Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].C(N(CC)CC)C.C(OC(Cl)=O)C.[NH2:29][C@H:30]([C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33]>CN(C)C=O>[NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([NH:29][C@H:30]([C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])=[O:8])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
19.9 g (92 mmols) of BOC-Val-OH are dissolved in 200 ml of freshly distilled dimethylformamide, while heating. After cooling to 0°C, 25.9 ml of absolute triethylamine are added and the solution cooled to -10°C before 8.64 ml of chlorocarbonic acid ethyl ester are added. After 10 minutes, a solution of 23.2 g (90 mmols) of H-Leu-OBzl, HCL in 90 ml of dimethylformamide is added at -10°C. The mixture is allowed to stand at -10°C for 30 minutes, at 0°C for 3 hours, and at 20°C for 16 hours. Undissolved matter is then filtered off and the filtrate concentrated to dryness under a high vacuum. The residue is dissolved in ethyl acetate and the solution washed with dilute citric acid solution, water, sodium bicarbonate solution, and water, dried with sodium sulfate, and evaporated. On addition of petroleum ether the product crystallizes overnight. Melting point 88.5° - 89.5°C; [α]D20 -22° (c = 2 in dimethylformamide); Rf2 = 0.73.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:15]([O:17][C@H:18]4[C@H:22]5[O:23][CH2:24][C@@H:25]([OH:26])[C@H:21]5[O:20][CH2:19]4)=[N:16][C:11]3=[CH:10][C:9]=2[Cl:35])=[CH:4][CH:3]=1.[N:36]1([C:42]([O:44][CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[N:36]1([C:42]([O:44][CH:45]2[CH2:50][CH2:49][N:48]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[N:13]=[C:12]5[N:14]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:15]([O:17][C@@H:18]6[CH2:19][O:20][C@@H:21]7[C@H:25]([OH:26])[CH2:24][O:23][C@H:22]67)=[N:16][C:11]5=[CH:10][C:9]=4[Cl:35])=[CH:4][CH:3]=3)[CH2:47][CH2:46]2)=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(-c3ccc(Br)cc3)nc21
Reactant: O=C(OC1CCNCC1)N1CCOCC1
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(-c3ccc(N4CCC(OC(=O)N5CCOCC5)CC4)cc3)nc21

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(5-(4-bromophenyl)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and piperidin-4-yl morpholine-4-carboxylate following a procedure analogous to that described for Intermediate 23. LC (method 1): tR=1.03 min; Mass spectrum (ESI+): m/z=716 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])=[CH:7][C:5]([NH2:6])=[C:4]([F:19])[CH:3]=1.[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2[CH2:26][CH2:27][CH2:28][CH2:29][C:21]1=2.C(O)(=O)C>O>[Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])=[CH:7][C:5]([N:6]2[C:23](=[O:24])[C:22]3[CH2:26][CH2:27][CH2:28][CH2:29][C:21]=3[C:20]2=[O:25])=[C:4]([F:19])[CH:3]=1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: CCCCCOC(=O)COc1cc(N)c(F)cc1Cl
Solvent: CC(=O)O
Solvent: O
Product: CCCCCOC(=O)COc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 89.4 %

Procedure:
A mixture of the compound (II) (12.0 g), 3,4,5,6-tetrahydrophthalic anhydride (7.56 g) and acetic acid (50 g) was heated at 90° to 95° C. for 7 hours. The reaction mixture was cooled to room temperature, and water (75 g) was added thereto. The precipitated crystals were collected by filtration to give the compound (I) (15.7 g).
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:15]([C:16]3[CH:17]=[N:18][NH:19][CH:20]=3)=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:25])[N:11]3[C:21]([O:23][CH3:24])=[O:22])[CH2:4][CH2:3][CH2:2]1.CS(O[CH:31]1[CH2:36][CH2:35][S:34](=[O:38])(=[O:37])[CH2:33][CH2:32]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[CH:1]1([O:5][C:6]2[C:15]([C:16]3[CH:20]=[N:19][N:18]([CH:31]4[CH2:36][CH2:35][S:34](=[O:38])(=[O:37])[CH2:33][CH2:32]4)[CH:17]=3)=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:25])[N:11]3[C:21]([O:23][CH3:24])=[O:22])[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)N1c2ccc(-c3cn[nH]c3)c(OC3CCC3)c2CC[C@@H]1C
Reactant: CS(=O)(=O)OC1CCS(=O)(=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)N1c2ccc(-c3cnn(C4CCS(=O)(=O)CC4)c3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 110 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
A mixture of (S)-methyl 5-cyclobutoxy-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (0.160 g, 0.47 mmol), 1,1-dioxidotetrahydro-2H-thiopyran-4-yl methanesulfonate (0.320 g, 1.40 mmol) and cesium carbonate (0.457 g, 1.40 mmol) in N,N-dimethylformamide (5 mL) stirred overnight at 110° C. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by preparative thin layer chromatography (eluting with 50% ethyl acetate/petroleum ether). The product was further purified by preparative-HPLC with the following conditions (Waters I): Column, Xbridge RP18 5 um, 19×150 mm; Mobile phase, water (0.05% ammonium bicarbonate) and acetonitrile (40% to 80% acetonitrile in 10 min; flow rate: 20 mL/min); Detector, UV 220&254 nm. This afforded of methyl (2S)-5-cyclobutoxy-6-[1-(1,1-dioxo-1λ6-thian-4-yl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate (0.040 g, 18%) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 1.18 (d, J=6.40 Hz, 3H), 1.29-1.31 (m, 1H), 1.47-1.49 (m, 1H), 1.60-1.62 (m, 1H), 2.01-2.08 (m, 4H), 2.11-2.24 (m, 1H), 2.45-2.47 (m, 1H), 2.63-2.68 (m, 4H), 2.90-2.94 (m, 1H), 3.10-3.17 (m, 2H), 3.45-3.47 (m, 2H), 3.78 (s, 3H), 4.06-1.10 (m, 1H), 4.45-4.58 (m, 2H), 7.22 (d, J=8.40 Hz, 1H), 7.31 (d, J=8.40 Hz, 1H), 7.81 (s, 2H). MS (ESI, pos. ion) m/z 474 [M+H]+.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1.C([O-])(=O)C.[Na+].S(=O)(=O)(O)O>C(O)(=O)C.O>[Br:1][C:9]1[CH:10]=[C:5]([O:4][CH3:3])[CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[C:8]=1[OH:11]
Reactant: COc1ccc(O)c([N+](=O)[O-])c1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(Br)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Bromine (16.0 g, 100 mmol) in acetic acid (20 mL) was added into a mixture of 4-methoxy-2-nitrophenol (16.9 g, 100 mmol, sodium acetate (16.4 g, 200 mmol) and acetic acid (100 mL). The mixture was stirred for 30 min at room temperature, and then at 70° C. for 2 h and poured into water (1.5 l) containing concentrated sulfuric acid (10 mL). The precipitated solid filtered and crystallized from (chloroform/hexane) to give a brownish solid, m.p. 116–118° C.; MS m/e 246 (M−H)+.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:25]1[CH:26]=[N:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[CH:30][CH:29]=2>>[CH:11]1[C:12]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20]([C:25]5[CH:26]=[N:27][C:28]6[C:33]([CH:34]=5)=[CH:32][CH:31]=[CH:30][CH:29]=6)([OH:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Product: OC1(c2cnc3ccccc3c2)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Yield: 44 %

Procedure:
Using a procedure similar to that described in example 1 except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and employing 3-bromoquinoline, the title compound was formed in 44% yield as a white solid, mp 205°-207° C. free base: 1H NMR (CDCl3, 300 MHz) 9.06 (d, J=3.6 Hz, 1H), 8.20 (d, J=3.0 Hz, 1H), 8.08 (d, J=8.1Hz, 1H), 7.80 (d, J=8.1Hz, 1H), 7.68 (dd, J=6.0, 5.9 Hz, 1H), 7.54 (dd, J=8.5, 9.0 Hz, 1H), 7.23 (m, 4H), 6.94 (m, 4H), 4.30 (s, 1H), 3.52 (s, 2H), 2.98 (m, 2H), 2.78 (m, 2H), 2.64 (d, J=1.4 Hz, 2H), 2.24 (dt, J=3.9, 11.6 Hz, 2H), 1.99 (s, 1H), 1.83 (m, 2H) MS (CI, CH4) m/z 433 (M+1.17), 415 (4), 211 (12), 89 (100), 79 (45), 73 (13) hydrochloride salt:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][C:12]1[NH:21][C:20](=[O:22])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:23])[CH:18]=2)[N:13]=1.[H-].[Na+].[CH3:26][N:27]([CH2:29][CH2:30]Cl)[CH3:28].O>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][C:12]1[N:21]([CH2:30][CH2:29][N:27]([CH3:28])[CH3:26])[C:20](=[O:22])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:23])[CH:18]=2)[N:13]=1
Reactant: COc1ccc(OC)c(Cc2nc3ccc(C)cc3c(=O)[nH]2)c1
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(OC)c(Cc2nc3ccc(C)cc3c(=O)n2CCN(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.1 %

Procedure:
A suspension of 0.62 g (2 mmol) of 2-(2,5-dimethoxyphenylmethyl)-6-methyl-4(3H)-quinazolinone and 0.19 g (2 mmol) of 50% sodium hydride in dioxane (10 ml) were stirred at room temperature for 1 hour. Then, to the resulting reaction mixture was added 0.22 g (2 mmol) of dimethylaminoethyl chloride dissolved in dioxane (10 ml), followed by heating at 60° C. for 5 hours. After cooling, to the mixture obtained were added 30 ml of water. The resulting mixture was extracted with dichloromethane and the dichloromethane layer was concentrated under reduced pressure. The thus obtained residue was purified by silica gel column chromatography (eluent; dichloromethane: ethanol=97:3) to obtain 0.10 g (yield 13 %) of 2-(2,5-dimethoxyphenylmethyl)-3-(2-dimethylaminoethyl)-6-methyl-4(3H)-quinazolinone as an oily substance. The thus obtained quinazolinone was dissolved in ether and to the resulting solution was added a 5% hydrogen chloride-ethanol solution and the precipitated crystals were collected by filtration to obtain 2-(2,5-dimethoxyphenylmethyl)-3-(2-dimethylaminoethyl)-6-methyl-4(3H)-quinazolinone hydrochloride. The melting point and infrared absorption spectrum of this hydrochloride were identical with those of Compound 24 obtained in Example 24, respectively.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[N:14]\[O:15][CH3:16])/[C:10]([NH:12][CH3:13])=[O:11].[H-].[Na+].Cl[C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1>CN(C=O)C.[Cl-].[Na+].O>[N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][C:20]=1[O:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[N:14]\[O:15][CH3:16])/[C:10]([NH:12][CH3:13])=[O:11]
Reactant: Clc1ccc2ccccc2n1
Reactant: CNC(=O)/C(=N/OC)c1ccccc1CO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1ccc2ccccc2n1
Reaction time: 0.17 h
Yield: 65.8 %

Procedure:
(E)-2-[2-(hydroxymethyl)phenyl]-2-methoxyimino-N-methylacetamide (0.44 g, 2 mmol) was dissolved in dry DMF (4 ml). 60% sodium hydride (0.10 g, 2.4 mmol) was added at room temperature, the mixture was stirred for 10 minutes, and then 2-chloroquinoline (0.36 g, 2.2 mmol) was added at room temperature. The resulting mixture was allowed to stand at room temperature overnight, and saturated brine was added. The mixture was extracted with ethyl acetate and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting crude product was purified by column chromatography on silica gel (ethyl acetate--n-hexane) to give the title compound (0.46 g) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH3:28])[C:25](O)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:16]([O:20][C:21](=[O:22])[NH:23][C@H:24]([C:25]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=2[N:8]=1)[CH3:28])([CH3:19])([CH3:18])[CH3:17]
Reactant: Nc1ccc(F)cc1Nc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 57.4 %

Procedure:
A mixture of 4-fluoro-N2-phenylbenzene-1,2-diamine (1.19 g, 5.88 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (1.22 g, 6.47 mmol), HOAt (881 mg, 6.47 mmol), 4-methylmorpholine (1.42 mL, 12.95 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.24 g, 6.47 mmol) in DCM (30 mL) was stirred at RT for 21 h. The reaction mixture was then partitioned between additional DCM and an aqueous solution of NaHCO3. The organic layer was dried and concentrated in vacuo and the resulting residue (2.40 g) was dissolved in AcOH (50 mL) and stirred for 48 h at 60° C. After cooling to RT, volatiles were evaporated under reduced pressure and the residue was partitioned between EtOAc and a saturated solution of NaHCO3. The organic layer was washed with brine, dried (Na2SO4) and then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-50% EtOAc in DCM) affording [(S)-1-(6-Fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tertbutyl ester as a yellow foam (1.20 g, 57%). LCMS: RT 3.50 min [M+H]+ 356.2
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:23])[C:6]=1[N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9][CH2:8]1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:66]([O:70][C:71]([NH:73][C:74]1[S:78][C:77]([C:79]2[C:84]([F:85])=[CH:83][CH:82]=[CH:81][C:80]=2[F:86])=[N:76][C:75]=1[C:87](O)=[O:88])=[O:72])([CH3:69])([CH3:68])[CH3:67]>C(Cl)Cl>[C:66]([O:70][C:71]([NH:73][C:74]1[S:78][C:77]([C:79]2[C:84]([F:85])=[CH:83][CH:82]=[CH:81][C:80]=2[F:86])=[N:76][C:75]=1[C:87]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:23])[C:6]=1[N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:9][CH2:8]1)=[O:88])=[O:72])([CH3:69])([CH3:67])[CH3:68]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CN(CC1CCN(c2c(N)cnn2C)CC1)C(=O)OC(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(CC1CCN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3NC(=O)OC(C)(C)C)cnn2C)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of Intermediate 1, tert-butyl methyl((1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-yl)methyl)carbamate (145 mg, 0.41 mmol) in MeOH (40 mL) was passed through the H-Cube® (full H2, 50° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to afford crude tert-butyl (1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-4-yl)methyl(methyl)carbamate as a red-brown oil (117 mg). To a solution of this amine (115 mg, 0.36 mmol) in DCM (20 mL) was added DIPEA (1.0 mL), PyBOP (0.46 g, 0.89 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 (127 mg, 0.36 mmol) and the mixture was stirred at room temperature for 18 hr. The mixture was diluted with DCM (80 mL) and washed with water (20 mL). The organic layer was separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (75% EtOAc/isohexane) gave tert-butyl (1-(4-(5-tert-butoxycarbonylamino-2-(2,6-difluorophenyl)thiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)piperidin-4-yl)methyl(methyl)carbamate as a lilac foam (200 mg). This foam (200 mg, 0.30 mmol) was stirred with HCl in 1,4-dioxane (4 M, 3.8 mL, 15.1 mmol) in MeOH (5 mL) at room temperature for 3 days. The solvents were removed under reduced pressure and the crude residue was re-dissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH and eluted with 7 N ammonia in MeOH to yield 101 as a beige solid (99 mg, 53% over three steps). 1H NMR (400 MHz, d6-DMSO) δ 8.75 (s, 1H), 7.59-7.49 (m, 3H), 7.44 (s, 1H), 7.32-7.22 (m, 2H), 6.90 (br s, 1H), 3.63 (s, 3H), 3.14-2.96 (m, 4H), 2.66 (d, J=6.8 Hz, 2H), 2.45 (s, 3H), 1.77 (d, J=12.6 Hz, 2H), 1.78-1.55 (m, 1H), 1.36-1.22 (m, 2H). LCMS (ES+) m/z 462 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:13]([CH3:16])([CH3:15])[CH3:14])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[CH:17]([NH2:20])([CH3:19])[CH3:18]>C1(C)C=CC=CC=1.CCCCCC.C(=O)=O>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:13]([CH3:16])([CH3:15])[CH3:14])[C:3]=1[C:4]([NH:6][C:7]([NH:20][CH:17]([CH3:19])[CH3:18])=[O:8])=[O:5]
Reactant: CC(C)N
Reactant: C[Si](C)(C)c1cccc(Cl)c1C(=O)N=C=O
Agent: O=C=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(C)NC(=O)NC(=O)c1c(Cl)cccc1[Si](C)(C)C
Reaction time: 0.5 h

Procedure:
2-Chloro-6-trimethylsilylbenzoyl isocyanate (1.3 g, 5 mmol) was dissolved in 40 mL toluene and isopropyl amine (1 g) added over a period of 30 seconds. After stirring 30 min, the solvent was removed to yield an oil. The oil was dissolved in hexane and cooled in dry ice to yield 1.2 g of crystals of the title compound. m.p. 113°-116° C.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]2[N:13]=[CH:14][CH:15]=[CH:16][C:4]=2[C:3]1=[O:17].I[CH2:19][CH2:20][CH3:21]>>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:19][CH2:20][CH3:21])[C:5]2[N:13]=[CH:14][CH:15]=[CH:16][C:4]=2[C:3]1=[O:17]
Reactant: CN1C(=O)c2cccnc2Nc2ccccc21
Reactant: CCCI
Product: CCCN1c2ccccc2N(C)C(=O)c2cccnc21
Yield: 36 %

Procedure:
Using a procedure analogous to that described in Example 2, the product 6,11-dihydro-6-methyl-11-propyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one, m.p. 96°-98° C. (recrystal from petroleum ether) was prepared from 6,11-dihydro-6-methyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one and 1-iodopropane. The yield was 36% of theory.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.BrC1C=C(O)C=CC=1.[CH3:19][O:20][C:21]1[CH:42]=[CH:41][C:24]([CH2:25][N:26]2[C:38]3[C:29](=[C:30]4[C:35](=[CH:36][CH:37]=3)[N:34]=[CH:33][CH:32]=[CH:31]4)[C:28](=[O:39])[C:27]2=[O:40])=[CH:23][CH:22]=1.FC(F)(F)C1OC(CN2C3C(=CC=CC=3)C(=O)C2=O)=CC=1>>[OH:39][C:28]1([C:8]2[C:7]([OH:10])=[CH:6][C:5]3[O:1][CH2:2][CH2:3][C:4]=3[CH:9]=2)[C:29]2=[C:30]3[C:35](=[CH:36][CH:37]=[C:38]2[N:26]([CH2:25][C:24]2[CH:41]=[CH:42][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[C:27]1=[O:40])[N:34]=[CH:33][CH:32]=[CH:31]3
Reactant: COc1ccc(CN2C(=O)C(=O)c3c2ccc2ncccc32)cc1
Reactant: Oc1ccc2c(c1)OCC2
Agent: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21
Agent: Oc1cccc(Br)c1
Product: COc1ccc(CN2C(=O)C(O)(c3cc4c(cc3O)OCC4)c3c2ccc2ncccc32)cc1

Procedure:
Following the procedure as described in PREPARATION 2A and making non-critical variations using 2,3-dihydrobenzofuran-6-ol to replace 3-bromophenol, and 3-(4-methoxybenzyl)-1H-pyrrolo[3,2-f]quinoline-1,2(3H)-dione to replace 1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione, 1-hydroxy-1-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-3-(4-methoxybenzyl)-1,3-dihydro-2H-pyrrolo[3,2-f]quinolin-2-one was obtained (58%) as a colorless solid: MS (ES+) m/z 455.0 (M+1).
Reaction SMILES: FC(F)(F)C(O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[CH:9][CH:8]=1)=O.[Br-:23].[Li+]>C1COCC1.C(#N)C>[Si:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][Br:23])=[CH:8][CH:9]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(COC(=O)C(F)(F)F)cc1
Reactant: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CBr)cc1
Yield: 88 %

Procedure:
The benzyl trifluoroacetate 8 (17.9 g) was dissolved in dry THF, and dry lithium bromide (5.06 g) was added with stirring. The mixture was refluxed overnight, cooled, diluted with acetonitrile, and extracted three times with hexane. The hexane layers were combined, dried, filtered, and concentrated, thereby leaving the product 10 as a white oil in 88% yield.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]([F:10])([F:9])[F:8])=[N:4][NH:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C.[CH3:22][C:23]1([CH3:26])[CH2:25][O:24]1>>[Br:1][C:2]1[C:3]([C:7]([F:10])([F:9])[F:8])=[N:4][N:5]([CH2:22][C:23]([CH3:26])([OH:24])[CH3:25])[CH:6]=1
Reactant: FC(F)(F)c1n[nH]cc1Br
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1cc(Br)c(C(F)(F)F)n1
Temperature: 90 °C

Procedure:
To a mixture of 4-bromo-3-trifluoromethyl-1H-pyrazole (200.0 mg, 0.9304 mmol), K2CO3 (200.0 mg, 1.447 mmol) and DMF (3 mL, 40 mmol) was added 2,2-dimethyloxirane (0.5 mL, 6 mmol), and the mixture was heated to 90° C. for 2 h in a sealed tube. The material was transferred to a separation funnel, extracting with EtOAc and washing with water (3×). The organic layer was loaded onto silica gel for column chromatography, eluting with 10-30% EtOAc/heptane. The fractions containing the 3-trifluoromethyl product were concentrated in vacuo to afford the title compound as a brown oil. 1H NMR (400 MHz, CD3OD): δ=1.17 (s, 6H), 4.13 (s, 2H), 7.87 (s, 1H). MS (ES+): m/z=287.00/289.00 (100/100) [MH+]. HPLC: tR=1.35 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[CH2:5]([SnH:9]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH3:8].N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>>[CH2:14]([Sn:9]([CH2:5][CH2:6][CH2:7][CH3:8])([CH2:10][CH2:11][CH2:12][CH3:13])/[CH:3]=[CH:2]/[CH2:1][OH:4])[CH2:15][CH2:16][CH3:17]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CCO
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Product: CCCC[Sn](/C=C/CO)(CCCC)CCCC
Temperature: 80 °C

Procedure:
To neat propargyl alcohol (1.77 mL) were added tributyltin hydride (10.3 mL) followed by 1,1′-azobis(cyclohexanecarbonitrile) (378 mg). The mixture was heated for 2.5 h at 80° C., cooled to RT and directly purified by CC (EA/Hept 5/95) to afford the desired compound (5.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]([CH2:19][NH2:20])=[CH:6]2.[C:21](OC(=O)C)(=[O:23])[CH3:22].Cl>N1C=CC=CC=1.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])=[CH:6]2
Reactant: COc1ccc2c(c1)C=C(CN)C(c1ccccc1)O2
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc2c(c1)C=C(CNC(C)=O)C(c1ccccc1)O2
Reaction time: 0.5 h

Procedure:
A solution of 0.42 g (1.57 mmol) of the amine obtained in Step C in 5 ml of anhydrous pyridine is cooled to 0° C.; 0.18 ml (1.97 mmol) of acetic anhydride is then added to the medium. After 30 minutes of stirring under argon, the medium is diluted with dichloromethane and then adjusted to an acid pH with a 1N hydrochloric acid solution. The aqueous phase is extracted with dichloromethane; the organic phase is then washed with a saturated solution of sodium hydrogen carbonate. The residue obtained, after evaporation of the solvent in vacuo, is purified on a silica column (eluant: AcOEt/PE: 70/30) to yield the title amide in the form of a white solid.