Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][NH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:17][C:18]([F:33])([F:32])[C:19]1[C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[N:21]([CH2:28][C:29](O)=[O:30])[N:20]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:29](=[O:30])[CH2:28][N:21]4[C:22]5[CH2:23][CH2:24][CH2:25][CH2:26][C:27]=5[C:19]([C:18]([F:32])([F:17])[F:33])=[N:20]4)[C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1CCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cn1nc(C(F)(F)F)c2c1CCCC2)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
To a mixture of 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (0.023 g, 0.11 mmol), 2-[3-(trifluoromethyl)-4,5,6,7-tetrahydroindazol-1-yl]acetic acid (0.027 g, 0.11 mmol) and NEt3 (0.050 mL, 0.36 mmol) in DMF (0.6 mL) was added HATU (0.050 g, 0.13 mmol). The mixture was stirred at rt for 30 min. It was then quenched with water. The mixture was partitioned between IPA/CHCl3 (1:2, 50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo, and purified by reverse phase HPLC to afford the desired product (0.027 g, 55%). 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.42 (dd, J=8.8, 4.4 Hz, 2H), 7.17 (dd, J=9.2, 8.0 Hz, 2H), 5.15 (s, 2H), 3.87 (m, 2H), 2.82 (t, J=6.2 Hz, 2H), 2.61 (m, 4H), 2.11 (m, 2H), 1.87 (m, 2H), 1.79 (m, 2H); MS: (ES) m/z calculated for C22H21F4N5O [M+H]+ 448.1, found 448.1.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[SH-:13].[K+:14]>C(O)(C)(C)C.CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][NH:8][C:9](=[S:13])[S-:10])=[CH:11][CH:12]=1.[K+:14]
Reactant: S=C=NCOc1ccc(Cl)cc1
Reactant: [SH-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CC(C)(C)O
Product: S=C([S-])NCOc1ccc(Cl)cc1

Procedure:
Potassium p-chlorophenoxymethyldithiocarbamate was prepared by the reaction of p-chlorophenoxymethyl isothiocyanate with potassium hydrosulfide in a mixture of t-butyl alcohol and acetone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH:25]([F:27])[F:26])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][NH:22][N:21]=1)=[CH:16][CH:15]=3.I[CH2:33][CH3:34]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH:25]([F:26])[F:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][N:22]([CH2:33][CH3:34])[N:21]=1)=[CH:16][CH:15]=3
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4cc[nH]n4)ccc3n(C(F)F)c21
Reactant: CCI
Product: CCn1ccc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C(F)F)n1

Procedure:
The process is carried out as indicated in Example 110 above, with compound A, 3-(2,4-dichlorophenyl)-9-difluoromethyl-1-methyl-6-(1H-pyrazol-3-yl)-1,9-dihydropyrido[2,3-b]indol-2-one, and iodoethane.
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[O:3][C:2]1=[O:12].[H-].[Na+].CN(C)C=O.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>O>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:1]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:4](=[O:11])[O:3][C:2]2=[O:12])=[CH:24][CH:23]=1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2c(=O)oc(=O)c3ccccc32)cc1
Temperature: 25 °C

Procedure:
To a mixture of 2H-3,1-benzoxazine-2,4(1H)-dione (18.7 g), sodium hydride (an oily, about 66%, 4.8 g) and N,N-dimethylformamide (70 ml) was added dropwise 4-methoxybenzyl chloride (17.6 ml), stirred at room temperature for 1 night. To the reaction mixture was added water and extracted with ethyl acetate. The extract was washed with water and a saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain the target compound (26.1 g).
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:9](SC)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[C:34]([F:36])[CH:35]=1)[CH2:31][NH2:32]>CO>[C:21]([O:20][C:18]([N:10]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[C:9]1[NH:32][CH2:31][C:30]1[CH:29]=[C:28]([F:27])[CH:35]=[C:34]([F:36])[CH:33]=1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Reactant: NCc1cc(F)cc(F)c1
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(NCc2cc(F)cc(F)c2)=N[C@@H](c2ccccc2)[C@H]1c1ccccc1
Temperature: 100 °C
Yield: 44.4 %

Procedure:
A mixture of intermediate 59 (0.50 g, 1.36 mmol), 3,5-difluorobenzylamine (0.481 mL, 4.07 mmol) and MeOH (0.1 mL) is heated at 100° C. for 3 days. The reaction mixture is cooled to RT, and is purified by chromatography on silica gel; gradient elution with heptane:EtOAc (75:25-60:40) gives 0.28 g of the product 89. 1H NMR (CDCl3) δ 7.10-6.60 (m, 14H), 5.45-5.35 (m, 2H), 4.75-4.55 (m, 2H), 1.16 (s, 9H); MS: m/z 464 (M++1).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:26])[C:11]2[CH:16]=[CH:15][CH:14]=[N:13][C:12]=2[O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24][CH3:25])[CH:19]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH:34]1([CH2:37][C:38](O)=[O:39])[CH2:36][CH2:35]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH:34]1([CH2:37][C:38]([NH:2][C@@H:3]2[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:26])[C:11]3[CH:16]=[CH:15][CH:14]=[N:13][C:12]=3[O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24][CH3:25])[CH:19]=3)[CH2:5][CH2:4]2)=[O:39])[CH2:36][CH2:35]1
Reactant: CSc1cccc(Oc2ncccc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Reactant: O=C(O)CC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1cccc(Oc2ncccc2C(=O)N[C@H]2CC[C@@H](NC(=O)CC3CC3)CC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-(cis-4-Aminocyclohexyl)-2-[3-(methylsulfanyl)phenoxy]nicotinamide hydrochloride (100 mg, 0.25 mmol) was dissolved in dimethylformamide (1.7 ml) and triethylamine (106 μl, 0.76 mmol) was added followed by cyclopropylacetic acid (28 mg, 0.25 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (97 mg, 0.51 mmol) and 1-hydroxybenzotriazole (38 mg, 0.28 mmol). The reaction was stirred under nitrogen at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was suspended in saturated aqueous sodium bicarbonate solution (5 ml) and extracted with ethyl acetate (3×10 ml). The organic phase was washed with brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was triturated with diethyl ether to give N-{cis-4-[(cyclopropylacetyl)amino]cyclohexyl}-2-[3-(methylsulfanyl)phenoxy]nicotinamide (99 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:14]O.C(N(CC)CC)C.S([Cl:27])(C)(=O)=O>C(Cl)Cl>[Cl:27][CH2:14][C:3]1[C:2]([CH3:1])=[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(CO)cccc1N1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(CCl)cccc1N1CCOCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
(2-methyl-3-morpholinophenyl)methanol (0.468 g, 2.26 mmol) was dissolved in dry DCM (14 mL) with triethylamine (0.669 mL, 4.82 mmol) and this stirred solution was cooled at 0° C. in an ice bath. Mesyl chloride (0.415 g, 3.62 mmol) was added dropwise and the reaction was allowed to reach rt overnight. The mixture was diluted in DCM (25 mL), washed with water (20 mL) and the water re-extracted with DCM (20 mL). The combined organics were dried over Na2SO4, filtered and the solvent removed under vacuum to afford 4-(3-(chloromethyl)-2-methylphenyl)morpholine as a crude oil (0.5 g, 98% yield).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:40])[C@@H:6]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:7][C:8]1[CH:31]=[CH:30][C:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][C@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19](O)=[O:20])=[O:14])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].[NH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([NH:49][C@@H:50]([CH2:54][S:55][C:56]([C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:51]([NH2:53])=[O:52])=[O:48].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:4][C:5](=[O:40])[C@H:6]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13](=[O:14])[NH:15][CH2:16][CH2:17][C@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19]([NH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([NH:49][C@@H:50]([CH2:54][S:55][C:56]([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[C:51]([NH2:53])=[O:52])=[O:48])=[O:20])=[CH:30][CH:31]=1)[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
Reactant: NCCCCCC(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(N)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCCCC(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(N)=O)cc1)NC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
457 mg (0.81 mmol) of the compound from example 2A was dissolved in 15 ml dichloromethane. 384 mg (0.81 mmol) of the compound from example 21A, 141 μl (0.81 mmol) N,N-diisopropylethylamine and 307 mg (0.81 mmol) HATU were added. The reaction mixture was heated for 30 min in a sealed tube at 60° C. in a microwave synthesizer. From the reaction mixture the solvent was removed under reduced pressure. The raw product was purified in two portions by preparative RP-HPLC on a C18 column with a water methanol gradient from 9/1 to 1/9. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 255 mg (0.22 mmol, 28% of theory) of the desired product.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.[NH2:16][C@@H:17]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1)[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[O:29]=[C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27](=[O:28])[N:19]1[CH2:18][C@@H:17]([NH:16][C:7]([C:5]1[S:6][C:2]([CH3:1])=[C:3]([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=2)[CH:4]=1)=[O:9])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1sc(C(=O)O)cc1-c1ccnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1sc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
To a 50 mL round-bottomed flask was added 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (200 mg, 0.90 mmol) [Prepared according to the procedure of Example 151], 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (291 mg, 0.87 mmol) [Prepared according to the procedure of preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-fluoro-L-phenylalanine (5.03 g, 17.8 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (512 mg, 1.09 mmol) in Chloroform (9 mL). DIEA (790 μL, 4.52 mmol) was added and the mixture stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (250 mg, 50%): LC-MS (ES) m/z=503 (M+H)+.
Reaction SMILES: CO.Cl([O-])(=O)(=O)=O.[CH2:8]([C:10]1([C:27]#[N:28])[C:19]2[NH+:14]([CH2:15][CH2:16][C:17]3[C:18]=2[N:20]=[C:21]2[C:26]=3[CH:25]=[CH:24][CH:23]=[CH:22]2)[CH2:13][CH2:12][CH2:11]1)[CH3:9].[B-].[Na+]>C(Cl)Cl>[CH2:8]([C:10]1([C:27]#[N:28])[CH:19]2[N:14]([CH2:15][CH2:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][C:18]=32)[CH2:13][CH2:12][CH2:11]1)[CH3:9]
Reactant: CCC1(C#N)CCC[NH+]2CCC3=c4ccccc4=NC3=C21
Agent: [B-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CO
Solvent: ClCCl
Product: CCC1(C#N)CCCN2CCc3c([nH]c4ccccc34)C21
Temperature: 5 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
In a 1-liter round-bottomed flask there were placed 200 ml methanol, 100 ml methylene chloride and 13.5 g (0.036 mole) of the perchlorate of step (c) above. The flask was cooled to about 5° C. and 5 g of sodium borohydrate were added in small quantities. The solution was then stirred for 2 hours at room temperature, concentrated, washed with water and extracted with methylene chloride. After drying and removing the solvent, there were obtained 8 g of yellow crystals, recrystallized from isopropyl ether, melted at 160° C. (yield 80%). The results of analysis are as follows:
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[CH:15]1([CH2:20][CH2:21][C:22](Cl)=[O:23])[CH2:19][CH2:18][CH2:17][CH2:16]1>N1C=CC=CC=1>[C:1]([C:5]1[C:6]([NH:14][C:22](=[O:23])[CH2:21][CH2:20][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)CCC1CCCC1
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Solvent: c1ccncc1
Product: CC(C)(C)c1c(NC(=O)CCC2CCCC2)nn2cccnc12
Yield: 77.6 %

Procedure:
A mixture from Example 105B (71.2 mg, 0.37 mmol) and 3-cyclopentylpropionyl chloride (94.4 mg, 0.59 mmol) in pyridine (2 mL) was stirred at ambient temperature for 5 h. The mixture was concentrated. Purification by reverse phase HPLC afforded 90.3 mg (77%) of the title compound. 1H NMR (300 MHz, DMSO-d6): δ ppm 1.04-1.15 (m, 2H), 1.44-1.81 (m, 18H), 2.27-2.31 (m, 2H), 6.99 (dd, J=7.0, 3.9 Hz, 1H), 8.48 (dd, J=3.9, 1.9 Hz, 1H), 8.92 (dd, J=7.1, 1.7 Hz, 1H), 9.67 (br s, 1H); MS (DCI) m/z 315 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([O:5][CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])=[O:4].[H][H]>[Pd]>[F:1][C:2]([F:14])([F:15])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:4]
Reactant: C=CCCCCC=COC(=O)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Product: CCCCCCCCOC(=O)C(F)(F)F

Procedure:
The resultant 1,7-octadienyl trifluoroacetate was hydrogenated at 150 psig of hydrogen at ambient temperature using 5% palladium on BaSO4 to produce trifluoroacetoxyoctane.
Reaction SMILES: [NH2:1][C:2]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:6]2[O:7][CH2:8][CH:9]3[CH:13]=[CH:12][CH2:11][N:10]3[C:5]2=[CH:4][CH:3]=1.[Br:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl.N1C=CC=CC=1>[Br:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[S:27]([NH:1][C:2]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:6]2[O:7][CH2:8][C:9]3[N:10]([CH:11]=[CH:12][CH:13]=3)[C:5]2=[CH:4][CH:3]=1)(=[O:29])=[O:28]
Reactant: COC(=O)c1c(N)ccc2c1OCC1C=CCN21
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCc1cccn1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.8 %

Procedure:
Methyl 7-amino-3a,4-dihydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-6-carboxylate (Intermediate 17, 0.370 g) was suspended in a mixture of DCM (6 mL) and pyridine (2.43 mL) and 2-bromo-4-fluorobenzenesulfonyl chloride (0.493 g) was added. The resultant deep red solution was stirred at room temperature overnight then concentrated in vacuo. The residue was diluted with DCM and water and passed through a phase separator. The organic layer was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 5-30% to give methyl 7-(2-bromo-4-fluorobenzenesulfonylamino]-4H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-6-carboxylate (0.107 g) as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:14])=O>C(Cl)(Cl)Cl.CN(C)C=O>[I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=C(O)c1ccccc1I
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1ccccc1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-iodobenzoic acid (5.00 g, 20.1 mmol) in chloroform (50 ml) were added oxalyl chloride (1.9 ml, 21.7 mmol) and N,N-dimethylformamide (5 drops with Pasteur pipette) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure and ethyl acetate (5 ml) was added to the residue to give a solution of 2-iodobenzoyl chloride in ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:6][CH2:5]2.[CH3:17]I>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:17])=[C:7]([N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:6][CH2:5]2
Reactant: Fc1ccc2c(c1)CCC(N1CCCC1)=C2
Reactant: CI
Solvent: C1CCOC1
Product: CC1=C(N2CCCC2)CCc2cc(F)ccc21

Procedure:
To 6-fluoro-2-pyrrolidinyl-3,4-dihydronaphthalene (13 g; 60.8 mmol) in 200 ml of dry tetrahydrofuran (THF) was added methyliodide (30 ml; 482 mmol) and the mixture was refluxed for 2 hours. The reaction mixture was allowed to cool with stirring while crystallization took place. The solids were collected by filtration to afford the subtitle compound.
Reaction SMILES: Cl.[F:2][C:3]1[CH:24]=[C:23]([OH:25])[CH:22]=[C:21]([F:26])[C:4]=1[CH2:5][N:6]1[C:10]2[N:11]=[C:12]([NH2:20])[N:13]=[C:14]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[C:9]=2[N:8]=[N:7]1.[CH3:27]I>CN(C=O)C.O>[F:2][C:3]1[CH:24]=[C:23]([O:25][CH3:27])[CH:22]=[C:21]([F:26])[C:4]=1[CH2:5][N:6]1[C:10]2[N:11]=[C:12]([NH2:20])[N:13]=[C:14]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[C:9]=2[N:8]=[N:7]1
Reactant: CI
Reactant: Nc1nc(-c2ccco2)c2nnn(Cc3c(F)cc(O)cc3F)c2n1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(F)c(Cn2nnc3c(-c4ccco4)nc(N)nc32)c(F)c1
Reaction time: 0.17 h
Yield: 100.1 %

Procedure:
A solution of 3-(2,6-difluoro-4-hydroxybenzyl)-7-(2-furyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine hydrochloride (130 mg, 0.34 mmol) in DMF (5 mL) at 0° C., was treated with CsCO3 (223 mg, 0.68 mmol), stirred for 10 min, treated with methyl iodide (21 μL, 0.34 mmol) and stirred at room temperature for 30 min. The reaction mixture was diluted with water (10 mL) and filtered to give the title compound (122 mg, 100%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[CH2:10]([O:12][CH2:13][CH2:14]Br)[CH3:11].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:10]([O:12][CH2:13][CH2:14][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1)[CH3:11]
Reactant: OCc1ccc(O)cc1
Reactant: CCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCOc1ccc(CO)cc1
Temperature: 90 °C
Reaction time: 72 h

Procedure:
A mixture of 4-hydroxybenzyl alcohol (3.00 g), 2-bromoethyl ethyl ether (4.1 ml), potassium carbonate (6.68 g) and DMF (30 ml) was stirred at 90° C. for 3 days. The reaction mixture was mixed with water and was extracted with ethyl acetate. The organic layer was washed with a 1 N aqueous solution of sodium hydroxide and an aqueous saturated solution of sodium chloride, and was dried with magnesium sulfate. After concentration under reduced pressure, the residue was subjected to separation and purification using column chromatography (ethyl acetate/hexane 1:2→1:1) to obtain 4-(2-ethoxyethoxy)benzyl alcohol (2.45 g) as a light yellow, oily substance.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH:8]=[N:9][OH:10])[CH2:3]1.[CH2:11]([N:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19])[CH:12]=[CH2:13]>>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH2:13][CH:12]([CH2:11][N:14]3[CH2:18][CH2:17][CH2:16][C:15]3=[O:19])[O:10][N:9]=2)[CH2:3]1
Reactant: CN1CCCC(C=NO)C1
Reactant: C=CCN1CCCC1=O
Product: CN1CCCC(C2=NOC(CN3CCCC3=O)C2)C1
Yield: 41.1 %

Procedure:
The desired compound was prepared by the method of Example 8 from 300 mg (2.11 mmol) of 1-methyl-piperidin-3-carbaldehyde oxime prepared in Example 5 and 528 mg (2 equivalents) of 1-allyl pyrrolidin-2-one prepared in Example 6 and purified by separation with silica gel column chromatography using chloroform/methanol (gradient of 20:1 to 10:1) as eluent to obtain 230.1 mg (41% yield) of 1-[3-(1-methyl-piperidin-3-yl)-4,5-dihydro-isoxazol-5-yl-methyl]-pyrrolidin-2-one. Subsequently, 1:1 acid addition salt with oxalic acid was obtained from the diethyl ether solution.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[CH3:18])[NH2:14]>CO.O>[NH2:10][C:11]1[CH:12]=[C:13]([NH:14][C:2]2[N:7]=[C:6]([NH:14][C:13]3[CH:15]=[CH:16][C:17]([CH3:18])=[C:11]([NH2:10])[CH:12]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:15]=[CH:16][C:17]=1[CH3:18]
Reactant: Cc1ccc(N)cc1N
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CO
Solvent: O
Product: Cc1ccc(Nc2ncc(F)c(Nc3ccc(C)c(N)c3)n2)cc1N
Temperature: 70 °C

Procedure:
2,4-Dichloro-5-fluoropyrimidine (50 mg, 0.30 mmol) was dissolved in a mixture of MeOH (1 ml) and H2O (0.1 ml). 3-amino-4-methylaniline (146 mg, 1.2 mmol) was added and the mixture was refluxed for 20 hours (70° C. oil-bath temperature). The mixture was cooled to 22° C., concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHCl3-Acetone, 2:1) to give N2,N4-bis(3-amino-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 8.11 (d, 1H, J=5.1 Hz), 7.98 (bs, 1H) (7.68 (dd, 1H, J=2.4, 8.1 Hz), 7.40-7.55 (m, 4H), 2.43 (s, 3H), 2.42 (s, 3H); LCMS: purity: 95.0%; MS (m/e): 338.66 (M+, 70).