Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].CC(C)(OC(N[C@H](CC1C=CC=CC=1)C([O:19][C@@H:20]([CH2:32][N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[CH2:21][O:22][N:23]=[C:24]([Cl:31])[C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)=O)=O)C>CO>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[OH:19][CH:20]([CH2:32][N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[CH2:21][O:22][N:23]=[C:24]([Cl:31])[C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O[C@H](CON=C(Cl)c1cccnc1)CN1CCCCC1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CO
Product: OC(CON=C(Cl)c1cccnc1)CN1CCCCC1
Reaction time: 1 h

Procedure:
2.16 g (3.26 mmole) of (S)—N-[2-[2-(R)-(1,1-dimethylethyloxycarbonylamino)-3-phenylpropionyloxy]-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride (Z)-2-butenedioate (1:1) (see Example 18) was suspended in 40 ml of methanol and boiled for 1 hour, then evaporated to dryness. The residue was triturated with 20 ml of ethyl acetate, the precipitate was filtered, washed with ethyl acetate. This crude product was recrystallized in isopropyl alcohol to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:23]=[CH:22][CH:21]=[CH:20][C:13]=2[C:14]([NH:16][CH2:17][C:18]#[CH:19])=[O:15])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[N:24]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:29]=1)=[N+:25]=[N-:26].O.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>S([O-])([O-])(=O)=O.[Cu+2].C(O)(C)(C)C>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([NH:11][C:12]2[N:23]=[CH:22][CH:21]=[CH:20][C:13]=2[C:14]([NH:16][CH2:17][C:18]2[N:26]=[N:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:29]=3)[CH:19]=2)=[O:15])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: [N-]=[N+]=NCc1cccc(Oc2ccccc2)c1
Reactant: C#CCNC(=O)c1cccnc1Nc1cc(OC)cc(OC)c1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1cc(Nc2ncccc2C(=O)NCc2cn(Cc3cccc(Oc4ccccc4)c3)nn2)cc(OC)c1
Temperature: 25 °C
Reaction time: 11 h
Yield: 78 %

Procedure:
Compound 8 (194 mg, 1 mmol) and 3,5-dimethoxyaniline (91,153 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(3,5-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide 10i as pure product. To a solution of 2-(3,5-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide (101,150 mg, 0.48 mmol) and 1-(azidomethyl)-3-phenoxybenzene (12a, 119 mg, 0.53 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 11 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 1i (201 mg, 78%); mp: 123-125° C.; 1H NMR (300 MHz, CDCl3) δ 10.55 (s, 1H), 8.27 (dd, J=2.2, 1.5 Hz, 1H), 7.82 (dd, J=2.2, 1.5 Hz, 1H), 7.72 (t, J=6.0 Hz, 1H), 7.58 (s, 1H), 7.33-7.28 (m, 1H), 7.08 (t, J=7.5 Hz, 1H), 6.97-6.90 (m, 7H), 6.62-6.58 (m, 1H), 6.08 (t, J=2.2 Hz 1H), 5.46 (s, 2H), 4.61 (d, J=5.2 Hz, 2H), 3.80 ppm (s, 6H); MS (ESI m/z): 537 [M+H]+ Yield: 78%
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21](=[S:23])[NH2:22])[NH:6]2.[C:24]([O:29][CH2:30][CH3:31])(=[O:28])[C:25]#[C:26][CH3:27].C(P(CCCC)CCCC)CCC.O1CCCC1>C1(C)C=CC=CC=1>[CH2:30]([O:29][C:24](=[O:28])[CH2:25][CH:26]1[S:23][C:21]([C:5]2[NH:6][C:7]3[C:3]([CH:4]=2)=[C:2]([CH3:1])[CH:10]=[CH:9][C:8]=3[N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[N:22][CH2:27]1)[CH3:31]
Reactant: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(N)=S)cc12
Reactant: CC#CC(=O)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1CN=C(c2cc3c(C)ccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Yield: 64 %

Procedure:
A solution of 4-methyl-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (1.62 g), ethyl but-2-ynoate (1.2 mL) and tributylphosphine (1.1 mL) in a mixed solvent of tetrahydrofuran (30 mL)-toluene (20 mL) was stirred at room temperature for 4 hr. The reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=10:90-35:65). The obtained crystals were crystallized from ethyl acetate-hexane to give the title compound (1.35 g, yield: 64%) as pale-yellow crystals. MS:478(MH+). melting point 109-110° C.
Reaction SMILES: C=O.[CH2:3]([OH:5])[CH3:4].OC[CH2:8][NH:9][CH2:10][C:11]([NH:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])[NH:20][C:21]2=[O:24])=[CH:16][CH:15]=1)=[O:12]>O>[OH:5][CH2:3][CH2:4][N:9]1[CH2:10][C:11](=[O:12])[N:13]([C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:34])([F:33])[F:32])[NH:20][C:21]3=[O:24])=[CH:16][CH:15]=2)[CH2:8]1
Reactant: CCO
Reactant: O=C(CNCCO)Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Agent: C=O
Solvent: O
Product: O=C1CN(CCO)CN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Yield: 27 %

Procedure:
A 37% formalin aqueous solution (3.8 μl, 0.0469 mmol) was added to an ethanol solution (2 ml) that contained the 2-(2-hydroxyethylamino)-N-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]acetamide (19 mg, 0.0469 mmol) obtained in step B. The obtained mixture was stirred under heating to reflux for 3 hours. Thereafter, water was added to the reaction solution, and the mixture was then extracted with ethyl acetate. The extract was washed with water and a saturated saline solution, and was then dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=25:1), so as to obtain 7-[3-(2-hydroxyethyl)-5-oxoimidazolidin-1-yl]-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (5.2 mg, 27%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14](I)[CH3:15].[H-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:14][CH3:15])[C@@H:9]([CH3:13])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(C(=O)OC(C)(C)C)[C@@H](C)C(=O)O
Temperature: 60 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonylamino)propanoic acid (0.7 g, 3.7 mmol) and ethyl iodide (2.6 ml, 32.2 mmol) in THF (10 ml) was added sodium hydride (60% w/w dispersion in mineral oil, 576 mg, 14.4 mmol). The reaction was sealed and stirred at 60° C. overnight, then partitioned between EtOAc and H2O. The aqueous layer was acidified to pH 4 with citric acid solution and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to provide (S)-2-(tert-butoxycarbonyl(ethyl)amino)propanoic acid (700 mg, 87%) as an oil.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:17]([NH2:21])=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:22][O:23][CH2:24][CH2:25][C:26](Cl)=[O:27]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[NH:21][C:26](=[O:27])[CH2:25][CH2:24][O:23][CH3:22])[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COCCC(=O)Cl
Reactant: Nc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COCCC(=O)Nc1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
(R)—N2-Indan-1-yl-quinoline-2,5-diamine (150 mg, 0.55 mmol) was dissolved in 3 mL pyridine and 3-methoxypropionyl chloride (70 mg, 0.0.57 mmol) and 4-dimethylamino pyridine (3 mg, 0.02 mmol) were added. The reaction mixture was stirred at 80° C. overnight and quenched by addition of 50 mL water and acetic acid until pH 5. The mixture was extracted three times with ethyl acetate (50 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0→0:100 gradient). The title compound was obtained as a brown solid (59 mg, 30%), MS: m/e=362.4 (M+H−).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[CH2:42][C:43](Cl)=[O:44]>>[CH3:36][N:34]([CH3:35])[CH2:33][CH2:32][CH2:31][O:30][C:26]1[CH:25]=[C:24]([NH:23][C:19]2[N:18]=[C:17]([C:16]3[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:43](=[O:44])[CH2:42][C:38]5[S:37][CH:41]=[CH:40][CH:39]=5)[CH:7]=[CH:6][CH:5]=4)=[N:9][N:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=34)[CH:22]=[CH:21][N:20]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CN(C)CCCOc1cccc(Nc2nccc(-c3c(-c4cccc(N)c4)nn4ccccc34)n2)c1
Reactant: O=C(Cl)Cc1cccs1
Product: CN(C)CCCOc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)Cc5cccs5)c4)nn4ccccc34)n2)c1
Yield: 48 %

Procedure:
The title compound was synthesized from 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-{[3-(dimethylamino)propyl]oxy}phenyl)-2-pyrimidinamine using acylation with 2-thienylacetyl chloride as described in Example 10, Step E to yield a light brown solid in 48% yield. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.8 (s, 2H) 2.1 (s, 6H) 2.3 (s, 2H) 3.9 (s, 2H) 3.9 (d, J=6.2 Hz, 2H) 6.5 (m, 2H) 7.0 (m, 2H) 7.1 (m, 2H) 7.3 (s, 2H) 7.4 (m, 2H) 7.5 (m, 2H) 7.7 (m, 1H) 7.9 (d, J=2.2 Hz, 1H) 8.2 (d, J=5.3 Hz, 1H) 8.5 (s, 1H) 8.8 (d, J=7.0 Hz, 1H) 9.5 (s, 1H) 10.3 (s, 1H). ES-LC/MS m/z 604 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:15][CH2:14][CH2:13][CH:12](O)[CH:11]=1)([O-:3])=[O:2].O1CCOCC1.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[C:10]1([C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:15][CH2:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=[N+]([O-])c1cnccc1C1=CC(O)CCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cnccc1C1=CC=CCC1
Temperature: 100 °C
Yield: 27 %

Procedure:
To a solution of 3-(3-nitropyridin-4-yl)cyclohex-2-enol (1.0 equiv.) was added dioxane (0.18 M) and p-TSA (1.1 equiv.). The solution was heated to 100° C. for 4 h. Cooled to room temperature, worked up with sat. NaHCO3 and ethyl acetate, the organic phase was dried with Na2SO4 and concentrated. The crude was purified via silica gel column chromatography eluting with 100% DCM to give 4-(cyclohexa-1,3-dienyl)-3-nitropyridine as a yellow oil (27% yield). LCMS (m/z): 203.1 (MH+), LC Rt=3.53 min, 1H-NMR (CDCl3): 9.02 (s, 1H), 8.70 (d, J=5.3, 1H), 7.30 (d, J=5.3, 1H), 6.15-6.17 (m, 1H), 6.02-6.11 (m, 2H), 2.35-2.38 (m, 4H).
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[C:34]([C:37]1[CH:38]=[CH:39][C:40]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[C:41]([N:43]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[S:44]([CH3:47])(=[O:46])=[O:45])[CH:42]=1)(=[O:36])[CH3:35].C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:48]([N:43]([C:41]1[CH:42]=[C:37]([C:34](=[O:36])[CH2:35][Br:1])[CH:38]=[CH:39][C:40]=1[O:55][CH2:56][C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1)[S:44]([CH3:47])(=[O:46])=[O:45])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: [Br-]
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(N(Cc2ccccc2)S(C)(=O)=O)c1
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)N(Cc1ccccc1)c1cc(C(=O)CBr)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
Phenyltrimethylammonium tribromide (1.19 g, 3.16 mmol) was added to a solution of N-(5-acetyl-2-benzyloxyphenyl)-N-benzylmethanesulfonamide (32) (1.23 g, 3.01 mmol) in anhydrous THF (15 mL) in three portions. The reaction mixture was stirred at rt for 16 h. An aqueous sodium bicarbonate solution (5%, 15 mL) was then added. The mixture was extracted with dichloromethane and combined organics were concentrated by rotary evaporation. The resulting residue was purified by Biotage silica gel column chromatography eluting with dichloromethane to give bromo ketone 33 as a solid (1.25 g, 85% yield): 1H NMR (500 MHz, CDCl3) δ 2.85 (s, 3H), 4.21 (s, 2H), 4.75 (br, 2H), 5.19 (s, 2H), 7.08 (d, 1H), 7.22 (m, 5H), 7.43 (m, 5H), 7.65 (d, 1H), 7.92 (dd, 1H).
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:9]1[C:10](=[O:22])[CH2:11][CH:12]([CH:16]2[CH2:21][CH2:20][CH2:19][S:18][CH2:17]2)[CH2:13][C:14]=1O)[CH2:6][CH2:7][CH3:8])[CH3:2].C(N(CC)CC)C.S(Cl)([Cl:32])=O>O1CCCC1>[Cl:32][C:14]1[CH2:13][CH:12]([CH:16]2[CH2:21][CH2:20][CH2:19][S:18][CH2:17]2)[CH2:11][C:10](=[O:22])[C:9]=1[C:5](=[N:4][O:3][CH2:1][CH3:2])[CH2:6][CH2:7][CH3:8]
Reactant: O=S(Cl)Cl
Reactant: CCCC(=NOCC)C1=C(O)CC(C2CCCSC2)CC1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(=NOCC)C1=C(Cl)CC(C2CCCSC2)CC1=O

Procedure:
10.0 g (31 mmol) of 2-(1-ethoxyiminobutyl-3-hydroxy-5-(tetrahydrothiopyran-3-yl)cyclohex-2-en-1-one were dissolved in 50 ml of tetrahydrofuran, and 4.7 ml of triethylamine were added, followed by 2.3 ml of thionyl chloride. After 3 hours the resulting precipitate was filtered off with suction, and washed with tetrahydrofuran, and the product-containing filtrate was concentrated. 3-Chloro-2-(1-ethoxyiminobutyl)-5-(tetrahydrothiopyran-3-yl)cyclohex-2-en-1-one was obtained as an oil (compound no. 90).
Reaction SMILES: Br.Br[CH2:3][CH2:4][NH2:5].COCCOC.Cl.[CH2:13]([NH:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31])[CH2:14][CH2:15][CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[CH2:13]([NH:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]1[O:31][CH2:3][CH2:4][N:5]=1)[CH2:14][CH2:15][CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: NCCBr
Reactant: CCCCCCCCCC=CCCCNc1ccccc1C(=O)Cl
Agent: Br
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: CCCCCCCCCC=CCCCNc1ccccc1C1=NCCO1

Procedure:
To a slurry of 15 g. of 2-bromoethylamine hydrobromide in 150 ml. of 1,2-dimethoxyethane are added simultaneously solutions of 31 g. of 2-(4-tetradecenylamino)benzoyl chloride hydrochloride in 60 ml. of 1,2-dimethoxyethane and 50 cc. of triethylamine (dropwise). Upon addition of 0.5 g. of 4-dimethylaminopyridine the mixture is stirred at room temperature overnight. The solution is refluxed for one hour and filtered. The solid is oven dried and partitioned between methylene chloride and water. The layers are separated and the organic phase dried over magnesium sulfate. The organic layer is concentrated and the residue collected and crystallized from cyclohexane and recrystallized from acetonitrile to yield the product.
Reaction SMILES: [OH:1][C@@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:3][C:4](OC)=[O:5].[BH4-].[Na+].B([O-])([O-])OC>CO>[OH:1][C@H:2]([CH2:3][CH2:4][OH:5])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CCCC[C@H](O)CC(=O)OC
Agent: COB([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCC[C@H](O)CCO
Temperature: 0 °C
Yield: 90 %

Procedure:
45.3 g (0.2 mol) of enantiomerically pure dimethyl (3S)-3-hydroxyoctanedioate were mixed in a Haake kneader at from 30 to 40° C. with 5.2 g of sodium borohydride (0.14 mol, 0.7 equivalents). The reaction mixture was kneaded until the reaction was complete (TLC monitoring, 40 min). The intermediate methyl borate was then taken up in methanol and hydrolyzed under acidic conditions. The desired methyl (6S)-6,8-dihydroxyoctanoate was extracted with ethyl acetate. After drying the organic phase, this was cooled to 0° C., and the product which crystallized out was filtered off. 34.5 g of methyl (6S)-6,8-dihydroxyoctanoate in the form of white crystals were obtained (90% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=1.C([Sn](CCCC)(CCCC)[C:24]1[S:28][CH:27]=[N:26][CH:25]=1)CCC>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>[Cl:8][C:6]1[CH:7]=[C:2]([C:24]2[S:28][CH:27]=[N:26][CH:25]=2)[N:3]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:5]=1
Reactant: C[C@H](Nc1nc(Cl)cc(Cl)n1)c1ccc(F)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C[C@H](Nc1nc(Cl)cc(-c2cncs2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 52.3 %

Procedure:
286 mg of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyrimidine-2-amine (Reference Example 1), 411 mg of 5-(tributylstannyl)thiazole and 115 mg of tetrakis(triphenylphosphine)palladium were added in turn to degassed dimethylformamide, and then the mixture was stirred at 100° C. for 5 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 175 mg of (S)-4-chloro-N-[1-(4-fluorophenyl)ethyl]-6-(thiazol-5-yl)pyrimidine-2-amine as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:12][NH:11][CH2:10][CH2:9][C:7]=2[N:8]=1.Br[C:14]1[CH:15]=[C:16]([CH:29]=[C:30]([CH3:32])[CH:31]=1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([CH3:28])[CH3:27])[CH:21]=1)=[O:18]>>[CH:26]([C:22]1[CH:21]=[C:20]([NH:19][C:17](=[O:18])[C:16]2[CH:15]=[C:14]([N:11]3[CH2:10][CH2:9][C:7]4[N:8]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=4[CH2:12]3)[CH:31]=[C:30]([CH3:32])[CH:29]=2)[CH:25]=[CH:24][CH:23]=1)([CH3:28])[CH3:27]
Reactant: CSc1ncc2c(n1)CCNC2
Reactant: Cc1cc(Br)cc(C(=O)Nc2cccc(C(C)C)c2)c1
Product: CSc1ncc2c(n1)CCN(c1cc(C)cc(C(=O)Nc3cccc(C(C)C)c3)c1)C2

Procedure:
In a manner similar to that described for Example 138, 2-(methylsulfanyl)-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidine and 3-bromo-N-(3-isopropylphenyl)-5-methylbenzamide were converted to the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18](O)=[O:19])[CH:8]=1)=[O:5].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1C2C(=NC=CC=2)N(OC(N(C)C)=[N+](C)C)N=1.Cl.[NH:66]1[CH:70]=[C:69]([CH2:71][NH2:72])[CH:68]=[N:67]1>CN(C=O)C.C(OCC)(=O)C>[NH:66]1[CH:70]=[C:69]([CH2:71][NH:72][C:18]([C:9]2[CH:8]=[C:7]([NH:6][C:4](=[O:5])[C:3]3[CH:21]=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[C:23]([Cl:25])=[CH:24][C:2]=3[Cl:1])[N:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:10]=2)=[O:19])[CH:68]=[N:67]1
Reactant: NCc1cn[nH]c1
Reactant: O=C(O)c1cc(NC(=O)c2cc(-c3ccccn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cn[nH]c1)c1cc(NC(=O)c2cc(-c3ccccn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29 %

Procedure:
To solution of 5-(2,4-dichloro-5-(pyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 111, 200 mg, 0.44 mmol) in DMF was added DIPEA (0.46 mL, 2.65 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (201 mg, 0.53 mmol). The reaction was stirred at room temperature for 10 minutes before the addition of (1H-pyrazol-4-yl)methanamine hydrochloride (64 mg, 0.49 mmol). The reaction was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate (50 mL) and extracted with water (3×5 mL) and brine (25 mL). The organic layer was collected, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 2% MeOH in DCM to afford the title compound (68 mg, 29%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH:11]([CH3:13])[CH3:12])[N:5]=[C:4]([NH:14][CH:15]([CH3:17])[CH3:16])[N:3]=1.[CH3:18][O-:19].[Na+]>CO>[CH:15]([NH:14][C:4]1[N:3]=[C:2]([O:19][CH3:18])[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH:11]([CH3:13])[CH3:12])[N:5]=1)([CH3:17])[CH3:16]
Reactant: CC(C)Nc1nc(Cl)c(C#N)c(NC(C)C)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(NC(C)C)nc(NC(C)C)c1C#N
Reaction time: 16 h
Yield: 121.1 %

Procedure:
To a solution of 6.3 grams of 4-chloro-2,6-bis(isopropylamino)-5-pyrimidinecarbonitrile in 100 ml of methanol was added a solution of methanolic sodium methoxide (0.805 grams of sodium in 50 ml of methanol). After complete addition, the reaction mixture was stirred for 16 hours. The reaction mixture was then heated under reflux for 5 hours. The excess methanol was removed under reduced pressure. The residue was extracted with a mixture of diethyl ether and water. The organic layer was separated and dried over magnesium sulfate. The mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure. The residue was recrystallized from cyclohexane, to give 4.5 grams of 2,6-bis(isopropylamino)-4-methoxy-5-pyrimidinecarbonitrile; mp, 131°-133°.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([O:13]C)=[O:12])=[N:9][CH:10]=1.[OH-].[Li+].CO>O>[CH3:1][C:2]([CH3:16])([CH3:15])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=[O:12])=[N:9][CH:10]=1
Reactant: COC(=O)c1ccc(C#CC(C)(C)C)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)C#Cc1ccc(C(=O)O)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a 500 mL round bottom flask was added methyl 5-(3,3-dimethylbut-1-ynyl)picolinate (4.5 g, 21 mmol), lithium hydroxide (5.02 g, 210 mmol), methanol (80 mL), and water (30 mL). The mixture was stirred at room temperature for 30 minutes, heated to reflux for 1 hour, then concentrated under vacuum. Water (100 mL) was added and the mixture was cooled to 0° C. Concentrated HCl was added slowly to the stirred solution until the pH of the solution reached 6. An off white precipitate formed and was filtered, washed with cold water (3×100 mL) and dried under vacuum to afford the product (3.97 g, 95%) as an off white solid. LC-MS 2.76 min, 202.9 (M−1).