Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[CH2:12][N:11]([CH2:24][C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[C:10]1=[O:30].Cl[C:32](OC1C=CC([N+]([O-])=O)=CC=1)=[O:33].Cl.Cl.[O:46]=[C:47]1[NH:55][C:50]2=[N:51][CH:52]=[CH:53][CH:54]=[C:49]2[N:48]1[CH:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1>O1CCCC1.ClCCl>[F:23][C:17]1[C:18]([F:22])=[CH:19][CH:20]=[CH:21][C:16]=1[C@H:13]1[CH2:12][N:11]([CH2:24][C:25]2[S:26][CH:27]=[CH:28][N:29]=2)[C:10](=[O:30])[C@H:9]([NH:8][C:32]([N:59]2[CH2:60][CH2:61][CH:56]([N:48]3[C:49]4[C:50](=[N:51][CH:52]=[CH:53][CH:54]=4)[NH:55][C:47]3=[O:46])[CH2:57][CH2:58]2)=[O:33])[CH2:15][CH2:14]1
Reactant: N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(Cc2nccs2)C1=O
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(Cc2nccs2)C1=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
Triethylamine (0.156 mL, 0.1.12 mmol) was added to a solution of (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(1,3-thiazol-2-ylmethyl)azepan-2-one (302 mg, 0.895 mmol) and 4-nitrophenyl chloroformate (217 mg, 1.074 mmol) in tetrahydrofuran (15 mL) at 0° C. After 30 min, 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine dihydrochloride (782 mg, 2.685 mmol), triethylamine (5.37 mmol) and dichloromethane (15 mL) were added and the mixture allowed to warm to ambient temperature. The reaction was stirred overnight, concentrated, diluted with saturated aqueous sodium bicarbonate and extracted with dichloromethane (2×). The organic layer was washed with water, saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (0% →8% methanol/dichloromethane) gave the title compound (400 mg). MS 582.2109 (M+1). 1H NMR (500 MHz, CDCl3) δ 8.06 (d, J=4.5 Hz, 1H), 7.73 (d, J=3.4 Hz, 1H), 7.35 (m, 2H), 7.0 (m, 2H), 6.98 (dd, J=5.4, 7.8 Hz, 1H), 6.85 (m, 1H), 6.21 (d, J=5.3 Hz, 1H), 5.0 (app q, J=15 Hz, 2H), 4.85 (dd, J=5.0, 11.1 Hz, 1H), 4.58 (m, 1H), 4.27 (br dd, 2H), 4.00 (dd, J=10.6, 15.1 Hz, 1H), 3.50 (d, J=15.1 Hz, 1H), 3.0 (br dd, 1H), 2.88 (dd, J=10.0, 10.0 Hz, 1H), 2.2-1.6 (m, 8H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([NH:14][NH:15][C:16]([O:18]C(C)(C)C)=O)[CH3:13])=[CH:8][CH:7]=1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O.C(Cl)Cl.C(Cl)(=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C>C(Cl)Cl>[C:16]([NH:15][NH:14][C@@H:12]([C:9]1[CH:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=1)[CH3:13])(=[O:18])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCOC(=O)c1ccc(C(C)NNC(=O)OC(C)(C)C)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc([C@@H](C)NNC(=O)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
Thus the slow moving enantiomer tert-butyl 2-{1-[4-(ethoxycarbonyl)phenyl]ethyl}hydrazinecarboxylate (0.74 g, 2.42 mmol) from a chiral separation as described above was treated with TFA/CH2Cl2 (1:1, 10 mL) for 1 h at r.t. The reaction was concentrated on a rotovap and the residual TFA was removed by co-evaporation from toluene. The resulting ethyl 4-(1-hydrazinoethyl)benzoate was then dissolved in CH2Cl2 (15 mL) and cooled to −78° C. A solution of benzoyl chloride (365 μL, 3.15 mmol) and 2,6-di-tert-butyl-4-methylpyridine (745 mg, 3.63 mmol) in CH2Cl2 (5 mL) was added slowly at −78° C. After 3 h at −78° C., the reaction mixture was loaded quickly on a SiO2 column and eluted with 30% EtOAc/hexane. Fractions containing product were concentrated and purified further on HPLC using Kromasil C8 column (10% to 70% CH3CN/H2O/0.1% TFA, 12 min), and again on silica gel column (30% EtOAc/Hexane) to give (R)-(+)-ethyl 4-[1-(2-benzoylhydrazino)ethyl]benzoate. HPLC/MS: m/z=313.3 (M+1)+, Rt=3.08 min. Daicel column Chiralcel OJ, 40° C., 0.5 mL/min, 10% isopropanol/90% n-heptane: t 35.79 min; [α]D20=+192.4° (c1, CHCl3); 1H NMR (500 MHz, CDCl3): δ 8.03 (2H, d, J=8.0 Hz), 7.94 (1H, br s), 7.66 (2H, d, J=7.5 Hz), 7.51 (1H, t, J=7.5 Hz), 7.54 (2H, d, J=8.0 Hz), 7.40 (2H, t, J=8.0 Hz), 4.39 (2H, q, J=7.0 Hz), 4.36 (1H, q, J=7.0 Hz), 1.46 (3H, d, J=6.0 Hz), 1.41 (3H, t, J=7.0 Hz); 13C NMR (500 MHz, CDCl3): δ 167.76, 166.69, 148.16, 132.70, 132.27, 130.21, 130.18, 128.94, 127.47, 127.15, 61.22, 60.21, 21.21, 14.58. (S)-(−)-ethyl 4-[1-(2-benzoylhydrazino)ethyl]-benzoate was similarly prepared from the faster moving isomer of tert-butyl 2-{1-[4-(ethoxycarbonyl)phenyl]ethyl}hydrazinecarboxylate. HPLC/MS: m/z=313.4 (M+1)+, Rt=3.09 min. Daicel column Chiralcel OJ, 40° C., 0.5 mL/min, 10% isopropanol/90% n-heptane: t 34.99 min; [α]D20=−194.4° (c1, CHCl3); 1H NMR (500 MHz, CDCl3): δ 8.02 (2H, d, J=8.0 Hz), 7.73 (1H, br s), 7.65 (2H, d, J=8.0 Hz), 7.49 (1H, t, J=8.0 Hz), 7.48 (2H, d, J=8.0 Hz), 7.39 (2H, t, J=8.0 Hz), 4.38 (2H, q, J=7.0 Hz), 4.34 (1H, q, J=7.0 Hz), 1.44 (3H, d, J=6.5 Hz), 1.41 (3H, t, J=7.0 Hz); 13C NMR (500 MHz, CDCl3): δ 167.81, 166.74, 148.73, 132.92, 132.15, 130.13, 130.02, 128.90, 127.43, 127.12, 61.20, 60.09, 21.52, 14.58.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[F:41][C:42]1([F:53])[CH2:46][CH2:45][N:44]([CH2:47][C@@H:48]([NH2:52])[CH:49]([CH3:51])[CH3:50])[CH2:43]1>CN(C=O)C>[F:53][C:42]1([F:41])[CH2:46][CH2:45][N:44]([CH2:47][C@@H:48]([NH:52][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([CH3:1])[CH:3]=2)[CH:49]([CH3:50])[CH3:51])[CH2:43]1
Reactant: Cc1ccc(C(=O)O)cc1C
Reactant: CC(C)[C@H](N)CN1CCC(F)(F)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1ccc(C(=O)N[C@H](CN2CCC(F)(F)C2)C(C)C)cc1C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 50.7 %

Procedure:
3,4-Dimethylbenzoic acid (130 mg, 0.87 mmol) and TBTU (279 mg, 0.87 mmol) was mixed in DMF (1.5 mL). The mixture was cooled to 0° C. and NMM (0.287 mL, 2.61 mmol) was dropwise added. After 10 min at 0° C. was (S)-1-(3,3-difluoropyrrolidin-1-yl)-3-methylbutan-2-amine (Compound O) (167 mg, 0.87 mmol) added. The resultant mixture was stirred at rt over night. The mixture was concentrated and the residue dissolved in DCM (5 mL). The organic phase was washed with HCl (1M aq. solution, 5 mL), NaHCO3 (saturated, 2×5 mL) and brine (5 mL), and filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (143 mg, 51%). 1H NMR (400 MHz, DMSO-d6) δ 0.65-1.03, 1.61-1.92, 2.00-2.21, 2.23, 2.53-3.03, 3.66-4.22, 7.19, 7.55, 7.61, 7.87. Total no of protons: 26.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][CH:5]=[CH:4][N:3]=1.O.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[C:24](#[N:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>[Cu]Br>[Br:8][C:7]1[C:2]2[N:3]([N:31]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:1]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1ccccc1
Reactant: Nc1ncccc1Br
Agent: [Cu]Br
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: O
Product: Brc1cccn2nc(-c3ccccc3)nc12
Temperature: 130 °C
Yield: 60 %

Procedure:
A mixture of 2-amino-3-bromopyridine (2.00 g, 11.2 mmol), copper (I) bromide (240 mg, 1.64 mmol), 1,10-phenanthroline monohydrate (336 mg, 1.68 mmol) and benzonitrile (25 mL) was heated in a 50-mL 3-necked flask to 130° C. During 4 d a gentle flow of (O2/N2 5:95) was bubbled through the reaction mixture (>99% conversion, HPLC method see below). The dark brown suspension was then cooled to 0-5° C. and filtered. The filter cake was washed with TBME (10 mL) and dried to yield crude 8-bromo-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine (1.85 g, 60%) as a light brown solid with 97.5% purity (HPLC area-%, HPLC method see below).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:48])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:44]([CH3:47])[CH2:45][CH3:46])[C@H:25]([O:42][CH3:43])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:40][CH3:41])[C@H:35]([C:37](O)=[O:38])[CH3:36])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[CH2:73]([O:80][CH2:81][C@@H:82]([NH2:90])[CH2:83][C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1)[C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:48])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:44]([CH3:47])[CH2:45][CH3:46])[C@H:25]([O:42][CH3:43])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:40][CH3:41])[C@@H:35]([CH3:36])[C:37]([NH:90][C@@H:82]([CH2:83][C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1)[CH2:81][O:80][CH2:73][C:74]1[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=1)=[O:38])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:11])[CH3:12])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C
Reactant: N[C@H](COCc1ccccc1)Cc1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](COCc1ccccc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C
Reaction time: 8 h

Procedure:
To a solution of 20 mg (29 μmol) of N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-2-carboxy-1-methoxypropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide in 1 ml of DMF were added, at RT, 15.3 μl (88 μmol) of N,N-diisopropylethylamine, 6.7 mg (44 μmol) of HOBt and 6.7 mg (35 mmol) of EDC, and the mixture was stirred for 30 min. Subsequently, 7.8 mg (32 μmol) of (2S)-1-(benzyloxy)-3-phenylpropan-2-amine hydrochloride were added. After stirring overnight, the reaction mixture was separated directly into its components via preparative HPLC. 26 mg (98% of theory) of the title compound were obtained.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:31][CH2:32][CH3:33])=[C:8]([O:28][CH2:29][CH3:30])[CH:9]=2)[N:4]=1.[C:34]1([P:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1(C)C=CC=CC=1>[Cl-:1].[CH2:29]([O:28][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[O:31][CH2:32][CH3:33])[N:4]=[C:3]([CH2:2][P+:40]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1)[CH3:30]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)c1c(CCl)nc2cc(OCC)c(OCC)cc2c1-c1ccc(OC)c(OC)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)nc2cc(OCC)c(OCC)cc2c1-c1ccc(OC)c(OC)c1
Product: [Cl-]
Yield: 87.7 %

Procedure:
A mixture of ethyl 2-chloromethyl-6,7-diethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylate (7.1 g), triphenylphosphine (3.9 g) and toluene (70 ml) was stirred under reflux for 2 hours. After cooling, the resulting solid was collected by filtration to give [6,7-diethoxy-4-(3,4-dimethoxyphenyl)-3-ethoxycarbonylquinolin-2-yl]methyl-triphenylphosphonium chloride (9.6 g, 87%). mp. 172°-174° C. (decomposition).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])([CH3:11])[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.C([Li])CCC.C(O[B:32]1[O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:40])([CH3:39])[O:33]1)(C)C>C1COCC1>[F:8][C:6]1[CH:5]=[C:4]([C:9]([O:12][Si:13]([CH:14]([CH3:15])[CH3:16])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:10])[CH3:11])[CH:3]=[C:2]([F:1])[C:7]=1[B:32]1[O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:40])([CH3:39])[O:33]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CC(C)[Si](OC(C)(C)c1cc(F)cc(F)c1)(C(C)C)C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[Si](OC(C)(C)c1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1)(C(C)C)C(C)C
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of (2-(3,5-difluorophenyl)propan-2-yloxy)triisopropylsilane (1.0 eq) in dry THF (0.2 M) under an atmosphere of N2 at −78° C. was added n-butyllithium (1 eq, 1.6 M in hexanes) slowly keeping the internal temperature below −65° C. The reaction was stirred for 2 hrs at −78° C., followed by the addition of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.15 eq). The reaction was allowed to warm to room temperature. Upon completion, the reaction was quenched with NaHCO3 (sat.) and extracted with EtOAc. The organics were washed with brine, dried over Na2SO4, filtered and concentrated to yield (2-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-yloxy)triisopropylsilane in 99%. 1H NMR (400 MHz, <cdcl3>) δ ppm 1.03-1.08 (m, 21H) 1.24 (s, 12H) 1.38 (s, 3H) 1.57 (s, 3H) 6.92-7.03 (m, 2H).
Reaction SMILES: Cl.[CH3:2][C:3](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH2:18])=[CH:12][CH:11]=1)[C:4]([O:6]CC)=[O:5].[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24]([CH:28]=1)[C:25](Cl)=[O:26]>>[CH3:2][C:3](=[CH:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][NH:18][C:25](=[O:26])[C:24]2[CH:28]=[C:20]([Cl:19])[CH:21]=[CH:22][C:23]=2[O:29][CH3:30])=[CH:14][CH:15]=1)[C:4]([OH:6])=[O:5]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: CCOC(=O)C(C)=Cc1ccc(CCN)cc1
Agent: Cl
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc(C=C(C)C(=O)O)cc1

Procedure:
By the reaction of ethyl α-methyl-4-(2-aminoethyl)-cinnamate hydrochloride (m.p. 270° C.) with 5-chloro-2-methoxybenzoyl chloride, there is obtained α-methyl-4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-cinnamic acid; m.p. 188°-191° C., after recrystallization from ethanol.
Reaction SMILES: Cl.Cl[C:3]1[N:16]2[C:7](=[N:8][C:9]3[C:14]([C:15]2=[O:17])=[C:13]([F:18])[CH:12]=[CH:11][CH:10]=3)[C:6]2[CH:19]=[CH:20][N:21](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]=2[N:4]=1.[NH2:32][C:33]1[C:34]([O:48][CH3:49])=[CH:35][C:36]([CH3:47])=[C:37]([N:39]([CH3:46])[C:40](=[O:45])[CH2:41][N:42]([CH3:44])[CH3:43])[CH:38]=1.[CH3:50][NH2:51]>FC(F)(F)CO.C1COCC1.CCOC(C)=O>[CH3:43][N:42]([CH3:44])[CH2:41][C:40]([N:39]([CH3:46])[C:37]1[C:36]([CH3:47])=[CH:35][C:34]([O:48][CH3:49])=[C:33]([NH:32][C:3]2[NH:4][C:5]3=[N:21][CH:20]=[CH:19][C:6]3=[C:7]([NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([F:18])[C:14]=3[C:15]([NH:51][CH3:50])=[O:17])[N:16]=2)[CH:38]=1)=[O:45]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2nc(Cl)n2c(=O)c4c(F)cccc4nc32)cc1
Reactant: COc1cc(C)c(N(C)C(=O)CN(C)C)cc1N
Reactant: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: OCC(F)(F)F
Product: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc(N(C)C(=O)CN(C)C)c(C)cc2OC)[nH]c2nccc1-2
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 5-chloro-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one HCl salt (0.5 g, 1.04 mmol) in 2,2,2-trifluoroethanol (10 mL) was added N1-[5-amino-2-methyl-4-(methyloxy)phenyl]-N1,N2,N2-trimethylglycinamide (0.275 g, 1.10 mmol). The resulting mixture was let stir at 50° C. for 90 min. Solvents were then removed under reduced pressure to afford a brown residue. Half of this material was dissolved in THF (10 mL) and a 2M solution of methyl amine in THF (2.5 mL, 4.90 mmol) was added. After stirring at rt for 30 min, the reaction was diluted with EtOAc and the organic layer was washed with water and a saturated brine solution and dried over sodium sulfate. Solvents were removed under reduced pressure and the residue purified by chromatography on SiO2. This material was dissolved in dioxane (6 mL) and 2N NaOH (4 mL) was added in a microwave safe vessel. The reaction was heated in a microwave at 120° C. for 15 min. The reaction was diluted with EtOAc and the organic layer was washed with water and a saturated brine solution and dried over sodium sulfate. Solvents were removed under reduced pressure and the residue purified by chromatography on SiO2 to afford 2-[(2-{[5-[(N,N-dimethylglycyl)(methyl)amino]-4-methyl-2-(methyloxy)phenyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide (119 mg, 0.223 mmol) as a beige solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.10 (s, 6 H) 2.12 (s, 3 H) 2.61 (d, J=15.75 Hz, 1 H) 2.77 (d, J=4.58 Hz, 3 H) 2.83 (d, J=15.75 Hz, 1 H) 3.03 (s, 3 H) 3.91 (s, 3 H) 6.34 (dd, J=3.11, 1.83 Hz, 1 H) 6.93-7.05 (m, 3 H) 7.44 (d, J=6.59 Hz, 1 H) 7.52 (s, 1 H) 8.16 (d, J=8.42 Hz, 1 H) 8.27 (s, 1 H) 8.54 (d, J=3.85 Hz, 1 H) 10.06 (s, 1H) 11.44 (br. s., 1H). ESIMS (M+H)+=535.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:19])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CS(C)=O.C1(C)C=CC=CC=1>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:11]([C:8]1[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:10][CH:9]=1)=[O:19])[CH3:26]
Reactant: COc1ccc(C(=O)Cc2ccccc2)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(C(=O)c1ccc(OC)cc1)c1ccccc1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A suspension of NaH (12.8 mmol, 512 mg) in DMSO (23 mL) was added 4′-methoxy-2-phenylacetophenone (12.8 mmol, 2.89 g) in 10 ml toluene dropwise under argon. After 30 minutes of stirring, ethyl bromoacetate (1.4 mL, 1 eq.) in 10 mL of toluene was added and the mixture was stirred at rt overnight. The reaction was quenched by addition of 2N HCl (4 mL), and then 60 mL of water. The mixture was extracted with CH2Cl2 (3×30 mL), dried over MgSO4 and concentrated under vacuum overnight to afforded 4.0 g (99%) of 4-(4-methoxy-phenyl)-4-oxo-3-phenyl-butyric acid ethyl ester.
Reaction SMILES: [CH:1]1([N:7]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:29]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>>[CH:1]1([N:7]([CH2:25][CH:26]2[CH2:27][CH2:28]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][N:39]4[CH2:38][CH2:37][N:36]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:41][CH2:40]4)=[CH:21][CH:22]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(NC(=O)c3cc(N(CC4CC4)C4CCCCC4)ncn3)cc2)CC1

Procedure:
Following the general method as outlined in Example 73, starting from 6-[cyclohexyl(cyclopropylmethyl)amino]-N-(4-formylphenyl)pyrimidine-4-carboxamide (Intermediate 24) and 1-boc-piperazine (Fluka), the title compound was obtained as a white solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]([CH:35]=O)[S:33][CH:34]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[O:20]=[S:17]1(=[O:21])[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:30]4[CH:31]=[C:32]([CH2:35][N:7]([CH2:6][CH3:5])[CH3:8])[S:33][CH:34]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH2:16]1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Reactant: CC1(C)OB(c2csc(C=O)c2)OC1(C)C
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)CC4)c3c2)cs1
Temperature: 150 °C
Yield: 5.4 %

Procedure:
To 5-bromo-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-1H-indole-7-carboxamide (400 mg, 1.08 mmol) in dioxane and water (4 mL/1 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thiophenecarbaldehyde (462 mg, 1.94 mmol), Pd(PPh3)4 (100 mg) and K2CO3 (447 mg, 3.24 mmol). The reaction mixture was heated to 150° C. for 20 minutes by microwave irradiation. The organic phase was concentrated and redissolved in DMSO (10 mL). The resulting solution was split to eight. NaBH3CN (30 mg), ZnCl2 (30 mg) and methyl ethylamine (50 mg) were added. The mixture was heated at 100° C. for 30 minutes which was then filtered and purified by HPLC with TFA to afford the title compound (13 mg).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][C:17]1=[O:21].C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: NCCCN1CCCC1=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: O=C1CCCN1CCCNc1ccc2ncc(Br)n2n1

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and 1-(3-aminopropyl)pyrrolidin-2-one according to general procedure 1 providing the intermediate (150 mg, 58%) as a white solid; Rf=0.58 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 7.55 (d, J=9.7 Hz, 1H), 7.39 (s, 1H), 6.68 (d, J=9.7 Hz, 1H), 3.53 (t, J=7.1 Hz, 2H), 3.43-3.38 (m, 4H), 2.39 (t, J=8.0 Hz, 2H), 2.08 (quin, J=7.6 Hz, 2H), 1.94 (quin, J=6.9 Hz, 2H); ES-MS: (M+H)=338, 340 m/z.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:11])=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].OC1[CH2:18][C:17]([CH3:20])([CH3:19])[NH:16][C:15]([CH3:22])([CH3:21])[CH2:14]1>CCCCO.CCCCO.CCCCO.CCCCO.[Ti].CO>[CH3:1][C:2]1[O:3][C:4]([CH3:11])=[CH:5][C:6]=1[C:7]([O:9][CH:10]1[CH2:18][C:17]([CH3:20])([CH3:19])[NH:16][C:15]([CH3:22])([CH3:21])[CH2:14]1)=[O:8]
Reactant: COC(=O)c1cc(C)oc1C
Reactant: CC1(C)CC(O)CC(C)(C)N1
Agent: [Ti]
Solvent: CO
Solvent: CCCCO
Product: Cc1cc(C(=O)OC2CC(C)(C)NC(C)(C)C2)c(C)o1

Procedure:
154 g (1 mole) of methyl 2,5-dimethylfuran-3-carboxylate and 157 g (1 mole) of 4-hydroxy-2,2,6,6-tetramethylpiperidine were heated together with 10 g of tetrabutyl orthotitanate for 10 hours at about 190° C., the methanol formed being distilled off. When the reaction is complete, the mixture is cooled and the reaction mass is dissolved in ethyl acetate. The solution is extracted by shaking, first with 10% strength sodium carbonate solution and then with water, after which it is dried and evaporated down, and the residue is distilled under reduced pressure. The desired product distils at 142° C./2 mm as a virtually colorless oil which soon solidifies to a solid of melting point 59°-61° C.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][NH:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:24][S:25]([Cl:28])(=[O:27])=[O:26]>C(Cl)(Cl)Cl>[ClH:28].[CH3:23][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][N:14]([CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[S:25]([CH3:24])(=[O:27])=[O:26]
Reactant: CN(C)CCCOc1ccccc1CNCCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Product: CN(C)CCCOc1ccccc1CN(CCc1ccccc1)S(C)(=O)=O
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of 10 g of N-[[2-[3-(dimethylamino)propoxy]phenyl]methyl]benzeneethanamine in 50 ml of chloroform is treated dropwise at 10° to 15° C. with 2.7 ml of methanesulfonyl chloride dissolved in 50 ml of chloroform, stirred for 1 hour at room temperature (some solid separates), refluxed for 1 hour (solution obtained), and maintained at room temperature for about 16 hours.