Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=O)[NH:7][N:8]1[C:17]([CH3:18])=[C:16]([Br:19])[C:15]2[C:10](=[C:11]([F:20])[CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:21])(C)(C)C.[CH:23](=O)C.C([BH3-])#N.[Na+].C(O)(=O)C>FC(F)(F)C(O)=O.[OH-].[K+]>[Br:19][C:16]1[C:15]2[C:10](=[C:11]([F:20])[CH:12]=[CH:13][CH:14]=2)[C:9](=[O:21])[N:8]([NH:7][CH2:6][CH3:23])[C:17]=1[CH3:18]
Reactant: Cc1c(Br)c2cccc(F)c2c(=O)n1NC(=O)OC(C)(C)C
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [K+]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CCNn1c(C)c(Br)c2cccc(F)c2c1=O
Reaction time: 1.5 h
Yield: 24.8 %

Procedure:
A solution of (4-bromo-8-fluoro-3-methyl-1-oxo-1H-isoquinolin-2-yl)-carbamic acid tert-butyl ester (100.0 mg, 0.2694 mmol) in trifluoroacetic acid (1 mL) was stirred at r.t. for 40 min and evaporated. LC-MS 07-07-2008 12-11-51.wiff:ca 2:1 mixture of the desired intermediate 2-amino-4-bromo-8-fluoro-3-methyl-2H-isoquinolin-1-one [B] (tR=1.01, m/z MH+271.3 & 273.3) and presumably its trifluoroacetyl derivative (tR=1.19, m/z MH+ 367.2 & 369.2). Alternatively, deprotection of BOC group was successfully carried out in conc. HCl solution in methanol under reflux (5 min). It was mixed with 2 ml methanol, 0.3 ml 20% KOH in water, refluxed for 5 min, allowed to cool and quenched with water (3 ml). The precipitate was filtered to 46.2 mg of pale yellow solid as 4:1 mixture of the above compounds. It was suspended in MeOH (3 ml), acetaldehyde (0.20 mL, 3.6 mmol) was added, followed by sodium cyanoborohydride (100.0 mg, 1.591 mmol) and acetic acid (0.4 mL, 7 mmol). It was stirred for 90 min and diluted with 5% aq. KOH (10 ml), allowed to stir for 20 min and filtered to give 20 mg of the title product. LC-MS (m/z) 299.4 & 301.4 (MH30), tR=1.42. 1H NMR (CDCl3, TMS=0 ppm): 1.21 (t, J=7.2 Hz, 3H, Et), 2.77 (overlapping s, 3H, Me), 2.68-3.2 (overlapping very br. d, 2H, Et), 5.89 (t, J=6.8 Hz, 1H, NH), 7.13 (dd, J=8.3, J (HF)=10.9, 1H, C7H), 7.63 (dt, J (d, H—F)=5.05 Hz, J (t)=8.1 Hz, 1H, C6H), 7.74 (d, J=8.3 Hz, 1H, C5H). 13C APT (CDCl3=77.44 ppm): 13.0 (Me of Et), 19.95 (Me), 46.26 (CH2), 99.72 (d, J (C—F)=3.5 Hz, C), 113.78 (d, J (C—F)=21.7 Hz, C7H), 122.24 (d, J (C—F)=4.1 Hz, C5H), 134.03 (d, J (C—F)=10.2 Hz, C6H), 138.02 (C), 142.16 (C3), 158.7 (d, J (C—F)=4.6 Hz, C), 162.56 (d, J (C—F)=264 Hz, C8F). 19F NMR (CFCl3=0 ppm): −110.92 (dd, J=4.5 Hz, J=10.9 Hz).
Reaction SMILES: O[CH2:2][NH:3][C:4](=[O:9])[C:5]([F:8])([F:7])[F:6].S(Cl)([Cl:12])=O>ClCCl>[Cl:12][CH2:2][NH:3][C:4](=[O:9])[C:5]([F:8])([F:7])[F:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(NCO)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCCl)C(F)(F)F

Procedure:
51.7 grams (g) (0.36 mole) of N-hydroxymethyl trifluoroacetamide were dissolved in 350 milliliters (ml) dichloromethane in a round-bottom flask equipped with a magnetic stirrer and reflux condenser. Thirty-three ml (0.45 mole) thionyl chloride were added dropwise with vigorous stirring. The reaction mixture was heated at reflux until the gas evolution ceased. The resulting mixture was then stripped under reduced pressure to yield the desired product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13][C:14]3[N:15]=[CH:16][N:17](C(OC(C)(C)C)=O)[CH:18]=3)[CH2:11][C@@H:10]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:9]([S:33]([CH3:36])(=[O:35])=[O:34])[CH2:8][C:7]=2[CH:37]=1)#[N:2].[SnH3]C1N=[CH:43][CH:42]=[CH:41][N:40]=1.[ClH:45].Cl.Cl.N1C=C(CN2C3C=CC(C4C=NC=CC=4)=CC=3CN(C(=O)C(F)(F)F)C(CC3C=CC=CC=3)C2)N=C1.C(C1C=CC2NC[C@@H](CC3C=CC=CC=3)N(C(=O)CC3C=CC=CC=3)CC=2C=1)#N>>[ClH:45].[ClH:45].[NH:17]1[CH:18]=[C:14]([CH2:13][N:12]2[C:6]3[CH:5]=[CH:4][C:3]([C:1]4[N:2]=[CH:43][CH:42]=[CH:41][N:40]=4)=[CH:37][C:7]=3[CH2:8][N:9]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:10]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:11]2)[N:15]=[CH:16]1
Reactant: CC(C)(C)OC(=O)n1cnc(CN2C[C@@H](Cc3ccccc3)N(S(C)(=O)=O)Cc3cc(C#N)ccc32)c1
Reactant: [SnH3]c1ncccn1
Agent: Cl
Agent: N#Cc1ccc2c(c1)CN(C(=O)Cc1ccccc1)[C@H](Cc1ccccc1)CN2
Agent: O=C(N1Cc2cc(-c3cccnc3)ccc2N(Cc2c[nH]cn2)CC1Cc1ccccc1)C(F)(F)F
Product: CS(=O)(=O)N1Cc2cc(-c3ncccn3)ccc2N(Cc2c[nH]cn2)CC1Cc1ccccc1

Procedure:
Example 332 was prepared as a yellow solid from Compound A of Example 231 and 2-stannylpyrimidine as described for Compound B of Example 231 and Compound C of Example 231. MS (M+H)+ 475.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([OH:11])[CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[C:29]3=[N:30][CH:31]=[N:32][C:33](Cl)=[C:28]3[CH:27]=[N:26]2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH2:21][CH:22]([N:25]2[C:29]3=[N:30][CH:31]=[N:32][C:33]([O:11][C:4]4[CH:3]=[C:2]([F:1])[C:9]([F:10])=[CH:8][C:5]=4[C:6]#[N:7])=[C:28]3[CH:27]=[N:26]2)[CH2:23][CH2:24]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: N#Cc1cc(F)c(F)cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4cc(F)c(F)cc4C#N)ncnc32)CC1
Yield: 13 %

Procedure:
A mixture of 4,5-difluoro-2-hydroxy-benzonitrile (Lancaster Synthesis Ltd. (Lancashire, UK; 14 mg, 0.089 mmol), 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 30 mg, 0.089 mmol), and potassium carbonate (27 mg, 0.196 mmol) in dimethylformamide (1 mL) was heated in a microwave oven at 160° C. for 10 min. Saturated sodium carbonate solution was added to the reaction mixture, and the mixture was then filtered through a pad of silica gel to remove the precipitate. The silica gel pad was washed with methanol and the solvents were evaporated from the filtrate. The residue was purified by HPLC to give 4-[4-(2-cyano-4,5-difluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (5 mg, 13%) as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH:11]=[CH:10]2.[CH3:23][NH2:24]>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([N:12]2[C:13]3[C:9](=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:24][CH3:23])=[CH:15][CH:14]=3)[CH:10]=[CH:11]2)=[CH:17][CH:18]=1
Reactant: CN
Reactant: Fc1ccc(-n2ccc3cc(OCCCCBr)ccc32)cc1
Product: CNCCCCOc1ccc2c(ccn2-c2ccc(F)cc2)c1

Procedure:
In analogy to example 3.3, 5-(4-Bromo-butoxy)-1-(4-fluoro-phenyl)-1H-indole and methylamine were converted to yield {4-[1-(4-Fluoro-phenyl)-1H-indol-5-yloxy]-butyl}-methyl-amine as colorless crystalline, mp 49-50° C., MS: 313 (MH+).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][C:10]2[C:5]3=[C:6]([N:12]([CH2:14][C:15]([O:17]CC)=[O:16])[CH:13]=[C:4]3[NH:3]1)[CH:7]=[CH:8][CH:9]=2.[OH-].[Li+:21].Cl>C1COCC1.CCO.O>[O:1]=[C:2]1[CH2:11][C:10]2[C:5]3=[C:6]([N:12]([CH2:14][C:15]([O-:17])=[O:16])[CH:13]=[C:4]3[NH:3]1)[CH:7]=[CH:8][CH:9]=2.[Li+:21]
Reactant: CCOC(=O)Cn1cc2c3c(cccc31)CC(=O)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=C([O-])Cn1cc2c3c(cccc31)CC(=O)N2
Reaction time: 0.25 h

Procedure:
To a solution of ethyl (4-oxo-4,5-dihydropyrrolo[2,3,4-ij]isoquinolin-1(3H)-yl)acetate from Step G (200 mg, 0.77 mmol) in THF (1 mL), EtOH (1 mL) and H2O (1 mL) was added 1.0 N lithium hydroxide (0.85 mL, 0.85 mmol). After 15 min, 1 N aqueous HCl was added to adjust the solution to pH 7 and the mixture was concentrated in vacuo to give the title compound. MS: m/z=231 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([N:13]2[CH:17]=NC=N2)=[N:4][C:5](=[O:12])[N:6]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH:7]=1.[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1CN>O1CCOCC1>[F:1][C:2]1[C:3]([NH:13][CH2:17][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[F:18])=[N:4][C:5](=[O:12])[N:6]([CH2:8][CH:9]([CH3:10])[CH3:11])[CH:7]=1
Reactant: CC(C)Cn1cc(F)c(-n2cncn2)nc1=O
Reactant: NCc1ccccc1F
Solvent: C1COCCO1
Product: CC(C)Cn1cc(F)c(NCc2ccccc2F)nc1=O
Temperature: 25 °C
Yield: 88.5 %

Procedure:
A solution of 5-fluoro-1-isobutyl-4-(1H-1,2,4-triazol-1-yl)pyrimidin-2(1H)-one (500 mg, 2.1 mmol) and 2-fluorobenzylamine (313 mg, 2.5 mmol) in dry 1,4-dioxane (10 mL) was heated to reflux for 1 h under nitrogen. After cooling to room temperature, the reaction mixture was concentrated in vacuo. Recrystallization from EtOAc/methyl tert-butylether afforded 5-fluoro-4-(2-fluorobenzylamino)-1-isobutylpyrimidin-2(1H)-one (545 mg, 89%) as an off white solid: mp 118-119° C.; 1H NMR (400 MHz, CDCl3) δ 7.45 (td, J=7.6, 1.7 Hz, 1H), 7.35-7.28 (m, 2H), 7.13 (ddd, J=21.9, 13.9, 7.3 Hz, 3H), 5.58 (s, 1H), 4.81 (d, J=5.4 Hz, 2H), 3.56 (d, J=7.5 Hz, 2H), 2.16 (dt, J=13.6, 6.8 Hz, 1H), 0.95 (d, J=6.7 Hz, 6H); ESIMS m/z 295 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH2:9]1.F[B-](F)(F)F.[C:20]([Si](C)(C)C)#[CH:21].CCN(CC)CC>CN(C=O)C.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.[Cu]I>[C:20]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH2:9]1)#[CH:21]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)C1(c2ccccc2Br)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#Cc1ccccc1C1(C(=O)OC)CC1
Temperature: 65 °C
Reaction time: 16 h

Procedure:
A solution of methyl 1-(2-bromophenyl)cyclopropanecarboxylate (I4) (658 mg, 2.58 mmol), PdCl2(PPh3)2 (91 mg, 0.13 mmol) t-Bu3PH.BF4 (37 mg, 0.13 mmol), CuI (25 mg, 0.13 mmol) and ethynyltrimethylsilane (0.44 mL, 3.1 mmol) in dry DMF (5.0 mL) was degassed with nitrogen for 10 minutes before the addition of Et3N (2.0 mL). After stirring at 65° C. under nitrogen for 16 hours the resulting mixture was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-20% EtOAc in petroleum benzine 40-60° C.) to give the title compound I5 as an orange oil (569 mg, 81%); 1H NMR (400 MHz, d6-DMSO) δ 7.67-7.12 (m, 4H), 3.57-3.47 (m, 3H), 1.64-1.49 (m, 2H), 1.26-1.16 (m, 2H), 0.22-0.13 (m, 9H). LCMS-A: rt 6.977 min; m/z 273 [M+H]+.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[C:9]([Si:13]([CH3:25])([CH3:24])[O:14][C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[CH:20][NH:21]2)=[CH:17][CH:16]=1)([CH3:12])([CH3:11])[CH3:10]>ClCCl>[C:9]([Si:13]([CH3:25])([CH3:24])[O:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([Cl:1])=[CH:20][NH:21]2)=[CH:17][CH:16]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc[nH]c2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(Cl)c[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
A solution of N-chlorosuccinimide (270 mg, 2 mmol) in dichloromethane (4 ml) is added within 30 min to a solution of 6-(tert-butyl-dimethyl-silanyloxy)-1H-indole (500 mg, 2 mmol) in dichloromethane (10 ml) at 0° C. under an argon atmosphere. The solution was naturally warmed to ambient temperature and stirred for 2 h. Ice water was added and the mixture was extracted two times with tert-butyl methyl ether. The combined extracts were dried over sodium sulfate and the solvent was removed under reduced pressure to give 560 mg (1.98 mmol, 98%) of the title compound as red solid which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=O)=[N:6][CH:7]=1.[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:15][C:14]2[CH:16]=[CH:17][C:11]([Cl:10])=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=Cc1ccc(Br)cn1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(NCc2ccc(Br)cn2)cc1

Procedure:
To 5-Bromo-pyridine-2-carbaldehyde (52, 1.00 g, 5.38 mmol) in acetonitrile (50.0 mL) were added p-chloroaniline (53, 0.686 g, 5.38 mmol), triethylsilane (6.00 mL, 0.0376 mol) and trifluoroacetic acid (3.00 mL, 0.0389 mol). The reaction was heated to reflux for 3 hours. The reaction was concentrated, poured into water and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a white solid (54, 0.75 g, 47.0%).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7](=[O:15])[C:6]=12.NC(C(O)=O)CCSC.CS(O)(=O)=O.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[NH2:1][C:2]1[N:3]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7](=[O:15])[C:6]=12
Reactant: COc1ccc(-n2nc3c(c2N)c(=O)[nH]c2ccccc23)cc1
Agent: CS(=O)(=O)O
Agent: CSCCC(N)C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: Nc1c2c(=O)[nH]c3ccccc3c2nn1-c1ccc(O)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
A mixture of 3-amino-2-(4-methoxyphenyl)-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (150 mg), DL-methionine (371 mg) and methanesulfonic acid (3 ml) was stirred at 100° C. for 3 hours. The reaction mixture was cooled, pH of the reaction mixture was adjusted to about 8 by adding an aqueous 20% sodium hydroxide solution and a 10% aqueous citric acid solution. The precipitated solid was collected by filtration, washed with water and then dried to obtain the target compound (132 mg).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([SH:24])=[CH:20][CH:19]=1>CN(C)C1C=CN=CC=1.C(O)C>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][C:2]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cc(Cl)nc2ccccc12
Reactant: Nc1ccc(S)cc1
Agent: CN(C)c1ccncc1
Solvent: CCO
Product: CCOC(=O)c1cc(Sc2ccc(N)cc2)nc2ccccc12
Yield: 36 %

Procedure:
2-Chloro-4-ethoxycarbonylquinoline (0.024 moles, 5.56 g), 4-aminothiophenol (0.024 moles, 3.0 g) and 4-dimethylaminopyridine (0.024 moles, 2.9 g) were stirred in 250 ml ethanol for 3 days. The reaction mixture was filtered, concentrated, ethyl acetate added, washed with water and dried over sodium sulfate. The solution was concentrated and the product purified by HPLC over silica gel eluted with 25% ethyl acetate/hexane to yield 2-(4-aminophenylthio)-4-ethoxycarbonylquinoline 2.8 g, 36%. Mass Spec (FD) 324. Calculated for C18H16N2O2S: C, 66.64; H, 4.97; N, 8.63. Found: C, 66.50; H, 5.00 N, 8.54.
Reaction SMILES: [CH3:1]I.[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8](=[S:10])[NH2:9]>CC(C)=O>[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]([S:10][CH3:1])=[NH:9]
Reactant: CI
Reactant: NC(=S)c1cccs1
Solvent: CC(C)=O
Product: CSC(=N)c1cccs1
Temperature: 23 °C
Yield: 97 %

Procedure:
Methyl iodide (66 g; 0.46 mol) is added drop wise at 0° C. to a solution of thiophene-2-carbothioamide (50 g; 0.33 mol) in 500 ml of acetone. After the addition, stirring is maintained for two hours at 23° C. The precipitate formed is filtered on frit and washed twice with 100 ml of acetone before being dried under vacuum (in a bell jar). A yellow powder is obtained with a yield of 97%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[O:21][CH3:20])=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: COc1ccccc1B(O)O
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Product: COc1ccc2c(-c3ccccc3OC)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 2-methoxy-phenylboronic acid to give [6-methoxy-1-(2-methoxy-phenyl)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 347(MH+).
Reaction SMILES: F[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[N:11]1([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:4])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: O=C(CF)c1ccccc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(CN1CCOCC1)c1ccccc1
Temperature: 110 °C

Procedure:
A mixture of 2-fluoroacetophenone (19.9 g), morpholine (21 cc) and potassium carbonate (27.6 g) in dimethyl sulphoxide (32 cc) is heated at 110° C. for 30 hours. The reaction mixture is diluted with water (100 cc) and extracted with ethyl acetate (4×100 cc); the organic solution is washed with distilled water (100 cc), dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.04-0.063 mm, diameter 9 cm, height 40 cm), eluting with a mixture of cyclohexane and ethyl acetate (80/20 by volume) and collecting 250 cc fractions. Fraction 24 to 44 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 2-(4-Morpholinyl)acetophenone (4.72 g) is obtained which is used as such for the subsequent syntheses.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:15])[CH:5]([CH:10]([CH3:14])[C:11]([CH3:13])=O)C(OC)=O.C([O-])([O-])=O.[Na+].[Na+]>>[CH3:1][O:2][C:3]1[C:4](=[O:15])[CH2:5][CH:10]([CH3:14])[C:11]=1[CH3:13]
Reactant: COCC(=O)C(C(=O)OC)C(C)C(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC1=C(C)C(C)CC1=O

Procedure:
2.16 g (10 mmol) of methyl 4-methoxy-2-[1-methylacetonyl]-acetoacetate are held at reflux temperature for 2 hours with 21.2 ml (5 mmol) of 2.5% Na2CO3 solution. The reaction mixture is extracted 3 times with 25 ml of CH2Cl2 each time. The combined organic phases are dried over magnesium sulphate and concentrated on a rotary evaporator to give 1.40 g (100%) or 2-methoxy-3,4-dimethyl-2-cyclopenten-1-one, content 96%.
Reaction SMILES: C(OC([NH:8][C:9]([CH3:59])([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][CH2:43][CH:44]([NH:51]C(OC(C)(C)C)=O)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:37]=1)[C:10]([O:12][CH2:13][C:14]1[CH:15]=[C:16]([CH:24]=[C:25]([N:27]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:28][CH2:29][CH3:30])[CH:26]=1)[C:17]([O:19]C(C)(C)C)=[O:18])=[O:11])=O)(C)(C)C.O1CCOCC1.[ClH:66]>>[ClH:66].[ClH:66].[NH2:8][C:9]([CH3:59])([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][CH2:43][CH:44]([NH2:51])[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:37]=1)[C:10]([O:12][CH2:13][C:14]1[CH:15]=[C:16]([CH:24]=[C:25]([N:27]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:28][CH2:29][CH3:30])[CH:26]=1)[C:17]([OH:19])=[O:18])=[O:11]
Reactant: CCCN(c1cc(COC(=O)C(C)(Cc2cccc(CCC(NC(=O)OC(C)(C)C)c3ccccc3)c2)NC(=O)OC(C)(C)C)cc(C(=O)OC(C)(C)C)c1)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Product: CCCN(c1cc(COC(=O)C(C)(N)Cc2cccc(CCC(N)c3ccccc3)c2)cc(C(=O)O)c1)S(C)(=O)=O
Reaction time: 16 h

Procedure:
Tert-butyl 3-({[2-[(tert-butoxycarbonyl)amino]-3-(3-{3-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}phenyl)-2-methylpropanoyl]oxy}methyl)-5-[(methylsulfonyl)(propyl)amino]benzoate (0.386 g, 0.461 mmol) was taken up in 2.0 mL HCl in dioxane (2.00 mL, 8.01 mmol, 4.0M solution). After 16 hr., the reaction was concentrated in vacuo, taken up in dichloromethane, and concentrated again (×2) to give 3-[({2-amino-3-[3-(3-amino-3-phenylpropyl)phenyl]-2-methylpropanoyl}oxy)methyl]-5-[(methylsulfonyl)(propyl)amino]benzoic acid dihydrochloride as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-])=O)=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:18].[H][H]>[Pd].C(O)C>[NH2:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH3:19])[C:6](=[O:18])[CH2:7][CH2:8]2
Reactant: CN(C)CCN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN(C)CCN1C(=O)CCc2cc(N)ccc21

Procedure:
A suspension of 1-(2-(dimethylamino)ethyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (1.48 g, 5.62 mmol) and palladium on activated carbon (10%, 300 mg, 0.28 mmol) in 20 mL ethanol was stirred under a balloon of hydrogen overnight. The suspension was filtered through a pad of celite. The filter pad was rinsed with 50 mL ethanol and the filtrate was concentrated to give a viscous oil. The crude product was used without further purification. (1.3 g, 100%). 1H-NMR (CDCl3) δ: 6.85 (d, J=8.7 Hz, 1H), 6.55 (dd, J=2.7, 8.7 Hz, 1H), 6.51 (d, J=2.7 Hz, 1H), 4.00 (t, J=7.5 Hz, 2H), 3.56 (br s, 2H), 2.80-2.75 (m, 2H), 2.60-2.55 (m, 2H), 2.47 (t, J=7.5 Hz, 2H), 2.31 (s, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([CH:19]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[OH:20])[C:16]([OH:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][CH2:28][C@@H:29]1[C@@H:34]2[CH2:35][C@@H:36]([C@H:37]([OH:50])[C:38]3[CH:47]=[CH:46][N:45]=[C:44]4[C:39]=3[CH:40]=[C:41]([O:48][CH3:49])[CH:42]=[CH:43]4)[N:31]([CH2:32][CH2:33]2)[CH2:30]1>ClCCl>[CH3:27][CH2:28][C@@H:29]1[C@@H:34]2[CH2:35][C@@H:36]([C@H:37]([OH:50])[C:38]3[CH:47]=[CH:46][N:45]=[C:44]4[C:39]=3[CH:40]=[C:41]([O:48][CH3:49])[CH:42]=[CH:43]4)[N:31]([CH2:32][CH2:33]2)[CH2:30]1.[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C@@H:15]([C@H:19]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[OH:20])[C:16]([OH:18])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(c1ccccc1OCc1ccccc1)C(O)C1CCCCC1
Agent: CC[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12
Solvent: ClCCl
Product: O=C(O)[C@@H](c1ccccc1OCc1ccccc1)[C@@H](O)C1CCCCC1
Yield: 42.4 %

Procedure:
To a solution of (2RS,3RS)-2-(2-benzyloxyphenyl)-3-cyclohexyl-3-hydroxypropionic acid (354 mg) in dichloromethane (7 ml) was added hydroquinine (326 mg) and the mixture was stirred to be a clear solution. The solvent was evaporated under reduced pressure and the residue was crystallized from ethyl acetate. Precipitates were recrystallized from a mixture of ethyl acetate and ethanol (50:1) to afford hydroquinine salt of (2S,3S)-2-(2-benzyloxyphenyl)-3-cyclohexyl-3-hydroxypropionic acid as crystals (150 mg).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]4[O:25][C:24]([C:26]([OH:28])=O)=[CH:23][C:22]=4[CH:29]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.Cl.[CH2:33]([NH:36][C:37](=[O:46])[C@H:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[NH2:39])[CH2:34][CH3:35].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[O:46]=[C:37]([NH:36][CH2:33][CH2:34][CH3:35])[CH:38]([NH:39][C:26]([C:24]1[O:25][C:21]2[CH:22]=[CH:29][C:18]([NH:17][C:15]([C:10]3[C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:30])([F:31])[F:1])=[CH:8][CH:7]=4)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:16])=[CH:19][C:20]=2[CH:23]=1)=[O:28])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(O)c1cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2o1
Reactant: CCCNC(=O)[C@@H](N)c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCNC(=O)C(NC(=O)c1cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2o1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product from step (d) (100 mg, 0.235 mmol), (S)-N-propyl-2-phenylglycinamide hydrochloride salt (1 eq.) and PyBrop (1.1 eq.) were dissolved in CH2Cl2 (2 mL), followed by the addition of diisopropylethylamine (3 eq.), and the reaction mixture was stirred at room temperature between 2 hours. The solvent was then evaporated, and the product was purified by prep-TLC using 2:1 EtOAc/hexane as eluting solvent, and the yield was 79 mg.