Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[C:5]([N+]([O-])=O)=[CH:6][C:7]([CH3:11])=[N+:8]([O-:10])[CH:9]=1.[CH:15]1([CH2:18][OH:19])[CH2:17][CH2:16]1>>[Br:3][C:4]1[C:5]([O:19][CH2:18][CH:15]2[CH2:17][CH2:16]2)=[CH:6][C:7]([CH3:11])=[N+:8]([O-:10])[CH:9]=1
Reactant: Cc1cc([N+](=O)[O-])c(Br)c[n+]1[O-]
Reactant: OCC1CC1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(OCC2CC2)c(Br)c[n+]1[O-]
Temperature: 80 °C
Reaction time: 4 h
Yield: 80.6 %

Procedure:
Powdered NaOH (3 g, 75 mmol) was added to a suspension of 5-bromo-2-methyl-4-nitropyridine 1-oxide (11.7 g, 50 mmol; CAN 62516-08-9) in cyclopropylmethanol (89 g, 100 mL, 1.23 mol). The mixture was stirred for 4 h at 80° C. After evaporation to dryness ethyl acetate (400 mL) and water (400 mL) were added. The layers were separated and the aqueous phase was extracted four more times with ethyl acetate (250 mL). The combined extracts were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated to a volume of 100 mL and heptane (100 mL) was added dropwise under stirring. The precipitate was collected washed with ethyl acetate/heptane 1/2 (3×20 mL) and dried in vacuo to give the title compound (10.4 g, 80%) as light brown solid; LC-MS (UV peak area, m/z) 100%, 258.0125 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[C:16]([C:20]1[CH:33]=[CH:32][C:23]([CH2:24][N:25]2[CH2:29][CH2:28]OS2(=O)=O)=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[C:16]([C:20]1[CH:21]=[CH:22][C:23]([CH2:24][NH:25][CH2:29][CH2:28][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]3[CH2:10][CH2:9]3)[CH:3]=2)=[CH:32][CH:33]=1)([CH3:18])([CH3:17])[CH3:19]
Reactant: CC(C)(C)c1ccc(CN2CCOS2(=O)=O)cc1
Reactant: Brc1cccc(C2CC2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CNCCc2cccc(C3CC3)c2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 57.1 %

Procedure:
To a solution of m-bromophenylcyclopropane (synthesized as described in J. Org. Chem. 1976, 41, 2262-2266) (100 mg, 0.51 mmol) in dry THF (3 ml) at −78° C. was added nBuLi (317 μl, 1.6M solution in hexane, 0.51 mmol) dropwise. The reaction mixture was stirred at −78° C. for 10 min and then a solution of 3-(4-tert-butylbenzyl)-[1,2,3]oxathiazolidine 2,2-dioxide (109 mg, 0.41 mmol) in THF (1 ml) was added dropwise. The reaction mixture was warmed to 0° C. over 3 hours and then quenched with 5 ml 20% (v/v) H2SO4. The reaction mixture was warmed to 60° C. overnight and then cooled to RT and poured into water. The aqueous phase was made basic with 1N NaOH and then extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give a crude residue which was purified by flash column chromatography to give (4-tert-butylbenzyl)-[2-(3-cyclopropylphenyl)-ethyl]-amine (72 mg, 58%) as a colorless oil. MS (ISP) 308.4 (M+H)+.
Reaction SMILES: [CH2:1]([SH:5])[CH2:2][CH2:3][SH:4].[CH2:6]([CH:8]1[O:10][CH2:9]1)Cl.[OH-].[Na+]>C(O)C>[OH:10][CH:8]1[CH2:9][S:5][CH2:1][CH2:2][CH2:3][S:4][CH2:6]1
Reactant: SCCCS
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OC1CSCCCSC1
Reaction time: 8 h
Yield: 43 %

Procedure:
A first solution of 1,3-propanedithiol (10.82 grams, 0.10 moles, commercially available from Alfa Aesar; Ward Hill, Mass.) and ethanol (45 milliliters) was placed in a 60-milliliter syringe. A second solution of epichlorohydrin (9.25 grams, 0.10 moles) and ethanol (45 milliliters) was placed in a second 60-milliliter syringe. Both solutions were slowly added dropwise to a mixture of sodium hydroxide (8.80 grams, 0.22 moles) and ethanol (250 milliliters) at room temperature over 10 hours. After stirring for an additional 8 hours, the reaction mixture was concentrated under vacuum, and then diluted with ethyl acetate (200 milliliters). The organic phase was washed with water (200 milliliters) and saturated sodium chloride in water (100 milliliters) and dried over magnesium sulfate. The solvent was removed under reduced pressure to give the crude product that was purified by column chromatography over silica gel using a mixture of ethyl acetate in hexane (30/70 parts by weight). The product was isolated as an oil. (6.99 grams, 43% yield).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH3:25])[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH2:9][N:8]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:7]1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:18]([N:8]1[CH2:9][CH:10]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[C:6]([CH2:4][OH:3])([CH3:25])[CH2:7]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)C1(C)CN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(CO)CN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 75.8 %

Procedure:
To a stirred solution of (3RS,4RS)-1-benzyl-4-(4-chloro-phenyl)-3-methyl-pyrrolidine-3-carboxylic acid ethyl ester (5.75 g, 16.7 mmol) in THF (200 mL) at 0° C., was added portion wise LiAlH4 (381 mg, 10.0 mmol) over 20 minutes. After one hour at this temperature, the reaction mixture was carefully quenched by addition of icy water and then of an aqueous solution of NaHCO3. The product was extracted with EtOAc several times, the combined organic phases were dried over NA2SO4 and purification by column chromatography (SiO2, EtOAc/H 1:4 to 1:1) yielded the title product (4.0 g, 76%) as a colorless viscous oil. ES-MS m/e: 316.2 (M+H+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.O[C:33]1([CH3:49])[CH2:38][CH2:37][CH2:36][CH2:35][C:34]1([C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1)[C:39](=[S:42])[NH:40][CH3:41].Cl>O1CCCC1>[CH2:49]=[C:33]1[CH2:38][CH2:37][CH2:36][CH2:35][C:34]1([C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1)[C:39](=[S:42])[NH:40][CH3:41]
Reactant: CNC(=S)C1(c2cccnc2)CCCCC1(C)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C1CCCCC1(C(=S)NC)c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.9 %

Procedure:
A solution of triphenylphosphine (2.35 g, 9 mmol) in anhydrous tetrahydrofuran (30 ml) was treated dropwise with diethyl azodicarboxylate (1.4 ml, 9 mmol) over 5 min at 0° C. The solution was stirred at this temperature for 30 min and ten treated with a solution of 2-hydroxy-2,N-dimethyl-1-(pyrid-3-yl)cyclohexane carbothioamide (1.59 g, 6 mmol) in anhydrous tetrahydrofuran (15 ml). The mixture was warmed to room temperature and stirred for 16 h. The solution was then poured into aqueous hydrochloric acid (0.5 M, 60 ml) and extracted with ethyl acetate (3×45 ml). The aqueous phase was basified with 2 M aqueous sodium carbonate solution and extracted with dichloromethane (3×45 ml). The organic extract was dried over magnesium sulphate and evaporated to give a pale brown oil This was subjected to flash chromatography over silica gel, eluting with ethyl acetate/methanol (98:2) to give (±)-2-methylene-N-methyl-1-(pyrid-3-yl)cyclohexane carbothioamide (0.25 g) as a colourless solid, m.p. 106.5°-108.5° C.;
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[C:6]#[N:7])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][C:33]1([CH3:41])[O:38][CH2:37][CH:36]([CH2:39]O)[CH2:35][O:34]1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C1(C)C=CC=CC=1>[CH3:32][C:33]1([CH3:41])[O:38][CH2:37][CH:36]([CH2:39][O:11][C:10]2[C:9]([CH3:12])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[CH2:1][CH3:2])[CH2:35][O:34]1
Reactant: CCc1cc(C#N)cc(C)c1O
Reactant: CC1(C)OCC(CO)CO1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCc1cc(C#N)cc(C)c1OCC1COC(C)(C)OC1
Reaction time: 0.25 h
Yield: 27.8 %

Procedure:
To a solution of 3-ethyl-4-hydroxy-5-methyl-benzonitrile (480 mg, 2.98 mmol) in THF (10 mL), triphenylphosphine (1.17 g, 4.47 mmol) and (2,2-dimethyl-[1,3]dioxan-5-yl)-methanol (478 mg, 3.28 mmol) is added. The mixture is cooled to 4° C. before DEAD (1.94 g, 4.47 mmol, 2.05 mL of a 40% solution in toluene) is added. Stirring is continued at 4° C. for 15 min, then at rt for 1 h. The solvent is removed in vacuo and the crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 4-(2,2-dimethyl-[1,3]dioxan-5-ylmethoxy)-3-ethyl-5-methyl-benzonitrile (240 mg) as a yellow oil; LC-MS: tR=1.04 min; [M+1+CH3CN]+=330.97. To a solution of this material (240 mg, 829 μmol) in methanol (5 mL), hydroxylamine hydrochloride (86 mg, 1.24 mmol) and NaHCO3 (104 mg, 1.24 mmol) is added. The mixture is stirred at 60° C. for 5 h before it is diluted with EA and washed with water. The org. extract is dried over MgSO4, filtered, concentrated and dried to give the title compound (280 mg) as a pale yellow oil; LC-MS: tR=0.72 min; [M+1+CH3CN]+=323.01.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.[C:20](Cl)(=[O:22])[CH3:21].O>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:20](=[O:22])[CH3:21])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1cc2ccc(-c3cc(F)ccc3C)cc2cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.2 %

Procedure:
To a solution of 7-(5-fluoro-2-methylphenyl)isoquinolin-3-amine (150 mg, 0.595 mmol) in pyridine (2 mL) was added acetyl chloride (56 mg, 0.714 mmol) dropwise at a temperature below 0° C. After the resulting mixture was stirred at room temperature for 2 h, water (2 mL) was added and it was concentrated under reduced pressure. The solid was washed with methanol and water to give the desired product (26.7 mg, 15.2%). LCMS (ESI): RT (min)=1.150, M+H+=294.8, method=A; 1H NMR (400 MHz, DMSO-d6) δ 10.62, (s, 1H), 9.14 (s, 1H), 8.47 (s, 1H), 8.00 (s, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.68 (d, J=6.8 Hz, 1H), 7.35 (s, 1H), 7.15 (d, J=8.8 Hz, 2H), 2.22 (s, 3H), 2.12 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[CH2:15][C:16](=O)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C(O)=O.[CH2:34]([NH:36][NH2:37])[CH3:35].CCOC(C)=O>CCN(CC)CC>[F:25][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[F:24])[CH2:17][C:16]1[CH:15]=[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10]2)[N:36]([CH2:34][CH3:35])[N:37]=1
Reactant: O=C(CC(=O)C1CCN(Cc2ccccc2)CC1)Cc1ccc(F)c(F)c1
Reactant: CCNN
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCn1nc(Cc2ccc(F)c(F)c2)cc1C1CCN(Cc2ccccc2)CC1
Reaction time: 0.06 h

Procedure:
The title compound was prepared from 1-(1-benzylpiperidin-4-yl)-4-(3,4-difluorophenyl)butane-1,3-dione and ethylhydrazine oxalate using a procedure similar to that described in Example 1, Step B. RF: 0.29 (2:1 EtOAc to hexanes with 1% (v/v) Et3N). It was the fast-eluting isomer on silica gel. 1H NMR (500 MHz, CDCl3): δ7.29˜7.33 (m, 4H), 7.23˜7.28 (m, 1H), 7.05˜7.14 (m, 2H), 6.97˜7.01 (m, 1H), 5.86 (s, 1H), 4.06 (q, 7.2 Hz, 2H), 3.84 (s, 2H), 3.55 (s, 2H), 2.97 (br d, 11.9 Hz, H), 2.64 (tt, 12.1 & 3.7 Hz, 1H), 2.12˜2.16 (m, 2H), 1.83 (br d, 13.1 Hz, 2H), 1.62˜1.71 (m, 2H), 1.35 (t, 7.2 Hz, 3H); ESI-MS 396.2 (M+H), HPLC A: 3.43 min., compared with 3.54 min. for its isomer.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.[N:9]1[CH:14]=[C:13]([CH2:15][OH:16])[CH:12]=[N:11][CH:10]=1.[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[N:9]1[CH:14]=[C:13]([CH2:15][O:16][C:2]2[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=2)[CH:12]=[N:11][CH:10]=1
Reactant: OCc1cncnc1
Reactant: CSc1nsc(Cl)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nsc(OCc2cncnc2)n1
Reaction time: 0.5 h
Yield: 48.1 %

Procedure:
Into 4 g of N,N-dimethylformamide were dissolved 304 mg of 5-chloro-3-methylthio-1,2,4-thiadiazole and 200 mg of 5-pyrimidylmethyl alcohol, 97 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 30 minutes. After stirring for 5 hours at room temperature, the reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with t-butyl methyl ether. The organic layer was concentrated, and the residue obtained was subjected to silica gel column chromatography to give 210 mg of 5-(5-pyrimidylmethyloxy)-3-methylthio-1,2,4-thiadiazole (hereinafter, referred to as the present compound (37)).
Reaction SMILES: C([O:3][C:4](=[O:17])[C:5]([OH:16])([CH3:15])[C:6]([NH:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[O:7])C.[OH-].[Li+]>O1CCCC1.O>[OH:16][C:5]([CH3:15])([C:6]([NH:8][CH2:9][CH2:10][C:11]([F:12])([F:13])[F:14])=[O:7])[C:4]([OH:17])=[O:3]
Reactant: CCOC(=O)C(C)(O)C(=O)NCCC(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)(C(=O)O)C(=O)NCCC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 2.30 g (7.87 mmol) 2-hydroxy-2-methyl-N-(3,3,3-trifluoro-propyl)-malonamic acid ethyl ester in 40 ml of tetrahydrofurane were added 0.33 g (7.87 mmol) of lithium hydroxide in 20 ml of water and the mixture was stirred overnight at room temperature. After concentration in vacuo water (50 ml) was added and the mixture was acidified to pH 1. Extraction with ethylacetate gave 1.46 g (81%) of the title compound as a solid, MS m/e (%): 228.1 (M−H, 100).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[F:10][C:11]([F:26])([F:25])[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)[OH:13].[H-].[Na+]>C1COCC1>[Cl:8][C:6]1[CH:5]=[C:4]([O:13][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)[C:11]([F:10])([F:26])[F:25])[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: OC(c1ccccc1-n1ccnc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nc(Cl)cc(OC(c2ccccc2-n2ccnc2)C(F)(F)F)n1
Temperature: 42.5 °C
Reaction time: 6 h
Yield: 99.9 %

Procedure:
2-Amino-4,6-dichloro pyrimidine (0.107 g, 0.65 mmol), 2,2,2-trifluoro-1-(2-imidazol-1-yl-phenyl)-ethanol (0.157 g, 0.65 mmol), and NaH (0.03 g, 0.78 mmol) were added to anhydrous THF (10 ml) under nitrogen. The reaction was stirred at 40-45° C. for 6 h, and was then cooled to room temperature, and quenched with water (0.2 ml). The reaction mixture was concentrated to give crude 4-chloro-6-[2,2,2-trifluoro-1-(2-imidazol-1-yl-phenyl)-ethoxy]-pyrimidin-2-ylamine (0.24 g, >90% pure by LCMS), which was directly used in the following step.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[NH2:24][C:25]1[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=1>>[CH2:32]([O:31][C:29]([C:28]1[CH:27]=[CH:26][C:25]([NH:24][C:1]([C:4]23[CH2:9][CH2:8][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:10][CH2:11]2)[CH2:6][CH2:5]3)=[O:3])=[CH:35][CH:34]=1)=[O:30])[CH3:33]
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: CCOC(=O)c1ccc(N)cc1
Product: CCOC(=O)c1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 34.2 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and ethyl 4-aminobenzoate (56.0 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(4-ethoxycarbonylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (24.9 mg).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1)[CH2:2][CH3:3].[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.O>C1(C)C=CC=CC=1>[OH:10][C:7]1[CH:8]=[CH:9][C:4]([C:1]2([C:14]3[CH:15]=[CH:16][C:11]([OH:17])=[CH:12][CH:13]=3)[CH2:3][CH2:2][CH:1]([CH2:4][CH2:5][CH3:6])[CH2:3][CH2:2]2)=[CH:5][CH:6]=1
Reactant: CCCC1CCC(=O)CC1
Reactant: Oc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC1CCC(c2ccc(O)cc2)(c2ccc(O)cc2)CC1
Temperature: 25 °C
Reaction time: 50 h
Yield: 91.5 %

Procedure:
1st stage 4-n-Propylcyclohexanone 650 g and phenol 1550 g were mixed, and hydrochloric acid gas was blown to the mixture with vigorously stirring at room temperature. The mixture was vigorously stirred for three hours and then left for 50 hours at room temperature. Meantime, the reaction solution was solidified. Warm water 1,000 ml and toluene 3,000 ml were added to the solid. The solid was heated and dissolved completely. The crystals deposited from the solution after cooling were filtered and washed with water and with toluene. After drying the crystals, white crystals 658 g of 1,1-bis(4-hydroxyphenyl)-4-n-propylcyclohexane was obtained by recrystallization from acetone.
Reaction SMILES: C([N:9]([C:17]1[O:18][C@H:19]([C:32]([F:35])([F:34])[F:33])[CH2:20][C@:21]([C:24]2[C:25]([F:31])=[N:26][CH:27]=[C:28]([Br:30])[CH:29]=2)([CH3:23])[N:22]=1)C(=O)OC(C)(C)C)(=O)C1C=CC=CC=1.Cl>CO>[Br:30][C:28]1[CH:29]=[C:24]([C@:21]2([CH3:23])[CH2:20][C@@H:19]([C:32]([F:33])([F:34])[F:35])[O:18][C:17]([NH2:9])=[N:22]2)[C:25]([F:31])=[N:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)c1ccccc1)C1=N[C@](C)(c2cc(Br)cnc2F)C[C@@H](C(F)(F)F)O1
Agent: Cl
Solvent: CO
Product: C[C@@]1(c2cc(Br)cnc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Temperature: 25 °C
Reaction time: 14 h
Yield: 65.1 %

Procedure:
The crude product (5k) from step 8 was dissolved in MeOH (5 mL). To this solution was added hydrogen chloride (4M in 1,4-dioxane; 8.0 mL, 32.0 mmol) and the reaction mixture was stirred at room temperature for 14 hours and was heated subsequently to 55° C. for 3.5 hours. The reaction mixture was concentrated, the residue was dissolved in water and the pH was adjusted to neutral with saturated sodium bicarbonate. The solution was extracted with DCM. The combined organic extracts were washed with brine and dried over sodium sulfate. The filtrate was concentrated and purified by silica gel column (gradient 0-5% MeOH/DCM) to afford the title compound (0.335 g, 0.941 mmol, 65.1% yield) as white solid. MS m/z=356, 358 [M]+/[M+2]+. Calculated for C11H10BrFF4N3O: 356.2
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]2[C:6]=1[CH2:7][CH2:8][N:9](C(=O)C(F)(F)F)[CH:10]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCO>C1COCC1>[CH3:3][O:4][C:5]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]2[C:6]=1[CH2:7][CH2:8][NH:9][CH:10]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccc(OC)c2c1CCN(C(=O)C(F)(F)F)C2c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(OC)c2c1CCNC2c1ccccc1
Yield: 98.3 %

Procedure:
Sodium borohydride (900 mg) was added to a mixed solution of a solution of 5,8-dimethoxy-1-phenyl-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline (4.21 g) in THF (30 mL), and EtOH (100 mL) at room temperature under stirring. The reaction mixture was stirred at room temperature for 3 hours and then stirred at 40° C. for 30 minutes, and concentrated under reduced pressure. To the resulting residue was added a 3 M aqueous HCl solution (30 mL), followed by refluxing for 5 minutes. After cooling, the mixture was made strong alkaline by using a 20% aqueous NaOH solution and extracted with chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 5,8-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (3.05 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:16]([O:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[N:17][C:18]([C:21](=[NH:24])[NH:22][OH:23])=[N:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:34](N1C=CN=C1)(N1C=CN=C1)=[O:35].N12CCCN=C1CCCCC2>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:15]1[C:16]([O:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[N:17][C:18]([C:21]2[NH:24][C:34](=[O:35])[O:23][N:22]=2)=[N:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(Oc2nc(C(=N)NO)ncc2NC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(Oc2nc(-c3noc(=O)[nH]3)ncc2NC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of Compound 6b (0.038 g; 0.0828 mmol) and 1,1′-carbonyldiimidazole (0.015 g; 0.091 mmol) in CH3CN (1 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.05 mL, 0.33 mmol) and the resulting mixture was stirred at rt for 20 h. The reaction mixture was washed with water, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield Compound 6c. MS: m/z 485.3 (M+H)+.
Reaction SMILES: C(OC1C(=O)N=C(CC2(N3C4=NC=CC=C4C=C3)CCCC2)N2CCN(C)C(=O)C=12)C1C=CC=CC=1.O[CH2:38][CH2:39][N:40]([CH:73]1[CH2:76][O:75][CH2:74]1)[C:41]([C:43]1[C:48]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[C:47]([OH:57])[N:46]=[C:45]([CH2:58][C:59]2([N:64]3[C:68]4=[N:69][CH:70]=[CH:71][CH:72]=[C:67]4[CH:66]=[CH:65]3)[CH2:63][CH2:62][CH2:61][CH2:60]2)[N:44]=1)=[O:42]>>[CH2:50]([O:49][C:48]1[C:47](=[O:57])[N:46]=[C:45]([CH2:58][C:59]2([N:64]3[C:68]4=[N:69][CH:70]=[CH:71][CH:72]=[C:67]4[CH:66]=[CH:65]3)[CH2:60][CH2:61][CH2:62][CH2:63]2)[N:44]2[CH2:38][CH2:39][N:40]([CH:73]3[CH2:76][O:75][CH2:74]3)[C:41](=[O:42])[C:43]=12)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: O=C(c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1COC1
Agent: CN1CCn2c(CC3(n4ccc5cccnc54)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Product: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(n4ccc5cccnc54)CCCC3)n2CCN1C1COC1

Procedure:
9-Benzyloxy-2-oxetan-3-yl-6-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (423) was prepared following the same method as described for 9-benzyloxy-2-methyl-6-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (407) from 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-oxetan-3-yl-amide (422) (200 mg, 0.40 mmol) and was obtained as white sticky solid (13 mg, 6%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=O.[CH:21]([N:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][C:32]=2[C:38]([F:41])([F:40])[F:39])[CH2:26][CH2:25]1)([CH3:23])[CH3:22]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([NH:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][N:27]2[CH2:26][CH2:25][N:24]([CH:21]([CH3:23])[CH3:22])[CH2:29][CH2:28]2)=[C:32]([C:38]([F:41])([F:40])[F:39])[CH:33]=1)=[O:20]
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1Cl
Reactant: CC(C)N1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Solvent: CO
Solvent: ClCCl
Product: CC(C)N1CCN(Cc2ccc(NC(=O)Cc3ccc(-n4cnc5cccnc54)cc3Cl)cc2C(F)(F)F)CC1

Procedure:
The title compound is prepared as described in Example 1 but using (2-chloro-4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid and 4-(4-isopropyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (see WO 03/099771). Title compound: ES-MS: 570.9 [M+H]+; single peak at tR=3.46 min (System 1); Rf=0.26 (CH2Cl2/MeOH+1% NH3aq, 9:1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH2:12]1>>[NH2:8][C:5]1[CH:4]=[N:3][C:2]([N:11]2[CH2:12][CH2:13][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:15][CH2:16]2)=[N:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Product: CC(C)(C)OC(=O)NC1CCN(c2ncc(N)cn2)CC1
Yield: 87.1 %

Procedure:
Following General procedure H, 2-chloro-5-nitropyrimidine (500 mg, 3.1 mmol) was reacted with tert-butyl piperidin-4-ylcarbamate (683 mg, 3.5 mmol) followed by reduction to afford the desired product (792 mg, 87%) as a purple solid: ESI MS m/z 294 [C14H23N5O2+H]+.