Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrC[C:45]1[CH:52]=[CH:51][CH:50]=C[C:46]=1[C:47]#[N:48]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:50]=[CH:51][CH:52]=[CH:45][C:46]=3[C:47]#[N:48])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: N#Cc1ccccc1CBr
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3ccccc3C#N)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)benzonitrile and isolated as white solid (6.1 mg, 37%). MS (m/e): 398.3 (MH+).
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: CSc1nc(C)cc(O)n1
Reactant: O=P(Cl)(Cl)Cl
Product: CSc1nc(C)cc(Cl)n1
Temperature: 25 °C
Yield: 80 %

Procedure:
4-Hydroxy-6-methyl-2-(methylthio)pyrimidine (9.20 g, 59 mmol) and phosphorous oxychloride (60 mL) were combined and refluxed for 3 hours. The reaction mixture was cooled to room temperature and poured onto crushed ice. The resultant aqueous mixture was extracted with ethyl acetate; and the organic layer washed with saturated aqueous sodium bicarbonate followed by a water wash, dried over magnesium sulfate, and dried in vacuo to give 4-chloro-6-methyl-2-(methylthio)pyrimidine (8.27 g, 80%), m.p. 37°-38° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]=2[CH3:17])=[CH:4][CH:3]=1.C([Li])CCC.[C:23](=[O:25])=[O:24]>C1COCC1>[C:23]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]=2[CH3:17])=[CH:4][CH:3]=1)([OH:25])=[O:24]
Reactant: O=C=O
Reactant: Cc1c(-c2ccc(Br)cc2)[nH]c2ncccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C(=O)O)cc2)[nH]c2ncccc12

Procedure:
2-(p-Bromophenyl)-3-methyl-pyrrolo-[2,3 -b]pyridine (1 g, 3.5 mmol) was dissolved in 200 ml dry THF, deaerated and cooled to -78° C. n-Butyllithium (5.19 ml, 8.4 mmol) was added dropwise and the mixture was allowed to reach room temperature CO2 (g) was bubbled through the solution for 10 min.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[S:7]1(=[O:23])=[O:22].[CH3:24][NH:25][CH3:26].Cl>>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:6]([CH2:5]/[CH:4]=[CH:3]/[CH2:2][N:25]([CH3:26])[CH3:24])[S:7]1(=[O:23])=[O:22]
Reactant: O=S1(=O)N(C/C=C/CBr)c2ccccc2N1c1ccccc1F
Reactant: CNC
Agent: Cl
Product: CN(C)C/C=C/CN1c2ccccc2N(c2ccccc2F)S1(=O)=O

Procedure:
In an analogous manner to general procedure V, 1-[(2E)-4-bromobut-2-en-1-yl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.13 g, 0.33 mmol) was treated with dimethyl amine to give (2E)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylbut-2-en-1-amine (90 mg) after treatment with HCl.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Cl)=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12])([O-:3])=[O:2].[C:15]([C:19]1[O:23][N:22]=[C:21]([OH:24])[CH:20]=1)([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:15]([C:19]1[O:23][N:22]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:6]=2)[C:21](=[O:24])[CH:20]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1cc(O)no1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(=O)n(-c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)o1
Temperature: 0 °C
Reaction time: 6 h
Yield: 18.7 %

Procedure:
After mixing 15.0 g of 2-nitro-5-chlorobenzotrifluoride, 11.3 g of 5-t-butyl-3-hydroxyisoxazole, 11.0 g of potassium carbonate, and 80 ml of dimethyl sulfoxide, the reaction was performed for 6 hours at 100° C. After the reaction was over, the reaction mixture was poured into ice-water and then extracted with ethyl acetate. The organic phase formed was recovered and applied to silica gel column chromatography. The main product thus obtained was recrystallized from a mixture of methanol and water to provide 4.1 g of the desired compound with a yield of 18.7%. The melting point thereof was 125° C. to 126° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH2:13][CH2:14][NH2:15])[NH:10][N:9]=2)=[CH:4][CH:3]=1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[N:19]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([CH2:13][CH2:14][NH:15][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([C:20]4[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=4)[CH:24]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: NCCc1nc(-c2ccc(Cl)cc2)n[nH]1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCCc1nc(-c2ccc(Cl)cc2)n[nH]1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 13 %

Procedure:
This compound was synthesized from 2-(3-(4-chlorophenyl)-1H-1,2,4-triazol-5-yl)ethanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (15 mg, yield 13%). 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 8.28-8.26 (d, J=7.8 Hz, 1H), 8.09-8.06 (m, 1H), 8.02-8.00 (d, J=8.5 Hz, 2H), 7.65-7.61 (t, J=7.8 Hz, 1H), 7.56-7.53 (m, 1H), 7.42-7.40 (d, J=8.5 Hz, 2H), 4.03-3.96 (q, J=6.0 Hz, 2H), 3.25-3.22 (d, J=6.0 Hz, 2H). MS (ESI) m/z: Calculated for C20H14ClF3N6O2: 462.08. found: 463.0 (M+H)+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][N:6]1[CH2:10][C:9]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[O:8][C:7]1=[O:16].C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)CCC>C1(C)C=CC=CC=1>[N:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][N:6]1[CH2:10][C:9]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[O:8][C:7]1=[O:16]
Reactant: O=C1OC2(CCCCC2)CN1Cc1cccc(I)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Solvent: Cc1ccccc1
Product: O=C1OC2(CCCCC2)CN1Cc1cccc(-c2ccccn2)c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
3-(3-Iodo-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one (0.148 mmol, 55 mg), 2-tributylstannanyl-pyridine (0.222 mmol, 81.72 mg), tetrakispalladium(0) (0.03 mmol, 34.2 mg) were combined and dissolved in toluene (5 mL). The reaction mixture was left to stir at 110° C. overnight. It was then filtered through silica and the filtrate was concentrated in vacuo. The residue was purified by SPE flash column chromatography using silica gel and ethyl/acetate/hexanes (0˜50%) as eluent. The product was impure by NMR. Therefore, it was dissolved in dichloromethane, and 2M hydrogen chloride in diethyl ether (10 mL) was added. This solution was concentrated in vacuo, the residue was dissolved in water (10 mL) and washed with hexanes. The aqueous layer was then neutralized using sodium bicarbonate and washed with dichloromethane. The organic layer was concentrated in vacuo to give the final product was a pale yellow gum (10 mg, 21%). 1H NMR (300 MHz, CDCl3): δ (ppm)=8.71 (m, 1H), 7.92 (m, 2H), 7.77 (m, 2H), 7.49 (m, 1H), 7.37 (m, 1H), 7.27 (m, 1H), 4.53 (s, 2H), 3.14 (s, 2H), 1.78 (m, 4H), 1.51 (m, 6H).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)[C:8]2=[O:32])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:33]([O-:36])([O-:35])=[O:34].[Na+:37].[Na+]>C(O)C.O>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][S:33]([O-:36])(=[O:35])=[O:34])[C:8]2=[O:32])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+:37]
Reactant: O=S([O-])[O-]
Reactant: O=c1n(CCCCCCCBr)c(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=c1n(CCCCCCCS(=O)(=O)[O-])c(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Reaction time: 20 h
Yield: 23.4 %

Procedure:
A solution of 1,4,5-triphenyl-3-(7-bromoheptyl)imidazol-2-one (2.0 g) in ethanol (10 ml) was refluxed with a solution of sodium sulphite (0.55 g) in water (5 ml) for 20 hours. More sodium sulphite (0.2 g) was added and refluxing continued for a further 20 hours. The mixture was evaporated to dryness, boiled in ethanol, filtered hot and evaporated to an oil. This was taken up in a small volume of ethanol, excess diethyl ether added and the precipitated solid filtered off and chromatographed on silica gel (dichloro-methane/methanol 5:1). The resulting oil in methanol/water 1:1 was passed down an Amberlyst 15 ion exchange resin (Na form) and evaporated to a solid. This was taken up in ethanol and precipitated with diethyl ether giving sodium 7-(3,4,5-triphenyl-2-oxo-2,3-dihydroimidazol-1-yl)heptane-sulphonate (0.49 g), 23%) as a white solid, m.p. 160° C.
Reaction SMILES: [O:1]1[CH:7]2[C:2]1([CH3:11])[CH2:3][CH:4]1[C:8]([CH3:10])([CH3:9])[CH:5]1[CH2:6]2.C([OH:14])C>>[C:4]12[C:8]([CH3:10])([CH3:9])[CH:5]1[CH2:6][CH:7]([OH:1])[C:2]([OH:14])([CH3:11])[CH:3]=2
Reactant: CCO
Reactant: CC12CC3C(CC1O2)C3(C)C
Product: CC1(O)C=C2C(CC1O)C2(C)C

Procedure:
subjecting 3,4-epoxycarane obtained above to a hydration reaction in the presence of a base catalyst in aqueous ethanol under pressure to obtain 3,4-carenediol of the formula [I].
Reaction SMILES: [CH3:1][O:2][C:3]1([C:6]([NH2:8])=[O:7])[CH2:5][CH2:4]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:20]([O:22][C:23]([CH3:25])=[CH2:24])=[O:21]>C1COCC1>[CH3:1][O:2][C:3]1([C:6]([NH:8][C:20](=[O:21])[O:22][C:23]([CH3:25])=[CH2:24])=[O:7])[CH2:5][CH2:4]1
Reactant: C=C(C)OC(=O)Cl
Reactant: COC1(C(N)=O)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)OC(=O)NC(=O)C1(OC)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106.3 %

Procedure:
A −78° C. solution of 1-methoxycyclopropane-1-carboxamide (0.23 g, 1.998 mmol) in THF (6 mL) was treated drop-wise with lithium bis(trimethylsilyl)amide (1M THF, 2.80 mL, 2.80 mmol), stirred for 0.5 h, treated drop-wise with a solution of isopropenyl chloroformate (0.262 mL, 2.397 mmol) in dry THF (1 mL), stirred for 1 h at −78° C., allowed to slowly warm to RT and stirred for 1 h. The mixture was quenched with satd. NaHCO3), extracted with EtOAc (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness to afford prop-1-en-2-yl (1-methoxycyclopropane-1-carbonyl)carbamate (0.423 g, 106%). MS (ESI) m/z: 222.1 (M+Na+).
Reaction SMILES: [CH:1]([C:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[NH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH:29]([S:31]([C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][C:42]([O:44]C)=[O:43])=[CH:36][CH:35]=1)(=[O:33])=[O:32])=[CH2:30]>C1COCC1>[CH:1]([C:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[N:16]([CH2:30][CH2:29][S:31]([C:34]2[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[CH:36][CH:35]=2)(=[O:32])=[O:33])[CH:15]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(C(c3ccccc3)c3ccccc3)c[nH]c2c1
Reactant: C=CS(=O)(=O)c1ccc(CCC(=O)OC)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(S(=O)(=O)CCn2cc(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a solution of 3-benzhydryl-6-chloro-1H-indole (1.0 eq) in THF (0.1 M), at −78° C., was added a 2.5 M solution of n-butyllithium (1.0 eq). After 0.5 h, the solution was warmed to room temperature and then treated with methyl 3-[4-(vinylsulfonyl)phenyl]propanoate (1.2 eq). The mixture was stirred for 3 h, quenched with saturated ammonium chloride solution, and extracted with ethyl acetate. The organic solution was washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and evaporated. The crude material was chromatographed with silica gel to give the desired product in 84% yield.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18](Cl)=[N:19][C:20]=4[CH3:21])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:29][CH:30]([F:32])[F:31])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.[O-:33][CH2:34][CH3:35].[Na+]>C(O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:33][CH2:34][CH3:35])=[N:19][C:20]=4[CH3:21])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:29][CH:30]([F:31])[F:32])[C:25]([F:27])([F:26])[F:28])=[CH:4][CH:3]=1
Reactant: Cc1nc(Cl)nc(C)c1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(C)c(N2CCCn3c2nc2c(Cl)ccc(C(OC(F)F)C(F)(F)F)c23)c(C)n1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A mixture of 9-chloro-1-(2-chloro-4,6-dimethylpyrimidin-5-yl)-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (142 mg, 0.286 mmol) and sodium ethoxide (20% solution in ethanol, 292 mg, 0.858 mmol) in ethanol (1.0 mL) was stirred at 50° C. for 5 hr. The mixture was concentrated in vacuo, diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was purified by preparative HPLC to give a mixture contained an intermediate of the title compound as the trifluoroacetic acid salt. The mixture was washed with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless crystal (65.3 mg, 0.286 mmol, 45%).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][C@@H:18]([CH3:22])[CH2:17]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[CH:25]1([CH2:28][NH:29][C:30](=[O:41])[NH:31][C:32]2[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=2)[CH2:27][CH2:26]1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[CH:25]1([CH2:28][NH:29][C:30]([NH:31][C:32]2[CH:33]=[CH:34][C:35]([C:36]([N:19]3[CH2:20][CH2:21][N:16]([CH2:15][C:12]4[CH:11]=[CH:10][C:9]([C:3]([OH:8])([C:4]([F:7])([F:6])[F:5])[C:2]([F:23])([F:1])[F:24])=[CH:14][CH:13]=4)[CH2:17][C@@H:18]3[CH3:22])=[O:37])=[CH:39][CH:40]=2)=[O:41])[CH2:27][CH2:26]1
Reactant: C[C@H]1CN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CCN1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)O)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CCN1C(=O)c1ccc(NC(=O)NCC2CC2)cc1
Temperature: 25 °C
Yield: 6.5 %

Procedure:
(S)-1,1,1,3,3,3-Hexafluoro-2-(4-((3-methylpiperazin-1-yl)methyl)phenyl)propan-2-ol (0.854 mmol, 0.304 g), 4-(3-(cyclopropylmethyl)ureido)benzoic acid (0.854 mmol, 0.2 g) and triethylamine (2.56 mmol, 0.356 mL, 0.259 g) were combined in dichloromethane and stirred at room temperature. 1-Propanephosphonic acid cyclic anhydride (1.28 mmol, 0.762 mL, 0.815 g; 50% solution in ethyl acetate) was added and the reaction allowed to stir for 1 hour. The reaction mixture was washed with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated under vacuum. The resulting residue was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 5% methanol/dichloromethane) to afford the title compound (32 mg).
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[OH:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH:31]=O)=[CH:23][CH:22]=1.Cl>CCOCC>[N:15]1([CH2:31][C:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:21]([OH:20])=[CH:22][CH:23]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=Cc1ccc(O)c2ccccc12
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: Oc1ccc(CN2CCCC2)c2ccccc12
Yield: 112.2 %

Procedure:
NaB(OAc)3H (6.4 g, 0.030 mol) was added in portions for 15 min to a mixture of pyrrolidine (2.1 mL, 0.025 mol) and 4-hydroxynaphthalene-1-carbaldehyde (3.40 g, 0.020 mol) in (C2H5)2O (80 mL) under vigorous stirring and cooling with an ice bath in an atmosphere of argon Ar. The mixture was stirred for 20 h and cooled with an ice bath. Concentrated HCl (18 mL) was added. The organic layer was separated and discarded. The aqueous one was alkalized with 10 N NaOH to pH 9 (30 mL) and extracted with (2×100 mL) (C2H5)2O. The combined extracts were dried with Na2SO4, and evaporated to give the title compound (5.1 g, 75%) was obtained as white crystals. LCMS-data: 228.1 and 229.1 (M+H)+, (calculated for C15H17NO 227.13). 1H NMR (400 MHz)-data (DMSO-d6, J, Hz): 9.18 (br s, 1H, OH); 6.83 (s, 2H, ArH); 3.79 (s, 3H, CH3); 3.44 (s, 2H, CH2Ar); 2.36-2.44 (m, 4H, CH2CH2CH2CH2,); 1.65-1.72 (m, 4H, CH2CH2CH2CH2,).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21]Cl)[CH:17]=3)[N:12]([CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:32][S-:33].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][S:33][CH3:32])[CH:17]=3)[N:12]([CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C[S-]
Reactant: COCCOCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)ccc21
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CSC)ccc21
Reaction time: 18 h
Yield: 77.5 %

Procedure:
To a suspension of N-(4-chlorobenzyl)-6-(chloromethyl)-1-[2-(2-methoxyethoxy)ethyl]-4-oxo-1,4-dihydro-3-quinolinecarboxamide (175 mg) prepared as described in Example No. 84, in DMF (1.5 11) is added sodium thiomethoxide (40 mg). The mixture is stirred for 18 h, then added to 25 ml of rapidly stirred water. The solid is filtered, washed well with water, dried in vacuo, and recrystallized from acetonitrile to afford 139 mg of the title compound as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[C:8](Cl)=[N:9][C:10]([Cl:14])=[N:11][C:12]=1[Cl:13])[CH3:2].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C(N(CC)CC)C>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[C:12]([Cl:13])=[N:11][C:10]([Cl:14])=[N:9][C:8]=1[N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[CH3:2]
Reactant: CCOC(=O)COc1c(Cl)nc(Cl)nc1Cl
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1c(Cl)nc(Cl)nc1N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
A mixture of (2,4,6-trichloro-pyrimidin-5-yloxy)-acetic acid ethyl ester (2.67 g, 9.35 mmol), morpholine (815 μL, 9.35 mmol) and triethylamine (2.6 mL, 18.7 mmol) in IMS (50 mL) was stirred at RT for 2 hours before the reaction was concentrated in vacuo. The resultant residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with further ethyl acetate and the combined organic extracts dried (Na2SO4) and concentrated in vacuo affording (2,4-Dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-acetic acid ethyl ester (2.97 g, 95%). LCMS: RT=3.35 min, [M+H]+=336/338/340.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([O:17][C:18](=[O:22])[CH:19]=[N+]=[N-])[CH3:16]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH2:10][O:11][CH2:19][C:18]([O:17][CH2:15][CH3:16])=[O:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Solvent: ClCCCl
Product: CCOC(=O)COC[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 65.4 %

Procedure:
To a solution of N-t-butyloxycarbonyl-(S)-prolinol (5.0 g, 25 mmol) in 1,2-dichloroethane (500 ml) rhodium(II)acetate (180 mg) was added and the mixture is was heated to 80° C. Ethyldiazoacetate (3.9 ml, 37 mmol) in 1,2-dichloroethane (180 ml) was added over a period of 90 min and the mixture was heated at 80° C. for 3 hours. Then another portion of ethyldiazoacetate (1.3 ml, 12 mmol) in 1,2-dichloroethane (40 ml) was added and the mixture was refluxed for 6 hours. The mixture was cooled to room temperature and washed with saturated sodium bicarbonate (2×100 ml) and brine (100 ml), dried over magnesium sulfate and concentrated in vacuo. The crude product was chromatographed on silica (300 g) with petrol ether/ethyl acetate 4:1 as eluent to give 4.7 g of (2S)-2-(((ethoxycarbonyl)methoxy)methyl)pyrrolidin-1-carboxylic acid tert-butylester. The obtained product was taken up in 50 ml of 1 M lithium hydroxide in water/methanol 1:3 and stirred at room temperature overnight. The mixture was concentrated in vacuo, water (20 mL) was added and washed with ether (20 mL). The aqueous phase was acidified to pH 4 with 1 M aqueous hydrogen chloride and extracted with ethyl acetate (200 ml), dried over magnesium sulfate and concentrated in vacuo to give 3.6 g of (2S)-2-(((carboxy)methoxy)methyl)pyrrolidin-1-carboxylic acid tert-butylester.
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[CH:7]1([C:13]2[CH:14]=[CH:15][C:16]([O:39][CH3:40])=[C:17]([C:19]3[N:20]=[C:21]([NH:24][C:25]([N:27]4[CH2:32][CH2:31][N:30]([CH:33]5[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]5)[CH2:29][CH2:28]4)=[O:26])[S:22][CH:23]=3)[CH:18]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.O>C(Cl)Cl>[CH:7]1([C:13]2[CH:14]=[CH:15][C:16]([O:39][CH3:40])=[C:17]([C:19]3[N:20]=[C:21]([NH:24][C:25]([N:27]4[CH2:28][CH2:29][N:30]([CH:33]5[CH2:38][CH2:37][CH2:36][N:35]([C:5](=[O:6])[NH:4][CH:1]([CH3:3])[CH3:2])[CH2:34]5)[CH2:31][CH2:32]4)=[O:26])[S:22][CH:23]=3)[CH:18]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CC(C)N=C=O
Reactant: COc1ccc(C2CCCCC2)cc1-c1csc(NC(=O)N2CCN(C3CCCNC3)CC2)n1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C2CCCCC2)cc1-c1csc(NC(=O)N2CCN(C3CCCN(C(=O)NC(C)C)C3)CC2)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
0.06 ml of isopropyl isocyanate was added to a solution of 0.2 g of the compound obtained in step 2.4 in 1.2 ml of DCM, at 0° C. The medium was stirred for 2 h at 0° C. then hydrolysed with 5 ml of water and diluted with 10 ml of DCM. The organic phase was washed twice with a saturated NaHCO3 solution then with a saturated NaCl solution. After drying over MgSO4, the organic phase was concentrated then purified by flash chromatography to produce 0.16 g of the expected product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])[CH3:19].[OH-].[K+]>CO>[C:1]([O:5][C:6](=[O:17])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:19][C:18](=[O:20])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(C=O)cn1
Reactant: CC(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)C=Cc1ccc(C=CC(=O)c2ccccc2)cn1
Temperature: 0 °C
Reaction time: 3 h
Yield: 24.8 %

Procedure:
3-(5-formyl-pyridin-2-yl)-acrylic acid tert-butyl ester (364 mg, 1.56 mmol) was dissolved in MeOH (10 ml) and the solution was cooled to 0° C. Acetophenone (188 mg, 1.56 mmol) and 1.7M KOH (1.8 ml) were added. The reaction was stirred at 0° C. for 3 h. The resulting solid was filtered on a Buckner funnel to give 130 mg of 3-[5-(3-oxo-3-phenyl-propenyl)-pyridin-2-yl]-acrylic acid tert-butyl ester as a yellow powder.