Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][O:14][C:15]([C:17]1[S:18][CH:19]=[CH:20][C:21]=1[N:22]([CH:32]1[CH2:41][CH2:40][C:35]2([O:39][CH2:38][CH2:37][O:36]2)[CH2:34][CH2:33]1)[C:23]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)=[O:24])=[O:16].[CH3:42][C:43]1([CH3:50])[CH2:48][CH2:47][C:46](=[O:49])[CH2:45][CH2:44]1>C1COCC1>[CH3:13][O:14][C:15]([C:17]1[S:18][C:19]([C:46]2([OH:49])[CH2:47][CH2:48][C:43]([CH3:50])([CH3:42])[CH2:44][CH2:45]2)=[CH:20][C:21]=1[N:22]([CH:32]1[CH2:41][CH2:40][C:35]2([O:39][CH2:38][CH2:37][O:36]2)[CH2:34][CH2:33]1)[C:23]([C@H:25]1[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]1)=[O:24])=[O:16]
Reactant: CC1(C)CCC(=O)CC1
Reactant: COC(=O)c1sccc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)c1sc(C2(O)CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC2(CC1)OCCO2
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
Diisopropylamine (5.75 g, 56.8 mmol) and dry THF (58 mL) were added to a dry 500 mL 3 neck round bottom flask under nitrogen. The solution was cooled to −40° C. and nBuLi (39 mL, 47.4 mmol) was added slowly while keeping the internal temperature at −40° C. After 15 min, a suspension of 3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-(trans-4-methyl-cyclohexanecarbo-nyl)-amino]-thiophene-2-carboxylic acid methyl ester (10.0 g, 23.7 mmol) in THF (70 mL) was added dropwise while maintaining the internal temperature at −40° C. After 30 min at −40° C., 4,4-dimethyl-cyclohexanone (5.88 g, 47.7 mmol) was added in one portion and stirred at −40° C. for 30 min. The reaction mixture was quenched with saturated NH4Cl, partitioned and the aqueous phase extracted with EtOAc. The combined organic phase was washed with brine, dried over MgSO4, filtered and evaporated to obtain crude 3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(1-hydroxy-4,4-dimethyl-cyclohexyl)-thiophene-2-carboxylic acid methyl ester (14.4 g) which was used for the next step without any purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[O:16][CH3:17].C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35]>C1COCC1>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34](=[O:35])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: COc1cc(CC(=O)OC(C)(C)C)ccc1N
Reactant: COc1ccccc1N=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccccc1NC(=O)Nc1ccc(CC(=O)OC(C)(C)C)cc1OC
Reaction time: 96 h
Yield: 89.7 %

Procedure:
To a stirred solution of tert-butyl 4-amino-3-methoxylphenylacetate (1.41 g, 5.94 mmol) and triethylamine (165 ml, 1.19 mmol) in THF (20 ml) was added 2-methoxyphenyl isocyanate (790 ml, 5.94 mmol), and the resulting mixture was stirred for 4 days. The mixture was concentrated to a small volume in vacuo, and hexane was added to the residue to give precipitate, which was collected to give tert-butyl 4-[N′-(2-methoxyphenyl)ureido]-3-methoxylphenylacetate (2.06 g, 90%) as a white crystalline material. mp 132–134° C.; 1H-NMR (CDCl3) δ 1.46 (s, 9 H), 3.50 (s, 2 H), 3.87 (s, 3 H), 3.88 (s, 3 H), 6.84 (s, 1 H), 6.87–6.90 (m, 2 H), 6.98–7.03 (m, 2 H), 7.12 (s, 1 H), 7.16 (s, 1 H), 8.06 (d, J=8.4 Hz, 1 H), 8.13 (dd, J=7.2, 2.0 Hz, 1 H); MS (ESI) m/z 387 (N++H).
Reaction SMILES: [Br:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1O.[C:19](=[O:22])([O-])[O-].[K+].[K+].I[CH3:26]>CN(C=O)C>[Br:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:26])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[O:22][CH3:19]
Reactant: CI
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(-c2cc3c(Br)c(O)ccc3o2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3c(Br)c(OC)ccc3o2)cc1
Temperature: 50 °C
Yield: 92.5 %

Procedure:
4-Bromo-2-(4-hydroxyphenyl)-benzofuran-5-ol 130 (0.601 g, 1.97 mmol) was taken into 25 mL DMF along with potassium carbonate (2.72 g, 19.7 mmol) and iodomethane (2.45 mL, 39.4 mmol). The mixture was heated overnight at 50° C. under a nitrogen atmosphere. The solution was filtered and the filtrate was diluted with ethyl acetate and washed with water (3×), dried over magnesium sulfate filtered and concentrated. The resulting material was purified by column chromatography on silica gel using 10% ethyl acetate in hexane as the eluent to yield the desired product (0.607 g, 92.5%) as a white solid: Mp. 115–117° C.; 1H NMR (DMSO-d6) δ 7.92 (d, 2 H, J=8.8 Hz), 7.60 (d, 1 H, J=8.6 Hz), 7.22 (s, 1 H), 7.09 (d, 1 H, J=8.9 Hz), 7.07 (d, 2 H, J=8.8 Hz), 3.88 (s, 3 H), 3.83 (s, 3 H); MS 333/335 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:23][O:24][CH2:25][CH3:26])[N:14]([CH2:15][CH2:16][CH2:17][O:18][N:19]=[C:20]([CH3:22])[CH3:21])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:5][C:4]=2[N:3]=1.C([BH3-])#N.[Na+].O1CCCC1.C(O)(=O)C>CO>[CH2:25]([O:24][CH2:23][C:13]1[N:14]([CH2:15][CH2:16][CH2:17][O:18][NH:19][CH:20]([CH3:21])[CH3:22])[C:10]2[C:9]3[N:8]=[CH:7][C:6]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=1)[CH3:26]
Reactant: CCOCc1nc2c(N)nc3cc(-c4ccccc4)cnc3c2n1CCCON=C(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: CCOCc1nc2c(N)nc3cc(-c4ccccc4)cnc3c2n1CCCONC(C)C
Yield: 99.6 %

Procedure:
A slurry of acetone O-{3-[4-amino-2-(ethoxymethyl)-7-phenyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]propyl}oxime (1.00 g, 2.31 mmol), 1 M sodium cyanoborohydride in tetrahydrofuran (4.62 mL, 4.62 mmol), methanol (12 mL), and acetic acid (4.5 mL) was stirred overnight at ambient temperature. The resulting solution was concentrated under reduced pressure and the residue was dissolved in chloroform (200 mL). The solution was washed with saturated aqueous sodium bicarbonate (2×40 mL) and brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield 1.0 g of 2-(ethoxymethyl)-1-{3-[(isopropylamino)oxy]propyl}-7-phenyl-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine as a yellow powder, mp 142.0-144.0° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])=[O:9])=[CH:4][CH:3]=1.[CH2:18]([C:20]1[C:24]([CH:25](O)[CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:23][N:22]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[N:21]=1)[CH3:19]>>[CH2:18]([C:20]1[C:24]([CH:25]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:9])=[CH:6][CH:7]=2)[CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:23][N:22]([C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[N:21]=1)[CH3:19]
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: CCc1nn(-c2ccc(OC)cc2)cc1C(O)CC(C)C
Product: CCc1nn(-c2ccc(OC)cc2)cc1C(CC(C)C)Nc1ccc(C(=O)NCCC(=O)O)cc1
Yield: 24.1 %

Procedure:
Using in 1-[3-ethyl-1-(4-methoxyphenyl)-1H-pyrazol-4-yl]-3-methylbutan-1-ol (0.5 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.41 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.2 g, 25%) was obtained as a white solid.
Reaction SMILES: [C:1](Cl)(=O)C.[CH3:5][C:6]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]>CO>[CH3:1][O:9][C:8](=[O:10])[C:7]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=1[CH3:5]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1cc([N+](=O)[O-])ccc1C
Reaction time: 0.17 h

Procedure:
Acetyl chloride (15 ml) was added to MeOH (500 ml) at room temperature. After 10 min, 2-methyl-5-nitro-benzoic acid (25.00 g, 138.00 mmol) was added. The reaction solution was heated for reflux for 18 h. The solution was then concentrated in vacuo. The residue was dissolved in diethyl ether and washed with H2O and saturated aqueous solution of NaHCO3 respectively. The organic phase was dried over MgSO4 and concentrated in vacuo to provide the title compound as a white solid.
Reaction SMILES: C(O)=O.[Br:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[S:16][CH3:17].C[O-].[Na+].Br[CH2:22][C:23](=[O:39])[CH2:24][C@H:25]1[C@H:30]([O:31][CH3:32])[CH2:29][CH2:28][CH2:27][N:26]1[C:33]([O:35][CH2:36][CH:37]=[CH2:38])=[O:34]>CO>[Br:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[N:10]([CH2:22][C:23](=[O:39])[CH2:24][C@H:25]3[C@H:30]([O:31][CH3:32])[CH2:29][CH2:28][CH2:27][N:26]3[C:33]([O:35][CH2:36][CH:37]=[CH2:38])=[O:34])[CH:11]=[N:12]2)=[CH:7][C:6]=1[S:16][CH3:17]
Reactant: CSc1cc2c(=O)[nH]cnc2cc1Br
Reactant: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)CBr
Agent: C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: CO
Product: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)Cn1cnc2cc(Br)c(SC)cc2c1=O

Procedure:
Under a nitrogen atmosphere in a flame dried flask at room temperature and with magnetic stirring, a suspension of 0.43 g (0.00136 mol) of 7-bromo-6-methylthioquinazolin-4(3H)-one formic acid salt in 5 ml of methanol was treated with two equivalents of sodium methoxide in methanol (approximately lN). After 15 minutes 0.53 g (0.0016 mol) of allyl trans-2-(3-bromo-2-oxopropyl)-3-methoxy-1-piperidinecarboxylate was added in one portion. After being stirred for an hour, the reaction mixture was evaporated under reduced pressure, and the residue was taken up in about 15 ml of water. The aqueous solution was extracted three times with 15 ml portions of dichloromethane. The combined extracts were dried over anhydrous sodium sulfate, filtered, and evaporated to afford the title compound: yield 0.16 g (86%). 1H-NMR(CDCl3): 1.3-2.0 ppm (multiplet, 4H, , CH3OCHCH2CH2CH2N), 2.6 (singlet, 3H, CH3S), 2.8-3.0 (multipl COCH2CH and NCH2), 3.3 (broad singlet, 1H, CH2CHNCO), 3.4-(singlet, 3H, CH3O), 4.0 (broad doublet, 1H, CHOCH3), 4.6 (broad doublet, 2H, CH2CH=CH2), 4.8-5.1 (multiple peaks, 2H, NCH2CO), 5.2-5.4 (multiplet, 2H CH2 =CH), 5.9 (octet, 1H, CH=CH2), 7.3 (singlet, 1H, aromatic H), 7.9 (singlet, 1H, aromatic H), 7.95 (singlet, 1H, N=CH--N).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:31])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:24]([CH:26]3[CH2:30][CH2:29][NH:28][CH2:27]3)=[O:25])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[CH:32]1([C:35](Cl)=[O:36])[CH2:34][CH2:33]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:31])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:24]([CH:26]3[CH2:30][CH2:29][N:28]([C:35]([CH:32]4[CH2:34][CH2:33]4)=[O:36])[CH2:27]3)=[O:25])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCNC2)C[C@H]1c1ccc(Cl)cc1
Reactant: O=C(Cl)C1CC1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(C(=O)C3CC3)C2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 73, the title [(3S,4R)-4-(4-chloro-phenyl)-1-(1-cyclopropanecarbonyl-pyrrolidine-3-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-1-(pyrrolidine-3-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester instead of rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using cyclopropanecarbonyl chloride instead of propionyl chloride and was obtained as a colorless oil. MS m/e: 514.4 [M]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=1)[C:6]([C:24]([O:26]CC)=[O:25])=[C:5]2[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[C:35]1([S:41](Cl)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:15]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:17][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([NH:1][S:41]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)(=[O:43])=[O:42])=[CH:10][CH:9]=3)[C:5]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:6]2[C:24]([OH:26])=[O:25])=[CH:13][CH:14]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(N)ccc2n1Cc1ccc(-c2ccccc2)cc1
Product: O=C(O)c1c(-c2ccccc2)c2cc(NS(=O)(=O)c3ccccc3)ccc2n1Cc1ccc(-c2ccccc2)cc1

Procedure:
The title compound was prepared from ethyl 5-amino-1-(1,1′-biphenyl-4-ylmethyl)-3-phenyl-1H-indole-2-carboxylate and phenylsulfonyl chloride followed the procedure of Example 1 Step 3 as a pale yellow solid: 1H NMR (DMSO-d6) δ 5.81 (s, 2H; 7.05-7.10 (m, 1H), 7.16 (d, J=8.3 Hz, 2H, 7.27 (d, J=8.3 Hz, 2H, 7.30-7.40 (m, 2H, 7.40-7.50 (m, 4H, 7.50-7.70 (m, 11H, 9.93 (s, 1H, 13.03 (br s, 1H; MS (ESI) m/z 557 [M-H]−; HRMS calcd for C34H27N2O4S: 559.1689; found (ESI+): 559.1688; Anal. calcd for C34H26N2O4S.0.5H2O: C, 71.94; H, 4.79; N, 4.94. Found: C, 71.81; H, 4.79; N, 5.07.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=3[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:21])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:28][CH3:29].Br[CH2:31][CH2:32][Cl:33].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:33][CH2:32][CH2:31][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=3[C:20]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:21])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:28][CH3:29]
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
{2-[(7-Hydroxy-6-methoxy-4-quinolyl)oxy]-5-methylphenyl}-(phenyl)methanone (500 mg), 1-bromo-2-chloroethane (245 mg), and potassium carbonate (897 mg) were suspended in N,N-dimethylformamide (20 ml), and the suspension was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (465 mg, yield 80%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9](=[O:19])[NH:10][C:11](=[O:18])[N:12]([CH2:14][CH2:15][CH:16]=O)[CH:13]=1.[F:20][C:21]([F:35])([F:34])[C:22]1[CH:27]=[CH:26][C:25]([C@:28]23[CH2:33][C@H:32]2[CH2:31][NH:30][CH2:29]3)=[CH:24][CH:23]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+].C(Cl)[Cl:53].CO>CC(O)=O>[ClH:53].[ClH:53].[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9](=[O:19])[NH:10][C:11](=[O:18])[N:12]([CH2:14][CH2:15][CH2:16][N:30]2[CH2:31][C@H:32]3[C@:28]([C:25]4[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:35])[F:34])=[CH:27][CH:26]=4)([CH2:33]3)[CH2:29]2)[CH:13]=1
Reactant: O=CCCn1cc(-c2ccncc2F)c(=O)[nH]c1=O
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Reactant: ClCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: Cl
Product: O=c1[nH]c(=O)n(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)cc1-c1ccncc1F
Temperature: 0 °C
Reaction time: 18 h
Yield: 16 %

Procedure:
3-[5-(3-Fluoro-pyridin-4-yl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl]-propionaldehyde (Prep69, 63 mg, 0.24 mmol) was dissolved in DCM-MeOH 1-1 (2 ml). The resulting solution was cooled at 0° C. and then (1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (54 mg, 0.24 mmol), AcOH (17 μl) and NaBH(AcO)3 (55 mg, 0.26 mmol) were added. The mixture was left to reach room temperature and the stirring was prolonged for further 18 hours. 1N NaOH was added and the product was extracted with DCM. The organic phase was dried (Na2SO4) and evaporated. The crude was redissolved in DCM and treated with PS-isocyanate (300 mg) overnight. The residue was finally purified with SCX cartridge, washing with MeOH and then collecting the product with MeOH—NH4OH (95-5) to give 17 mg of the title compound (16% yield).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([NH:8][C:9]2[N:10]=[CH:11][C:12]3[N:17]=[N:16][N:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24](O)([CH3:26])[CH3:25])=[CH:20][CH:19]=4)[C:13]=3[N:14]=2)[CH:5]=[N:4]1)[CH3:2].C(N(S(F)(F)[F:34])CC)C>ClCCl>[CH2:1]([N:3]1[CH:7]=[C:6]([NH:8][C:9]2[N:10]=[CH:11][C:12]3[N:17]=[N:16][N:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:34])([CH3:26])[CH3:25])=[CH:20][CH:19]=4)[C:13]=3[N:14]=2)[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1cc(Nc2ncc3nnn(-c4ccc(C(C)(C)O)cc4)c3n2)cn1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CCn1cc(Nc2ncc3nnn(-c4ccc(C(C)(C)F)cc4)c3n2)cn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A suspension of 2-{4-[5-(1-ethyl-1H-pyrazol-4-ylamino)-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-phenyl}-propan-2-ol (138 mg, 0.38 mmol) in dichloromethane (3 ml) is cooled to −78° C. Diethylaminosulfurtrifluoride (201 μl, 1.52 mmol) is added. The reaction mixture is allowed to reach room temperature over 1 hour. The reaction mixture is evaporated and the residue is treated with water and saturated sodium hydrogen carbonate solution. The solids are filtered off and chromatographed on a silica gel column with dichloromethane/methanol as eluent to afford (1-ethyl-1H-pyrazol-4-yl)-{3-[4-(1-fluoro-1-methyl-ethyl)-phenyl]-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl}-amine (“A128”) as yellow powder; HPLC/MS1.93 min (A), [M+H] 367;
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:8][CH:9]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:24][C:25]1[CH:26]=[CH:27][C:28]2[N:29]([CH:31]=[C:32]([C:34]([CH3:41])([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:33]=2)[N:30]=1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[ClH:24].[ClH:24].[C:18]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([CH:31]=[C:32]([C:34]([CH3:40])([CH3:41])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:33]=4)[N:30]=3)[CH2:10]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)C1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)C(C)(C)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)C3)ccc2n1
Product: Cl
Temperature: 170 °C
Reaction time: 8 h
Yield: 115.8 %

Procedure:
1.53 g of 3-(diphenylmethoxy)-1-pyrrolidinepropanamine and 660 mg of ehtyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate were dissolved in 3 ml of 1-methyl-2-pyrrolidone, followed by stirring in an oil bath (170° C.) for 8 hours. After cooling, saturated aqueous solution of sodium bicarbonate was added, followed by extraction with ethyl acetate; the extract was washed with water and saturated saline, dried over magnesium sulfate. The solution was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (50:5:1). The desired fraction was collected, concentrated, dissolved in 5 ml of ethyl acetate; 0.81 ml of 4N-hydrogenchloride in ethyl acetate was added, followed by concentration. Ethyl ether was added to the residue; the powder was collected by filtration and dried to yield 877 mg of the title compound.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[CH2:3][CH2:4][C:5]([O-:7])=[O:6].[Na+].[H-].[Na+].F[C:19]1[CH:26]=[C:25]([O:27][CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22]>O1CCCC1>[C:21]([C:20]1[CH:23]=[CH:24][C:25]([O:27][CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)=[CH:26][C:19]=1[O:1][CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])#[N:22]
Reactant: Cc1ccccc1C(O)CCC(=O)[O-]
Reactant: N#Cc1ccc(OCc2cccnc2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1C(CCC(=O)O)Oc1cc(OCc2cccnc2)ccc1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of sodium 4-hydroxy-4-(2-methyl-phenyl)butanoate, thought to be the (R)-enantiomer, (3 g) and sodium hydride (1.5 g; 60% w/v dispersion in mineral oil; 37.5 mmol) in tetrahydrofuran (50 mL) is stirred at ambient temperature for 1 hour under an atmosphere of argon and is then warmed to 55° C. It is then treated with 2-fluoro-4-(3-pyridyl-methoxy)benzonitrile (3 g), in one portion, and stirring is continued at 55° C. for 15 hours. The reaction mixture is then cooled, concentrated in vacuo, and diluted with water (100 mL). The pH of the mixture is adjusted to 5 by treatment with concentrated hydrochloric acid and is then extracted with ethyl acetate (4×100 mL). The combined extracts are dried over magnesium sulphate and concentrated in vacuo, to give an oily residue. This residue is recrystallized from isopropyl ether to give 4-[2-cyano-5-(3-pyridylmethoxy)phenoxy]-4-(2-methylphenyl)butanoic acid, thought to be the (R)-enantiomer, (1.5 g) in the form of a white solid, m.p. 130-134° C. Chiral HPLC assay showed a 98% enantiomeric excess. [Elemental analysis:- C,71.12; H,5.49;N,6.62%; Calculated:- C,71.64; H,5.47;N, 6.97%].
Reaction SMILES: [OH2:1].C(OC(CC[N:9]1[CH2:14][CH2:13][N:12]([CH:15]=[O:16])[CH2:11][CH2:10]1)=O)C.OO>O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+].C(OCC)(=O)C>[CH:15]([N:12]1[CH2:13][CH2:14][N:9]([OH:1])[CH2:10][CH2:11]1)=[O:16]
Reactant: O
Reactant: CCOC(=O)CCN1CCN(C=O)CC1
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=CN1CCN(O)CC1
Reaction time: 1 h

Procedure:
Water (500 ml) was added to the above crude 4-ethoxycarbonylethyl-1-formylpiperazine (114 g) to dissolve and thereto sodium tungstate dihydrate (7.25 g) was added. Thereto 31% aqueous hydrogen peroxide solution (82 ml) was added dropwise at 30° to 35° C. and the mixture was stirred at the same temperature for 1 hour. After further stirring the mixture at room temperature for 3 hours and then with heating at 50° to 55° C. for 5 hours, ethyl acetate (300 ml) was added and the mixture was shaken. The aqueous layer was separated and water was distilled off under reduced pressure to give black-brown oil, which was then purified by silica-gel column chromatography (silica gel 2 Kg, eluent: chloroform - methanol=10:1) and recrystallized from ethyl acetate to give 1-formyl-4-hydroxypiperazine (38.2 g), m.p. 118°-124° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][OH:10].[Cl:11][C:12]1[CH:17]=[C:16](CCl)[N:15]=[C:14]([NH2:20])[N:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][O:10][C:16]1[CH:17]=[C:12]([Cl:11])[N:13]=[C:14]([NH2:20])[N:15]=1
Reactant: Nc1nc(Cl)cc(CCl)n1
Reactant: OCc1ccc(Cl)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(Cl)cc(OCc2ccc(Cl)cc2Br)n1
Temperature: 100 °C

Procedure:
A mixture of (2-bromo-4-chlorophenyl)methanol (173 mg, 1. mmol), 4-chloro-6-(chloromethyl)pyrimidin-2-amine (178 mg, 1.16 mmol) and K2CO3 (175 mg, 1.00 mmol) in DMF (5 mL) was heated to 100° C. for 12 h. The reaction was cooled to RT, concentrated in vacuo, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification on normal phase silica gel (EtOAc/petroleum ether) provided 4-((2-bromo-4-chlorobenzyl)oxy)-6-chloropyrimidin-2-amine as a white solid.