Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[S:41][C:40]([CH3:42])=[N:39][C:38]=1[CH3:43]>>[CH3:42][C:40]1[S:41][C:37]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)=[C:38]([CH3:43])[N:39]=1
Reactant: Cc1nc(C)c(Br)s1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: Cc1nc(C)c(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)s1

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one and 5-bromo-2,4-dimethyl-thiazole following a procedure analogous to that described in Example 171. Mass spectrum (ESI+): m/z=465 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[C@H:7]([C@@H:16]([NH2:20])[CH:17]([CH3:19])[CH3:18])[NH:8][C:9](=[O:15])[CH:10]([OH:14])[CH2:11][CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].[C:22]([NH:29][C@H:30]([C:34](O)=[O:35])[CH:31]([CH3:33])[CH3:32])([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[C:1]([O:5][C:6](=[O:21])[CH:7]([CH:16]([NH2:20])[CH:17]([CH3:18])[CH3:19])[N:8]([C:34](=[O:35])[C@H:30]([CH:31]([CH3:32])[CH3:33])[NH:29][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C:9](=[O:15])[CH:10]([OH:14])[CH2:11][CH2:12][CH3:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCC(O)C(=O)N[C@H](C(=O)OC(C)(C)C)[C@@H](N)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCC(O)C(=O)N(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(C(=O)OC(C)(C)C)C(N)C(C)C
Reaction time: 2 h

Procedure:
The ester compound thus formed was admixed with 155.9 mg (0.718 mmol) of Boc-L-valine, 176.1 mg (1.303 mmol) of N-hydroxyl-benzotriazole and 3.5 ml of dichloromethane. The resulting reaction mixture was cooled with ice, admixed with 499.4 mg (2.605 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, stirred for 2 hours, and further stirred at room temperature for 16.5 hours. The reaction mixture was diluted with 7 ml of dichloromethane, successively washed with 6 ml of a 1% aqueous citric acid solution, 6 ml of water, 6 ml of a saturated aqueous sodium hydrogen carbonate solution and 6 ml of water, dried over anhydrous sodium sulfate, and distilled to remove the solvent therefrom so that crude Boc-L-valyl-(2RS, 3RS)-3-amino-2 hydroxypentanoyl-D-leucine t-butyl ester was obtained as an amorphous material. The crude product was used in the next reaction step without a purification operation.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[B:10]([O:19]C(C)C)([O:15]C(C)C)[O:11]C(C)C>>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([O:11][B:10]([OH:19])[OH:15])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1cccc(Br)c1
Product: COc1cccc(OB(O)O)c1
Yield: 82 %

Procedure:
3-Methoxyphenylboric acid was prepared in the same manner as described in Example 33B from 3-bromoanisole and triisopropyl borate in 82% yield. This was used in the next step without any further purification.
Reaction SMILES: [C:1]1(=[O:14])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3][NH:2]1.[H-].[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([CH2:17][N:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]3[C:1](=[O:14])[NH:2][CH2:3][CH2:4][C:5]2=3)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1NCCc2[nH]c3ccccc3c21
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: O=C1NCCc2c1c1ccccc1n2Cc1ccccc1
Yield: 41.9 %

Procedure:
2,3,4,5-Tetrahydro-1H-pyrido[4,3-b]indol-1-one (559 mg) was treated with sodium hydride (73% dispersion in oil; 197 mg) and was then stirred with benzyl bromide (513 mg) at room temperature for 30 min. Purification by FCC eluting with dichloromethan: ethanol (80:1) gave the title compound (347 mg), m.p. 209°-212°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][NH:30][CH2:31]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][N:30]([C:16]1[C:17]([F:19])=[C:18]3[C:13]([C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10][N:9]3[C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:14][C:15]=1[F:21])[CH2:31]2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Reactant: Clc1cccc2c1CNC2
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(N3Cc4cccc(Cl)c4C3)c(F)cc2c1=O
Yield: 24.5 %

Procedure:
178 mg of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 89 mg of 4-chloroisoindoline, 137 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 60 mg of the target compound.
Reaction SMILES: C(C1C=C(O)C(=CC=1)O)(C)(C)C.[C:13]1(=[O:19])[O:18][C:16](=[O:17])[CH:15]=[CH:14]1.[CH2:20]([NH2:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C=CC1C=CC=CC=1>[CH2:20]([NH:38][C:13](=[O:19])/[CH:14]=[CH:15]\[C:16]([OH:18])=[O:17])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: O=C1C=CC(=O)O1
Reactant: CCCCCCCCCCCCCCCCCCN
Agent: CC(C)(C)c1ccc(O)c(O)c1
Solvent: C=Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCNC(=O)/C=C\C(=O)O
Temperature: 85 °C

Procedure:
In a 21-4-necked glass reaction flask, supplied with dispersion wheel (circumference of 8 cm), reflux cooler, nitrogen supply pipe, thermometer and dosage device, 91.9 gr. of styrene =0.88 moles (purity >99%, stabilized with 0.005% 4-tert-butylcatechol), 79.2 gr of maleic acid anhydride =0.808 moles (purity >99%) and 215.2 gr. distilled stearyl amine =0.8 mole (Arneen 18 D , the Akzo Nobel company) are heated while stirring to a temperature of 85° C., until a clear solution of the reaction product, maleic acid monostearyl amide in styrene is formed.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[F:15])[C:8]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23](Cl)(=[O:25])[CH3:24].C(N(CC)C(C)C)(C)C>>[C:23]([O:22][C:19]1[CH:18]=[CH:17][C:16]([C:8]2[C:9]3[C:14](=[C:13]([F:15])[CH:12]=[CH:11][CH:10]=3)[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:7]=2)=[CH:21][CH:20]=1)(=[O:25])[CH3:24]
Reactant: Oc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)cc1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Oc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)cc1

Procedure:
Prepared according to Method E from 4-(1-cyclopentyl-7-fluoro-1H-indazol-3-yl)phenol (0.30 g, 1.0 mmol), acetyl chloride (0.086 mL, 1.2 mmol) and N,N-diisopropylethylamine (0.21 mL, 1.2 mmol) to give 0.31 g to the title compound as a white solid, mp 90–91° C.;
Reaction SMILES: [CH2:1]([NH2:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C@@H:16]12[C:25](=O)[O:24][C:22](=[O:23])[C@@H:17]1[CH2:18][CH:19]=[CH:20][CH2:21]2.[BH4-].[Na+].Cl>O.CC(O)C>[OH:24][CH2:25][CH:16]1[CH:17]([C:22]([NH:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:23])[CH2:18][CH:19]=[CH:20][CH2:21]1
Reactant: O=C1OC(=O)[C@@H]2CC=CC[C@H]12
Reactant: CCCCCCCCCCCCCCN
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCNC(=O)C1CC=CCC1CO
Temperature: 140 °C
Reaction time: 5 h
Yield: 93.1 %

Procedure:
1-Tetradecylamine (3.51 g) was added to cis-4-cyclohexene-1,2-dicarboxylic anhydride (2.50 g) and stirred for 5 hours at 140° C. The reaction mixture was suspended into a mixed solution of 2-propanol (125 ml) and water (21 ml) and then sodium borohydride (3.11 g) was added thereto at room temperature. After being stirred for 67.5 hours at room temperature, the reaction mixture was acidified with dilute hydrochloric acid. The resulting solid was collected by filtration under a vacuum, washed with water, and dried, thereby yielding the entitled compound (5.38 g) as white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH2:5][OH:6].Cl[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][N:10]=1.O>CN(C=O)C>[OH:6][CH2:5][CH2:4][CH2:3][O:7][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][N:10]=1
Reactant: OCCCO
Reactant: N#Cc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCCCO)nc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82.5 %

Procedure:
Sodium hydride (0.42 g, 60% suspension in mineral oil, 10.61 mmol) was added to a solution of 1,3-propanediol (2.30 mL, 31.83 mmol) in DMF (22 mL) at 0° C., and the mixture was stirred at rt for 20 minutes. To the resultant pale yellow slurry was added 6-chloronicotinonitrile (1.50 g, 10.61 mmol) in one portion. The mixture was stirred at rt for 18 h. It was then poured into water. The precipitates were filtered and the filtrate was extracted with ethyl acetate. The organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (1.56 g, 83%) as a white solid. 1H NMR (300 MHz, CD2Cl2) δ 8.47 (d, 1H), 7.82-7.79 (m, 1H), 6.84-6.82 (m, 1H), 4.53 (t, 2H), 3.75 (t, 2H), 2.06-1.99 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[N:6][C:7]=1[O:8][CH3:9].Br[CH2:12][C:13]1[C:23]([F:24])=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([F:25])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([O:10][CH2:12][C:13]2[C:23]([F:24])=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([F:25])[CH:14]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: CCOC(=O)c1cc(F)c(CBr)cc1F
Reactant: COc1ncc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1cc(F)c(COc2cnc(OC)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.2 %

Procedure:
To a solution of 5-chloro-6-methoxypyridin-3-ol (Preparation 56, 98 mg, 0.612 mmol) in acetone (10 mL) were added ethyl 4-(bromomethyl)-2,5-difluorobenzoate (Preparation 19, 171 mg, 0.612 mmol) and potassium carbonate (170 mg, 1.224 mmol). The mixture was stirred for 18 hours at room temperature under a nitrogen atmosphere. The reaction mixture was diluted with water (20 mL), and extracted with DCM (2×30 mL). Combined organic extracts were dried over sodium sulphate, and evaporated to a yellow solid. The solid was purified by silica gel chromatography eluting with DCM/heptanes (3:2) to afford the title compound as a white solid (112 mg, 51%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:50])[C:5]2[N:6]=[CH:7][N:8]([C:48]=2[N:49]=1)[C@@H:9]1[O:47][C@H:34]([CH2:35][O:36][Si:37]([CH:44]([CH3:46])[CH3:45])([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39])[C@@H:22]([O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])[C@H:10]1[O:11][Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14].[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([CH2:58][CH2:59][OH:60])=[CH:54][CH:53]=1>>[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([CH2:58][CH2:59][O:60][C:2]2[N:3]=[C:4]([NH2:50])[C:5]3[N:6]=[CH:7][N:8]([C:48]=3[N:49]=2)[C@@H:9]2[O:47][C@H:34]([CH2:35][O:36][Si:37]([CH:38]([CH3:40])[CH3:39])([CH:41]([CH3:43])[CH3:42])[CH:44]([CH3:46])[CH3:45])[C@@H:22]([O:23][Si:24]([CH:31]([CH3:32])[CH3:33])([CH:28]([CH3:29])[CH3:30])[CH:25]([CH3:26])[CH3:27])[C@H:10]2[O:11][Si:12]([CH:19]([CH3:20])[CH3:21])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:14])[CH3:15])=[CH:54][CH:53]=1
Reactant: OCCc1ccc(Cl)cc1
Reactant: CC(C)[Si](OC[C@H]1O[C@@H](n2cnc3c(N)nc(Cl)nc32)[C@H](O[Si](C(C)C)(C(C)C)C(C)C)[C@@H]1O[Si](C(C)C)(C(C)C)C(C)C)(C(C)C)C(C)C
Product: CC(C)[Si](OC[C@H]1O[C@@H](n2cnc3c(N)nc(OCCc4ccc(Cl)cc4)nc32)[C@H](O[Si](C(C)C)(C(C)C)C(C)C)[C@@H]1O[Si](C(C)C)(C(C)C)C(C)C)(C(C)C)C(C)C
Temperature: 50 °C
Reaction time: 48 h

Procedure:
A mixture of 2-chloro-2′,3′,5′-tris-O-(triisopropylsilyl)adenosine (Example 6, 5.0 g) and 15 ml of 2-(4-chlorophenyl)ethyl alcohol was purged with nitrogen and heated to 50° C. Sodium hydride (1.56 g, 60% dispersion in mineral oil) was added at a rate so as to control gas evolution. After 48 hours of heating LC and LC/MS analysis showed a mixture of products with one and two protecting groups respectively (2 isomers). The reaction mixture was allowed to cool to room temperature and carefully quenched with 40 mL of water. The resulting mixture was extracted with ethyl acetate (70 ml). The layers were separated and the aqueous layer was again extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with brine (80 mL), dried over MgSO4 and concentrated under reduced pressure to afford a clear oil (18 g). This was purified by silica gel chromatography eluting progressively with CH2Cl2, 1%, 2%, 5% and then 10% MeOH in CH2Cl2. The fractions containing the desired products were combined and concentrated to yield 3.2 g of a gummy white solid. This mixture of silylated displacement products was taken to the next step.
Reaction SMILES: [Cl:1][C:2]1([Cl:13])[CH:7]2[CH2:8][CH:4]([CH:5]=[CH:6]2)[C:3]1([C:11]#[N:12])[C:9]#[N:10].[H][H]>C(OCC)(=O)C.[Pt]>[Cl:1][C:2]1([Cl:13])[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[C:3]1([C:11]#[N:12])[C:9]#[N:10]
Reactant: N#CC1(C#N)C2C=CC(C2)C1(Cl)Cl
Reactant: [H][H]
Agent: [Pt]
Solvent: CCOC(C)=O
Product: N#CC1(C#N)C2CCC(C2)C1(Cl)Cl
Temperature: 40 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
30 g (0.14 mol) of the (IV) prepared in Example 1 are dissolved in 170 ml of ethyl acetate, the solution is introduced into an autoclave, and 2 g of 1% strength platinum on carbon are added. The mixture is warmed to 40° C., and hydrogen is forced in until a pressure of 10 bar is reached. After approx. 2 hours, the reaction is complete. The catalyst is filtered off and the solvent is evaporated. 30 g (99%) of 3,3-dichlorobicyclo[2,2,1]heptane-2,2-dicarbonitrile, m.p. 148° C., are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.Cl.[CH3:13]O>>[CH3:13][O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=1
Reactant: CO
Reactant: Nc1ccc(CC(=O)O)cc1
Agent: Cl
Product: COC(=O)Cc1ccc(N)cc1
Reaction time: 8 h
Yield: 74 %

Procedure:
To a solution of 4-aminophenylacetic acid (10 g, 66.2 mmol) in methanol (150 mL) at room temperature was added HCl conc. (37% 25 mL). The mixture became yellow and was stirred overnight. The reaction mixture was then quenched with a saturated aqueous solution of NaHCO3. The methanol was evaporated under reduced pressure and the aqueous layer was extracted several times with AcOEt. The combined organic extracts were dried over (MgSO4) and evaporated. The crude residue was purified by flash chromatography using hexane/AcOEt (4:1) as solvent mixture yielding 3 as a yellow oil (9.44 g, 74%).
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([OH:12])=O)[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[NH:45]1[CH2:59][CH2:58][CH2:57][C@H:46]1[C:47]([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:48].Cl.C(N(CC)C(C)C)(C)C>ClCCl>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([N:45]1[CH2:59][CH2:58][CH2:57][C@H:46]1[C:47]([O:49][CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)=[O:48])=[O:12])[CH2:3][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Yield: 98.5 %

Procedure:
To a stirred solution of 11.64 g of Boc-D-Cha-OH in 100 mL of dichloromethane at 0° C. was added 6.36 g of HOBt and 9.72 g of DCC. After 20 minutes a solution of 10.35 g of H-Pro-OBzl.HCl in 40 mL of dichloromethane adjusted with N,N-diisopropyl ethylamine to pH 8 was added. After 16 h the reaction mixture was filtered and the filtrate was washed successively with water, 0.1 N hydrochloric acid, water, aqueous 5% sodium hydrogencarbonate and brine. All aqueous washes were extracted twice with ethyl acetate, all organic extracts combined, dried over sodium sulfate and concentrated. To the residue was added a mixture of ethyl acetate/heptanes=1/1 (v/v), the resulting suspension filtered and the filtrate purified by chromatography on silica gel (eluent: ethyl acetate/heptanes=1/1 v/v) to yield 19.34 g of Boc-D-Cha-Pro-OBzl.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][CH:14]([N:16]4[CH2:21][CH2:20][N:19]([C:22](=[O:24])[CH3:23])[CH2:18][CH2:17]4)[CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1.[NH3:25]>C(O)(C)C>[NH2:25][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][CH:14]([N:16]4[CH2:21][CH2:20][N:19]([C:22](=[O:24])[CH3:23])[CH2:18][CH2:17]4)[CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1
Reactant: N
Reactant: CC(=O)N1CCN(C2CC(c3nc(I)c4c(Cl)nccn34)C2)CC1
Solvent: CC(C)O
Product: CC(=O)N1CCN(C2CC(c3nc(I)c4c(N)nccn34)C2)CC1
Temperature: 110 °C

Procedure:
1-{4-[3-(8-Chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclobutyl]piperazin-1-yl}ethanone (13.2 g, 0.029 mol) was dissolved in isopropyl alcohol (100 mL) into a Parr pressure reactor. The vessel was cooled to −78° C. and saturated with ammonia gas and sealed. The reaction was heated for 19 h at 110° C., at which point the reaction was cooled and the solvent concentrated in vacuo. The crude product was purified via silica gel chromatography eluting with 5-10% MeOH (7M NH3): CH2Cl2 to yield the title compounds as an off white solid; MS (ES+): m/z 440.89 (100) [MH], 441.89 (20) [MH++]; HPLC: tR=0.46 min (OpenLynx, polar—5 min); 1H NMR (CDCl3, 400 MHz) δ 2.09 (s, 3 H) 2.28-2.48 (m, 6 H) 2.54-2.71 (m, 2 H) 2.80-2.99 (m, 1 H) 3.27-3.43 (m, 1 H) 3.43-3.54 (m, 2 H) 3.56-3.70 (m, 2 H) 7.02 (d, J=5.05 Hz, 1 H) 7.16 (d, J=5.05 Hz, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[C:17](=O)[CH3:18])[CH:5]=[CH:6][CH:7]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:26].[Na+]>CO.C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH:17]([NH2:26])[CH3:18])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cc2ccccc2n1-c1cccc(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC(N)c1cc2ccccc2n1-c1cccc(F)c1
Temperature: 65 °C
Yield: 95.9 %

Procedure:
A mixture of 1-[1-(3-fluorophenyl)-1H-indol-2-yl]ethanone (0.40 g, 1.6 mmol) and ammonium acetate (1.22 g, 15.8 mmol) in methanol (5.0 mL) and acetonitrile (5.0 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling to room temperature, sodium cyanoborohydride (0.20 g, 3.2 mmol) was added to the resultant mixture. The reaction was heated at 65° C. overnight. The reaction was cooled to room temperature and quenched with saturated NaHCO3 solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give crude product (0.39 g, 97%), which was used directly in the next step. LCMS calculated for C16H13FN (M-NH2)+: m/z=238.1. Found: 238.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[NH:21])[C:10]([C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])([CH3:12])[CH3:11])=[C:4]([F:22])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:30][C:31](=[O:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33].Cl>C1(C)C=CC=CC=1.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:30][C:31]([OH:37])([C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:21]=[C:9]2[C:10]([C:13]2[C:14]([Cl:20])=[CH:15][CH:16]=[CH:17][C:18]=2[Cl:19])([CH3:11])[CH3:12])=[C:4]([F:22])[CH:3]=1
Reactant: CC(C)(C(=N)Nc1ccc(Br)cc1F)c1c(Cl)cccc1Cl
Reactant: CCOC(=O)C(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C1(O)CN(c2ccc(Br)cc2F)C(C(C)(C)c2c(Cl)cccc2Cl)=N1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 95.8 %

Procedure:
To a mixture of N-(4-bromo-2-fluorophenyl)-2-(2,6-dichlorophenyl)-2-methylpropanimidamide (48.0 g, 119 mmol), K2CO3 (41.0 g, 297 mmol) in toluene (180 mL) and THF (180 mL) at 55° C. was added slowly a solution of ethyl 3-bromo-2-oxopropanoate (23.3 mL, 166 mmol) in 24 mL of THF over 50 minutes. The reaction mixture was kept at 55° C. for 1.5 hours. A white slurry was observed. The reaction mixture was cooled to 5° C. HCl (0.5N, 450 mL) was added drop-wise (end point pH=9˜10). After addition, the suspension was cooled to 0° C. The solid was collected by filtration, washed with water (2×50 mL), and then dried in a vacuum oven at 60° C. overnight. Ethyl 1-(4-bromo-2-fluorophenyl)-2-(2-(2,6-dichlorophenyl)propan-2-yl)-4-hydroxy-4,5-dihydro-1H-imidazole-4-carboxylate (59 g, 114 mmol, 96% yield) was obtained as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 7.11 (m, 3H), 6.96 (m, 2H), 6.72 (t, 1H, J=8.28 Hz), 4.35 (m, 2H), 4.25 (d, 1H, J=10.5 Hz), 3.80 (d, 1H, J=10.8 Hz), 1.98 (s, 3H), 1.93 (s, 3H), 1.38 (t, 3H, J=7.03 Hz); 13C-NMR (CDCl3, 126 MHz) δ 173.0, 171.5, 159.8, 157.8, 137.3, 135.7, 132.1, 131.1, 128.1, 127.4, 125.6, 122.2, 120.1, 93.5, 62.5, 45.5, 30.2, 14.0; MS m/e 517.05 (M+H+); HPLC (XBridge 5μ C18 4.6×50 mm, 4 mL/min, Solvent A: 10% MeOH/water with 0.2% H3PO4, Solvent B: 90% MeOH/water with 0.2% H3PO4, gradient with 0-100% B over 4 minutes): 2.74 minutes.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1.S(OC)(O[CH3:20])(=O)=O>C1COCC1>[CH3:20][O:3][CH2:4][C:5]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1
Reactant: COS(=O)(=O)OC
Reactant: CCOC(=O)C1(CO)CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(COC)CCCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
60% NaH (40.3 mg, 1.007 mmol) was added to a cold (−20° C.) solution of ethyl 2-(hydroxymethyl)tetrahydro-2H-pyran-2-carboxylate (158 mg, 0.839 mmol) in THF (3 mL) and the mixture was allowed to warm to rt over ˜30 min. Neat dimethyl sulfate (127 mg, 1.007 mmol) was added at 0° C. and allowed to warm to rt and stirred overnight. Excess dimethyl sulfate was quenched with TEA, and then acidified with 1N HCl, product was extracted with ether, washed with water, brine and dried (MgSO4). Crude isolate was purified by silica gel FCC (0-2% MeOH in DCM) to afford ethyl 2-(methoxymethyl)tetrahydro-2H-pyran-2-carboxylate. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.34-4.22 (m, J=7.2, 7.2, 7.2, 4.1 Hz, 2H), 3.96-3.87 (m, 1H), 3.86-3.77 (m, 1H), 3.55-3.43 (m, 2H), 3.36 (s, 3H), 2.17-2.07 (m, 1H), 1.80-1.70 (m, 1H), 1.69-1.56 (m, 2H), 1.55-1.42 (m, 3H), 1.32 (t, J=7.2 Hz, 3H).