Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:40])[CH2:4][CH2:5][NH:6][C:7](=[O:39])[C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH2:36][CH:37]=[CH2:38])([CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:15][CH:16]=[CH2:17])=[CH:10][CH:9]=1.[Li+].[OH-].Cl>C1COCC1>[CH2:15]([C:14]([C:11]1[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:40])=[O:2])=[O:39])=[CH:13][CH:12]=1)([CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:34])([F:35])[F:33])=[CH:28][CH:27]=2)=[CH:24][CH:25]=1)[CH2:36][CH:37]=[CH2:38])[CH:16]=[CH2:17]
Reactant: C=CCC(CC=C)(COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CCC(CC=C)(COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)NCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
A solution of 3-{4-[1-allyl-1-(4′-trifluoromethyl-biphenyl-4-yloxymethyl)-but-3-enyl]-benzoylamino}-propionic acid methyl ester (0.0279 g, 0.0506 mmol) in THF (1.0 mL) is treated with 1N LiOH (1.0 mL) and stirred overnight at room temperature. The reaction mixture is acidified with 1N HCl (2.2 mL) and extracted with EtOAc (3×10 mL). Combined extracts are dried over MgSO4, filtered, and concentrated to provide 3-{4-[1-allyl-1-(4′-trifluoromethyl-biphenyl-4-yloxymethyl)-but-3-enyl]-benzoylamino}-propionic acid (0.0189 g, 69%) as a white solid. MS (ES): 538.3 [M+H]+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:23]=[CH:22][C:12]([CH2:13][NH:14][C:15]3[C:16]([NH2:21])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[N:30]1([CH2:35][CH2:36][O:37][C:38]2[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1.C(Cl)(Cl)Cl>ClCCl.CO>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:23]=[CH:22][C:12]([CH2:13][NH:14][C:15]3[C:16]([NH:21][C:42](=[O:43])[C:41]4[CH:40]=[CH:39][C:38]([O:37][CH2:36][CH2:35][N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)=[CH:46][CH:45]=4)=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccc(OCCN2CCCC2)cc1
Reactant: Nc1ccccc1NCc1ccc(OCCN2CCCC2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: O=C(Nc1ccccc1NCc1ccc(OCCN2CCCC2)cc1)c1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C

Procedure:
To a solution of N1-[4-[2-(1-pyrrolidinyl)ethoxy]-benzyl]-1,2-benzenediamine (220 mg, 0.706 mmol) in dry dichloromethane (2 mL) was added pyridine (0.114 mL, 1.41 mmol, 2.0 eq.). To the resulting solution was added a suspension of 4-[2-(1-pyrrolidinyl)ethoxy]benzoyl chloride (179 mg, 0.706 mmol, 1.0 eq.) in dry dichloromethane (3 mL), portionwise, at 0° C., following the reaction by tlc (9:1 CHCl3:MeOH, 1% TEA). Once the aniline had been consumed, the reaction was allowed to warm to ambient temperature. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution (15 mL) then diluted with ethyl acetate (60 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (15 mL), water (15 mL), brine (15 mL), dried over MgSO4, filtered then the solvent was removed under reduced pressure. The desired product was obtained after flash chromatography (eluting with 20:1 CHCl3:MeOH, 0.5% TEA) as a brown foam (361 mg, 97%).
Reaction SMILES: [CH2:1]1[C:4]2([CH2:7][N:6]([CH2:8][C:9]3[CH:26]=[CH:25][C:12]([O:13][CH:14]4[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]4)=[CH:11][CH:10]=3)[CH2:5]2)[CH2:3][O:2]1.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+]>ClCCl>[NH:16]1[CH2:17][CH:14]([O:13][C:12]2[CH:25]=[CH:26][C:9]([CH2:8][N:6]3[CH2:5][C:4]4([CH2:1][O:2][CH2:3]4)[CH2:7]3)=[CH:10][CH:11]=2)[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(CN3CC4(COC4)C3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc(OC2CNC2)ccc1CN1CC2(COC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
3A (0.19 g, 0.52 mmol) was dissolved in dichloromethane (20 mL) and TFA (1.95 mL, 26 mmol) was added. The reaction mixture was stirred at room temperature for two hours. K2CO3 (5 g) was added in portions and the mixture was stirred for 20 min. A saturated solution of K2CO3 (aq) was added and the mixture was transferred to a separatory funnel. The layers were separated and the aqueous layer was further extracted several times with dichloromethane. The combined organic solutions were dried (phase separator) and evaporated. There was obtained 128 mg (94%) of 3B as an oil. 1H NMR (500 MHz, CDCl3): δ 3.34 (s, 4H), 3.45 (s, 2H), 3.80 (m, 2H), 3.92 (m, 2H), 4.72 (s, 4H), 4.98 (m, 1H), 6.69 (d, 2H), 7.13 (d, 2H), MS (APCI+) m/z 261 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][N:10]3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Al](C)C.[Br:21][C:22]1[CH:23]=[C:24]([CH3:32])[C:25]([C:28](OC)=[O:29])=[N:26][CH:27]=1>O1CCOCC1>[C:1]1([C:7]2[N:8]=[C:9]3[N:14]=[C:13]([NH:15][C:28]([C:25]4[C:24]([CH3:32])=[CH:23][C:22]([Br:21])=[CH:27][N:26]=4)=[O:29])[CH:12]=[CH:11][N:10]3[CH:16]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccn2cc(-c3ccccc3)nc2n1
Reactant: COC(=O)c1ncc(Br)cc1C
Agent: C[Al](C)C
Solvent: C1COCCO1
Product: Cc1cc(Br)cnc1C(=O)Nc1ccn2cc(-c3ccccc3)nc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To an argon purged solution of 2-phenylimidazo[1,2-a]pyrimidin-7-amine (example 1, step 1, 80 mg, 0.381 mmol) in dioxane (5 ml) was added trimethyl aluminum solution (0.571 ml, 1.14 mmol, 3 eq). The resulting solution was stirred for 1 hour at RT. Then methyl 5-bromo-3-methylpicolinate (88 mg, 0.381 mmol) was added and the mixture was heated to reflux and stirred for 18 hours. The title compound (84 mg, 54%) was isolated from the crude product by flash chromatography on a 20 g SiO2 column using dichloromethane/methanol 0-10% as eluent. MS (m/e)=408.2 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[O:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24]Br)[CH:19]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:24][C:20]3[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=3)[C:17]([OH:26])=[O:16])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: COC(=O)c1cccc(CBr)c1
Product: Cc1ccc(-c2ccc(OCc3cccc(C(=O)O)c3)cc2)cc1

Procedure:
3-(4′-Methyl-biphenyl-4-yloxymethyl)-benzoic acid was prepared using general procedure A from 4′-methyl-biphenyl-4-ol (purchased from Maybridge plc, Tintagel, Cornwall, UK or from Intermediate 5) and 3-(bromomethyl)benzoic acid methyl ester (available from Lancaster Synthesis Ltd., Morcambe, Lancashire, UK). Yield: 66 mg. Mass spectrum (ES) MH+=319.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5](C)([CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:6](OCC)=O)C.[OH-].[Na+]>C(O)C>[CH3:6][CH:5]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:4]([OH:23])=[O:3]
Reactant: CCOC(=O)C(C)(CCCCOc1ccccc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(CCCCOc1ccccc1)C(=O)O

Procedure:
242 g of methyl-(4-phenoxybutyl)-malonic acid diethyl ester, 1000 ml of a 20% sodium hydroxide solution and 100 ml of ethanol were refluxed for 12 hours.
Reaction SMILES: [NH2:1][CH2:2][C@:3]1([CH2:18][OH:19])[O:7][C@@H:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:17].[CH:20]1[C:32]2[CH:31]([CH2:33][O:34][C:35]([NH:37][C@H:38]([C:43](O)=[O:44])[CH2:39][CH:40]([CH3:42])[CH3:41])=[O:36])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.C(N(C(C)C)CC)(C)C.C(NCC(NC[C@]1(CO)O[C@@H](N2C=C(C)C(=O)NC2=O)C[C@@H]1O)=O)(=O)C>CN(C=O)C>[CH:29]1[C:30]2[CH:31]([CH2:33][O:34][C:35]([NH:37][C@H:38]([C:43]([NH:1][CH2:2][C@:3]3([CH2:18][OH:19])[O:7][C@@H:6]([N:8]4[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]4=[O:10])[CH2:5][C@@H:4]3[OH:17])=[O:44])[CH2:39][CH:40]([CH3:42])[CH3:41])=[O:36])[C:32]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]=2[CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@](CN)(CO)O2)c(=O)[nH]c1=O
Agent: CC(=O)NCC(=O)NC[C@]1(CO)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn([C@H]2C[C@H](O)[C@](CO)(CNC(=O)[C@H](CC(C)C)NC(=O)OCC3c4ccccc4-c4ccccc43)O2)c(=O)[nH]c1=O

Procedure:
4′-C-(Aminomethyl)thymidine (4) (0.025 g, 0.1 mmol), N-(9-fluorenylmethyloxycarbonyl)leucine (0.071 g, 0.2 mmol), TSTU (0.09 g, 0.3 mmol) and diisopropylethylamine (0.065 g, 0.5 mmol, 0.087 mL) were combined in DMF (1 mL) according to the procedure used to prepare compound (19). The title compound (20) was obtained as an amorphous solid (0.056 g). δH(300 MHz, CD3OD) 7.86–7.37(8H, m, Fmoc), 7.74(1H, s, H-6), 6.24(1H, dd, H-1′), 4.56(1H, dd, H-3′), 3.68(2H, 2d, H-5′), 3.40(2H, 2d, 4′-C—CH2), 2.37(2H, m, H-2′), 1.70(3H, m, leucyl CH, CH2), 1.66(3H, s, 5-CH3), 1.05(3H, d, leucyl CH3), 1.02(3H, d, leucyl CH3); ES +ve m/z 607(M+H)+, 629(M+Na)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][C:24]1[C:25]([C:33]#[N:34])=[N:26][C:27]([CH:30]2[CH2:32][CH2:31]2)=[CH:28][CH:29]=1)=[N+]=[N-].O1CCCC1>O>[CH:30]1([C:27]2[N:26]=[C:25]3[C:33]([NH2:34])=[N:20][CH2:23][C:24]3=[CH:29][CH:28]=2)[CH2:32][CH2:31]1
Reactant: N#Cc1nc(C2CC2)ccc1CN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NC1=NCc2ccc(C3CC3)nc21
Reaction time: 3 h
Yield: 90.4 %

Procedure:
Triphenylphosphine (365 mg, 1.39 mmol) was added at room temperature to a solution of the 3-(azidomethyl)-6-cyclopropyl-2-pyridinecarbonitrile (230 mg, 1.15 mmol) in a tetrahydrofuran (4 ml) —H2O (0.2 ml) mixed solvent and the mixture was stirred for 3 hours. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography, to yield the title compound (180 mg, 90%) as a white amorphous solid from the ethyl acetate-methanol-29% NH3(aq) (30:10:1) elution fraction.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].O[C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=1
Reactant: Cc1onc(-c2ccccc2)c1CO
Reactant: Oc1ccc(C(F)(F)F)cn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(F)(F)F)cn1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 51.5 %

Procedure:
To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (95 mg, 0.50 mmol) in THF (6 mL) was added 2-hydroxy-5-trifluoromethylpyridine (90 mg, 0.55 mmol) and triphenylphosphine (197 mg, 0.75 mmol) at ambient temperature under an argon atmosphere. Then diethyl azodicarboxylate (120 μL, 0.75 mmol) was added and the reaction mixture was stirred for 2.5 h at 50° C. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 0:100) afforded the title compound (86 mg, 51%) as a colourless oil. MS: m/e=335.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])=[CH:11][C:12]([Cl:18])=[C:13]([CH:17]=1)[C:14](O)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:17]=[C:13]([C:14]([N:42]2[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]2)=[O:15])[C:12]([Cl:18])=[CH:11][C:10]=1[C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(OCc2ccccc2)c(C(=O)OCc2ccccc2)cc1Cl
Reactant: CN1CCNCC1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2cc(OCc3ccccc3)c(C(=O)OCc3ccccc3)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
To a solution of 5-(benzyloxy)-4-((benzyloxy)carbonyl)-2-chlorobenzoic acid (may be prepared as described in D74) (500 mg, 1.260 mmol) in N,N-Dimethylformamide (DMF) (5 mL) were added DIPEA (0.660 mL, 3.78 mmol), 1-methylpiperazine (0.182 mL, 1.638 mmol), 1-hydroxy-7-azabenzotriazole (206 mg, 1.512 mmol) and EDC (435 mg, 2.268 mmol). The mixture was stirred at room temperature for 8 hrs. The solvent was removed in vacuo. The residue was redissolved in DCM (10 mL) and washed with water (10 mL), dried over MgSO4 and concentrated in vacuo. Purification by column (Si, Isolute, 10% 2M NH3 in MeOH/DCM) gave the title product as a yellow solid (400 mg, 66% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N+:3]=1[O-:10].[OH-:11].[Na+].Cl>>[OH:10][N:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]1=[O:11]
Reactant: COc1cc[n+]([O-])c(Cl)c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: COc1ccn(O)c(=O)c1
Yield: 20 %

Procedure:
2-Chloro-4-methoxypyridine-1-oxide (3.3 g) is dissolved in 10% w/v aqueous NaOH (33 ml) and the mixture is heated on a steam bath for 3.5 hours when it is cooled and acidified with concentrated HCl to a pH of 2.5 to yield white crystals. Recrystallisation of these from water gives 1-hydroxy-4-methoxypyrid-2-one (0.75 g, 20%), m.p. 174°-175° C., δ(D2O) 5.9 (s, 1H), 6.00 (q, 1H), 7.5 (d, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH2:9][CH2:8]2)(=[O:3])[CH3:2].[N+:14]([O-])([O-:16])=[O:15].[K+]>OS(O)(=O)=O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[CH2:10][CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2c(c1)CCC2
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])CCC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 15.1 %

Procedure:
To a solution of 5.59 g (31.9 mmol) of 5-acetamidoindan in 55 mL of H2SO4 kept in an ice-bath was added portionwise 3.62 g of KNO3 (35.8 mmol). The solution was stirred in the ice-bath for 2 h and at room temperature overnight. It was added to 500 mL of ice-water and stirred for 1 h. The precipitate was filtered, washed with water, and dried to leave a black solid, which was separated by chromatography (silica gel, eluted with hexane/ethyl acetate=10:1) to give 1.06 g (15%) of a yellow solid. 1H NMR (CDCl3), 2.142 (m, 2), 2.279 (s, 3), 3.00 (m, 4), 8.44 (s, 1), 8.575 (s, 1), 10.389 (s, 1).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)[CH:4]=[N:3][CH:2]=1.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[C:5]([C:7]2[CH:14]=[CH:13][C:10](/[CH:11]=[CH:23]/[CH:24]=[O:25])=[CH:9][CH:8]=2)[CH:4]=[N:3][CH:2]=1
Reactant: O=Cc1ccc(-c2cncnc2)cc1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1ccc(-c2cncnc2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(5-pyrimidinyl)-benzaldehyde (prepared as described in WO 9828264) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 211 (M+H)+.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1([OH:13])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[C:6]([C:7]1([OH:13])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)#[CH:5]
Reactant: C[Si](C)(C)C#CC1(O)CCOCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C#CC1(O)CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-{(trimethylsilyl)ethynyl}tetrahydropyran-4-ol (1.0 g, 5.04 mmol) in THF (SnL), a 1 M solution of tetrabutyl ammonium fluoride in THF (5.29 mL, 5.29 mmol) was added and the reaction was stirred 2 hours at room temperature. The reaction mixture was then poured into an aqueous 5% NH4OAc solution and diluted with ethyl acetate. The isolated organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude residue obtained was used as such for the next step. 1H NMR (400 MHz, acetone-d6): 4.61 (s, 1H), 3.87-3.77 (m, 2H), 3.60-3.50 (m, 2H), 2.98 (s, 1H), 1.89-1.81 (m, 2H), 1.77-1.65 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:31]2)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C:9]1=[S:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C(=O)C1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C(=S)C1
Yield: 132.6 %

Procedure:
A mixture of 1-benzyl-4-(tert-butyloxycarbonyl)piperazin-2-one (1.0 mg, 3.4 mmol) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide (Lawesson's Reagent) (837 mg, 2.1 mmol) were heated at 90° C. in toluene (10 mL), under nitrogen for 45 min. The mixture was cooled then partitioned between EtOAc (3×50 mL) and water (50 mL). The combined organic layers were dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel, eluting with CH2Cl2 :EtOAc (100:0→95:5→90:10) to afford the title compound (853 mg, 82%) as a colourless solid. mp. 126-129° C. 1H NMR (250 MHz, CDCl3) δ 1.47 (9H, s), 3.40-3.44 (2H, m), 3.60-3.65 (2H, m), 4.67 (2H, s), 5.31 (2H, s), 7.31-7.39 (5H, m). MS (ES+) (307, M+1).
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([C:26]4[N:27]=[CH:28][C:29]5[C:34]([CH:35]=4)=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH:20]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)C1C=CC=CC=1.CCN(C(C)C)C(C)C.C(Cl)(=O)OC(Cl)C>ClC(Cl)C>[CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[C:26]([C:21]2[CH:20]=[C:19]([NH:18][C:14]3[C:15]4[CH2:16][CH2:17][NH:8][CH2:9][C:10]=4[N:11]=[CH:12][N:13]=3)[CH:24]=[CH:23][C:22]=2[CH3:25])[N:27]=1
Reactant: Cc1ccc(Nc2ncnc3c2CCN(Cc2ccccc2)C3)cc1-c1cc2ccccc2cn1
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Nc2ncnc3c2CCNC3)cc1-c1cc2ccccc2cn1
Temperature: 90 °C
Reaction time: 12 h

Procedure:
To a solution of 7-benzyl-N-(3-(isoquinolin-3-yl)-4-methylphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (500 mg, 1.09 mmol) in dichloroethane (14 ml) is added DIEA (284 mg, 2.2 mmol) and 1-chloroethyl carbonochloridate (313 mg, 2.2 mmol). The reaction mixture is stirred at 90° C. for 12 hours, and cooled. The solvent is removed by rotary evaporation. The residue is redissolved in methanol (20 ml) and stirred at room temperature for 15 hours. After concentration, the crude product is purified by silica gel flash chromatography (eluted with 5% methanol in ethyl acetate) to afford N-(3-(isoquinolin-3-yl)-4-methylphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine as a dark yellow solid. LC-MS m/z: 368.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([CH:11]([CH3:13])[CH3:12])=[C:4]([NH2:14])[CH:3]=1.CC(C)([O-])C.[K+].[H][H]>[Ru].C(O)(C)(C)C>[NH2:1][CH:2]1[CH:7]([CH:8]([CH3:9])[CH3:10])[CH2:6][CH:5]([CH:11]([CH3:13])[CH3:12])[CH:4]([NH2:14])[CH2:3]1
Reactant: CC(C)c1cc(C(C)C)c(N)cc1N
Reactant: [H][H]
Agent: [Ru]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CC(C)C1CC(C(C)C)C(N)CC1N
Yield: 27.5 %

Procedure:
A suitable autoclave was charged with 20.7 g (0.108 mol) of purified 1,3-diamino-4,6-diisopropylbenzene, 0.3 g (2.7 mmol) of potassium t-butoxide, 2.0 g of 5% Ru on alumina, and 100 mL of t-butanol. The autoclave was heated to 190° C. at 25.5 MPa hydrogen for 24 hours. It was then cooled and its contents filtered. The solvent was removed from the filtrate in vacuo and the resulting liquid distilled through a 20.3 cm Vigreaux column at about 4 mm Hg/115°-118° C. to give 5.9 g (28%) of 1,3-diamino-4,6-diisopropylcyclohexane.
Reaction SMILES: C([O:3][C:4]([O:6][CH:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:35])/[CH:20]=[CH:21]/[C:22]2[CH:23]=[N:24][N:25]([CH3:34])[C:26]=2[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:14][CH:13]=1)[C:8]([NH2:10])=[O:9])=O)C.C1CCN2C(=NCCC2)CC1>C(#N)C>[O:3]=[C:4]1[NH:10][C:8](=[O:9])[CH:7]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:35])/[CH:20]=[CH:21]/[C:22]3[CH:23]=[N:24][N:25]([CH3:34])[C:26]=3[C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:16][CH:17]=2)[O:6]1
Reactant: CCOC(=O)OC(Cc1ccc(NC(=O)/C=C/c2cnn(C)c2-c2ccc(F)cc2)cc1)C(N)=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Cn1ncc(/C=C/C(=O)Nc2ccc(CC3OC(=O)NC3=O)cc2)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.2 %

Procedure:
A mixture of 2-(ethoxycarbonyloxy)-3-[4-({(2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-2-propenoyl}amino)phenyl]propionamide (420 mg), 1,8-diazabicyclo[5.4.0]-7-undecene (266 mg) and acetonitrile (10 ml) was stirred at room temperature for 1 hr. The reaction mixture was concentrated and diluted with ethyl acetate. The mixture was successively washed with a 1N aqueous hydrochloric acid solution, water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give (2E)-N-{4-[(2,4-dioxo-1,3-oxazolidin-5-yl)methyl]phenyl}-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]acrylamide (293 mg, 77%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([NH:9][CH2:10][CH:11]3[CH2:15][CH2:14][NH:13][CH2:12]3)O[C:4]=2[CH:3]=1.Cl.C(O[C:24]([N:26]1CC[C@@H](CN)C1)=O)(C)(C)C.ClC1C=NC2C(=CC=C(Cl)C=2)N=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:16][CH:17]=1)[N:6]=[C:7]([NH:9][CH2:10][C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)[CH:24]=[N:26]2
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CN)C1
Reactant: Clc1ccc2nc(NCC3CCNC3)oc2c1
Agent: Cl
Agent: Clc1ccc2nc(Cl)cnc2c1
Solvent: C1COCCO1
Product: Clc1ccc2nc(NC[C@@H]3CCNC3)cnc2c1

Procedure:
In analogy to the procedure described for the synthesis of (6-Chloro-benzooxazol-2-yl)-pyrrolidin-3-ylmethyl-amine; hydrochloride (example 1, step 2) the title compound was prepared from (S)-3-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 2,6-dichloro-quinoxaline (commercially available) and subsequent cleavage of the tert-butyloxy carbonyl-protecting group through treatment with HCl in dioxane. MS (m/e): 263.1 (MH+).
Reaction SMILES: CO[C:3](=[O:20])[C@@H:4]([N:6]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH2:7][CH:8]=[O:9])[CH3:5].[NH2:21][C@H:22]([CH2:34]O)[CH2:23][CH2:24][N:25]1[CH2:32][CH2:31][C:28]2([CH2:30][CH2:29]2)[C@H:27]([OH:33])[CH2:26]1>C1(C)C=CC=CC=1>[CH2:13]([O:12][C:10]([N:6]1[C@@H:4]([CH3:5])[C:3](=[O:20])[N:21]2[C@@H:22]([CH2:23][CH2:24][N:25]3[CH2:32][CH2:31][C:28]4([CH2:29][CH2:30]4)[C@H:27]([OH:33])[CH2:26]3)[CH2:34][O:9][CH:8]2[CH2:7]1)=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)[C@H](C)N(CC=O)C(=O)OCc1ccccc1
Reactant: N[C@H](CO)CCN1CCC2(CC2)[C@H](O)C1
Solvent: Cc1ccccc1
Product: C[C@H]1C(=O)N2C(CN1C(=O)OCc1ccccc1)OC[C@@H]2CCN1CCC2(CC2)[C@H](O)C1
Yield: 84.3 %

Procedure:
A solution of (S)-2-[benzyloxycarbonyl-(2-oxo-ethyl)-amino]-propionic acid methyl ester (intermediate 1; 570 mg, 2.04 mmol) and (S)-6-((S)-3-amino-4-hydroxy-butyl)-6-aza-spiro[2.5]octan-4-ol (445 mg, 2.04 mmol) in toluene (6 mL) was heated at reflux for 16 h, then the reaction mixture was concentrated. Chromatography (SiO2; DCM→DCM/MeOH/25% aq. ammonia solution 90:10:0.25) produced the title compound (763 mg, 84%) as a 70:30 mixture of (R)- and (S)-epimers. White foam, MS (ISP)=446.2 (M+H)+.