Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[N:28]1[CH:33]=[CH:32][CH:31]=[N:30][C:29]=1[N:34]1[CH:38]=[C:37]([NH2:39])[C:36]([C:40]([F:43])([F:42])[F:41])=[N:35]1.C1C=CC2N(O)N=NC=2C=1.[C:54]12([CH2:64][C:65](O)=[O:66])[CH2:63][CH:58]3[CH2:59][CH:60]([CH2:62][CH:56]([CH2:57]3)[CH2:55]1)[CH2:61]2.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:54]12([CH2:64][C:65]([NH:39][C:37]3[C:36]([C:40]([F:43])([F:41])[F:42])=[N:35][N:34]([C:29]4[N:28]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH:38]=3)=[O:66])[CH2:61][CH:60]3[CH2:59][CH:58]([CH2:57][CH:56]([CH2:62]3)[CH2:55]1)[CH2:63]2
Reactant: O=C(O)CC12CC3CC(CC(C3)C1)C2
Reactant: Nc1cn(-c2ncccn2)nc1C(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nc1cn(-c2ncccn2)nc1C(F)(F)F
Reaction time: 6 h

Procedure:
BOP (35 mg, 0.08 mmol) is added to a solution of 1-pyrimidin-2-yl-3-trifluoromethyl-1H-pyrazol-4-ylamine (15 mg, 0.065 mmol), HOBt (5 mg), 1-adamantaneacetic acid (16 mg, 0.08 mmol) and DIEA (17 μL, 0.1 mmol) in DMF (0.5 mL) at RT. The mixture is stirred for 6 h. H2O is added to the mixture and is extracted with EtOAc (3×10 mL). The organic phase is dried. The crude material is purified by PTLC using 4% MeOH in CH2Cl2 to afford the title compound. 1H NMR (CDCl3): 9.38 (s, 1H), 8.6-81 (m, 2H), 7.30 (m, 1H), 2.16 (s, 2H), 2.01-1.97 (m, 3H), 1.80-1.50 (m, 12H). MS (M+1)=406.11; RT=1.4 min. *IC50.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1.[CH2:18]([C:20]1([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH2:22][O:21]1)[CH3:19]>CN(C=O)C>[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:22][C:20]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)([OH:21])[CH2:18][CH3:19])[C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1
Reactant: CCC1(c2ccncc2)CO1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(O)(Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A flask was charged with sodium hydride (0.581 g, 50-60%) in dry DMF (10 mL) at 0° C. and to it was added 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (0.8 g). The reaction mixture was stirred at RT for 30 min., and then to this was added 4-(2-ethyloxiran-2-yl)pyridine (0.758 g) dissolved in DMF (2 mL), stirred at RT for 12 h. The reaction mixture was diluted with ice-water and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated. The crude product was triturated with diethyl ether to obtain the desired compound. 1H NMR (DMSO-d6, oxalate salt) δ (ppm): 8.45 (d, 2H), 7.40 (m, 4H), 7.0 (d, 1H), 4.38 (m, 1H), 4.22 (m, 1H), 3.60 (m, 2H), 3.35 (m, 2H), 3.10 (m, 2H), 2.90 (s, 3H), 2.10 (m, 2H), 0.6 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]2[C:10]([C:21]([O:23]C)=[O:22])=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[S:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Li+]>O1CCCC1.CO.O.CN(C=O)C>[CH3:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][C:9]2[C:10]([C:21]([OH:23])=[O:22])=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[S:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(NC(=O)c2ccc(C)cc2)csc1-c1ccc(C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2csc(-c3ccc(C)cc3)c2C(=O)O)cc1

Procedure:
The ester 180 and lithium hydroxide in tetrahydrofuran: methanol:water (3:2:1) is stirred at room temperature for 4 h. The mixture is diluted with DMF and purified by HPLC to provide 181.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[N:15][N:14]([CH:17]([CH3:21])[CH:18]=[N:19]O)[C:13]=3[CH:22]=2)[CH:5]=[C:4]([F:23])[C:3]=1[C:24]([F:27])([F:26])[F:25]>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[N:15][N:14]([CH:17]([CH3:21])[C:18]#[N:19])[C:13]=3[CH:22]=2)[CH:5]=[C:4]([F:23])[C:3]=1[C:24]([F:27])([F:26])[F:25]
Reactant: CC(C=NO)n1nnc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc21
Solvent: CC(=O)OC(C)=O
Product: CC(C#N)n1nnc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc21
Reaction time: 20 h

Procedure:
A solution of 6-[(2-chloro-α,α,α,6-tetrafluoro-p-tolyl)oxy]-α-methyl-1H-benzotriazole-1-acetaldehyde oxime (5.0 g, 0.012 mol) in acetic anhydride is allowed to stand at 22° C. for 20 hours and concentrated in vacuo to give an oil residue. The residue is chromatographed on silica gel using chloroform as eluant to afford the title compound (I), 2.0 g, mp 118°-119° C., identified by elemental and NMR analyses and the title compound (II), 2.1 g, mp 95°-97° C., identified by elemental and NMR analyses.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][C:4](=[O:7])[N:3]1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]#[N:19])=[CH:10][CH:9]=1.[OH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>>[OH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[C:5]2[C:4](=[O:7])[N:3]([C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]([C:18]#[N:19])=[CH:10][CH:9]=3)[C:2](=[O:1])[NH:6]2)=[CH:23][CH:22]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: N#Cc1ccc(N2C(=O)CNC2=O)c2ccccc12
Product: N#Cc1ccc(N2C(=O)NC(=Cc3ccc(O)cc3)C2=O)c2ccccc12

Procedure:
The title compound was obtained as an off-white solid (37.3 mg, 17.6%), mp>275° C. from compound 1C and 4-hydroxybenzaldehyde in the same manner as that used in the preparation of Example 1 by acidifying the aqueous washings and recrystallization of the crude product from MeOH. LC/MS m/z 356 [M+H]+.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([C:19]1[CH:20]=[C:21]([C:28]2[CH:29]=[N:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=2)[C:22]([OH:27])=[C:23]([CH:26]=1)[CH:24]=O)([CH3:18])([CH3:17])[CH3:16].[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.C(O)C.[ClH:47]>O1CCCC1>[ClH:47].[C:15]([C:19]1[CH:20]=[C:21]([C:28]2[CH:29]=[N:30][C:31]([C:34]([F:36])([F:35])[F:37])=[CH:32][CH:33]=2)[C:22]([OH:27])=[C:23]([CH2:24][N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH:26]=1)([CH3:17])([CH3:16])[CH3:18]
Reactant: C1CCNCC1
Reactant: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(C(F)(F)F)nc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)c1cc(CN2CCCCC2)c(O)c(-c2ccc(C(F)(F)F)nc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
Sodium triacetoxyborohydride (0.30 g, 1.4 mmol) was added to a solution of 5-(tert-butyl)-2-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)benzaldehyde (0.35 g, 1.1 mmol) and piperidine (0.13 mL, 1.3 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature under nitrogen for 16 hours. Additional piperidine (013 mL, 1.3 mmol) and sodium triacetoxyborohydride (0.30 g, 1.4 mmol) were added and the reaction was stirred under nitrogen for 4 hours. The reaction was partitioned between ethyl acetate (25 mL) and saturated aqueous sodium bicarbonate solution (25 mL). The organic phase was dried with sodium sulfate, filtered and concentrated under reduced pressure to give a yellow syrup. The product was purified using flash chromatography on silica eluting with a solvent gradient of 0 to 100% ethyl acetate in hexanes to give a yellow syrup which was dissolved in 1.25 M hydrochloric acid in ethanol (10 mL, 12.5 mmol). The mixture stood for 20 minutes and was concentrated under reduced pressure to give a white solid which was triturated with diethyl ether (10 mL) and the solid was filtered off to afford 4-(tert-butyl)-2-(piperidin-1-ylmethyl)-6-(6-(trifluoromethyl)pyridin-3-yl)phenol hydrochloride (0.29 g, 62% yield) as a white solid.
Reaction SMILES: C([Li])CCC.[C:6]([O:9][CH2:10][CH3:11])(=[O:8])[CH3:7].[C:12]([C:14]1[CH:34]=[CH:33][C:17]2[O:18][C:19]([CH3:32])([CH3:31])[CH:20]=[C:21]([N:22]3[CH:27]=[CH:26][C:25]([CH:28]=[O:29])=[CH:24][C:23]3=[O:30])[C:16]=2[CH:15]=1)#[N:13].P([O-])([O-])([O-])=O>O1CCCC1.C(NC(C)C)(C)C.CCCCCC>[C:12]([C:14]1[CH:34]=[CH:33][C:17]2[O:18][C:19]([CH3:31])([CH3:32])[CH:20]=[C:21]([N:22]3[CH:27]=[CH:26][C:25]([CH:28]([OH:29])[CH2:7][C:6]([O:9][CH2:10][CH3:11])=[O:8])=[CH:24][C:23]3=[O:30])[C:16]=2[CH:15]=1)#[N:13]
Reactant: CCOC(C)=O
Reactant: CC1(C)C=C(n2ccc(C=O)cc2=O)c2cc(C#N)ccc2O1
Agent: O=P([O-])([O-])[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CCOC(=O)CC(O)c1ccn(C2=CC(C)(C)Oc3ccc(C#N)cc32)c(=O)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In 40 ml of anhydrous tetrahydrofuran, is dissolved 3.64 ml of diisopropylamine. The resulting solution is cooled to 0° C. After dropping 15.4 ml of 1.62M solution of n-butyllithium in n-hexane thereto and stirring the resulting mixture for 10 minutes at that temperature, it is cooled to -78° C. and stirred for 20 minutes. Then, 2.34 ml of ethyl acetate is dropped and stirred at that temperature for 30 minutes. Then, 160 ml of an anhydrous tetrahydrofuran solution containing 6.13 g of the 6-cyano-2,2-dimethyl-4-(1,2-dihydro-2-oxo-4-formyl-1-pyridinyl)-2H-benzo[b]pyran obtained in Example 25 is added at that temperature over a period of 55 minutes, and the whole mixture is reacted first at that temperature for one hour, then at 0° C. for 30 minutes and then at room temperature for 30 minutes. After stopping the reaction by adding 0.2M phosphate buffer, the reaction mixture is extracted with ethyl acetate. The organic layer is washed successively with 2N aqueous hydrochloric acid, water and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The inorganic matter is filtered off, and the filtrate is concentrated under reduced pressure. The residue thus obtained is purified by silica gel column chromatography using 3/1 mixture of ethyl acetate/n-hexane as a developing solvent. Thus, 5.88 g of 6-cyano-2,2-dimethyl-4-{1,2-dihydro-2-oxo-4-(1-hydroxy-2- ethoxycarbonylethyl)- 1-pyridinyl}-2H-benzo[b]pyran is obtained.
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].C([Li])CCC.[C:32](=[O:34])=[O:33].Cl>C1COCC1>[CH3:4][C:2]([NH:5][S:6]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[C:10]=1[C:32]([OH:34])=[O:33])(=[O:8])=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1cn(CCOC2CCCCO2)c2ccccc12
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1c(C(=O)O)n(CCOC2CCCCO2)c2ccccc12
Temperature: -60 °C
Yield: 90.2 %

Procedure:
A solution of 1.8 g (4.7 mmol) of N-(1,1-dimethylethyl)-1-[2-(tetrahydro-2-pyranyloxy)-ethyl]-1H-indole-3-sulfonamide was dissolved in 30 mL anhydrous THF and cooled to -60° C. under nitrogen atmosphere. To this was added dropwise, with stirring, 8.0 mL (12.8 mmol) 1.6M butyllithium in hexanes and the mixture allowed to warm to 0° C. for 20 minutes then recooled to -60° C. A large excess of crushed dry ice (4 g CO2) was added all at once then the mixture was stirred overnight at ambient temperature. Hydrochloric acid (1N, 15 mL) plus ice was then added and the mixture extracted three times with ethyl acetate. The organic extracts were washed once with brine, dried (Na2SO4) and evaporated in vacuo. The solid residue was triturated and collected by filtration with n-butyl chloride and hexane to afford 1.80 g of the title compound, m.p. 149°-151° C. dec.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([CH3:7])[CH:6]=1.[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[N:27]=[CH:26][C:25]4=[CH:28][CH:29]=[C:30](B5OC(C)(C)C(C)(C)O5)[N:24]4[N:23]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1>>[CH3:7][N:5]1[CH:6]=[C:2]([C:30]2[N:24]3[C:25]([CH:26]=[N:27][C:22]([NH:21][C:18]4[CH:19]=[CH:20][C:15]([N:12]5[CH2:13][CH2:14][N:9]([CH3:8])[CH2:10][CH2:11]5)=[CH:16][CH:17]=4)=[N:23]3)=[CH:28][CH:29]=2)[N:3]=[CH:4]1
Reactant: Cn1cnc(Br)c1
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(B5OC(C)(C)C(C)(C)O5)n4n3)cc2)CC1
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5cn(C)cn5)n4n3)cc2)CC1

Procedure:
[7-(1-Methyl-1H-imidazol-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 4-bromo-1-methyl-1H-imidazole and [4-(4-methyl-piperazin-1-yl)-phenyl]-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine in an analogous manner to Example 1042b. Product isolated as a yellow solid (16 mg, 17%). m.p.=200-202° C.; LCMS (m/e) 389 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.63 (s, 1H), 7.92 (d, 1H, J=1.3 Hz), 7.57-7.47 (m, 3H), 7.30-7.24 (m, 1H), 7.02-6.96 (m, 2H), 6.81 (d, 1H, J=4.8 Hz), 6.57 (bs, 1H), 3.74 (s, 3H), 3.24-3.18 (m, 4H), 2.66-2.57 (m, 4H), 2.38 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C([CH2:18][NH2:19])O>C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Ti+4]>[CH2:4]([C:3]1[O:2][CH2:1][CH2:18][N:19]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCC(=O)OC
Reactant: NCCO
Agent: [Ti+4]
Agent: CC(=O)[O-]
Product: CCCCCCCCCCCC1=NCCO1

Procedure:
Following the procedure of Example 1, lauric acid methyl ester was reacted with ethanolamine in the presence of titanium tetraacetate to form 2-undecyl-2-oxazoline. The quantities used were as follows:
Reaction SMILES: C([N:8]1[CH2:15][C@H:14]([F:16])[CH2:13][C@H:9]1[C:10](O)=O)(OC(C)(C)C)=O.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[C:23]([NH2:28])[CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:21]1[CH:26]=[CH:25][C:24]2[NH:27][C:10]([C@@H:9]3[CH2:13][C@@H:14]([F:16])[CH2:15][NH:8]3)=[N:28][C:23]=2[CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)O
Product: CC(C)(C)c1ccc2[nH]c([C@@H]3C[C@@H](F)CN3)nc2c1

Procedure:
The title compound was prepared according to Method 4 using N-Boc-trans-4-fluoro-L-proline and 4-tert-butyl-1,2-diaminobenzene. The final residue was washed with ethyl acetate and diluted with water, basified with saturated lithium hydroxide solution (pH=8), extracted with ethyl acetate and dried over anhydrous Na2SO4 and concentrated under reduced pressure.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:8][C:9](=[O:13])[NH:10][C:11]=1[CH3:12])=[O:5])[CH3:2].C[Li].Cl[C:23]([O:25][CH3:26])=[O:24]>O1CCCC1.C(OCC)C>[C:23]([N:8]1[CH:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:11]([CH3:12])[NH:10][C:9]1=[O:13])([O:25][CH3:26])=[O:24]
Reactant: CCOC(=O)C1=C(C)NC(=O)NC1c1ccccc1
Reactant: COC(=O)Cl
Agent: [Li]C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C1=C(C)NC(=O)N(C(=O)OC)C1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of ethyl-6-methyl-4-phenyl-3,4-dihydropyrimidine-2(1H)one-5-carboxylate (5.0 mmol) in dry tetrahydrofuran (b 10 mL) under nitrogen at -78° C. was added dropwise 1.5 M methyllithium (11 mmol) in diethyl ether and the reaction mixture allowed to warm to 25° C. After 30 minutes, the reaction mixture was recooled to -78° C. and methyl chloroformate (5.5 mmol) was added. The reaction mixture was allowed to warm to 25° C., then quenched with saturated aqueous ammonium chloride and extracted with methylene chloride. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluted with methanol:methylene chloride (5:95) and recrystallized from acetonitrile to give the title product as a solid (mp=179°-180.5° C.).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][NH:10][CH2:9][CH2:8]2.Br>>[CH2:11]1[C:12]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[OH:2])[CH2:8][CH2:9][NH:10]1
Reactant: COc1cccc2c1CNCC2
Agent: Br
Product: Oc1cccc2c1CNCC2
Temperature: 25 °C
Yield: 80.4 %

Procedure:
Combine 8-methoxy-tetrahydroisoquinoline (665.7 mg, 4.08 mmol) and 48% HBr at room temperature. Reflux the reaction for 3 hours and then cool to room temperature. Recrystallize the product from EtOH and diethyl ether to afford 754.2 mg, 3.28 mmol (80% yield) of the title compound as a tarnish white solid: 1H NMR (500 MHz, DMSO-d6); 2.9 (2H, t, J=6.16, 5.86 Hz), 3.2-3.4 (2H, m), 4.0 (2H, s), 6.6-6.8 (2H, m), 7.0-7.1 (1H, m), 8.8-9.1 (2H, br m), 9.9 (1H, s); MS m/z 148 (M−1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1B(O)O>>[CH3:17][O:16][C:12]1[C:11]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH3:8])=[C:10]([Cl:9])[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccccc1Br
Reactant: COc1cccc(Cl)c1B(O)O
Product: COc1cccc(Cl)c1-c1ccccc1C
Yield: 61.5 %

Procedure:
Treatment of 1-bromo-2-methylbenzene (5.0 g, 26.88 mmol) with (2-chloro-6-methyoxyphenyl)boronic acid (13.8 g, 80.6 mol) generally according to the procedure described for Intermediate 37 afforded 3.85 g (62%) of 6-chloro-2′-methylbiphenyl-2-yl methyl ether. Treatment of 6-chloro-2′-methylbiphenyl-2-yl methyl ether with hydrogen bromide (100 mL, 30 wt. % in acetic acid) generally according to the procedure described for Example 395 afforded brown oil. The oil was reacted with sodium hydride (0.61 g, 25.38 mmol) and allyl bromide (3.07 g, 25.38 mmol) followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-6-chloro-2′-methylbiphenyl-2-ol. Treatment of 3-allyl-6-chloro-2′-methylbiphenyl-2-ol (4.38 g, 16.92 mmol) with m-chloroperoxybenzoic acid (4.38 g, 25.38 mmol, 77%) and potassium carbonate (2.81 g, 20.30 mmol) generally according to the procedure described for Intermediate 9 afforded 2.4 g (52%) of (±)-[7-(2-methylphenyl)-6-chloro-2,3-dihydro-1-benzofuran-2-yl]methanol. Treatment (±)-[7-(2-methylphenyl)-6-chloro-2,3-dihydro-1-benzofuran-2-yl]methanol (2.4 g, 8.73 mmol) with p-toluenesulfonyl chloride (2.50 g, 13.1 mmol) generally according to the procedure described for Intermediate 10 gave 3.2 g (85%) of (±)-[6-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of (±)-[6-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.21 g, 0.49 mmol) with sodium azide (0.35 g, 5.38 mmol) generally according to the procedure described for Intermediate 98 afforded 0.14 g, (99%) of (±)-2-(azidomethyl)-7-(2-methylphenyl)-6-chloro-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-7-(2-methylphenyl)-6-chloro-2,3-dihydro-1-benzofuran (0.14 g, 0.468 mmol) in tetrahydrofuran (10 m]L) with polymer-supported triphenylphosphine (0.24 g, 0.936 mmol) generally according to the procedure described for Example 154 provided 0.028 g (18%) of (±)-{[6-chloro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}amine as a white solid, hydrochloride salt. mp 204-206° C.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([CH:10]=O)[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1.Cl.NO.C([N:17](CC)CC)C.CCCP(=O)=O.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([C:4]2[N:9]=[C:8]([C:10]#[N:17])[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1ccnc(C2CC2)n1
Reactant: CCN(CC)CC
Agent: CCCP(=O)=O
Agent: Cl
Agent: NO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccnc(C2CC2)n1
Temperature: 110 °C
Reaction time: 18 h
Yield: 73.5 %

Procedure:
To a solution of 2-cyclopropylpyrimidine-4-carbaldehyde (29.13 g, 196.6 mmol) in N,N-dimethylformamide (200 mL) was added hydroxylamine hydrochloride (13.9 g, 197 mmol) followed by triethylamine (35 mL, 250 mmol) dissolved in N,N-dimethylformamide (40 mL) at room temperature. A 50% solution of propylphosphonic anhydride in N,N-dimethylformamide (140 mL, 230 mmol) was added and the reaction mixture was stirred at 110° C. for 18 h. The reaction mixture was cooled to room temperature and a saturated aqueous solution of sodium bicarbonate was added with ethyl acetate. The mixture was stirred vigorously and solid sodium bicarbonate was added. The mixture was filtered to remove undissolved solids and the layers were separated. The aqueous layer was extracted with ethyl acetate (3×) The combined organics were washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was dried under high vacuum to afford 2-cyclopropylpyrimidine-4-carbonitrile (20.97 g). The material was used without further purification. 1H NMR (400 MHz, CDCl3) δ 1.15-1.22 (m, 4H), 7.36 (s, 1H), 8.76 (s, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:21][NH:22][O:23][CH3:24].N1C=CC=CC=1>C(Cl)Cl.CN(C=O)C>[CH3:24][O:23][N:22]([CH3:21])[C:11](=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CNOC
Reactant: O=C(O)CCCCc1ccccc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CON(C)C(=O)CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
To a solution of 2 g (11.22 mmol) of 5-phenylvaleric acid in 75 mL of CH2Cl2 at 0° C. under argon is added 2 drops of DMF followed by 7 mL (14.03 mmol) of oxalyl chloride. This stirred at 25° C. for 1 hour, then 1.4 g (14.03 mmol) of N,O-dimethylhydroxylamine hydrochloride and 2.7 mL (33.66 mmol, 3 eq) of pyridine are added sequentially and stirred for 72 hours at 25° C. The reaction is partitioned between CH2Cl2 and 1 N HCl. The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo to give 2.5 g (100%) of 5-phenylpentanoic acid-methoxy-methyl-amide in the form of a yellow oil.
Reaction SMILES: [CH:1]([CH:3]1[CH2:7][CH:6]([CH:8]=O)[CH2:5][CH:4]1[O:10][C:11](=[O:13])[CH3:12])=O.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:14]([N:21]1[CH2:1][CH:3]2[CH2:7][CH:6]([CH2:5][CH:4]2[O:10][C:11](=[O:13])[CH3:12])[CH2:8]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)OC1CC(C=O)CC1C=O
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OC1CC2CC1CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To the above solution of acetic acid 2,4-diformyl-cyclopentyl ester was added at room temperature benzyl amine (5.8 mmol) and acetic acid (5.8 mmol) under nitrogen. After 2 h at room temperature sodium triacetoxy borohydride (25 mmol) was added and the reaction mixture was allowed to stir at room temperature for 18 h. The reaction mixture was quenched by the addition of saturated sodium bicarbonate solution (100 mL) and the phases were separated. The aqueous layer was extracted with dichloromethane (3×100 mL). The solvents were removed via rotary evaporation and the residue was purified by silica gel chromatography to afford a yellow oil (3.6 mmol). 1H NMR (CDCl3, 400 MHz): δ 7.37 (m, 2H), 7.23 (m, 3H), 5.15–4.95 (m, 1H), 3.63–3.35 (m, 2H), 2.84–2.55 (m, 2H), 2.25–2.15 (m, 4H), 2.08 (s, 3H), 1.80–1.70 (m, 2H), 1.62–1.25 (m, 2H); APCl MS m/z 260.2 (M+H)+.