Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:6]([N:8]1[CH2:34][CH2:33][CH2:32][C@H:9]1[C:10]([NH:12][C@H:13]([C:17]([C:19]([C:22]([C:25]([C:28]([F:31])([F:30])[F:29])([F:27])[F:26])([F:24])[F:23])([F:21])[F:20])=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].Cl.CN1CCOCC1.[N:43]1[CH:48]=[CH:47][CH:46]=[C:45]([CH2:49][CH2:50][C:51](Cl)=[O:52])[CH:44]=1>C(Cl)Cl>[N:43]1[CH:48]=[CH:47][CH:46]=[C:45]([CH2:49][CH2:50][C:51]([NH:1][C@H:2]([C:6]([N:8]2[CH2:34][CH2:33][CH2:32][C@H:9]2[C:10]([NH:12][CH:13]([CH:14]([CH3:15])[CH3:16])[C:17](=[O:18])[C:19]([F:21])([F:20])[C:22]([F:23])([F:24])[C:25]([F:26])([F:27])[C:28]([F:31])([F:29])[F:30])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:52])[CH:44]=1
Reactant: O=C(Cl)CCc1cccnc1
Reactant: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)CCc1cccnc1)C(C)C)C(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: -20 °C
Reaction time: 1.5 h

Procedure:
Dissolve H-Val-Pro-Val-CF2CF2CF2CF3.hydrochloride (221.0 mg, 0.40 mmol) in methylene chloride (10 mL) and cool to -20° C. while stirring. Add N-methylmorpholine (0.2 mL, 2.0 mmol) and immediately follow with a dropwise addition of 3-(3-pyridyl)propanoyl chloride in methylene chloride (5 mL) at such a rate as to maintain the internal reaction temperature at -10° C. or less. After completion of the addition, allow the reaction mixture to warm to room temperature. After 1.5 hours at room temperature, dilute the reaction mixture with methylene chloride (20 mL) and wash with 1N HCl (2×20 mL), saturated NaHCO3 (2×20 mL) and brine (1×20 mL). Dry (MgSO4) and concentrate in vacuo to give the title product in crude form. Immediately purify the crude product by flash chromatograpy (2×15 cm column eluted with 1:27 MeOH--CH2Cl2) to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:18][CH2:17][C:9]2[N:10]=[N:11][C:12](SCC)=[CH:13][C:8]=2[CH2:7]1)=[O:5])[CH3:2].C(OC(N1CCC2[N:28]=[N:29]C(S)=CC=2C1)=O)C.C(Br)C>>[CH2:1]([O:3][C:4]([N:6]1[CH2:18][CH2:17][C:9]2[N:10]=[N:11][C:12]([NH:28][NH2:29])=[CH:13][C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2nnc(SCC)cc2C1
Reactant: CCOC(=O)N1CCc2nnc(S)cc2C1
Solvent: CCBr
Product: CCOC(=O)N1CCc2nnc(NN)cc2C1

Procedure:
The 3-ethylmercapto-5,6,7,8-tetrahydro-6-pyrido[4,3-c]pyridazinecarboxylic acid ethyl ester, required as starting material, may be obtained in a manner analogous to that described in Example 41 (b), from 5,6,7,8-tetrahydro-3-mercapto-6-pyrido[4,3-c]pyridazinecarboxylic acid ethyl ester and ethyl bromide. M.P. 54°-56° from ligroin.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](=O)[CH2:10][S:11]([CH:13]2[N:16]([C:17]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=P(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:15](=[O:44])[CH:14]2[NH:45][C:46]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O1CCOCC1>[C:1]1([CH2:7][CH2:8][C:9]2[CH2:10][S:11](=[O:12])[C@@H:13]3[CH:14]([NH:45][C:46]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)([C:59]4[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=4)[C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[C:15](=[O:44])[N:16]3[C:17]=2[C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)C(N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1S(=O)CC(=O)CCc1ccccc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C1=C(CCc2ccccc2)CS(=O)[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N12

Procedure:
4-(4-phenyl-2-oxobutylsulphinyl)-1-(1-t-butoxycarbonyl-1-triphenylphosphoranylidenemethyl)-3-(triphenylmethylamino) azetidin-2-one (200 mg) was refluxed in dry dioxan (5 ml) under nitrogen for 8 hours. The mixture was evaporated to give a foam. The crude foam was chromatographed on silica gel eluting with ethyl acetate/petroleum ether mixtures to give t-butyl 3-phenylethyl-7-triphenylmethylamino-3-cephem-4-carboxylate-1-oxide as a yellow solid (87 mg.)
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@@:19]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)([CH2:22][CH2:23][CH2:24][OH:25])[O:18][C:17]3=[O:33])[CH3:15])=[CH:10][CH:9]=2)[CH:3]=1.[OH-:34].[Na+]>>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C@:19]2([CH2:22][CH2:23][CH2:24][OH:25])[O:18][C:17](=[O:33])[N:16]([C@H:14]([C:11]3[CH:12]=[CH:13][C:8]([C:4]4[CH:3]=[C:2]([OH:34])[N:7]=[CH:6][N:5]=4)=[CH:9][CH:10]=3)[CH3:15])[CH2:21][CH2:20]2)=[CH:27][CH:28]=1
Reactant: [OH-]
Reactant: C[C@@H](c1ccc(-c2cc(Cl)ncn2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Agent: [Na+]
Product: C[C@@H](c1ccc(-c2cc(O)ncn2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Temperature: 110 °C
Yield: 78 %

Procedure:
A mixture of (R)-3-((S)-1-(4-(6-chloropyrimidin-4-yl)phenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (20 mg, 0.0426 mmol) in 15% aq NaOH (5 mL) was heated to 110° C. overnight. Then the solvent was evaporated, and the residue was washed with EtOAc. The solid was filted off and the filtrate was dried, and condensed in vacuum to give the crude product, which was purified by preparative HPLC to afford (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(6-hydroxypyrimidin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one (15 mg, 78%). LC-MS Method 2 tR=0.91 min, m/z=452, 408. 1H NMR (CD3OD): δ=1.31 (m, 1H), 1.59 (m, 3H), 1.95 (m, 2H), 2.25 (m, 1H), 2.35 (m, 1H), 2.46 (m, 1H), 3.15 (m, 1H), 3.48 (m, 2H), 5.59 (m, 1H), 6.81 (s, 1H), 7.12 (m, 4H), 7.33 (m, 2H), 7.79 (m, 2H), 8.25 (s, 1H).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[C:5]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:6]([O:16][C:17]2[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([O:27]CC)=[O:26])=[CH:19][CH:18]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=2)[CH3:3].[OH-].[Na+]>C1COCC1.CCO>[CH3:3][CH:2]([C:4]1[C:5]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[C:6]([O:16][C:17]2[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=2)[CH3:1]
Reactant: CCOC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3)c(C(C)C)cc3cc(OC)ccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2c(Oc3ccc(/C=C/C(=O)O)cc3)c(-c3ccccc3)c(C(C)C)cc2c1
Yield: 77.6 %

Procedure:
Ethyl ester 74 (0.45 g, 0.97 mmol) was saponified with 1 N NaOH in THF and EtOH to give 0.33 g (78%) of the title compound (75) as a light yellow solid. 1H NMR (400 MHz, CDCl3): δ 1.19 (d, J=6.8 Hz, 6H), 2.90 (sept, J=6.8 Hz, 1H), 3.94 (s, 3H), 6.22 (d, J=15.9 Hz, 1H), 6.56 (d, J=8.8 Hz, 2H), 7.04 (dd, J1=9.1 Hz, J2=2.4 Hz, 1H), 7.06-7.15 (m, 2H), 7.18-7.30 (m, 6H), 7.62 (d, J=16.0 Hz, 1H), 7.65 (s, 1H), 7.69 (d, J=9.1 Hz, 1H). LCMS (ESI): m/z 439 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:4][CH2:3]1.[C:15]1([CH:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:22][C:23](O)=[O:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:23](=[O:24])[CH2:22][CH:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:11][CH2:10]2)[CH2:4][CH2:3]1
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Reactant: CN1CCC(CN2CCNCC2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CN1CCC(CN2CCN(C(=O)CC(c3ccccc3)c3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a solution of 1-(1-methyl-piperidin-4ylmethyl)-piperazine (0.25 g, 1.26 mmol) in dry CH2Cl2 (25 ml) was added 3,3-diphenylpropanoic acid (0.26 g, 1.15 mmol) under nitrogen. To the reaction was added EDC (0.48 g, 2.53 mmol) and DMAP (cat) and the reaction mixture stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue dissolved in ethyl acetate:water (10:1) (100 ml). The organic was washed with water (25 ml, 2×) and 10% NaOH (25 ml) and dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using CH2Cl2:MeOH (5:1) to give desired product in 69% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[S:8]1[C:12]([Sn](C)(C)C)=[CH:11][N:10]=[CH:9]1>C1C=CC=CC=1.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>[S:8]1[C:12]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:11][N:10]=[CH:9]1
Reactant: C[Sn](C)(C)c1cncs1
Reactant: Brc1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: c1cncc(-c2cncs2)c1
Temperature: 25 °C

Procedure:
At room temperature, tetrakis(triphenylphosphine)palladium (470 mg) was added to 3-bromopyridine (805 μl) and a solution of (5-thiazolyl)trimethyltin (2.07 g) in benzene (80 ml), followed by heating under reflux overnight. After the reaction mixture was allowed to cool down to room temperature, it was washed with a saturated aqueous solution (100 ml) of sodium bicarbonate. The water layer was extracted with ethyl acetate (3×20 ml). The organic layers were combine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=2:1), whereby the title compound (1.68 g, purity: 85%) was obtained as a colorless solid.
Reaction SMILES: NC(N)=O.[CH3:5][S:6][CH2:7][CH2:8][CH2:9][NH:10][S:11]([C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([NH2:21])[C:15]=1[OH:22])(=[O:13])=[O:12].[Br:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>>[Br:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31]([NH:21][C:16]1[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([S:11]([NH:10][CH2:9][CH2:8][CH2:7][S:6][CH3:5])(=[O:13])=[O:12])[C:15]=1[OH:22])=[O:32]
Reactant: O=C=Nc1ccccc1Br
Reactant: CSCCCNS(=O)(=O)c1c(Cl)ccc(N)c1O
Agent: NC(N)=O
Product: CSCCCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccc2Br)c1O
Yield: 73.7 %

Procedure:
Following the general procedure for urea formation outlined in example 15, N-(3-methylthiopropyl)-3-amino-6-chloro-2-hydroxybenzenesulfonamide (250 mg, 0.80 mmol) and 2-bromophenylisocyanate (191 mg, 0.97 mmol) were coupled to form the desired urea (300 mg, 74%). 1H NMR (MeOD-d4): δ 8.28 (d, 1H), 7.91 (d, 1H), 7.58 (d, 1H), 7.32 (t, 1H), 7.05 (d, 1H), 7.00 (t, 1H), 3.08 (t, 2H), 2.48 (t, 2H), 1.98 (s, 3H), 1.74 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([Cl:10])=[CH:8][C:7](Br)=[CH:6][C:5]=1[Cl:12].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.CCOC(C)=O.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>[CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][C:5]=1[Cl:12]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1c(Cl)cc(Br)cc1Cl
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+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1c(Cl)cc(-c2ccccc2)cc1Cl
Yield: 104.7 %

Procedure:
To a solution of 2,6-dichloro-4-bromobenzoic acid methyl ester (0.55 g) in THF (10 mL) was added benzeneboronic acid (1.30 g), Pd(PPh3)4 (0.16 g) and 2M Na2CO3 (5 mL). The mixture was refluxed for 4 h under N2. After cooling, the mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by preparative TLC (silica gel; eluent: hexane to EtOAc/hexane 1/1) to yield crude 2,6-dichloro-4-phenylbenzoic acid methyl ester (0.57 g). ESMS: m/z 281 (MH+).
Reaction SMILES: B(Br)(Br)Br.CO.[CH3:7][O:8][C:9]([C:11]1([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=3)[C:15]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:13][CH2:12]1)=[O:10]>ClCCl>[CH3:7][O:8][C:9]([C:11]1([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[C:15]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:12][CH2:13]1)=[O:10]
Reactant: COC(=O)C1(c2onc(-c3ccc(OC)cc3)c2-c2ccccc2)CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1(c2onc(-c3ccc(O)cc3)c2-c2ccccc2)CC1
Temperature: -10 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A solution consisting of boron tribromide (114 mL of a 1 M solution in dichloromethane) and dichloromethane (100 mL) is cooled in an ice/salt/methanol bath to −10° C. and a solution consisting of 1-[3-(4-methoxy-phenyl)-4-phenyl-isoxazol-5-yl]-cyclopropanecarboxylic acid methyl ester (10 g) dichloromethane (150 mL) is added dropwise while the temperature is maintained at −10° C. over 1 hour. The reaction mixture is allowed to warm to 0° C. and stirred for 4 hours until all starting material is consumed. The solution is cooled to −10° C. and 5% sodium bicarbonate solution (250 mL) is added slowly by addition funnel while maintaining the temperature below 0° C. The reaction flask is removed from the cold bath and water added, the organic layer is separated, dried, and concentrated to give 1-[3-(4-hydroxy-phenyl)-4-phenyl-isoxazol-5-yl]-cyclopropanecarboxylic acid methyl ester (9.6 g.)
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.C([O:28][C:29](=[O:47])[C:30]([CH3:46])([N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1)[CH3:31])C>>[CH3:46][C:30]([N:32]1[CH:36]=[C:35]([C:2]2[CH:25]=[CH:24][C:5]3[C:6]4[N:7]=[C:8]([C:14]5[N:15]([CH2:19][C:20]([F:22])([F:23])[F:21])[N:16]=[CH:17][N:18]=5)[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:34]=[N:33]1)([CH3:31])[C:29]([OH:47])=[O:28]
Reactant: CCOC(=O)C(C)(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CC(C)(C(=O)O)n1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1

Procedure:
Following the procedure for 114, 8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 2-Methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propionic acid ethyl ester to give 211. MS (ESI+) 505.1
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:4](Cl)[N:3]=1.C(O)CCC.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:4]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:3]=1
Reactant: CCC(CC)n1cnc2c(Cl)nc(Cl)nc21
Reactant: Nc1ccccc1
Solvent: CC(C)O
Solvent: CCCCO
Product: CCC(CC)n1cnc2c(Nc3ccccc3)nc(Cl)nc21
Reaction time: 22 h

Procedure:
The operation is carried out as in Stage 2 of Example 3 starting from 200 mg (0.77 mmoles) of the product obtained in Stage 1 of Example 3 and 4 ml of butanol and using 0.088 ml (0.96 mmoles) of aniline in place of the benzylamine. Agitation is carried out at ambient temperature then the reaction medium is taken to a temperature of 80 to 85° C. for 22 hours, left to return to ambient temperature, diluted with 4 ml of isopropanol, left for two days at a temperature of approximately 0° C., followed by separating, washing with 10 ml of isopropanol and drying at a temperature of approximately 50° C.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH3:18])[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:14]([O:13][C:11]([N:7]1[CH2:8][CH2:9][CH2:10][C:5]([CH2:3][OH:2])([CH3:18])[CH2:6]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)C1(C)CCCN(C(=O)OC(C)(C)C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(CO)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To a 0° C. stirred solution of Intermediate 54 (1.17 g, 4.56 mmol) in dry THF (20 ml) was added LiAlH4 (1.0 M in THF, 9.11 ml, 9.11 mmol) dropwise and the reaction was allowed to warm to room temperature. Upon completion as indicated by TLC, the reaction was carefully quenched with saturated NH4Cl and EtOAc was added. The layers were separated, the aqueous layer was extracted with EtOAc (3×15 ml) and the organic extracts were combined. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to yield 0.844 g (42.1%) of 3-hydroxymethyl-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 55). 1H NMR (400 MHz, CDCl3) δ ppm 0.9 (s, 3 H), 1.3 (m, 2 H), 1.5 (s, 9 H), 1.5 (m, 3 H), 2.9 (s, 1 H), 3.1 (s, 1 H), 3.5 (d, J=11.5 Hz, 1 H), 3.8 (m, 2 H).
Reaction SMILES: BrC1C=C(F)C=CC=1O[C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][N:6]=1.[NH3:37]>>[NH2:37][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:21][CH2:20]3)=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][N:6]=1
Reactant: COc1cc2c(Oc3ccc(F)cc3Br)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: N
Product: COc1cc2c(N)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Using an analogous procedure to that described in the second last paragraph of the portion of Example 1 that is concerned with the preparation of starting materials, 4-(2-bromo-4-fluorophenoxy)-7-(N-tert-butoxycarbonylpiperidin-4-ylmethoxy)-6-methoxyquinazoline was reacted with ammonia to give 4-amino-7-(N-tert-butoxycarbonylpiperidin-4-ylmethoxy)-6-methoxyquinazoline; NMR Spectrum: (DMSOd6) 1.21 (m, 2H), 1.4 (s, 9H), 1.76 (d, 2H), 2.0 (br s, 1H), 2.77 (t, 2H), 3.88 (s, 3H), 3.97 (d, 2H), 3.99 (br s, 2H), 7.05 (s, 1H), 7.36 (br s, 2H), 7.55 (s, 1H), 8.24 (s, 1H); Mass Spectrum: M+H+ 389.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[CH:5]=[C:4]([CH2:11][CH:12]=[CH2:13])[C:3]=1[OH:14].[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[CH:5]=[C:4]([CH2:11][CH2:12][CH3:13])[C:3]=1[OH:14]
Reactant: C=CCc1cc2c(c(C)c1O)CCO2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCc1cc2c(c(C)c1O)CCO2

Procedure:
A solution of 37 (0.500 g, 2.63 mmol) in absolute ethanol (25 mL) was hydrogenated over 5% palladium on carbon (0.060 g) at 3 atmospheres pressure. After hydrogen uptake was complete (30 minutes) the catalyst was removed by filtration through celite. The filter cake was washed with an additional portion of ethanol (30 mL) and the combined filtrate and washings concentrated to a white crystalline solid. Recrystallization from hexane gave 38. 38: mp 72°-73° C.
Reaction SMILES: S(O[CH2:12][CH:13]1[O:17][CH2:16][N:15]([C:18]2[CH:27]=[C:26]3[C:21]([C:22](=[O:37])[N:23]4[C:34]5[C:29](=[CH:30][C:31]([F:35])=[CH:32][CH:33]=5)[C:28](=[O:36])[C:24]4=[N:25]3)=[CH:20][CH:19]=2)[CH2:14]1)(C1C=CC(C)=CC=1)(=O)=O.[N-:38]=[N+:39]=[N-:40].[Na+].C(Cl)(Cl)Cl>CN(C=O)C>[N:38]([CH2:12][CH:13]1[O:17][CH2:16][N:15]([C:18]2[CH:27]=[C:26]3[C:21]([C:22](=[O:37])[N:23]4[C:34]5[C:29](=[CH:30][C:31]([F:35])=[CH:32][CH:33]=5)[C:28](=[O:36])[C:24]4=[N:25]3)=[CH:20][CH:19]=2)[CH2:14]1)=[N+:39]=[N-:40]
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(c3ccc4c(=O)n5c(nc4c3)C(=O)c3cc(F)ccc3-5)CO2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: [N-]=[N+]=NCC1CN(c2ccc3c(=O)n4c(nc3c2)C(=O)c2cc(F)ccc2-4)CO1

Procedure:
To a solution of 3-(5-tosyloxymethyloxazolidin-3-yl)-8-fluoroindolo[2,1-b]-quinazoline-6,12-dione (0.2 mmol) in DMF is added sodium azide (0.21 mmol). The reaction mixture is allowed to stir for 18 h at room temperature after which time CHCl3 is added and the organic layer is washed with water, dried (MgSO4) and the solvent is evaporated. Silica gel chromatography (1% MeOH/CHCl3) gives 3-(5-azidomethyloxazolidin-3-yl)-8-fluoroindolo[2,1-b]quinazoline-6,12-dione.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][NH:13][C:12](=[O:16])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:17]([Si:21]([O:34][C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([CH2:42]Br)[CH:36]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:20])([CH3:19])[CH3:18]>CCCCCC.CN(C=O)C>[Si:21]([O:34][C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([CH:36]=1)[CH2:42][N:13]1[CH2:14][CH2:15][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[CH2:11][C:12]1=[O:16])([C:17]([CH3:19])([CH3:20])[CH3:18])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: CC(C)(C)[Si](Oc1ccc(Cl)c(CBr)c1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc2Cl)C(=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% dispersion in mineral oil) (3.50 g, 0.0874 mmol) was washed with hexane, suspended in DMF (100 mL) at 0° C. with stirring under Ar, then treated with tert-Butyl-3-oxopiperazine-1-carboxylate (15.0 g, 0.728 mol). After 1 h, tert-butyl(3-bromomethyl-4-chlorophenoxy) diphenylsilane (33.34 g, 0.0728 mol) in DMF (50 mL) was added dropwise, and the reaction mixture was left to warm to room temperature overnight. The reaction mixture partitioned between EtOAc/hexane (50/50) and H2O, the aqueous layer washed with EtOAc/hexane, the organics combined, washed with H2O, brine, and dried (Na2SO4). Filtration and concentration to dryness gave the title compound which was used without purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32]Cl)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][N:38]3[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]3)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[N:3]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Reactant: CN1CCNCC1
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCN3CCN(C)CC3)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (Example 226) and 1-methylpiperazine (Fluka) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C25H36N7O4SF2[(M+H)+] 568.2512, observed 568.2519. CDK4 IC50=0.001; CDK1 IC50=0.039; CDK2 IC50=0.017; IC90=0.274 μM.