Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[C@@H:10]([CH:21]=[CH2:22])[CH2:11][C:12]2=[O:20])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:23][CH3:24])[CH:4]=[CH:5]2.Cl>C(O)C.[Pd]>[O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[C@@H:10]([CH2:21][CH3:22])[CH2:11][C:12]2=[O:20])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:23][CH3:24])[CH:4]=[CH:5]2
Reactant: C=C[C@H]1CC(=O)[C@@H]2Oc3c(OC)ccc4c3[C@@]23CCN(C)[C@H](C4)[C@H]13
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC[C@H]1CC(=O)[C@@H]2Oc3c(OC)ccc4c3[C@@]23CCN(C)[C@H](C4)[C@H]13

Procedure:
To a solution of 4,5α-epoxy-3-methoxy-17-methyl-8β-vinylmorphinan-6-one (9.0 g) in 95% ethanol was added 2 ml of concentrated hydrochloric acid followed by 10% palladium/charcoal (1.0 g.). The mixture was hydrogenated at an initial pressure of 50 psi for 2.5 hours. The reaction mixture was filtered, the filtrate made acidic by the addition of hydrochloric acid and evaporated to a crystalline solid. The solid was recrystallized from ethyl acetate with the addition of ethanol to give, after drying, 8.7 g (90%) of the 8-ethyl product TR-5059.HCl, mp 285°-288° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16](=[O:20])OCC)=[N:5]2.[Br:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16]([N:31]1[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([Br:21])[CH:23]=3)[CH2:33][CH2:32]1)=[O:20])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(Cl)c(Cl)cc2nc1OC
Reactant: Brc1cccc(N2CCNCC2)c1
Product: COc1nc2cc(Cl)c(Cl)cc2nc1NC(=O)N1CCN(c2cccc(Br)c2)CC1
Yield: 72 %

Procedure:
Ethyl N-(6,7-dichloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3-bromo phenyl)piperazine were reacted by the same way with the example 176 to obtain the titled compound (yield, 72%). 1H NMR (300 MHz, CDCl3) δ 3.29-3.31 (m, 4H), 3.74-3.76 (m, 4H), 4.16 (s, 3H), 6.85-6.87 (m, 1H), 7.02-7.04 (m, 1H), 7.06-7.07 (m, 1H), 7.13-7.15 (m, 1H), 7.32 (br s, 1H), 7.86 (br s, 1H), 7.86 (br s, 1H), 7.91 (br s, 1H).
Reaction SMILES: Cl[C:2]1[N:18]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[N:19]1([CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][NH:10][C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:33][C:30]4[CH:31]=[CH:32][C:27]([O:26][CH2:25][CH2:24][N:19]5[CH2:23][CH2:22][CH2:21][CH2:20]5)=[CH:28][CH:29]=4)[N:18]=3)[CH:9]=[CH:8][CH:7]=2)[CH:13]=1
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Reactant: Clc1nc2c(NCc3cccnc3)cccn2n1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: c1cncc(CNc2cccn3nc(Nc4ccc(OCCN5CCCC5)cc4)nc23)c1

Procedure:
N(8)-Pyridin-3-ylmethyl-N(2)-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-pyridin-3-ylmethyl-amine (75.0 mg, 0.289 mmol) and 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (67.0 mg, 0.325 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (33.0 mg, 0.0604 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.031 g, 25%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.67 (s, 1H), 8.56 (d, J=4.2 Hz, 1H), 7.83 (d, J=6.6 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.47 (d, J=8.8 Hz, 2H), 7.31-7.25 (m, 1H), 6.92 (d, J=8.8 Hz, 2H), 6.66 (t, J=7.1 Hz, 1H), 6.56 (s, 1H), 6.31 (d, J=7.6 Hz, 1H), 5.18 (t, J=5.4 Hz, 1H), 4.51 (d, J=5.6 Hz, 2H), 4.10 (t, J=6.0 Hz, 2H), 2.89 (t, J=5.9 Hz, 2H), 2.66-2.59 (m, 4H), 1.85-1.77 (m, 4H). MS=430 (MH)+.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C(O)C>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([CH2:3][CH2:2][C:1]#[N:4])[CH2:15][CH2:14]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: C=CC#N
Solvent: CCO
Product: COc1ccccc1N1CCN(CCC#N)CC1
Reaction time: 18 h
Yield: 91.7 %

Procedure:
A solution of acrylonitrile (1.06 g, 20 mmol) in ethanol (50 ml) was added to a stirred solution of 2-methoxyphenylpiperazine (3.84 g, 20 mmol) in ethanol (100 ml). After 18 h, the solvent was evaporated in vacuo to give the product (4.5 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[Br:11]Br>C(O)(=O)C>[NH2:1][C:2]1[C:6]([Br:11])=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1sccc1N
Reactant: BrBr
Solvent: CC(=O)O
Product: COC(=O)c1scc(Br)c1N
Reaction time: 16 h
Yield: 33.3 %

Procedure:
To a solution of methyl 3-aminothiophene-2-carboxylate (1 g, 6.36 mmol) in acetic acid (10 mL) was added a solution of bromine (0.32 mL, 6.36 mmol) in acetic acid (1 mL) slowly for 5 min at rt and stirred at the same temperature for 16 h. The reaction mixture was poured into ice cold water and extracted with chloroform (3×100 mL). The combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using hexane-EtOAc (95:5) as eluents to give the product as a pale yellow color solid (0.5 g, 33%), mp 58-60° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[C:20]2[C:21]([O:26][CH3:27])=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[N:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1.C(=O)([O-])[O-:29].[K+].[K+].OO.O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]([NH2:17])=[O:29])=[CH:14][C:13]=2[C:20]2[C:21]([O:26][CH3:27])=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[N:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1
Reactant: COc1ncccc1-c1cc(C#N)ccc1Oc1cnc(C2CC2)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ncccc1-c1cc(C(N)=O)ccc1Oc1cnc(C2CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 105 %

Procedure:
To a solution of 4-(5-chloro-6-cyclopropylpyridin-3-yloxy)-3-(2-methoxypyridin-3-yl)benzonitrile (Preparation 39, 478 mg, 1.27 mmol) in dimethyl sulfoxide (5 mL) was added potassium carbonate (1.05 g, 7.62 mmol) followed by a 30% aqueous solution of hydrogen peroxide (650 μL, 6.35 mmol). The reaction was stirred 1 hour at room temperature. Water (50 mL) was added and the solution was extracted by ethyl acetate (3×20 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with 3% methanol in dichloromethane to afford the title compound as a white solid (528 mg, 87%).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:60])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si](C(C)(C)C)(C)C)[CH:46]([O:58][CH3:59])[CH2:45]2)[CH:7]([CH3:61])[CH:6]([O:62][Si:63]([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:65])[CH3:64])[CH2:5][C:4]1=[O:70])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:60])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:58][CH3:59])[CH2:45]2)[CH:7]([CH3:61])[CH:6]([O:62][Si:63]([C:66]([CH3:67])([CH3:68])[CH3:69])([CH3:65])[CH3:64])[CH2:5][C:4]1=[O:70])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.8 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(tert-butyldimethylsiloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone (2.37 g) (STEP 11A) in dry methylene chloride (25 ml) was added a solution of 10% p-toluenesulfonic acid in methanol (25 ml), and the mixture was stirred at room temperature. After 10 minutes, the mixture was cooled to 0° C. and quenched with saturated sodium bicarbonate. The mixture was diluted with ethyl acetate and the layers were separated. The organic layer was washed with saturated sodium bicarbonate and brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (2.1 g). 1H NMR consistent with the desired structure.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@H:17]([C:19]4[N:24]=[C:23]5[CH:25]=[CH:26][N:27](S(C6C=CC(C)=CC=6)(=O)=O)[C:22]5=[CH:21][C:20]=4[F:38])[CH3:18])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C@H:17]([C:19]4[N:24]=[C:23]5[CH:25]=[CH:26][NH:27][C:22]5=[CH:21][C:20]=4[F:38])[CH3:18])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc([C@H](C)Nc4nccc(Nc5cc(C6CC6)[nH]n5)n4)c(F)cc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](Nc1nccc(Nc2cc(C3CC3)[nH]n2)n1)c1nc2cc[nH]c2cc1F
Temperature: 50 °C
Yield: 29.2 %

Procedure:
To a mixture of (S)—N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-(1-(6-fluoro-1-tosyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)pyrimidine-2,4-diamine (120 mg, 0.226 mmol) in MeOH (10 mL) was added aqueous NaOH (18 mg, 2 mL H2O). The mixture was heated at 50° C. for 5 h. The reaction mixture was quenched by adding a sat'd, aq. NH4Cl solution and extracted with EtOAc (50 mL×3), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford (S)—N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-(1-(6-fluoro-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)pyrimidine-2,4-diamine as white solid (25 mg, 30%). 1H NMR (500 MHz, MeOD) δ 7.79-7.81 (d, 1H), 7.53-7.59 (m, 2H), 6.62 (s, 1H), 6.03-6.27 (m, 2H), 5.54-5.59 (m, 1H), 1.95 (m, 1H), 1.59 (m, 3H), 1.01 (m, 2H), 0.78 (m, 2H); MS (ESI): m/z=379.1 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)([OH:28])=[O:27]>C(=O)(O)[O-].[Na+].COCCOC>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([S:10](=[O:12])(=[O:11])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)=[CH:3][C:2]=1[C:32]1[CH:33]=[CH:34][C:29]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(N3CCOCC3)cc2)cc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(S(=O)(=O)Nc2ccc(N3CCOCC3)cc2)cc1-c1ccc(C(=O)O)cc1

Procedure:
A mixture of 3-bromo-4-methoxy-N-(4-morpholin-4-yl-phenyl)-benzenesulfonamide (460 mg) and 4-carboxy-phenyl boronic acid (196 mg) in saturated sodium bicarbonate solution (4 ml) and DME (8 ml) was heated to reflux in the presence of tetrakis(triphenylphosphine)palladium0 for 16 h. The mixture was allowed to cool and was evaporated. The residue was then suspended in water and 2M HCl added until the effervescence ceased. The resulting light grey solid was collected and dried (490 mg)
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][C@H:6]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]([F:26])[F:25])=[C:19]([O:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)[CH:18]=1)[CH2:7][C:8]1[C:13]([Cl:14])=[CH:12][N+:11]([O-:15])=[CH:10][C:9]=1[Cl:16])=[O:4].[N+:32]([C:35]1[CH:40]=[CH:39][C:38]([CH2:41][S:42](Cl)(=[O:44])=[O:43])=[CH:37][CH:36]=1)([O-:34])=[O:33]>N1C=CC=CC=1.CCOC(C)=O>[Cl:16][C:9]1[CH:10]=[N+:11]([O-:15])[CH:12]=[C:13]([Cl:14])[C:8]=1[CH2:7][C@@H:6]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]([F:26])[F:25])=[C:19]([O:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)[CH:18]=1)[O:5][C:3](=[O:4])[CH2:2][NH:1][S:42]([CH2:41][C:38]1[CH:37]=[CH:36][C:35]([N+:32]([O-:34])=[O:33])=[CH:40][CH:39]=1)(=[O:43])=[O:44]
Reactant: NCC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: O=[N+]([O-])c1ccc(CS(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(CNS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-4-(2-(2-aminoacetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (prepared in an analogous manner to that described in Scheme 1, Step 1-2) (243 mg, 0.509 mmol) dissolved in pyridine (1 mL), cooled at 0° C., (4-nitrophenyl)methanesulfonyl chloride (100 mg, 0.424 mmol) was added. The mixture was stirred at 0° C. for 2 hours. The mixture was then diluted with EtOAc and washed with HCl 0.1N, NaHCO3 sat. sol. and brine. The organic phase was dried over Na2SO4 and the solvent was evaporated. (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-((4-nitrophenyl)methyl-sulfonamido)acetoxy)ethyl)pyridine 1-oxide was obtained (287 mg, 0.42 mmol, quantitative yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.[CH3:11][O:12][CH2:13][C:14](Cl)=[O:15].N1C=CC=CC=1>CN(C=O)C>[CH3:11][O:12][CH2:13][C:14]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2)=[O:15]
Reactant: COCC(=O)Cl
Reactant: Nc1ccc2c(c1)CCC2
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COCC(=O)Nc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 82.5 %

Procedure:
To a solution of 5-aminoindan (4.66 g, 35.0 mmol) in anhydrous DMF (26 ml) was slowly added methoxyacetyl chloride (5.70 g, 52.50 mmol) followed by pyridine (8.5 ml, 105.0 mmol). The red solution was stirred at room temperature for 3.5 hours under argon, then it was partitioned between ethyl acetate (200 ml) and 1N HCl (120 ml). The organic layer was washed with more 1N HCl (120 ml), brine (100 ml), dried (Na2SO4) and concentrated in vacuo. The residue was triturated with diethyl ether; the white precipitate was collected by filtration, washed with diethyl ether to afford the title compound (5.93 g, 83%), m.p. 104-105° C.; 1H-NMR (250 MHz, CDCl3, TMS) 2.06 (m, 2H, 2-CH2), 2.87 (m, 4H, 1-CH2 and 3-CH2), 3.50 (s, 3H, OCH3), 4.00 (s, 2H, 2-CH2OMe), 7.22 (m (overlap with CHCl3 peak), 2H, 6-H, 7-H), 7.52 (s, 1H, 4-H), 8.18 (s, 1H, CONH); MS (ESI, m/z): 432 [(2M+Na)+, 30%], 206 [(M+H)+, 100%]. Found C, 70.10; H, 7.38; N, 6.81; C12H15NO2 requires C, 70.22; H, 7.37; N, 6.82%.
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13]O)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].C[N+](C)=C[Cl:20].[Cl-]>>[C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13][Cl:20])=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: C[N+](C)=CCl
Reactant: N#Cc1ccc(Cn2cncc2CO)cc1
Agent: [Cl-]
Product: N#Cc1ccc(Cn2cncc2CCl)cc1

Procedure:
combining 1-(4-Cyanobenzyl)-5-Hydroxymethyl-imidazole of formula IA ##STR37## with Vilsmeier reagent to obtain 1-(4-Cyanobenzyl)-5-Chloromethylimidazole of formula IF: ##STR38##
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C(N(CC)C(C)C)(C)C>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: C1COCCN1
Reactant: Cc1cc(Cl)nc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1cc(N2CCOCC2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.5 %

Procedure:
Part A: A mixture of 2,4-dichloro-6-methylpyrimidine (4 g, 24.54 mmoles), morpholine (2.14 mL, 24.54 mmoles) and N,N-diisopropylethylamine (4.52 mL) in ethanol (60 mL) was stirred at 0° C. for 3 hours, 25° C. for 24 hours, followed by reflux for 1 hour. The solvent was removed under vacuum and the residue was partitioned between ethyl acetate (200 mL) and aq. sodium hydroxide (1 M, 50 mL). The organic layer was washed with water and brine and dried and concentrated in vacuo. The residue was recrystallized from ethyl acetate/hexanes to give 2-chloro-4-morpholino-6-methylpyrimidine (3.8 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Br[CH2:18][CH2:19][CH2:20][Cl:21]>>[Cl:21][CH2:20][CH2:19][CH2:18][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:4]2[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([F:1])[CH:3]=2)=[CH:11][CH:12]=1
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1F
Reactant: ClCCCBr
Product: N#Cc1ccc(-c2ccc(OCCCCl)cc2)cc1F
Yield: 98 %

Procedure:
The product from Example 166B and 1-bromo-3-chloropropane were processed as described in Example 164C to provide the title compound (98% yield). 1HNMR (300 MHz, CDCl3) δ2.25 (m, 2H), 3.80 (m, 2H), 4.20 (m, 2H), 7.00-7.65 (m, 7H); MS (DCI) m/z 290 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:14])[N:5]([C:7]2[CH:12]=[C:11](Cl)[N:10]=[CH:9][N:8]=2)[N:6]=1.[CH3:15][NH2:16]>CC(O)C>[NH2:14][C:4]1[N:5]([C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:16][CH3:15])[CH:12]=2)[N:6]=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(N)n(-c2cc(Cl)ncn2)n1
Reactant: CN
Solvent: CC(C)O
Product: CNc1cc(-n2nc(C)cc2N)ncn1
Temperature: 50 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
5-Methyl-2-(6-chloro-pyrimidin-4-yl)-2H-pyrazol-3-ylamine (2.09 g, 10 mmol) was mixed with methyl amine (40% in water, 9 mL) and 2-propanol (30 mL). The mixture was heated at 50° C. in a sealed tube. After 4 h, the reaction mixture was cooled to room temperature and condensed, triturated with water, and filtered. The solid was washed with water, air-dried to give [6-(5-amino-3-methyl-pyrazol-1-yl)-pyrimidin-4-yl]-methyl-amine (2.08 g, Yield 97%): 1H NMR 400 MHz (d6-DMSO) δ 8.80 (s, 1H), 7.44 (s, 1H), 6.82-6.74 (m, 3H), 5.19 (s, 1H), 2.83 (s, 3H), 2.06 (s, 3H); MS m/z 210.64 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:6][C:5]([CH3:15])=[CH:4][C:3]=1[CH2:16][NH:17][C:18]1[C:19]([CH3:26])=[C:20]([OH:25])[CH:21]=[CH:22][C:23]=1[CH3:24].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36].O>CN(C=O)C>[F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:6][C:5]([CH3:15])=[CH:4][C:3]=1[CH2:16][NH:17][C:18]1[C:19]([CH3:26])=[C:20]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:25][CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36]
Reactant: Cc1cc(CNc2c(C)ccc(O)c2C)c(F)c(-c2cccc(F)c2)c1
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(CNc2c(C)ccc(OCC(=O)OC(C)C)c2C)c(F)c(-c2cccc(F)c2)c1
Reaction time: 1 h
Yield: 74.4 %

Procedure:
To a solution of 3-[[2-fluoro-3-(3-fluorophenyl)-5-methyl-phenyl]methylamino]-2,4-dimethyl-phenol (114 mg, 0.32 mmol, 1.0 eq) in DMF (10 mL) was added Cs2CO3 (158 mg, 0.48 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 30 min the isopropyl bromoacetate (70 mg, 0.39 mmol, 1.2 eq) was added. The reaction mixture was stirred a further 1 h then poured into water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether:EtOAc, 30:1 to 20:1) to give the title compound as colorless oil (108 mg, 76%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=1.C(N(CC)CC)C.[C:26]1([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:3]=[C:2]([N:35]3[CH2:36][CH2:37][N:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:33][CH2:34]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: CP(C)(=O)c1ccc(Nc2ncnc(Cl)n2)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CP(C)(=O)c1ccc(Nc2ncnc(N3CCN(c4ccccc4)CC3)n2)cc1

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine (prepared as in Example 92: 0.12 mmol) in 2 mL of ethanol is added 50 μL of triethylamine and 1-Phenylpiperazine (19 mg, 0.12 mmol). The mixture is microwaved at 120 degrees until formation of the desired compound. The reaction mixture is filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[C:14]([CH:15]=O)=[C:13]([O:21][CH3:22])[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:23]([O:26][CH2:27][CH3:28])(=[O:25])[CH3:24]>O1CCCC1>[CH2:3]([O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[C:14](/[CH:15]=[CH:24]/[C:23]([O:26][CH2:27][CH3:28])=[O:25])=[C:13]([O:21][CH3:22])[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1cc(OCc2ccccc2)cc(OC)c1C=O
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1c(OC)cc(OCc2ccccc2)cc1OC
Yield: 64 %

Procedure:
To a solution of 4-hydroxy-2,6-dimethoxybenzaldehyde (1.0 g, 5.49 mmol), benzyl alcohol (0.65 g, 6.01 mmol) and tributylphosphine (1.5 g, 7.41 mmol) in tetrahydrofuran (120 ml) was added 1,1′-(azodicarbonyl)dipiperidine (1.8 g, 7.13 mmol) by small portions, and the mixture was stirred at room temperature for 18 hrs. Diethyl ether (120 ml) was added to the reaction mixture, the precipitated insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography (ethyl acetate:hexane=2:3-1:1) to give 4-benzyloxy-2,6-dimethoxybenzaldehyde (1.2 g) as pale-yellow crystals. Separately, a solution of ethyl diethylphosphono acetate (1.1 g, 4.91 mmol) and 60% sodium hydride (0.17 g, 4.25 mmol) in tetrahydrofuran (40 ml) was stirred under ice-cooling for 10 min. A solution of 4-benzyloxy-2,6-dimethoxybenzaldehyde (1.2 g) was added, and the mixture was stirred while elevating the temperature to room temperature for 5 hrs. The reaction solution was diluted with ethyl acetate, washed successively with aqueous citric acid solution, water and aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was washed with diethyl ether-hexane to give the title compound (1.2 g) as colorless crystals. yield 64%. MS 343.1 (MH+).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[O:11]1[C:15]2[CH:16]=[CH:17]C=CC=2N=C1>>[O:11]1[CH2:15][CH:16]1[CH2:17][O:10][C:7]1[CH:8]=[CH:9][C:4]2[N:3]=[CH:2][S:1][C:5]=2[CH:6]=1
Reactant: Oc1ccc2ncsc2c1
Reactant: c1ccc2ocnc2c1
Product: c1nc2ccc(OCC3CO3)cc2s1

Procedure:
Compound 48 was prepared in the manner of compound 6 substituting compound 16 for compound 8 in partC-5 of Example 1.