Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][NH:6][C:7]([C:9]1[NH:18][C:12]2=[CH:13][N:14]=[C:15]([Cl:17])[CH:16]=[C:11]2[CH:10]=1)=[O:8])C.[OH-].[Na+]>C1COCC1>[Cl:17][C:15]1[CH:16]=[C:11]2[CH:10]=[C:9]([C:7]([NH:6][CH2:5][C:4]([OH:19])=[O:3])=[O:8])[NH:18][C:12]2=[CH:13][N:14]=1
Reactant: CCOC(=O)CNC(=O)c1cc2cc(Cl)ncc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of [(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino] acetic acid ethyl ester (EXAMPLE 39, 500 mg, 1.8 mmol) in THF (30 mL) was added sodium hydroxide solution (1.8 mL, 2M, 3.6 mmol) and the reaction stirred at rt for 4 h. The solvent was removed in vacuo and the solid partitioned between hydrochloric acid (1M, 100 mL) and ethyl acetate (2×100 mL). The aqueous layer was concentrated in vacuo and the solid residue suspended in water (10 mL), filtered and dried to give the title compound as an off-white solid. δH (d6 DMSO): 3.97 (2H, d), 7.18 (1H, s), 7.76 (1H, s), 8.57 (1H, s), 9.17 (1H, t), 12.32 (1H, s); m/z (ES+)=254 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]1[CH:19]=[C:18]2[C:14]([C:15]3[CH:23]=[N:22][CH:21]=[N:20][C:16]=3[NH:17]2)=[CH:13][CH:12]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[F:48][C:49]([F:58])([F:57])[C:50]1[CH:51]=[C:52]([NH2:56])[CH:53]=[N:54][CH:55]=1.C(O)(C(F)(F)F)=O.F[P-](F)(F)(F)(F)F>CC#N.O.CN(C=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:56][C:52]2[CH:53]=[N:54][CH:55]=[C:50]([C:49]([F:58])([F:48])[F:57])[CH:51]=2)=[O:8])=[CH:4][C:3]=1[C:11]1[CH:19]=[C:18]2[C:14]([C:15]3[CH:23]=[N:22][CH:21]=[N:20][C:16]=3[NH:17]2)=[CH:13][CH:12]=1
Reactant: Nc1cncc(C(F)(F)F)c1
Reactant: Cc1ccc(C(=O)O)cc1-c1ccc2c(c1)[nH]c1ncncc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: Cc1ccc(C(=O)Nc2cncc(C(F)(F)F)c2)cc1-c1ccc2c(c1)[nH]c1ncncc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 20 %

Procedure:
To a vial was added 4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)benzoic acid (15.2 mg, 0.0501 mmol), DMF (0.32 mL), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (22.9 mg, 0.0601 mmol). This mixture was stirred 15 min at RT. To the mixture was then added 5-(trifluoromethyl)pyridin-3-amine (10.6 mg, 0.0651 mmol. The resulting mixture was stirred at 70° C. for 18 h. LCMS indicated complete consumption of the activated ester (M+H 422) and showed product (M+H 448). The product was isolated by prep HPLC/MS using a 19 mm×100 mm C18 column; 28% CH3CN—H2O (0.1% TFA), 1 min, to 48% at 6 min; 30 mL/min. The HPLC fractions containing the product were freeze dried to yield a light yellow solid, 5.6 mg, 20% yield. FMR showed that it was the mono TFA salt; and contained some residual PF6. 1H NMR (DMSO-d6) δ 13.29 (s, 1H, NH); 10.76 (s, 1H, amide NH); 9.72 (s, 1H); 9.22 (s, 1H); 9.20 (s, 1H); 8.69 (s, 1H); 8.62 (s, 1H); 8.44 (d, 1H); 7.98 (m, 2H); 7.66 (s, 1H); 7.56 (d, 1H); 7.53 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]=[C:10]([C:16](=[O:21])[CH2:17][CH:18]([CH3:20])[CH3:19])[C:11]([O:13]CC)=O)=[CH:4][CH:3]=1>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[CH:9][C:10]([C:16](=[O:21])[CH2:17][CH:18]([CH3:19])[CH3:20])=[C:11]2[OH:13]
Reactant: CCOC(=O)C(=CNc1ccc(Br)cc1)C(=O)CC(C)C
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CC(C)CC(=O)c1cnc2ccc(Br)cc2c1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 23.6 %

Procedure:
To Dowtherm at 250° C. was added a solution of ethyl 2-[(4-bromophenylamino)methylene]-5-methyl-3-oxohexanoate (700 mg, 6.75 mmol) in Dowtherm (5 mL) portionwise and the reaction mixture was stirred for 1.5 h. The reaction mixture was cooled to room temperature, diluted with hexanes and the resulting precipitate was filtered to afford the desired product (490 mg, 23%) as a white solid: 1H NMR (500 MHz, DMSO-d6) δ 12.65 (s, 1H), 8.55 (d, J=6.4 Hz, 1H), 8.30 (d, J=2.3 Hz, 1H), 7.88 (dd, J=8.7, 2.3 Hz, 1H), 7.61 (d, J=8.8 Hz, 1H), 2.99 (d, J=6.8 Hz, 2H), 2.21-2.04 (m, 1H), 0.91 (d, J=6.7 Hz, 6H).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([N:6]1[C:5](=[O:12])[O:4][C:2](=[O:3])[C:1]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:7]12)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Product: O=c1oc(=O)n(Cc2ccccc2)c2ccccc12

Procedure:
Reagents: Isatoic anhydride (6.13 mmols, 1 g); Sodium hydride (9.2 mmols, 0.22 g); Benzyl bromide (12.3 mmols, 1.4 g). Yield: 0.2 g (15%), white solid, m.p.=139° C.-140° C.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([CH:7]=O)[CH2:3][CH2:2]1.[CH2:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]3[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=3[N:20]=[C:19]2[C@H:28]([NH2:30])[CH3:29])=[CH:14][CH:13]=1)[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.ClCCl>[CH2:9]([O:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[C:22]3[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=3[N:20]=[C:19]2[C@H:28]([NH:30][CH2:7][CH:4]2[CH2:3][CH2:2][S:1][CH2:6][CH2:5]2)[CH3:29])=[CH:16][CH:17]=1)[CH3:10]
Reactant: O=CC1CCSCC1
Reactant: CCOc1ccc(-n2c([C@@H](C)N)nc3cc(F)ccc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CCOc1ccc(-n2c([C@@H](C)NCC3CCSCC3)nc3cc(F)ccc32)cc1
Reaction time: 4 h
Yield: 49.3 %

Procedure:
Tetrahydro-thiopyran-4-carbaldehyde (35.80 g, 275.4 mmol) was added to a solution of compound A2 (80.73 g, 270 mmol) in dichloroethane (700 mL) at −20° C., followed by sodium triacetoxyborohydride (85.84 g, 405 mmol). The mixture was kept at that temperature for 4 h. The solution was diluted with dichloromethane, washed by saturated aqueous sodium bicarbonate, water, brine and dried over anhydrous sodium sulfate The solvent was evaporated and the residue was purified by flash column to yield A3 as a yellow solid (55 g). MS(ESI+) 414.1 (MH+).
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([C:9]1[N:13]=[C:12]([NH:14][C:15]3[C:20]([O:21][C:22]4[C:23]([CH3:28])=[N:24][CH:25]=[CH:26][CH:27]=4)=[CH:19][C:18]([S:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)=[CH:17][N:16]=3)[S:11][N:10]=1)[CH2:2]2.C(N(CC)CC)C.[C:43]([O:46][CH2:47][C:48](Cl)=[O:49])(=[O:45])[CH3:44]>C(Cl)Cl>[C:43]([O:46][CH2:47][C:48]([N:8]1[CH:5]2[CH2:6][CH2:7][CH:1]1[CH2:2][CH:3]([C:9]1[N:13]=[C:12]([NH:14][C:15]3[C:20]([O:21][C:22]4[C:23]([CH3:28])=[N:24][CH:25]=[CH:26][CH:27]=4)=[CH:19][C:18]([S:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)=[CH:17][N:16]=3)[S:11][N:10]=1)[CH2:4]2)=[O:49])(=[O:45])[CH3:44]
Reactant: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc(C2CC3CCC(C2)N3)ns1
Reactant: CC(=O)OCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(=O)N1C2CCC1CC(c1nsc(Nc3ncc(Sc4ccccn4)cc3Oc3cccnc3C)n1)C2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
3-(8-Azabicyclo[3.2.1]octan-3-yl)-N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-1,2,4-thiadiazol-5-amine (80 mg, 0.159 mmol; prepared in Example 174, step C) was dissolved in CH2Cl2, and triethylamine (88.6 μL, 0.635 mmol) and 2-chloro-2-oxoethyl acetate (25.6 μL, 0.238 mmol) were added. The reaction was stirred at ambient temperature for 5 minutes. The reaction was partitioned between CH2Cl2 and saturated aqueous NaHCO3, dried over sodium sulfate, filtered and concentrated to afford 2-(3-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-8-azabicyclo[3.2.1]octan-8-yl)-2-oxoethyl acetate (95.9 mg, 0.159 mmol, 100% yield) as a crude foam.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[Na+].Cl.[NH2:30][OH:31]>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=[N:30][OH:31])[CH3:22])=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)c1ccc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=NO)c1ccc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of example 208 (0.060 g, 0.197 mmol) in ethanol (1.3 ml), sodium acetate (0.016 g, 0.197 mmol) and hydroxylamine hydrochloride (0.013 g, 0.197 mmol) were added and stirred at RT for 12 h. The reaction mixture was concentrated and the residue was washed with bicarbonate solution, dichloromethane and dried under vacuum to afford the title compound as a ca. 9:1 mixture of two isomers. Off-white solid (0.030 g, 48%). M.P.: 259-261° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 11.95 (s, 0.9H), 11.28 (s, 0.1H), 8.88 (d, J=2.6 Hz, 1H), 8.74 (d, J=8.8 Hz, 0.1H), 8.61 (d, J=8.4 Hz, 0.1H), 8.52 (d, J=8.8 Hz, 0.9H), 8.36 (d, J=8.4 Hz, 0.9H), 8.00 (m, 3H), 7.81 (dd, J=8.4, 1.6 Hz, 1H), 7.53 (dd, J=8.3, 4.1 Hz, 1H), 6.24 (s, 0.2H), 6.15 (s, 1.8H), 2.74 (s, 0.3H), 2.30 (s, 2.7H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][N:7]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C:8]1=[O:23].O1CCCC1.C([Li])(CC)C.[F:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46]Br)=[CH:44][CH:43]=1>C(OCC)(=O)C.CCCCCC.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:46][C:45]2[CH:48]=[CH:49][C:42]([F:41])=[CH:43][CH:44]=2)([CH2:12][CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C:8]1=[O:23]
Reactant: Fc1ccc(CBr)cc1
Reactant: COc1cc(CN2CCC(CCCO[Si](C)(C)C(C)(C)C)C2=O)cc(OC)c1OC
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc(CN2CCC(CCCO[Si](C)(C)C(C)(C)C)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzyl)-3-(3-(t-butyldimethylsilyloxy)propyl)-2-oxopyrrolidine (0.71 g, 1.62 mmol) and tetrahydrofuran (10 mL). Cool to −78° C. using a dry-ice/acetone bath. Add a solution of sec-butyl lithium (1.37 mL, 1.3 M in hexane, 1.78 mmol). After 30 minutes, add 4-fluorobenzyl bromide (0.34 g, 1.78 mmol). After 15 minutes, warm slowly to ambient temperature. After 12 hours, add water and extract three times with ethyl acetate. Dry the combined organic layers over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 1/1 ethyl acetate/hexane to give the title compound.
Reaction SMILES: [OH:1][CH:2]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:3][C:4]1[C:8]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=2[S:6][C:5]=1[C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17]>CC#N>[CH3:17][C:16]([CH3:19])([CH3:18])[C:15]([C:5]1[S:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:4]=1[CH2:3][C:2](=[O:1])[C:21]([CH3:22])([CH3:23])[CH3:24])=[O:20]
Reactant: COc1ccc2sc(C(=O)C(C)(C)C)c(CC(O)C(C)(C)C)c2c1
Solvent: CC#N
Product: COc1ccc2sc(C(=O)C(C)(C)C)c(CC(=O)C(C)(C)C)c2c1

Procedure:
The title compound was prepared from 1-[3-(2-hydroxy-3,3-dimethylbutyl)-5-methoxy-1-benzothien-2-yl]-2,2-dimethylpropan-1-one from the Step A above using the procedure in Step B, Example 18. It was isolated as a white solid following RP-HPLC purification (70˜100% MeCN) and lyophilization. 1H NMR (CDCl3, 500 MHz) 7.72 (d, 8.9 Hz, 1H), 7.13 (dd, 2.4 & 8.8 Hz, 1H), 7.03 (d, 2.6 Hz, 1H), 4.40 (s, 2H), 3.88 (s, 3H), 1.41 (s, 9H), 1.35 (s, 9H). LC-MS: 4.27 min. (m/Z=369.2, 263.2, 347.3).
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:10]1([NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16].N1CCCCC1>CO>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[N:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH2:17]
Reactant: Nc1ccccc1N
Reactant: O=Cc1ccccc1O
Solvent: C1CCNCC1
Solvent: CO
Product: Nc1ccccc1N=Cc1ccccc1O
Reaction time: 1 h

Procedure:
Under agitation, 73.3 g. of salicylaldehyde is added dropwise under ice cooling gradually to a solution of 6.4 g. of o-phenylenediamine in 225 ml. of methanol and 0.6 ml. of piperidine. The mixture is allowed to stand for one hour; the thus-separated precipitate is vacuum-filtered, washed twice with ice-cold methanol, and 112 g. of N-(2-hydroxybenzal)-o-phenylenediamine is obtained as a crude product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.Cl.[F:35][C@@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([N:21]2[C:16]3[CH:17]=[C:18]4[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]=3[CH:23]=[N:22]2)[CH2:12][N:11]([S:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([N:38]3[CH2:39][CH2:40][C@@H:36]([F:35])[CH2:37]3)[CH:3]=2)(=[O:10])=[O:9])[CH2:20][CH2:19]4)=[CH:25][CH:26]=1
Reactant: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1cncc(Br)c1)C2
Reactant: F[C@@H]1CCNC1
Agent: Cl
Product: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1cncc(N3CC[C@@H](F)C3)c1)C2

Procedure:
The title compound was prepared by the method of Preparation 12c using (R)-6-(5-bromopyridine-3-sulfonyl)-1-(4-fluorophenyl)-4a-methoxymethyl-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triazacyclopenta[b]naphthalene and (R)-3-fluoropyrrolidine hydrochloride. LCMS (Method F): 542 (M+H)+, Retention time 4.9 minutes.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[Br:22][C:23]1[CH:24]=[CH:25][C:26]([Cl:31])=[C:27]([CH:30]=1)[CH2:28][OH:29]>C(Cl)Cl>[Br:22][C:23]1[CH:24]=[CH:25][C:26]([Cl:31])=[C:27]([CH:30]=1)[CH:28]=[O:29]
Reactant: OCc1cc(Br)ccc1Cl
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1cc(Br)ccc1Cl
Reaction time: 5 h
Yield: 85.8 %

Procedure:
Pyridinium dichromate (3.82 g, 10.2 mmol) was added to a solution of 5-bromo-2-chlorobenzylalcohol (1.5 g, 6.8 mmol) in CH2Cl2 (30 mL). The reaction was stirred for 5 hours and then celite was added. The mixture was stirred for 20 mins and then filtered through a pad of celite washing with ether. The filtrate was concentrated to a brown oil. The residue was purified by flash silica gel chromatography (0% to 10% EtOAc in hexanes) to give the title compound as a clear oil (1.28 g, 86%). 1H NMR (400 MHz, CDCl3): δ 7.35 (d, J=8.6 Hz, 1H), 7.65 (dd, J=8.3, 2.5 Hz, 1H), 8.04 (d, J=2.5 Hz, 1H), 10.41 (s, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C@@H:8]1[CH2:12][CH2:11][O:10][CH2:9]1)=[O:6].[H-].[Na+]>C1COCC1>[O:10]1[CH2:11][CH2:12][C@@H:8]([N:7]2[CH2:2][CH2:3][NH:4][C:5]2=[O:6])[CH2:9]1
Reactant: O=C(NCCCl)N[C@@H]1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1NCCN1[C@@H]1CCOC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
A −20° C. solution of (R)-1-(2-chloroethyl)-3-(tetrahydrofuran-3-yl)urea (0.522 g, 2.71 mmol) in THF (30 mL) was treated with NaH (60% in mineral oil, 0.130 g, 3.25 mmol) and the mixture stirred at RT overnight as the cooling bath expired. The mixture was treated with satd. NH4Cl, dried over MgSO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford (R)-1-(tetrahydrofuran-3-yl)imidazolidin-2-one (280 mg, 66%). MS (ESI) m/z: 157.1 (M+H+).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH2:24][CH2:23]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=1)[CH2:24][CH2:23]2
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Clc1ccc2c(c1)CCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2cc(Cl)ccc21
Yield: 68.1 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 307 mg of 5-chloroindoline and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.16 ml of pyridine and 4 ml of dimethylformamide. 255 mg of 2-[2-(5-chloro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[OH:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][N:9]1[N:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[N:10]1
Reactant: OCCCCCCCCCBr
Reactant: c1ccc(-c2nn[nH]c2-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: OCCCCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
4,5-Diphenyl-1,2,3-triazole was treated with 9-bromononan-1-ol and potassium carbonate in butanone to give after chromatography the title compound as a light brown oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([CH3:12])[N:3]=1.[O:13]1[CH:17]=[CH:16][N:15]=[C:14]1[NH2:18]>>[CH3:12][C:4]1[N:3]=[C:2]([NH:18][C:14]2[O:13][CH:17]=[CH:16][N:15]=2)[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=1
Reactant: Nc1ncco1
Reactant: COC(=O)c1cc(C)nc(Cl)n1
Product: COC(=O)c1cc(C)nc(Nc2ncco2)n1
Yield: 22 %

Procedure:
The title compound is prepared in 22% yield (83 mg, a pale yellow solid) from methyl 2-chloro-6-methylpyrimidine-4-carboxylate (300 mg, 1.6 mmol) and oxazol-2-amine (200 mg, 2.4 mmol) by the similar manner in Step-1 of Carboxylic acid-4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=1[CH3:7].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:64]1([C:70]2[CH:76]=[CH:75][C:73]([NH2:74])=[CH:72][CH:71]=2)[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH:64]1([C:70]2[CH:71]=[CH:72][C:73]([NH:74][C:2]3[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=3[CH3:7])=[CH:75][CH:76]=2)[CH2:65][CH2:66][CH2:67][CH2:68][CH2:69]1
Reactant: Nc1ccc(C2CCCCC2)cc1
Reactant: COC(=S)c1cc(Br)c(C)s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=S)c1cc(Nc2ccc(C3CCCCC3)cc2)c(C)s1
Yield: 46.7 %

Procedure:
The same procedure as in Example 197, step (a) was followed using 122 mg (0.457 mmol) of methyl 4-bromo-5-methylthiothiophene-2-carboxylate (as prepared in Example 241, step (a)), 9.9 mg (9.7 mol %) of palladium (II) acetate, 42.3 mg (14.9 mol %) of racemic-BINAP, 206 mg (0.632 mmol) of cesium carbonate, 102 mg (0.582 mmol) of 4-cyclohexylaniline and 913 μL of toluene, and chromatographed as before using 20-40% CH2Cl2-hexane to afford 73.8 mg (45%) of the title compound as a light green resin: 1H-NMR (CDCl3, 400 MHz) δ7.74 (s, 1H), 7.15 (d, 2H, J=8.4 Hz), 6.98 (d, 2H, J=8.4 Hz), 6.12 (s, 1H), 3.88 (s, 3H), 2.48 (m, 1H), 2.39 (s, 3H), 1.87 (m, 4H), 1.76 (br d, 1H, J=12.5 Hz), 1.41 (m, 4H) and 1.28 (m, 1H). Mass spectrum (ESI, m/z): Calcd. for C19H23NO2S2, 362.1 (M+H), found 362.4.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)=[CH:15][C:3]=1[C:4]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=1[CH3:14])=[O:5].[BH4-].[Na+]>C(O)C.O>[CH3:12][C:11]1[CH:10]=[C:9]([CH3:13])[CH:8]=[C:7]([CH3:14])[C:6]=1[CH:4]([C:3]1[CH:15]=[C:16]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[CH:17]=[CH:18][C:2]=1[Cl:1])[OH:5]
Reactant: Cc1cc(C)c(C(=O)c2cc(-n3ccnc3)ccc2Cl)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c(C(O)c2cc(-n3ccnc3)ccc2Cl)c(C)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 85.7 %

Procedure:
To a suspension of 10.9 g of 2-chloro-5-(1-imidazolyl)-2',4',6'-trimethylbenzophenone in 65 ml of ethanol is added a solution of 1.4 g of sodium borohydride in 14 ml of water. The mixture is stirred at 50° C. for 18 hours, and then the reaction mixture is poured into ice-cold water. The crystals precipitated are filtered off and recrystallized from ethanol to give 9.4 g of α-(2,4,6-trimethylphenyl)-2-chloro-5-(1-imidazolyl)benzenemethanol as white crystals, melting at 206°-207° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:10][CH3:11])[CH2:4][NH:5][C:6](=[O:9])[CH:7]=[CH2:8].[NH:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17]>>[CH3:1][O:2][CH:3]([O:10][CH3:11])[CH2:4][NH:5][C:6](=[O:9])[CH2:7][CH2:8][N:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17]
Reactant: O=C1CCCN1
Reactant: C=CC(=O)NCC(OC)OC
Product: COC(CNC(=O)CCN1CCCC1=O)OC
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
10 g (62.8 mmol) of the acrylamido acetal from Example 2 are mixed with 6 g (70.5 mmol) of pyrrolidone and, after addition of one drop of Triton B, the mixture is warmed to 80° C. After 10 minutes, the reaction is terminated. The thin-layer chromatogram shows no UV absorbing acetal. The product is subsequently freed from traces of solvent under a high vacuum. It is a single compound according to TLC. NMR data: 2 methylene protons at each of 2.0, 2.4, 2.5, 3.3, 3.4 and 3.6 ppm(t), 6 methoxy protons at 3.35 ppm(s), 1 acetal proton at 4.4 ppm(t), 1 amide proton at 7.2 ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([CH3:13])[C:10]2[C:14](Br)=[C:15](Br)[S:16][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([CH3:13])[C:10]2[CH:14]=[CH:15][S:16][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2sc(Br)c(Br)c2C(C)C1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)N1CCc2sccc2C(C)C1
Reaction time: 8 h

Procedure:
The product of step c) (800 mg, 2.0 mmol) was dissolved in 150 mL EtOH and treated with 800 mg of 10% Pd/C (wet, Degussa grade E101). After stirring overnight, another 300 mg of Pd was added and stirring was continued 3 hours. The reaction was filtered through celite, diluted with DCM (300 mL), and washed with water (1×300 mL). The organic layer was dried over MgSO4 and concentrated to give 475 mg of the subtitle compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].[ClH:14].[NH:15]1[CH2:20][CH2:19][CH:18]=[C:17]([C:21]([O:23][CH3:24])=[O:22])[CH2:16]1.Cl>CO.CC(C)=O>[ClH:14].[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:15]2[CH2:20][CH2:19][CH:18]=[C:17]([C:21]([O:23][CH3:24])=[O:22])[CH2:16]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COC(=O)C1=CCCNC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Product: COC(=O)C1=CCCN(Cc2ccc(O)cc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.8 %

Procedure:
4-Hydroxybenzaldehyde (1.34 g.) and sodium cyanoborohydride (0.7 g.) were added to a solution of methyl 1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride (3.1 g.) in methanol (30 ml.). The mixture was stirred for 3 days at 25° C., evaporated and water (30 ml.) added to the residue followed by concentrated hydrochloric acid to pH 1. This mixture was extracted with ether (2×20 ml.) and the extracts discarded. The aqueous phase was basified to pH 9 with 10% w/v sodium carbonate solution and then extracted with ether (2×30 ml.). The combined extracts were dried (MgSO4) and evaporated. The oil obtained was dissolved in acetone and treated with a slight excess of ethereal hydrogen chloride. The solid which was precipitated was collected by filtration to give methyl 1-(4-hydroxybenzyl)-1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride (2.05 g.). A portion was recrystallised from methanol and acetone to give pure material of m.p. 212°-214° C. (dec.).