl-methanone (mp 112-114° C.; MS ((+) ESI) m/z 270/272 (M+H)+) was treated with propynylmagnesium bromide to give (4-amino-3′-chloro-biphenyl-3-yl)-dipropynyl-methanol which was reacted with 1,1′-carbonyldiimidazole to afford the title compound. Yellow solid: mp 151° C. (decomposed); 1H-NMR (DMSO-d6) δ10.8 (s, 1H), 7.71 (dd, 1H, J=8.52,1.94 Hz), 7.69 (m, 2H), 7.61 (d, 1H, J=7.64 Hz), 7.50 (t, 1H, J=7.85 Hz), 7.43 (d, 1H, J=7.99 Hz), 7.06 (d, 1H, J=8.23 Hz), 2.0 (s, 6H); MS (APCI) m/z 336 ([M+H]+, 20%).
Reaction SMILES: [CH:1]([C:4]1[N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH:23][C:24]([NH:26][S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])=[O:25])=[CH:17][CH:16]=2)[C:7]2=[N:8][C:9]([CH3:13])=[CH:10][C:11]([CH3:12])=[C:6]2[N:5]=1)(C)[CH3:2].[C:37](Cl)(=O)[CH2:38]CCC>>[CH2:1]([C:4]1[N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH:23][C:24]([NH:26][S:27]([C:30]3[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=3)(=[O:29])=[O:28])=[O:25])=[CH:17][CH:16]=2)[C:7]2=[N:8][C:9]([CH3:13])=[CH:10][C:11]([CH3:12])=[C:6]2[N:5]=1)[CH2:2][CH2:37][CH3:38]
Reactant: CCCCC(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3c(C(C)C)nc4c(C)cc(C)nc43)cc2)cc1
Product: CCCCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 5 of Example 1 from 2-{4-[(3-amino-5-bromo-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol (step 4 of Example 9) and pentanoyl chloride.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][CH3:17]>>[CH2:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)[CH2:16][CH3:17]
Reactant: CCCOCCCCCCl
Reactant: O=C1CCNCC1
Product: CCCOCCCCCN1CCC(=O)CC1

Procedure:
1-(5-Propoxypentyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-5-propoxypentane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14](=[O:16])[CH3:15])=[CH:8][CH:7]=1)CCC.Br[C:26]1[N:27]=[C:28]([N:36]2[CH2:41][CH2:40][N:39]([CH2:42][CH3:43])[CH2:38][CH2:37]2)[C:29]2[C:34]([CH:35]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:42]([N:39]1[CH2:38][CH2:37][N:36]([C:28]2[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:35]=[C:26]([C:6]3[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][C:14](=[O:16])[CH3:15])=[CH:10][CH:11]=3)[N:27]=2)[CH2:41][CH2:40]1)[CH3:43]
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(CCC(C)=O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCN1CCN(c2nc(-c3ccc(CCC(C)=O)cc3)cc3ccccc23)CC1
Yield: 62.7 %

Procedure:
4-(4-Tributylstannylphenyl)-2-butanone (2.46 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (1.41 g) were heated under reflux in the presence of tetrakistriphenylphosphinepalladium(0) (0.22 g) in xylene in nitrogen atmosphere overnight. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted in 2N hydrochloric acid, and the resulting aqueous layer was washed with ethyl acetate, adjusted to pH 10 with a 8N aqueous solution of sodium hydroxide, and then extracted with ethyl acetate. The extract was washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (toluene/acetone system), to give 1-(4-ethylpiperazin-1-yl)-3-[4-(3-oxobutyl)phenyl]isoquinoline (1.07 g) as a pale yellow viscous oil.
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.N([O-])=O.[Na+].[BrH:17]>O.[Cu]Br>[Br:17][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Br
Reactant: COc1ccc2nc(N)sc2c1
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2nc(Br)sc2c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
[(2-(6-Methoxybenzothiazolyl))carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester ##STR32## Slurry 2-amino-6-methoxybenzothiazole (0.255 mol) in water (325 mL), heat to reflux and add 48% hydrobromic acid (130 mL). Maintain at reflux for 20 minutes, cool to 0° C. and add a solution of sodium nitrite (17.56 g, 0.255 mol) in water (90 mL), maintaining a temperature of 0° C. Stir at 0° C. for 15 minutes and add by dropwise addition (while keeping cold) to a rapidly stirring mixture of copper (I) bromide (42.03 g,0.293 mol) in 48% hydrobromic acid (86 mL) and water (225 mL). Stir at room temperature for 20 minutes. Allow to stand overnight, extract into methylene chloride and dry (MgSO4). Evaporate the solvent in vacuo and purify by chromatography to give 2-bromo-6-methoxybenzothiazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:4]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:35]2[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=2)[CH2:38]Cl)[CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32]>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:38][C:37]2[CH:40]=[CH:41][CH:42]=[C:35]([C:27]3[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:25]([O:24][CH3:23])[CH:26]=3)[CH:36]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1cc(-c2cccc(CCl)c2)cc(OC)c1OC
Reactant: COc1cccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Product: COc1cccc(N(Cc2cccc(-c3cc(OC)c(OC)c(OC)c3)c2)C2CCN(C(=O)OC(C)(C)C)CC2)c1

Procedure:
4-(m-Anisidino)-1-(tert-butoxycarbonyl)piperidine (613 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (586 mg) was treated in the same manner as described in Preparation Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][CH2:6][C@H:5]([CH2:9][N:10]3[C:14]4[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=4[N:12]=[CH:11]3)[CH2:4]2)[CH2:2]1.[NH2:21][CH2:22][C:23]([CH3:29])([CH3:28])[C:24]([O:26][CH3:27])=[O:25]>C(O)(C)C>[C:19]([C:16]1[CH:17]=[CH:18][C:13]2[N:12]=[CH:11][N:10]([CH2:9][CH:5]3[CH2:6][CH2:7][CH2:8][C:3]([CH2:2][NH:21][CH2:22][C:23]([CH3:29])([CH3:28])[C:24]([O:26][CH3:27])=[O:25])([OH:1])[CH2:4]3)[C:14]=2[CH:15]=1)#[N:20]
Reactant: COC(=O)C(C)(C)CN
Reactant: N#Cc1ccc2ncn(C[C@H]3CCCC4(CO4)C3)c2c1
Solvent: CC(C)O
Product: COC(=O)C(C)(C)CNCC1(O)CCCC(Cn2cnc3ccc(C#N)cc32)C1
Yield: 66.2 %

Procedure:
A solution of 1-[(55)-1-oxaspiro[2.5]oct-5-ylmethyl]-1H-benzimidazole-6-carbonitrile (1.064 g, 3.98 mmol) and methyl 3-amino-2,2-dimethylpropanoate (0.679 g, 5.17 mmol) in isopropanol (13.27 mL) was stirred at 100° C. for 1 day. Reaction was concentrated and purified via silica gel chromatography (ISCO, 120 g silica gel column. Solvent A was DCM and solvent B was 0.1M NH3 in MeOH; 0-10% B over 15 min; 10% B over 6 min) to give methyl 3-[({3-[(6-cyano-1H-benzimidazol-1-yl)methyl]-1-hydroxycyclohexaneyl}methyl)amino]-2,2-dimethylpropanoate as a sticky solid (1.05 g, 66.1% yield). MS (m/z) 399.2 (M+H+).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([Cl:34])=[CH:12][C:13]([CH3:33])=[C:14]([NH:16][C:17]2[N:25]3[C:20]([CH2:21][O:22][CH2:23][C@H:24]3[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[N:19][N:18]=2)[CH:15]=1)(C)(C)C.Cl>CO>[Cl:34][C:11]1[CH:12]=[C:13]([CH3:33])[C:14]([NH:16][C:17]2[N:25]3[C:20]([CH2:21][O:22][CH2:23][C@H:24]3[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[N:19][N:18]=2)=[CH:15][C:10]=1[O:9][CH2:8][CH2:7][OH:6]
Reactant: Cc1cc(Cl)c(OCCO[Si](C)(C)C(C)(C)C)cc1Nc1nnc2n1[C@H](c1ccc(F)cc1)COC2
Agent: Cl
Solvent: CO
Product: Cc1cc(Cl)c(OCCO)cc1Nc1nnc2n1[C@H](c1ccc(F)cc1)COC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.8 %

Procedure:
To a stirring room temperature solution of {5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-chloro-2-methyl-phenyl}-[(R)-5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-yl]-amine (700 mg, 1.31 mmol) in MeOH (20 mL) was added 6N aqueous HCl (1.5 mL). The mixture was stirred at room temperature for 10 minutes and then concentrated to dryness under reduced pressure. The residue was partitioned between saturated aqueous sodium carbonate and EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed through silica gel (MeOH/CH2Cl2/NH4OH 5%/74.75%/0.25%) to give 520 mg (95%) of 2-{2-Chloro-5-[(R)-5-(4-fluoro-phenyl)-5,6-dihydro-8H-[1,2,4]triazolo[3,4-c][1,4]oxazin-3-ylamino]-4-methyl-phenoxy}-ethanol, MP=161-162° C., MS (M+H)=420.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[N+:12]([C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:1][C:2]1[N:3]=[C:4]([O:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: Clc1nc(Cl)c2sccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=[N+]([O-])c1cccc(Oc2nc(Cl)nc3ccsc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
The compound (2.9 g, 14.2 mmol) obtained in Step 2 was dissolved in N,N-dimethylsulfoneamide (70 mL), and 3-nitrophenol (1.9 g, 14.2 mmol) and cesium carbonate (9.2 g, 28.4 mmol) were added thereto, followed by stirring room temperature for 1 hour. After the reaction was complete, distilled water was added to the reaction mixture, and the resulting solid was filtered under a reduced pressure with washing with distilled water. The resulting solid was dried under a reduced pressure to obtain the title compound (yield: 4.0 g, 91.8%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[N:11]=[C:12]([S:20]C)[N:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[C:14]=12.[BrH:22]>CC(O)=O>[BrH:22].[NH2:19][C:15]1[C:14]2[N:13]([C:12](=[S:20])[NH:11][C:10]=2[C:2]2[NH:1][C:9]3[C:4]([CH:3]=2)=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:18]=[CH:17][N:16]=1
Reactant: CSc1nc(-c2cc3ccccc3[nH]2)c2c(N)nccn12
Agent: Br
Solvent: CC(=O)O
Product: Nc1nccn2c(=S)[nH]c(-c3cc4ccccc4[nH]3)c12
Temperature: 120 °C

Procedure:
A solution of 1-(1H-indol-2-yl)-3-(methylthio)imidazo[1,5-a]pyrazin-8-amine (250 mg, 0.85 mmol) in AcOH (10 mL) was treated with 48% hydrogen bromide (0.6 mL) and the mixture heated 120° C. for 24 h. The reaction mixture was then cooled and the suspended solid isolated by filtration and washed with hexane to afford 240 mg of 8-amino-1-(1H-indol-2-yl)imidazo[1,5-a]pyrazine-3(2H)-thione hydrobromide. 1H NMR (400 MHz, MeOD) δ ppm 6.89 (d, J=6.06 Hz, 1H), 7.03 (s, 1H), 7.17 (tt, J=7.07, 0.76 Hz, 1H), 7.31 (tt, J=7.33, 1.01 Hz, 1H), 7.52 (dd, J=0.76 Hz, 1H), 7.63-7.76 (m, 2H); MS (ES+): m/z 282.07 [MH+].
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][N:5]([CH3:10])[C:6]=1[C:7](O)=[O:8].C(N1C=CN=C1)([N:13]1C=CN=C1)=O.[Cl-].[NH4+].C(N(CC)CC)C>C(Cl)Cl>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH3:10])[C:6]=1[C:7]([NH2:13])=[O:8]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cn1ncc(I)c1C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1ncc(I)c1C(N)=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 74.9 %

Procedure:
A round-bottom flash was charged with 4-iodo-1-methyl-1H-pyrazole-5-carboxylic acid (297 g, 1.18 mol), DCM (2.97 L), and 1,1′-carbonyldiimidazole (CDI) (207 g, 97% by mass, 1.24 mol). The reaction mixture was stirred at room temperature for 45 min. Ammonium chloride (189 g, 3.53 mol) and triethylamine (498 mL, 3.53 mol) were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was suspended in H2O (˜3 L) and granulated at room temperature for 1 h. The solid was collected via filtration, washed with H2O, and dried in a vacuum oven to afford 4-iodo-1-methyl-1H-pyrazole-5-carboxamide as a colorless solid (222 g, 75% yield).