Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=1)[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][OH:25])[CH2:20][CH2:19]1)=[O:17]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:25][CH2:24][CH:21]2[CH2:22][CH2:23][N:18]([C:16](=[O:17])[C:15]3[CH:26]=[CH:27][CH:28]=[C:13]([CH3:12])[CH:14]=3)[CH2:19][CH2:20]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cccc(C(=O)N2CCC(CO)CC2)c1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)c3cccc(C)c3)CC2)cc1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
53.3 g (0.28 mol) of 4-methylbenzenesulphonyl chloride in 60 ml of pyridine are added to a solution of 52 g (0.22 mol) of 1-(3-methylbenzoyl)-4-piperidinemethanol in 100 ml of pyridine. The mixture is stirred at 20° C. for 4 h, and then poured into ice. The phase is extracted with dichloromethane, and the organic phase washed with 10 N aqueous hydrochloric acid solution and dried over magnesium sulphate. The solvents are evaporated off under reduced pressure and 70 g of white solid are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=[S:11].[NH2:12][C:13]1[C:18]([NH2:19])=[CH:17][CH:16]=[CH:15][C:14]=1[OH:20]>>[NH2:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:20])[C:13]=1[NH:12][C:10]([NH:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8])=[S:11]
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: Nc1cccc(O)c1N
Product: Nc1cccc(O)c1NC(=S)Nc1c(Cl)cccc1Cl
Temperature: 25 °C
Yield: 61 %

Procedure:
1.0 equivalent of 2,6-dichlorophenyl isothiocyanate was treated with 1.0 equivalent of 2,3-diaminophenol and heated to reflux for 1 h. After cooling to RT, the precipitate was filtered off with suction, washed with ether, and dried. The desired thiourea was obtained in a yield of 61%. M.p.: 202-204° C.
Reaction SMILES: C1(OP([O-])(OC2C=CC=CC=2)=O)C=CC=CC=1.[NH2:18][C:19]1[CH:20]=[N+:21]([CH2:25][CH2:26][S:27][C:28]2[CH2:34][C@H:33]3[N:30]([C:31](=[O:38])[C@@H:32]3[C@H:35]([OH:37])[CH3:36])[C:29]=2[C:39]([O:41]CC2C=CC([N+]([O-])=O)=CC=2)=[O:40])[CH:22]=[CH:23][CH:24]=1.C1COCC1.CCOCC>P([O-])([O-])([O-])=O.[Pd]>[NH2:18][C:19]1[CH:20]=[N+:21]([CH2:25][CH2:26][S:27][C:28]2[CH2:34][C@H:33]3[N:30]([C:31](=[O:38])[C@@H:32]3[C@H:35]([OH:37])[CH3:36])[C:29]=2[C:39]([O-:41])=[O:40])[CH:22]=[CH:23][CH:24]=1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SCC[n+]3cccc(N)c3)C[C@H]12
Agent: [Pd]
Agent: O=P([O-])(Oc1ccccc1)Oc1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(SCC[n+]3cccc(N)c3)C[C@H]12
Reaction time: 1 h
Yield: 128.8 %

Procedure:
To a mixture of p-nitrobenzyl (5R, 6S)-3(2-(3-aminopyridinio)ethyl thio)-6-(1-(R)-hydroxyethyl)-7-oxo-1-azabicyclo(3.2.0)hept-2-ene-2-carboxylate diphenylphosphate (0.730 g, 1.0 mmol) and 10% palladium-on-charcoal (0.7 g) in 25 mL of a phosphate buffer (0.05 m, pH 7.4) was added 8 mL of THF and 20 mL of ether. This mixture was then hydrogenated (Parr) at 40 psi for 1 h. The resulting mixture was filtered through a pad of Celite and the filter cake was washed with H2O and ether. The aqueous phase was separated, washed with ether (2×) and then residual volatiles were removed in vacuo. The aqueous solution was immediately applied to a C18 reverse-phase column which was eluted with H2O. Lyophilization of the relevent fractions afforded 0.45 g of an off-white solid. This material was repurified by reverse-phase hplc to give the desired product (0.123 g, 35%) as an ivory-colored solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Br[C:11]1[CH:20]=[N:19][CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][N:19]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH2:20]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccncc1Br
Reactant: NCc1ccc(Cl)cc1
Product: COC(=O)C1=CCN(NCc2ccc(Cl)cc2)C=C1
Yield: 72 %

Procedure:
The title compound was prepared in 72% yield from 4-chlorobenzylamine and methyl 3-bromoisonicotinate according to the procedure for Preparation 4A. 1H NMR (400 MHz, CDCl3): δ 8.14 (s, 1H), 7.94 (d, 1H, J=5.0 Hz), 7.82 (br s, 1H), 7.62 (d, 1H, J=5.0 Hz), 7.24-7.32 (m, 4H), 4.47 (d, 2H, J=5.7 Hz), 3.89 (s, 3H). [M+H] calc'd for C14H13ClN2O2, 277, 279; found 277, 279.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[CH:15](Cl)[O:16]C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[OH:1][C:2]1[C:11]([CH:15]=[O:16])=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(OC)cc1O
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(OC)c(C=O)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
At from 0 to 5° C., a solution of 209.0 g (1.1 mol) of titanium tetrachloride in 150 ml of methylene chloride was added dropwise to a solution of 50.1 g (0.275 mol) of methyl 2-hydroxy-4-methoxybenzoate and 88 g (0.725 mol) of dichloromethoxymethane in 400 ml of methylene chloride, and the mixture was stirred at room temperature overnight. The mixture was then stirred into ice-water and extracted with methylene chloride. The combined organic phases were washed with sodium bicarbonate solution, water and sodium chloride solution and dried, and the solvent was then removed. Silica gel chromatography using cyclohexane/ethyl acetate=1:1 gave 24.5 g (42%) of methyl 2-hydroxy-3-formyl-4-methoxybenzoate in the form of a colorless solid of m.p.: 123–1240° C.
Reaction SMILES: [CH3:1][N:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([Li])[CH:4]=1.[C:19]([NH:23][Si:24](Cl)([CH3:26])[CH3:25])([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[CH3:20][C:19]([NH:23][Si:24]([CH3:26])([CH3:25])[CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([N:2]([CH3:1])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4]1)([CH3:22])[CH3:21]
Reactant: [Li]C1C=C(N(C)c2ccccc2)c2ccccc21
Reactant: CC(C)(C)N[Si](C)(C)Cl
Solvent: C1CCOC1
Product: CN(C1=CC([Si](C)(C)NC(C)(C)C)c2ccccc21)c1ccccc1
Reaction time: 25 h
Yield: 97.5 %

Procedure:
(3-(Methylphenylamino)-1H-indenyl)lithium (3.10 g, 13.64 mmol) was dissolved in 50 mL of THF and added dropwise to a solution of t-butylaminodimethylsilylchloride (2.17 g, 16.35 mmol) in 35 mL. of THF over a 30 minute period, with stirring continued for 25 hours. The solvent was evaporated and the resulting oil was subjected to vacuum for 4 hours. This oil was dissolved in 100 mL of hexane and filtered of from LiCl. Solvent removal in vacuo and overnight vacuum devolatilization provided the product (4.66g, 13.3 mmol) as a dark red oil in 98 percent yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2.C([O-])([O-])=O.[Cs+].[Cs+].BrC1C=CC(S(O[C@@H:32]2[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:34]([C:44]([O:46][CH3:47])=[O:45])[CH2:33]2)(=O)=O)=CC=1>CN1C(=O)CCC1.O.CCOC(C)=O>[Cl:1][C:2]1[C:3]([O:14][C@H:32]2[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C@H:34]([C:44]([O:46][CH3:47])=[O:45])[CH2:33]2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2
Reactant: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
Reactant: COc1ccc2nc(Cl)c(O)nc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@@H]1C[C@@H](Oc2nc3cc(OC)ccc3nc2Cl)CN1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 18 h
Yield: 35 %

Procedure:
A solution (0.35M) of the product of step 2 in NMP was treated with Cs2CO3 (1.5 eq) and 1-tert-butyl 2-methyl (2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate (1.1 eq). The resulting mixture was stirred at 50° C. for 18 hours, then a further portion (0.1 eq) of 1-tert-butyl 2-methyl (2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate was added. After stirring for 2 hours, the mixture was cooled and diluted with H2O and EtOAc. The organic phases were washed with aqueous HCl (1 N), saturated aqueous NaHCO3 and brine. The dried organic phase was concentrated to a residue that was purified by flash-chromatography (0-60% EtOAc/petroleum ether) to give the title compound (35% for two steps) as a solid. MS (ES−) m/z 438 (M+H)+
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[CH2:7][CH:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23]OS(C4C=CC(C)=CC=4)(=O)=O)=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH2:5][C:4]([CH3:36])([CH3:35])[NH:3]1.[NH3:38]>CO>[NH2:38][CH2:23][CH2:22][CH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH:8][CH:6]3[CH2:5][C:4]([CH3:36])([CH3:35])[NH:3][C:2]([CH3:37])([CH3:1])[CH2:7]3)[N:14]=2)=[CH:20][CH:19]=1
Reactant: N
Reactant: Cc1ccc(S(=O)(=O)OCCCc2ccc(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)cc2)cc1
Solvent: CO
Product: CC1(C)CC(Nc2nccc(-c3ccc(CCCN)cc3)n2)CC(C)(C)N1

Procedure:
The title compound was prepared from toluene-4-sulfonic acid 3-{4-[2-(2,2,6,6-tetramethyl-piperidin-4-ylamino)-pyrimidin-4-yl]-phenyl}-propyl ester and ammonia in MeOH.
Reaction SMILES: [C:1](=[N:4][OH:5])([NH2:3])[CH3:2].[H-].[Na+].[Cl:8][C:9]1[C:10]([N:24]2[C:28]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)=[N:27][N:26]=[C:25]2[C:35](OCC)=O)=[C:11]2[C:16](=[CH:17][C:18]=1[Cl:19])[N:15]=[C:14]([O:20][CH3:21])[C:13]([O:22][CH3:23])=[N:12]2>C1(C)C=CC=CC=1>[Cl:8][C:9]1[C:10]([N:24]2[C:28]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)=[N:27][N:26]=[C:25]2[C:35]2[O:5][N:4]=[C:1]([CH3:2])[N:3]=2)=[C:11]2[C:16](=[CH:17][C:18]=1[Cl:19])[N:15]=[C:14]([O:20][CH3:21])[C:13]([O:22][CH3:23])=[N:12]2
Reactant: CC(N)=NO
Reactant: CCOC(=O)c1nnc(-c2cccnc2)n1-c1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1nc2cc(Cl)c(Cl)c(-n3c(-c4cccnc4)nnc3-c3nc(C)no3)c2nc1OC
Yield: 81.6 %

Procedure:
Acetamide oxime (120 mg, 1.62 mmol) followed by sodium hydride (80% w/w dispersion in oil, 8 mg, 0.27 mmol) were added to a stirred suspension of 6,7-dichloro-2,3-dimethoxy-5-[3-ethoxycarbonyl-5-(3-pyridyl)-4H-1,2,4-triazol-4-yl]quinoxaline (Preparation 94, 250 mg, 0.53 mmol) in dry toluene (15 mL) at room temperature under nitrogen. The mixture was heated under reflux for 3.5 hours, cooled and the solution partitioned between ethyl acetate and brine. The aqueous phase was extracted with ethyl acetate (2×20 mL), the combined organic extracts dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, by gradient elution using hexane:ethyl acetate (7:3 changing to 1:1, by volume) to give the title compound (210 mg, 82%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:33].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:33])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(c2ccccc2)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCC(c2ccccc2)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-[5-chloro-8-(4-phenylpiperidin-1-yl)quinolin-7-yl]ethanone (0.0293 g, 0.0803 mmol) and ammonium acetate (0.0619 g, 0.803 mmol) in methanol (0.3 mL) and acetonitrile (0.3 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.20 mL, 0.20 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The organic layers were combined, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C22H25ClN3 (M+H)+: m/z=366.2; Found: 366.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[NH:12][CH2:11][CH2:10][C:9]=2[N:8]=1.[F:21][C:22]1[C:23]([Cl:30])=[C:24]([CH:27]=[CH:28][CH:29]=1)CBr.[CH3:31]C([O-])(C)C.[K+]>CS(C)=O>[Cl:30][C:23]1[C:22]([F:21])=[C:29]([CH:28]=[CH:27][CH:24]=1)[CH2:31][N:12]1[CH2:11][CH2:10][C:9]2[N:8]=[C:7]([O:6][CH2:5][C:4]3[CH:18]=[CH:19][CH:20]=[C:2]([F:1])[CH:3]=3)[CH:16]=[CH:15][C:14]=2[C:13]1=[O:17]
Reactant: Fc1cccc(CBr)c1Cl
Reactant: CC(C)(C)[O-]
Reactant: O=C1NCCc2nc(OCc3cccc(F)c3)ccc21
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1c2ccc(OCc3cccc(F)c3)nc2CCN1Cc1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-((3-fluorobenzyl)oxy)-7,8-dihydro-1,6-naphthyridin-5(6H)-one (20 mg, 0.05 mmol, prepared above as in Example 1.1) in DMSO (1 mL) was treated with 3-fluoro-2-chlorobenzyl bromide (20 mg 0.12 mmol) and KOtBu (20 mg, 0.18 mmol). The reaction mixture was stirred at RT overnight and then purified directly by RP-HPLC to give indicated compound. LC-MS (M+H)=415.3.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:20][CH2:19][C:18]3[CH:21]=[CH:22][C:15]([Br:14])=[CH:16][CH:17]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: NCc1ccc(Br)cc1
Reactant: CSc1ncnc2cc(N)ncc12
Product: Nc1cc2ncnc(NCc3ccc(Br)cc3)c2cn1
Temperature: 140 °C
Reaction time: 1 h
Yield: 47.7 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (234 mg, 1.22 mmol) (described in a previous experimental) and 4-bromobenzylamine (0.84 g, 4.52 mmol) is stirred under N2 at 140° C. for 1 h, and the resulting product chromatographed on silica gel (10% EtOH/EtOAc) to give 7-amino-4-(4-bromobenzylamino)pyrido[4,3-d]pyrimidine (192 mg, 48%) as a cream solid. 1H NMR (DMSO) δ 9.09 (1H, s), 8.87 (1H, t, J=5.7 Hz), 8.25 (1H, s), 7.51 (2H, d, J=8.3 Hz), 7.31 (2H, d, J=8.3 Hz), 6.46 (2H, brs) 6.37 (1H, s), 4.70 (2H, d, J=5.8 Hz).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[CH2:5]([O:12][C:13](=[O:39])[N:14]([CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[C:24](C=O)[CH:23]=2)[CH:16]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[BH-](OC(C)=O)(OC(C)=O)O[C:42](C)=O.[Na+].[OH-].[Na+]>ClCCCl>[CH2:5]([O:12][C:13](=[O:39])[N:14]([CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1)[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[C:24]([CH2:42][NH:4][CH2:1][CH2:2][CH3:3])[CH:23]=2)[CH:16]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=Cc1cc(Oc2cccc(N(C(=O)OCc3ccccc3)C3CCCCC3)c2)ccc1[N+](=O)[O-]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCCN
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: CCCNCc1cc(Oc2cccc(N(C(=O)OCc3ccccc3)C3CCCCC3)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of propylamine (0.00356 mol) in DCE (70 mL) was stirred at room temperature. Cyclohexyl-[3-(3-formyl-4-nitro-phenoxy)-phenyl]-carbamic acid benzyl ester (0.00274 mol) was added. NaBH(OAc)3 (0.00438 mol) was added. The reaction mixture was stirred overnight at room temperature. A 10% NaOH solution was added and this mixture was extracted with diisopropyl ether. The separated organic layer was dried (MgSO4), filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: 100:0 to 96:4 CH2Cl2:CH3OH ). The product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: O=[C:2]([CH3:10])[CH2:3][N:4]1[CH2:8][CH2:7][N:6]=[C:5]1[CH3:9].[CH3:11][NH2:12]>[Pt]=O.C(O)C>[CH3:11][NH:12][CH:2]([CH3:10])[CH2:3][N:4]1[CH2:8][CH2:7][N:6]=[C:5]1[CH3:9]
Reactant: CC(=O)CN1CCN=C1C
Reactant: CN
Agent: O=[Pt]
Solvent: CCO
Product: CNC(C)CN1CCN=C1C
Reaction time: 1 h

Procedure:
A suspension of 0.20 g. of platinum oxide in 20 ml. of absolute ethanol is hydrogenated at 50 p.s.i. for one hour. To this is added a mixture of 7.0 g. of 1-(2-oxopropyl)-2-methyl-2-imidazoline, 3.1 g. of methylamine and 30 ml. of ethanol. The mixture is shaken under ca. 50 p.s.i. of hydrogen until one equivalent is absorbed. Filtration of the catalyst and removal of solvent in vacuo gives 1-(2-methylaminopropyl)-2-methyl-2-imidazoline.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][N:40]([CH3:56])[CH:41]1[CH2:46][CH2:45][N:44]([C:47]2[CH:52]=[C:51](B(O)O)[CH:50]=[CH:49][N:48]=2)[CH2:43][CH2:42]1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:39][N:40]([CH3:56])[CH:41]1[CH2:42][CH2:43][N:44]([C:47]2[CH:52]=[C:51]([C:2]3[C:10]4[C:9]([NH:11][C@H:12]([C:14]5[N:19]([C:20]6[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=6)[C:18](=[O:26])[C:17]6=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]6[N:15]=5)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=4[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=3)[CH:50]=[CH:49][N:48]=2)[CH2:45][CH2:46]1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CN(C)C1CCN(c2cc(B(O)O)ccn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3ccnc(N5CCC(N(C)C)CC5)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 104.3 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.08 mmol) was treated with (2-(4-(dimethylamino)piperidin-1-yl)pyridin-4-yl)boronic acid (43 mg, 0.17 mmol), tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.01 mmol), aqueous solution 2M of sodium carbonate (200 μl, 0.4 mmol) and 5 ml N,N-dimethylformide as a solvent according to the method described in Preparation 186 but stirring at 100° C. overnight. The crude was purified by reverse phase using SP1® Purification System (hexane-ethyl acetate) to obtain 60 mg (75% yield) of the title compound. Purity 75%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:19]>>[ClH:19].[CH3:18][S:15]([CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)(=[O:17])=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC(CS(C)(=O)=O)CC1
Agent: Cl
Product: CS(=O)(=O)CC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Methanesulfonylmethyl-piperidine-1-carboxylic acid tert-butyl ester as white solid (6 g) was suspended in hydrochloric acid (4N solution in 1,4-dioxane) at 0° C. The ice bath was removed and the mixture was stirred at room temperature overnight. It was concentrated to give 4-methanesulfonylmethyl-piperidine hydrochloride as white solid (4.52 g).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.FC(F)(F)C(O)=O.[NH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[C@H:27]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:26][CH2:25]2>CC#N.O1CCOCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[C@H:27]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:26][CH2:25]3)=[N:3][CH:4]=1)#[N:7]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCN)ccc21
Reactant: N#Cc1ccc(Cl)nc1
Solvent: C1COCCO1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3ccc(C#N)cn3)ccc21
Temperature: 25 °C
Yield: 54.2 %

Procedure:
A mixture of 6-chloronicotinonitrile (0.78 9, 5.54 mmol) and ethyl [(1S)-5-(3-aminopropoxy)-2,3-dihydro-1H-inden-1-yl]acetate trifluoroacetate (Example 263, 2.17 g, 5.54 mmol) in CH3CN (14 mL) and 1,4-dioxane (14 mL) was heated to reflux for 8 h, cooled to rt, and then concentrated under reduced pressure. The product (1.14 g, 54%) was isolated after column chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD2Cl2) δ 8.20 (s, 1H), 7.45 (dd, 1H), 6.94 (d, 1H), 6.67 (s, 1H), 6.58 (dd, 1H), 6.32 (d, 1H), 5.42 (b, 1H), 4.02 (q, 2H), 3.95 (t, 2H), 3.50-3.35 (m, 3H), 2.85-2.68 (m, 2H), 2.59 (dd, 1H), 2.32-2.20 (m, 2H), 2.00 (qt, 2H), 1.70-1.60 (m, 1H), 1.17 (t, 3H).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([OH:21])[C:14](Br)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:23]([C:25]1[O:26][CH:27]=[CH:28][C:29]=1B1OC(C)(C)C(C)(C)O1)=[O:24]>>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([OH:21])[C:14]([C:29]3[CH:28]=[CH:27][O:26][C:25]=3[CH:23]=[O:24])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1(C)OB(c2ccoc2C=O)OC1(C)C
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1O
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2C=O)c1O

Procedure:
Prepared by proceeding in a similar manner to Intermediate 26, starting from methyl 6-(benzenesulfonylmethyl)-3-bromo-2-hydroxybenzoate (Intermediate 40) and 2-formylfuran-3-boronic acid pinacol ester
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][NH:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1.[N-:17]=[C:18]=[O:19].[K+]>CO.O.O.CO>[CH3:15][O:14][C:12](=[O:13])[CH2:11][N:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:17][C:18]1=[O:19]
Reactant: [N-]=C=O
Reactant: COC(=O)CNCC(=O)c1ccc(Cl)cc1
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)Cn1cc(-c2ccc(Cl)cc2)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3.41 g (12.27 mmol) of the compound from Example 231A in 14 ml methanol/water (7:3) is added dropwise to a solution of 995 mg (12.27 mmol) of potassium isocyanate in 11 ml methanol/water (7:3). This is stirred for 1 hr at RT. The thick suspension is diluted with 7.4 ml water and 39 ml methanol to facilitate stirring, then heated under reflux for 1 hr and then left to stand overnight at RT. After cooling to 0° C., the precipitate is filtered off, washed with ice-cold water and dried overnight in the drying cabinet at 60° C. 2.84 g (76% of theory) of the title compound are obtained.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.C(N(C(C)C)CC)(C)C.[CH3:18][O:19][CH2:20]Cl.O>C(Cl)Cl>[CH3:18][O:19][CH2:20][O:7][C:6]1[CH:5]=[CH:4][C:3]([CH3:8])=[CH:2][CH:1]=1
Reactant: Cc1ccc(O)cc1
Reactant: COCCl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc(C)cc1
Temperature: 25 °C

Procedure:
4-Cresol (59 g) was dissolved in 500 ml of methylene chloride, followed by addition of 238 ml of diisopropylethylamine and 66 g of chloromethyl methyl ether, and stirred at room temperature for two nights. The reaction solution was poured into water, which was then extracted with methylene chloride. After washing in 2N hydrogen chloride and then washing in saturated aqueous sodium chloride, the extract was dried over anhydrous sodium sulfate to yield residue. The residue was subjected to chromatography which was eluted with chloroform, to obtain 4-tolyl methoxymethyl ether.