Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([OH:17])=O)=[N:13][CH:14]=1)C1C=CC=CC=1.C(OC1C=CC(C([CH2:34][CH2:35][NH:36][C:37]2[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:38]=2[CH:45]2[CH2:54][CH2:53][C:52]3[CH:51]=[C:50]([O:55][C:56](=[O:61])[C:57]([CH3:60])([CH3:59])[CH3:58])[CH:49]=[CH:48][C:47]=3[CH2:46]2)=O)=NC=1)C1C=CC=CC=1>>[CH2:35]([N:36]([C:15]([C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][N:13]=1)=[O:17])[C:37]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:38]=1[CH:45]1[CH2:54][CH2:53][C:52]2[CH:51]=[C:50]([O:55][C:56](=[O:61])[C:57]([CH3:60])([CH3:59])[CH3:58])[CH:49]=[CH:48][C:47]=2[CH2:46]1)[CH3:34]
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCC(=O)c2ccc(OCc3ccccc3)cn2)c1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cn1
Product: CCN(C(=O)c1ccc(O)cn1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1

Procedure:
Synthesized from 6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester and 5-benzyloxypyridine-2-carboxylic acid according to an analogous synthetic method to Example 152, pivalic acid 6-{2-[(5-benzyloxypyridine-2-carbonyl)ethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (163 mg) was used according to an analogous synthetic method to Example 22 to provide the title compound (124 mg).
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=[O:24])[NH:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21](=[O:23])[CH3:22])[CH:16]=1)(C)(C)C.ClC(OC1C=CC=CC=1)=O.[CH3:35][C@H:36]1[CH2:41][NH:40][C@H:39]([CH3:42])[CH2:38][N:37]1[C:43]1[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[C:45]([C:51]([F:54])([F:53])[F:52])[CH:44]=1>N1C=CC=CC=1.O.C(Cl)(Cl)Cl>[C:21]([C:17]1[CH:16]=[C:15]([NH:14][C:13]([N:40]2[CH2:41][C@H:36]([CH3:35])[N:37]([C:43]3[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[C:45]([C:51]([F:53])([F:52])[F:54])[CH:44]=3)[CH2:38][C@H:39]2[CH3:42])=[O:24])[CH:20]=[CH:19][N:18]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)c1cc(NC(=O)OC(C)(C)C)ccn1
Reactant: C[C@@H]1CN(c2ccc(C#N)c(C(F)(F)F)c2)[C@@H](C)CN1
Agent: O=C(Cl)Oc1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)c1cc(NC(=O)N2C[C@H](C)N(c3ccc(C#N)c(C(F)(F)F)c3)C[C@H]2C)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
While stirring with ice-cooling, 12.5 ml of trifluoroacetic acid was added to 12.5 ml of chloroform solution containing 1.41 g of 2-acetyl-4-pyridinylcarbamic acid t-butyl ester. The mixture was immediately warmed up to room temperature and stirred for 2 hours and 40 minutes. The solvent was evaporated under reduced pressure to obtain a crude amine. This compound was dissolved in 25 ml of pyridine, and the solution was mixed with 0.83 ml of phenyl chloroformate while stirring with ice-cooling and then immediately warmed up to room temperature. After 8 hours and 30 minutes, this was mixed with 10 ml of pyridine solution containing 1.4 g of (2S,5R)-4-(2,5-dimethylpiperazin-1-yl)-2-trifluoromethylbenzonitrile and heated under reflux for 1 hour. The reaction mixture cooled to room temperature was mixed with water and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by a silica gel column chromatography to obtain 1.03 g of the title compound from methanol-chloroform (1:99, v/v) eluate.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C@@H:12]([CH2:13][C:14](=[O:22])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3.[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+]>C1COCC1.C(Cl)Cl>[OH:22][C@@H:14]1[CH2:15][CH2:16][C@@:17]2([CH3:18])[C@H:12]([CH2:11][CH2:10][C@@H:9]3[C@@H:19]2[CH2:20][CH2:21][C@@:4]2([CH3:5])[C@H:6]3[CH2:7][CH2:8][C@@H:3]2[O:2][CH3:1])[CH2:13]1
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CO[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -75 °C
Reaction time: 3 h
Yield: 83.1 %

Procedure:
A solution of 17β-methoxy-5β-androstan-3-one (130 mg, 0.42 mmol) in dry THF (15 mL) was treated with lithium tri(tert-butoxy)aluminum hydride (1 mL, 1M in THF, 1 mmol) at −73° C. After stirring the mixture at −75° C. for 3 hr and then at −10° C. for 1.5 hr, the mixture was quenched with NaOH solution (1N, 2 mL). The solvents were removed and the residue was extracted with EtOAc. The organic layer was washed with water, and brine. After drying over anhyd. MgSO4 the solution was filtered and evaporated to yield the crude product. This crude product was then dissolved in a small amount of CH2Cl2 and poured on a column of silica gel. Elution with toluene:acetone mixture (9:1) gave 3α-hydroxy-17β-methoxy-5β-androstane (107 mg); mp 151-156° C.; TLC Rf (hexane:acetone 7:3)=0.18.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:15][C:16]1[N:23]=[CH:22][CH:21]=[C:20](Br)[C:17]=1[C:18]#[N:19]>CN(C=O)C>[Br:15][C:16]1[C:17]([C:18]#[N:19])=[C:20]([N:12]2[CH2:11][CH2:10][CH:9]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:14][CH2:13]2)[CH:21]=[CH:22][N:23]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: N#Cc1c(Br)ccnc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(N2CCC(c3ccccc3)CC2)ccnc1Br
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 95.4 %

Procedure:
To a suspension of NaH (0.146 g, 3.818 mmol, 60%) in DMF (20 ml) cooled at 0° C. was added 4-phenylpiperidine (0.616 g, 3.818 mmol). The resulting mixture was stirred for 5 min., then compound D1 (1 g, 3.016 mmol) was added. The resulting reaction mixture was stirred for 1 h. The reaction mixture was then quenched with NH4Cl (aqueous sat. solution) and extracted with Et2O. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; DCM/7M solution of NH3 in MeOH gradient as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D6 (0.985 g, 75%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]>C(OCC)(=O)C.CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CCOC(=O)C=Cc1ccc(OC)c(F)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(OC)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
A solution of Intermediate 7 (3.01 g) in ethyl acetate (50 ml) and methanol (25 ml) was added with 10% palladium/carbon (300 mg, Merck), and stirred at room temperature for 2 hours under hydrogen atmosphere. The reaction mixture was filtered, and the solvent of the filtrate was evaporated under reduced pressure to obtain the title compound (Intermediate 8, 3.02 g).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:3]=1.Cl.[NH:22]1[CH2:27][CH2:26][CH2:25][CH:24]([NH:28][C:29]2[N:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=2)[CH2:23]1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:4]2[N:3]=[C:2]([N:22]3[CH2:27][CH2:26][CH2:25][CH:24]([NH:28][C:29]4[CH:30]=[CH:31][C:32]([C:35]#[N:36])=[CH:33][N:34]=4)[CH2:23]3)[C:7]([C:8]#[N:9])=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=2)=[CH:15][CH:16]=1
Reactant: N#Cc1c(C(F)(F)F)cc(-c2ccc(Cl)cc2)nc1Cl
Reactant: N#Cc1ccc(NC2CCCNC2)nc1
Agent: Cl
Product: N#Cc1ccc(NC2CCCN(c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)c3C#N)C2)nc1

Procedure:
Analogously to the preparation of Example 20, 60 mg (0.19 mmol) of 2-chloro-6-(4-chlorophenyl)-4-(trifluoromethyl)pyridine-3-carbonitrile and 56 mg (0.23 mmol) of 6-(piperidin-3-ylamino)pyridine-3-carbonitrile hydrochloride (Example 10A) were used to obtain, after separation by means of preparative HPLC (method 13), 46 mg (50% of theory) of the product in solid form.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16](O)=[O:17])=[CH:10][CH:9]=1.[OH-].[Na+].[O-]S([O-])(=O)=O.[Na+].[Na+]>C(OCC)C.C1COCC1.CCCCCC.O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][OH:17])=[CH:12][CH:13]=1
Reactant: O=C(O)CCc1ccc(Br)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: OCCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of lithium aluminum hydride (2.39 g, 62.9 mmol) in diethyl ether (100 mL) at 0° C. was added 3-(4-bromophenyl)propionic acid (9.59 g, 41.9 mmol) in THF (100 mL). After stirring at rt for 2 h, the reaction mixture was cooled to 0° C. and H2O (2.5 mL), NaOH (15% aq., 2.5 mL), H2O (5 mL), Et2O (200 mL), hexane (50 ml), and anhydrous Na2SO4 were added sequentially. The suspension was stirred at it for 1 h and was filtered, and the filtrate was concentrated to afford 3-(4-bromophenyl)-propanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:41])[CH2:9][CH2:10][N:11]([CH2:13][C:14]1[C:15]([C:25]2[CH2:30][CH2:29][N:28](C(OCC3C=CC=CC=3)=O)[CH2:27][CH:26]=2)=[N:16][N:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH:18]=1)[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[CH3:41][N:8]([CH2:9][CH2:10][N:11]([CH3:12])[CH2:13][C:14]1[C:15]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:16][N:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH:18]=1)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(CCN(C)C(=O)OC(C)(C)C)Cc1cn(C2CCCCO2)nc1C1=CCN(C(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(CCN(C)C(=O)OC(C)(C)C)Cc1cn(C2CCCCO2)nc1C1CCNCC1
Yield: 71.7 %

Procedure:
A mixture of benzyl 4-(4-(((2-(tert-butoxycarbonyl(methyl)amino)ethyl)(methyl)amino)methyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2 g, 3.52 mmol, 1.00 equiv) and 10% palladium on carbon (2 g) catalyst in methanol (100 mL) was stirred under 1 atmosphere of hydrogen at room temperature for 6 h. The catalyst was removed by filtration and the filtrate was concentrated under vacuum to yield 1.1 g (72%) of (R/S) tert-butyl methyl(2-(methyl-((3-(piperidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methyl)amino)ethyl)carbamate as a brown oil. 1H-NMR (300 MHz, CDCl3): δ 7.46 (s, 1H), 5.33-5.32 (m, 1H), 4.24-4.06 (m, 1H), 3.75-3.66 (m, 1H), 3.51 (s, 1H), 3.41-3.15 (m, 6H), 2.95-2.70 (m, 6H), 2.62-2.40 (m, 2H), 2.22 (s, 3H), 1.55-1.41 (m, 10H), 1.35-1.21 (m, 1H) ppm. LCMS (method A, ESI): RT=1.49 min, m/z=436.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=O)[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.C([NH2:15])=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:11][CH:12]=1)[C:6](=[O:7])[NH:15][C:9]2=[O:8]
Reactant: O=C1OC(=O)c2cc(F)ccc21
Reactant: NC=O
Product: O=C1NC(=O)c2cc(F)ccc21
Temperature: 200 °C
Yield: 100 %

Procedure:
A mixture of 144 mmol 4-fluorophthalic anhydride and 1.16 mol formamide was heated at 200° C. for 2 h. The reaction mixture was poured onto ice-water and the resulting crystals collected by filtration and dried in vacuo to afford the title compound as a yellow solid (100% yield). MS (m/e): 164.4 ([M−H]−, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][N:12]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20][N:19]([CH2:26][C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:37]([C:40]1[CH:48]=[CH:47][C:43]([CH2:44][CH2:45]Br)=[CH:42][CH:41]=1)([O-:39])=[O:38].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([CH2:11][N:12]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20][N:19]([CH2:26][C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:18][CH2:17][CH2:16][N:15]([CH2:45][CH2:44][C:43]2[CH:42]=[CH:41][C:40]([N+:37]([O-:39])=[O:38])=[CH:48][CH:47]=2)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CN1CCCNCCN(CC(=O)OCc2ccccc2)CCCNCC1)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(CN1CCCN(CCc2ccc([N+](=O)[O-])cc2)CCN(CC(=O)OCc2ccccc2)CCCNCC1)OCc1ccccc1
Yield: 70 %

Procedure:
A solution of compound (4) (1.19 g, 2.39 mmol), 4-nitrophenethyl bromide (1.09 g, 4.78 mmol), anhydrous K2CO3 (0.99 g, 7.17 mmol) and KI (1.19 g, 7.17 mmol) dissolved in dry toluene (150 ml) was stirred under reflux for 24 hours. The solvent was evaporated from the reaction mixture under reduced pressure, and CH2Cl2 (250 ml) was added thereto. The resultant brown slurry was filtered through a celite pad, and washed with CH2Cl2 (2×30 ml). The solvent was evaporated from the combined filtrate under reduced pressure. The residue thus obtained was purified via alumina (basic) column chromatography using EtOAc/methanol (10:2) as an eluent to provide compound (16) as a yellow oil (1.08 g, 70% yield). 1H NMR (500 MHz, CDCl3): δ 8.14-8.12 (dd, 2H), 7.49-7.47 (dd, 2H), 7.33-7.28 (m, 10H), 5.09 (s, 2H), 5.03 (s, 4H), 3.46 (s, 2H), 3.36 (s, 2H), 3.25 (s, 2H), 2.87 (brs, 2H), 2.76-2.72 (m, 4H), 2.65-2.63 (m, 6H), 2.59-2.57 (m, 2H), 2.44-2.42 (m, 2H), 1.69 (brs, 2H), 1.62-1.59 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 171.3, 170.8, 148.1, 146.9, 135.7, 129.3, 128.5, 128.2, 128.1, 123.3, 66.0, 65.8, 58.1, 55.5, 53.6, 53.1, 52.5, 52.0, 51.2, 49.6, 47.9, 47.2, 25.7; HRMS (FAB) calculated for C36H48N5O6: 646.3605 [(M+H)+], measured value: 646.3602 [(M+H)+].
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17]CC)=O)[C:11](=O)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)(=O)C.[CH:25]([NH2:27])=[NH:26]>>[CH2:2]([N:9]1[CH2:14][CH2:13][CH:12]2[C:11](=[N:27][CH:25]=[N:26][C:15]2=[O:17])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N=CN
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Agent: Cl
Solvent: CC(=O)O
Product: O=C1N=CN=C2CN(Cc3ccccc3)CCC12

Procedure:
Various N-substituted-7-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine derivatives are prepared using a general procedure described below. Accordingly, ethyl 1-benzyl-3-oxopiperidine-4-carboxylate hydrochloride is reacted with formamidine acetate to yield 7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(4aH)-one, which, in turn, is reacted with POCl3 to afford the 4-chloro derivative. The intermediate chloro derivative is then condensed with substituted aniline or amine to give the desired N-substituted-7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine. Debenzylation using standard procedures known in the art followed by nucleophilic displacement of an appropriate 2-halo-pyridine yields the appropriate N-substituted-7-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine. As a representative example, synthesis of N-(4-tert-butylphenyl)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine is depicted in Scheme 1.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][C@@H:4]([CH3:7])[N:3]1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[P:18]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O.C(N(CC)CC)C.Cl[SiH](Cl)Cl.[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[CH3:1][C@@H:2]1[CH2:6][CH2:5][C@@H:4]([CH3:7])[N:3]1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[P:18]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C[C@@H]1CC[C@@H](C)N1c1c(P(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12
Agent: Cl[SiH](Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: C[C@@H]1CC[C@@H](C)N1c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12
Temperature: 120 °C
Reaction time: 6.5 h
Yield: 84.8 %

Procedure:
To a solution of 3.3 g (7.8 mmol) of the 1-((2R,5R)-2,5-dimethylpyrrolidinyl)-2-diphenylphosphinylnaphthalene in 100 ml of xylene were added 6.8 ml (49.14 mmol) of triethylamine and 4.7 ml (46.8 mmol) of trichlorosilane, and the mixture was slowly heated up to 120° C., at which the mixture was stirred for 6.5 hours. After cooling to room temperature, the reaction mixture was poured into 250 ml of 2N NaOH and extracted with benzene. The extract was washed with water and dried over anhydrous magnesium sulfate. The crude product was purified by silica gel column chromatography (hexane/acetone=20/1 by volume) to give 2.71 g of the title compound in a yield of 85%.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[CH:6]=[C:5]([Cl:10])[N:4]=1.[C:11](#[N:15])[CH2:12][C:13]#[N:14].[H-].[Na+]>C1COCC1>[Cl:10][C:5]1[N:4]=[C:3]([S:2][CH3:1])[N:8]=[C:7]([CH:12]([C:11]#[N:15])[C:13]#[N:14])[CH:6]=1
Reactant: N#CCC#N
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nc(Cl)cc(C(C#N)C#N)n1
Temperature: 60 °C
Yield: 76.5 %

Procedure:
2-Methylthio-4,6-dichloropyrimidine (1b) (10 g, 51.27 mmoles) was suspended in 150 mL of dry THF along with malononitrile (3.72 g, 56.14 mmoles) and trans-dichloro-bis(triphenylphosphine)palladium (II) (2.0 g, 2.85 mmoles). The reaction mixture was purged with a stream of nitrogen gas for five minutes with rapid stirring before the cautious portion wise addition of sodium hydride (60% oil dispersion, 6.15 g, 154 mmoles). Note that the reaction is exothermic and THF starts to reflux upon addition of NaH. Nitrogen purging was continued throughout the addition. Upon completion of the sodium hydride addition, the nitrogen purge was ceased and the reaction mixture was placed into a pre-heated oil bath at ˜70° C. The reaction mixture was heated under a blanket of nitrogen for 2 hours or until complete (color changes from a yellow to orange brown). The reaction was cooled and cautiously quenched with 30 mL of aq. 1N HCl solution and when gas formation ceased the majority of the solvent was removed under reduced pressure. The concentrated mixture was diluted with aq. 0.25 N HCl solution with stirring and the orange brown precipitate was collected via suction filtration, washed with water and vacuum-dried. The crude cake was transferred to a round bottomed flask containing acetonitrile (250 mL) and stirred vigorously for one hour. The precipitate was isolated via suction filtration, washed with acetonitrile and cautiously washed with DCM. The cake was then re-suspended in acetonitrile, warmed to ˜60° C., allowed to cool while stirring, and re-isolated via suction filtration and vacuum-dried. 8.81 g of a pale yellow solid was obtained (77% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.N1C=CC=CC=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](Cl)=[O:26])=[CH:20][CH:19]=1.Cl>C(Cl)Cl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](=[C:5]2[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:9])[OH:26])=[CH:20][CH:19]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)OC(=O)C(=C(O)Cc2ccc(Cl)cc2)C(=O)O1
Temperature: -10 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
To a mixture of 2,2-dimethyl-1,3-dioxane-4,6-dione (52.7 g, 366 mmol) in DCM (205 mL) at −10° C. in an ice/methanol bath was added pyridine (72.5 mL, 897 mmol) over 10 minutes. To the resulting solution at −10° C. was added a solution of 2-(4-chlorophenyl)acetyl chloride (69.1 g, 366 mmol) in DCM (144 mL) dropwise over 1 hour. The mixture was stirred at −10° C. for 1 hour, then at room temperature for 1 hour. The mixture was poured into a mixture of 2 M HCl (820 mL) and ice (400 mL) and the aqueous layer was extracted with DCM (2×200 mL). The combined DCM layers were washed with 1 N HCl (100 mL) and brine (100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give 103 g of title compound. (95% yield). LC/MS (FA) ES− 295. 1H NMR (400 MHz, CDCl3) δ: 15.25 (br s, 1H), 7.34-7.26 (m, 4H), 4.37 (s, 2H), 1.72 (s, 6H).
Reaction SMILES: CO.[H-].[Na+].[F:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.C[O:15][C:16](=[O:24])[CH:17]([CH3:23])[CH2:18][C:19]([O:21][CH3:22])=[O:20]>C1(C)C=CC=CC=1>[CH3:22][O:21][C:19](=[O:20])[C:18](=[CH:10][C:9]1[CH:12]=[CH:13][C:6]([F:5])=[CH:7][CH:8]=1)[CH:17]([CH3:23])[C:16]([OH:24])=[O:15]
Reactant: COC(=O)CC(C)C(=O)OC
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C(=Cc1ccc(F)cc1)C(C)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.7 %

Procedure:
After careful addition of absolute methanol (0.1 mL) to a suspension of sodium hydride (60% in mineral oil, 20 g, 0.5 mol) in anhydrous toluene (200 mL), a solution of 4-fluoro-benzaldehyde (31 g, 0.25 mol) and 2-methyl-succinic acid dimethyl ester (60 g, 0.38 mol) in anhydrous toluene (100 mL) was added at room temperature under a stream of nitrogen. The resulting mixture was stirred at room temperature for 30 minutes and then quenched by the slow addition of water (20 mL). The mixture was acidified by the addition of concentrated hydrochloric acid, and extracted with ethyl acetate (200 mL×3). The combined organic layers were dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (elution with 30% ethyl acetate in petroleum ether) to afford 2-(4-fluoro-benzylidene)-3-methyl-succinic acid 1-methyl ester (20 g, 33%) as a white solid. 1H NMR (400 MHz, acetone-d6) δ ppm 7.77 (s, 1H), 7.54 (d, J=8.8 Hz, 2H), 7.25 (d, J=8.8 Hz, 2H), 3.82 (q, 7.2 Hz, 1H), 1.40 (d, J=6.8 Hz, 3H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[CH:15]1([CH2:18]Br)[CH2:17][CH2:16]1.[H-].[Na+]>>[CH:15]1([CH2:18][N:8]([C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=2)[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)[CH2:17][CH2:16]1
Reactant: BrCC1CC1
Reactant: Ic1ccc(Nc2ncccn2)cc1
Agent: [H-]
Agent: [Na+]
Product: Ic1ccc(N(CC2CC2)c2ncccn2)cc1
Yield: 91.4 %

Procedure:
In the same manner as in Reference Example 13, N-(4-iodophenyl)pyrimidin-2-amine (150 mg) and cyclopropylmethyl bromide (82 mg) were reacted in the presence of sodium hydride to obtain N-(cyclopropylmethyl)-N-(4-iodophenyl)pyrimidin-2-amine (162 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[SH:18])[CH3:8])([CH3:4])([CH3:3])[CH3:2].ClN1C(=O)CCC1=O.S(Cl)Cl.[NH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32]1.C(=O)(O)[O-].[Na+]>C1COCC1.ClCCCl>[C:1]([O:5][C:6](=[O:19])[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[S:18][C:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[NH:31][CH:32]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CCc1cc(F)ccc1S)C(=O)OC(C)(C)C
Reactant: c1ccc2[nH]ccc2c1
Agent: ClSCl
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CN(CCc1cc(F)ccc1Sc1c[nH]c2ccccc12)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
[2-(5-Fluoro-2-mercapto-phenyl)-ethyl]-methyl-carbamic acid tert-butyl ester (240 mg, 0.84 mmol) is dissolved in dry THF (3 mL) and added dropwise to a solution of N-chlorosuccinimide (112 mg, 0.84 mmol) in 1,2-dichloroethane (3 mL) at 0° C. The mixture is allowed to heat to ambient temperature and is stirred for 30 minutes. The resulting sulfenyl chloride solution is added dropwise to a solution of 1H-indole (147 mg, 1.26 mmol) in dry THF (3 mL) at 0° C. The mixture is stirred for 15 minutes at 0° C. before adding saturated sodium bicarbonate solution (15 mL). The mixture is extracted with ethyl acetate (3×20 mL) and the combined organic fractions are washed with brine, dried (MgSO4) and concentrated in vacuo. The product is purified by silica gel chromatography eluting with ethyl acetate-heptane, first (1:10) then (1:4). Upon evaporation of the volatiles 99 mg (29%) of the title compound is isolated.