Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([CH2:14][O:15][CH3:16])[N:8]=[CH:9]2)=[C:2]=[S:3].[OH:17][CH2:18][CH2:19][CH:20]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][NH:21]1>C(O)C>[OH:17][CH2:18][CH2:19][CH:20]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][N:21]1[C:2](=[S:3])[NH:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([CH2:14][O:15][CH3:16])[N:8]=[CH:9]2
Reactant: OCCC1Cc2ccccc2CN1
Reactant: COCc1cc2c(N=C=S)cccc2cn1
Solvent: CCO
Product: COCc1cc2c(NC(=S)N3Cc4ccccc4CC3CCO)cccc2cn1
Temperature: 20 °C
Reaction time: 24 h
Yield: 64.9 %

Procedure:
5-Isothiocyanato-3-methoxymethylisoquinoline (18.2 g) is added to a solution of (RS)-3-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquinoline (14 g) in ethanol (250 cc). The mixture is stirred for 24 hours at a temperature of about 20° C. The precipitate formed is filtered off and washed with ethanol (2×10 cc) and diethyl ether (2×10 cc). (RS)-3-(2-Hydroxyethyl)-N-(3-methoxymethylisoquinol-5-yl)-1,2,3,4-tetrahydroisoquinoline-2-carbothioamide (20.9 g), m.p. 152° C., is thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH3:21])[CH2:14][CH2:15][O:16][CH2:17][C:18]([OH:20])=O)(=[O:12])=[O:11])=[C:5]([CH3:22])[C:4]=1[CH3:23].[CH3:24][N:25]([CH:27]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1)[CH3:26]>C1COCC1>[CH3:26][N:25]([CH:27]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH:28]1[CH2:29][CH2:30][CH:31]([NH:34][C:18](=[O:20])[CH2:17][O:16][CH2:15][CH2:14][N:13]([S:10]([C:6]2[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:23])[C:5]=2[CH3:22])(=[O:11])=[O:12])[CH3:21])[CH2:32][CH2:33]1)[CH3:24]
Reactant: COc1cc(C)c(S(=O)(=O)N(C)CCOCC(=O)O)c(C)c1C
Reactant: CN(C)C(c1ccccc1)C1CCC(N)CC1
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N(C)CCOCC(=O)NC2CCC(C(c3ccccc3)N(C)C)CC2)c(C)c1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
N,N′-Carbonyldiimidazole (195 mg, 1.2 mmol) was added to a soln. of {2-[(4-methoxy-2,3,6-trimethylbenzenesulfonyl)-methylamino]-ethoxy}-acetic acid (Intermediate C) (346 mg, 1 mmol) in THF (5 ml) and the mixture was stirred at RT for 1 h. A soln. of 4-(dimethylaminophenylmethyl)-cyclohexylamine (Intermediate VII) (256 mg, 1.1 mmol) in THF (5 ml) was then added and the reaction mixture was stirred at RT for 3 d. Thereafter, the soln. was concentrated i. vac., the residue was taken up in NaHCO3 soln. and the mixture was extracted with MC (3×30 ml). The combined organic phases were dried with Na2SO4 and concentrated i. vac. Further purification was carried out by means of flash chromatography with CHCl3/MeOH (95:5).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][O:10][C:9]2(O)[CH2:12][CH2:13][CH:14]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH2:15][CH:8]2[CH2:7]1)=O)C.C([O-])(=O)C.[NH4+:30]>CO>[OH:10][CH2:11][CH:6]1[CH2:7][C:8]2[CH2:15][CH:14]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH2:13][CH2:12][C:9]=2[NH:30][C:4]1=[O:3]
Reactant: CCOC(=O)C1COC2(O)CCC(Cc3ccc(OC)cc3)CC2C1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Product: COc1ccc(CC2CCC3=C(C2)CC(CO)C(=O)N3)cc1

Procedure:
3,4,4a,5,6,7,8,8a-Octahydro-3-ethoxycarbonyl-8a-hydroxy-6-(4-methoxyphenyl)methyl-2H-benzo[b]pyran (21 g) in methanol (100 ml) was heated under reflux with ammonium acetate (40 g) for 18 hours. The mixture was evaporated to dryness and the residue partitioned between water and chloroform. The chloroform extract was dried (Na2SO4), treated with charcoal and evaporated to give an oil. This was crystallised from ethylacetate to give the title compound mp 165°-168° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17]2[C:22]([C:23]#[N:24])=[CH:21][N:20]=[C:19]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])[CH:18]=2)[CH2:11][CH2:10]1)(C)(C)C.Cl.O1CCOCC1>>[NH2:7][CH2:8][CH:9]1[CH2:10][CH2:11][CH:12]([CH2:15][NH:16][C:17]2[C:22]([C:23]#[N:24])=[CH:21][N:20]=[C:19]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])[CH:18]=2)[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)NCC1CCC(CNc2cc(NCc3ccccc3Cl)ncc2C#N)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1cnc(NCc2ccccc2Cl)cc1NCC1CCC(CN)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 114.6 %

Procedure:
A mixture of (4-{[2-(2-chloro-benzylamino)-5-cyano-pyridin-4-ylamino]-methyl}-cyclohexylmethyl)-carbamic acid tert-butyl ester (12 mg, 0.025 mmol) and 4 N HCl/dioxane (3 mL) was stirred at ambient temperature for 18 h. Evaporation of the volatiles in vacuo afforded the HCl salt of 4-[(4-aminomethyl-cyclohexylmethyl)-amino]-6-(2-chloro-benzylamino)-nicotinonitrile as a white solid (11 mg, 100%), m/z 384 (M+H)+.
Reaction SMILES: [CH2:1]([Sn](CCCC)(CCCC)C=C)[CH2:2]CC.Br[C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[C:19]([CH3:35])=[CH:20][N:21]2[S:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:28])=[O:27]>CC#N>[CH3:35][C:19]1[C:18]2[C:22](=[CH:23][CH:24]=[CH:25][C:17]=2[CH:1]=[CH2:2])[N:21]([S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH:20]=1
Reactant: Cc1cn(S(=O)(=O)c2ccccc2)c2cccc(Br)c12
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: C=Cc1cccc2c1c(C)cn2S(=O)(=O)c1ccccc1
Yield: 204.7 %

Procedure:
Tributyl(vinyl)stannane (0.400 mL, 1.37 mmol) and Pd(PPh3)2OAc2 (51 mg, 0.069 mmol) were added to 4-bromo-3-methyl-1-(phenylsulfonyl)-1H-indole (240 mg, 0.69 mmol; Intermediate 29) in dry MeCN (4 mL). The reaction mixture was irradiated with micro-waves at 180° C. for 720 s. The mixture was combined with earlier batches of this intermediate (followed this experimental and starting with 4-bromo-3-methyl-1-(phenylsulfonyl)-1H-indole, 50 and 310 mg; Intermediate 29), filtered and concentrated. Purification was performed by flash chromatography (30% hexane in DCM). This afforded the product (420 mg, 82%) as a white solid. MS (ESI+) for C17H15NO2S m/z 298 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[C:5]([NH2:17])[N:6]=[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]3=2)[N:3]=1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH3:12][C:10]1[C:9]2[C:4](=[C:5]([NH2:17])[N:6]=[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]3=2)[N:3]=[CH:2][CH:11]=1
Reactant: [H][H]
Reactant: Cc1cc(Cl)nc2c(N)nc3ccccc3c12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccnc2c(N)nc3ccccc3c12

Procedure:
To a solution of 3-chloro-1-methylbenzo[f][1,7]naphthyridin-5-amine (from step 3) in ethyl acetate/methanol (1:2, 0.03 M) was added 10% wt palladium on carbon (0.2 eq.). The reaction vessel was shaken on a hydrogen Pan apparatus under 50 psi of hydrogen overnight. The mixture was filtered through a pad of celite, washing with dichloromethane. The filtrate was concentrated en vacuo and purified by a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 1-methylbenzo[f][1,7]naphthyridin-5-amine as a white solid. 1H NMR (CDCl3): δ 8.63 (d, 1H), 8.44 (d, 1H), 7.71 (dd, 1H), 7.54 (m, 1H), 7.45 (d, 1H), 7.30 (m, 1H), 6.20 (bs, 2H), 3.01 (s, 3H). LRMS [M+H]=210.1.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O)[CH3:2].[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19].CCN(CC)CC>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1ccccc1B(O)O
Reactant: Oc1ccccc1Br
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1ccccc1Oc1ccccc1Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 31 %

Procedure:
To a solution of 2-ethylphenylboronic acid (4.50 g, 30 mmol), 2-bromophenol (3.54 g, 20 mmol), and Cu(OAc)2 (1.86 g, 10 mmol) in anhydrous CH2Cl2 (50 mL) were added activated 4 Å molecular sieves (˜0.5 g), followed by anhydrous Et3N (7.0 mL, 50 mmol). The resulting dark green solution was stirred at rt for 48 h. The solvent was removed under vacuum and the residue was triturated several times with ether (˜200 mL). The combined organic solutions were washed with satd aq NH4Cl, and 1 N aq HCl aqueous solution, and solvent was removed under vacuum to give a crude product. Flash column chromatography gave 1-bromo-2-(2-ethylphenoxy)benzene (1.72 g, 31%) as a clear oil; 1H NMR (CDCl3, 400 MHz) δ: 7.62 (dd, 1H), 7.28 (m, 1H), 7.22-7.08 (m, 3H), 6.96 (m, 1H), 6.78 (m, 2H), 2.64 (q, 2H), 1.22 (t, 3H); MS no ionization was observed.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]=[C:13]([O:15][CH:16]([F:18])[F:17])[N:12]([CH3:19])[N:11]=2)=[CH:6][CH:5]=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:14]1[C:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)=[N:11][N:12]([CH3:19])[C:13]=1[O:15][CH:16]([F:18])[F:17]
Reactant: BrBr
Reactant: Cn1nc(-c2ccc(Cl)cc2)cc1OC(F)F
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1nc(-c2ccc(Cl)cc2)c(Br)c1OC(F)F
Reaction time: 16 h

Procedure:
7.9 g (43 mmol) of bromine were added to a solution of 10.1 g (39 mmol) of 3-(4-chlorophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole in 100 ml of carbon tetrachloride, and the mixture was then stirred for 16 h. The solution was then washed with sat. aqueous sodium bicarbonate solution, dried over magnesium sulfate and finally concentrated. Yield: 12.9 g. 1H-NMR (270 MHz, in CDCl3): δ[ppm]=3.84 (s, 3H), 6.69 (t, 1H), 7.40 (d, 2H), 7.81 (d, 2H).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[NH:5][CH:4]=1)=[O:2].CC(C)([O-])C.[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(OCC)(=O)C>CN(C)C=O>[C:27]1([CH2:26][CH2:25][CH2:24][CH2:23][N:5]2[C:6]3[C:11](=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=3)[C:3]([CH:1]=[O:2])=[CH:4]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc2[nH]cc(C=O)c2c1
Reactant: BrCCCCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)c(C=O)cn2CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.2 %

Procedure:
A solution of methyl 3-formylindole-5-carboxylate (2.234 g, 11.0 mmol) and potassium tert-butoxide (1.259 g, 11.2 mmol) in dry N,N-dimethylformamide (50 ml) was added with 1-bromo-4-phenylbutane (2.385 g, 11.2 mmol) and left under stirring at room temperature for 18 h. After that the solvent was evaporated off under reduced pressure, the resulting residue was partitioned between a NaCl saturated solution (50 ml) and chloroform (50 ml) and the aqueous phase was extracted with chloroform (3×50 ml). After drying and evaporating off the solvent under reduced pressure, a crude was obtained which was purified by chromatography through a silica gel column, eluting with n-hexane:ethyl acetate, 70:30, thereby obtaining 2.847 g of the title compound (87% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.[OH-:24].[Na+].OO>O1CCCC1.CO.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][C@@H:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:15]([OH:24])[CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CC=C(c2ccccc2)CC1
Reactant: [OH-]
Agent: B
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC[C@@H](c2ccccc2)[C@H](O)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1-benzyloxycarbonyl-4-phenyl-1,2,3,6-tetrahydropyridine (1.0 g) in tetrahydrofuran (20 mL) was cooled to 0° C. and treated with borane:tetrahydrofuran (3.75 mL of 1M solution in tetrahydrofuran). The reaction mixture was stirred for 16 hours at ambient temperature, diluted with methanol (50 mL), and treated with 3N sodium hydroxide (1.25 mL). The resulting reaction mixture was cooled to 0° C. and treated with 30% hydrogen peroxide solution (0.58 mL). After refluxing for 2 hours, the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and the aqueous layer was extracted with ethyl acetate. Combined organic layers were dried and evaporated to afford the crude product (0.88 g). Chromatography, eluting with hexane:ethyl acetate (3:1) afforded the trans-1-benzyloxycarbonyl-3-hydroxy-4-phenylpiperidine (0.31 g); MS: m/z=312(M+1); NMR: 1.54-1.72 (m, 2), 3.51 (m, 1), 4.02 (m, 1), 4.17 (m, 1), 4.86 (d, 1, J=5), 5.1 (s, 2), 7.17-7.37 (m, 10).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:30])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)=O)[CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:31])[C:5]([C:32]([OH:34])=[O:33])=[CH:4]1)[CH3:2].Cl.[NH2:36][OH:37]>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:30])=[C:10]([N:13]3[CH2:14][CH2:15][N:16]([CH2:19][C:20](=[N:36][OH:37])[C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[CH2:17][CH2:18]3)[CH:11]=2)[C:6](=[O:31])[C:5]([C:32]([OH:34])=[O:33])=[CH:4]1)[CH3:2]
Reactant: NO
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC(=O)c4ccc(OC)cc4)CC3)cc21
Agent: Cl
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC(=NO)c4ccc(OC)cc4)CC3)cc21

Procedure:
1-Ethyl-6-fluoro-7-{4-[2-hydroxyimino-2-(4-methoxy-phenyl)ethyl]-1-piperazinyl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was prepared from 1-ethyl-6-fluoro-7-{4-[2-(4-methoxyphenyl)-2-oxoethyl]-1-piperazinyl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.47 g, 1 mmole) and hydroxylamine hydrochloride (0.14 g, 2 mol) by a method similar to that described for Example 3 (74% yield). Mp: 221° C. (dec). 1H NMR (DMSO-d6) δ 1.38 (t, 3H, J=7.2), 2.61 and 3.24 (two m, 8H), 3.41 and 3.77 (two s, 2H), 3.78 (s, 3H), 4.56 (q, 2H, J=7.2), 6.93 (m, 2H),7.15 (d, 1H, J=7.6),7.72 (m, 2H), 7.89 (d, 1H, J=13.6), 8.93 (s, 1H), 10.95 and 11.26 (two s, 1H), 15.29 (br s, 1H). Anal. Calcd. for C25H27FN4O5•0.25 H2O: C, 61.66; H, 5.69; N, 11.50. Found: C, 61.61; H, 5.70; N, 11.27.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=2)=[CH:4][N:3]=1.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17].O>N1C=CC=CC=1>[OH:14][C:10]1[CH:9]=[C:8]([C:5]2[N:6]=[CH:7][C:2]([NH:1][C:16](=[O:17])[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:3][CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cnc(-c2cccc(O)c2)cn1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cnc(-c2cccc(O)c2)cn1)Oc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of 2-amino-5-(3-hydroxyphenyl)pyrazine (89 mg) in pyridine (10 mL) was added under ice-cooling phenyl chloroformate (63 μL). The mixture was stirred for 1 hour and then poured into water (30 mL) and extracted with ethyl acetate (20 mL×3). The extract was washed with saturated saline solution and then dried over anhydrous Na2SO4. The concentration of the solvent left a crystal residue, which was washed with ethyl ether (10 mL) to give the subject compound (51 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]([C:29]1[CH:50]=[CH:49][C:32]([C:33]([NH:35][C@H:36]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:34])=[CH:31][CH:30]=1)=[CH:10][C:11]1[CH:28]=[N:27][C:14]2[N:15]=[C:16]([NH:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[N:17]=[C:18]([OH:19])[C:13]=2[CH:12]=1>C(O)(=O)C.CO.[Pt](=O)=O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH:9]([C:29]1[CH:50]=[CH:49][C:32]([C:33]([NH:35][C@H:36]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:34])=[CH:31][CH:30]=1)[CH2:10][CH:11]1[CH2:28][NH:27][C:14]2[N:15]=[C:16]([NH:20][C:21](=[O:26])[C:22]([CH3:23])([CH3:25])[CH3:24])[N:17]=[C:18]([OH:19])[C:13]=2[CH2:12]1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(C(=Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)COC2CCCCO2)cc1)C(=O)OCC
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(C(COC2CCCCO2)CC2CNc3nc(NC(=O)C(C)(C)C)nc(O)c3C2)cc1)C(=O)OCC
Yield: 59.8 %

Procedure:
A solution of 1.16 g (1.68 mm) of diethyl N-[4-{1-(tetrahydropyr-2-yloxy)-3-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)prop-2-en-2-yl}benzoyl]glutamate and 174 mg (20%) of amorphous platinum (IV) oxide in 150 ml of glacial acetic acid was hydrogenated for 10 hours at 50 psi. The reaction mixture was diluted with 50 ml of methanol and filtered through Celite. The filtrate was concentrated and diluted with ethyl acetate. The solid which formed after cooling for 15 hour was collected by filtration, washed with cold ethyl acetate and dried to give 700 mg (68%) of diethyl N-[4-{1-(tetrahydropyr-2-yloxy)-3-(2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)prop-2-yl}benzoyl]glutamate. mp 183°-186° C. Analysis calculated for C36H51O9N5 : C, 61.95; H, 7.37; N, 10.04. Found: C, 62.00; H, 7.17; N, 9.83. NMR (CDCL3), delta, 1.23 (t, 3H, J=7 Hz), 1.26 (s, 9H), 1.32 (t, 3H, J=7 Hz), 2.26-2.82 (m, 9H), 2.06-2.12 (m, 2H), 2.26-2.38 (m, 1H), 2.43-2.58 (m, 2H), 2.62-2.83 (m, 1H), 2.84-3.10 (m, 2H) 3.12-3.21 and 2.32-3.40 (m, m, 1H), 3.41-3.52 (m, 2H), 3.68-3.92 (m, 2H), 4.13 (q, 2H, J=7 Hz), 4.25 (q, 2H, J=7 Hz), 4.44-4.63 (m, 2H, CH, NH), 4.78-4.84 (m, 1H) 7.02 (brd, 1H, NH, J=7.1 Hz), 7.29 (brs, NH), 7.31-7.37 (m, 2H), 7.75-7.78 (m, 2H), 11.20 (brs, NH).
Reaction SMILES: [CH:1]1([N:6]2[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([OH:15])[CH:12]=3)[C:7]2=[O:16])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][C:25]1[CH:26]=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([C:38]([O:40][CH3:41])=[O:39])[CH:32]=2)[CH:28]=[CH:29][CH:30]=1>CC(C)=O>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([CH2:24][O:15][C:11]3[CH:12]=[C:13]4[C:8](=[CH:9][CH:10]=3)[C:7](=[O:16])[N:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH2:14]4)[CH:26]=2)=[CH:32][C:33]=1[C:38]([O:40][CH3:41])=[O:39]
Reactant: O=C1c2ccc(O)cc2CN1C1CCCC1
Reactant: COC(=O)c1cc(-c2cccc(CBr)c2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(-c2cccc(COc3ccc4c(c3)CN(C3CCCC3)C4=O)c2)ccc1Cl

Procedure:
To a solution of 2-cyclopentyl-5-hydroxyisoindolin-1-one (50 mg, 0.23 mmol) in acetone (15 mL), K2CO3 (181 mg, 1.31 mmol) was added methyl 3′-(bromo-methyl)-4-chlorobiphenyl-3-carboxylate (92 mg, 0.27 mmol) and the mixture was heated at reflux for 1 h. The reaction mixture was filtered and the solvent was evaporated in vacuo to obtain methyl 4-chloro-3′-((2-cyclopentyl-1-oxoisoindolin-5-yloxy)methyl)biphenyl-3-carboxylate as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:23])([CH3:22])[O:6][CH2:7][C@H:8]1[C@H:12]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C:9]21[O:11][CH2:10]2)([CH3:4])[CH3:3].[I-].[Li+]>C(Cl)Cl>[CH3:4][C:2]([Si:5]([CH3:22])([CH3:23])[O:6][CH2:7][CH:8]1[CH:12]([CH2:13][O:14][Si:15]([C:18]([CH3:20])([CH3:19])[CH3:21])([CH3:16])[CH3:17])[CH2:10][C:9]1=[O:11])([CH3:3])[CH3:1]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1[C@H](CO[Si](C)(C)C(C)(C)C)C12CO2
Agent: [I-]
Agent: [Li+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC1CC(=O)C1CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 12.752 g (35.6 mmol) of [4R,5R]-4,5-bis(((1,1-dimethylethyl)-dimethylsilyl)oxymethyl)-1-oxaspiro[2,2]pentane, from Step D, in 50 mL of methylene chloride was added to a solution of 3.814 g (28.5 mmol) of lithium iodide in 200 mL of methylene chloride which had been cooled in an ice bath. After stirring the reaction mixture for 1 h at 0° C., the ice bath was removed and the reaction mixture was stirred for 20 minutes at ambient temperature. The reaction mixture was then washed with 5% aqueous sodium bicarbonate solution, 5% sodium bisulfite solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 12.317 g (96.6% crude yield) of the title compound which was taken on to the next step without purification; MS DCI-NH3M/Z: 376 (M+NH4)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:16])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[CH:27][C:26]=1[N+:35]([O-:37])=[O:36]>ClCCl>[OH:16][C:3]1([CH2:2][NH:1][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=[CH:27][C:26]=2[N+:35]([O-:37])=[O:36])[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:7][CH2:8]1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CN)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(O)(CNc2c([N+](=O)[O-])cnc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
To a solution of tert-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate (78.4 mmol, prepared as described above) in dichloromethane (300 mL) was added triethylamine (11 mL, 79 mmol) and 4-chloro-3-nitroquinoline (12.7 g, 61.2 mmol). The mixture was stirred at rt for 1 h, then heated at reflux for 1 h. The solution was transferred to a separatory funnel and extracted with water (100 mL). The organic layer was isolated and upon standing a precipitate formed. The solid was isolated by filtration and washed with dichloromethane and water and dried. Additional solid precipitated from the mother liquor and was isolated. The two yellow solids were combined and dried to yield tert-butyl 4-hydroxy-4-{[(3-nitroquinolin-4-yl)amino]methyl}piperidine-1-carboxylate (20.23 g, 82%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1.[NH2:26][C:27]1[C:28]([Cl:41])=[CH:29][C:30]([CH:35]([CH2:37][C:38](=[O:40])[CH3:39])[CH3:36])=[C:31]([CH:34]=1)[C:32]#[N:33].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].O1CCOCC1>[Cl:41][C:28]1[CH:29]=[C:30]([CH:35]([CH2:37][C:38](=[O:40])[CH3:39])[CH3:36])[C:31]([C:32]#[N:33])=[CH:34][C:27]=1[NH:26][C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1
Reactant: COc1ccc(CN(c2nc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: CC(=O)CC(C)c1cc(Cl)c(N)cc1C#N
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)c(C(C)CC(C)=O)cc3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 90 °C
Yield: 62 %

Procedure:
2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (100 mg, 0.282 mmol), 5-amino-4-chloro-2-(4-oxopentan-2-yl)benzonitrile (67 mg, 0.282 mmol), palladium (II) acetate (18.9 mg, 0.085 mmol), DPPF (15.6 mg, 0.028 mmol), Xantphos (16.3 mg, 0.028 mmol), and cesium carbonate (184 mg, 0.564 mmol) were combined in a 10 dram vial and dioxane (2 mL) was added. The vial was evacuated and backfilled with N2 3×, then heated at 90° C. for 1 h. The reaction was cooled to room temperature and the reaction mixture was filtered through celite, rinsing with EtOAc. The solvent was removed in vacuo and the material was purified by ISCO Companion (0-100% EtOAc/Hexane). 2-((2-chloro-5-cyano-4-(4-oxopentan-2yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (97 mg) was obtained as a yellow foam.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:22])[N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[CH2:23]([O:25][C:26]([C:28]1[N:29]([CH3:34])[C:30]([SH:33])=[N:31][CH:32]=1)=[O:27])[CH3:24]>>[CH2:23]([O:25][C:26]([C:28]1[N:29]([CH3:34])[C:30]([S:33][C:2]2[S:6][C:5]([NH:7][C:8]([N:9]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:10]3[CH2:15][CH2:14][S:13][CH2:12][CH2:11]3)=[O:22])=[N:4][CH:3]=2)=[N:31][CH:32]=1)=[O:27])[CH3:24]
Reactant: O=C(Nc1ncc(Br)s1)N(C1CCCCC1)C1CCSCC1
Reactant: CCOC(=O)c1cnc(S)n1C
Product: CCOC(=O)c1cnc(Sc2cnc(NC(=O)N(C3CCCCC3)C3CCSCC3)s2)n1C

Procedure:
Prepared as described in general procedure (E) using 3-(5-bromo-thiazol-2-yl)-1-cyclohexyl-1-(tetrahydro-thiopyran-4-yl)-urea (Example 190) and 2-mercapto-3-methyl-3H-imidazole-4-carboxylic acid ethyl ester.