Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][CH2:8][CH3:9])[C:5]#[N:6])[CH2:2][CH3:3].S(=O)(=O)(O)[OH:11]>>[CH2:1]([CH:4]([CH2:7][CH2:8][CH3:9])[C:5]([NH2:6])=[O:11])[CH2:2][CH3:3]
Reactant: CCCC(C#N)CCC
Reactant: O=S(=O)(O)O
Product: CCCC(CCC)C(N)=O

Procedure:
Process according to claim 1, whereby the di-n-propyl acetonitrile is hydrolysed by means of 75% aqueous sulphuric acid in the proportion of 1.7 g of dilute acid/g of nitrile at the temperature of 140° C. and then the crude di-n-propyl acetamide thus obtained is hydrolysed in the same aqueous sulphuric acid medium in the presence of 1.4 to 1.5 mol of sodium nitrite/mol of nitrile at a temperature of 50°-60° C.
Reaction SMILES: [NH2:1][C:2]([N:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12])=[C:3]([C:7]#[N:8])[C:4](=[S:6])[NH2:5].OO.O>C(O)C>[NH2:5][C:4]1[S:6][N:1]=[C:2]([N:9]([CH2:10][CH2:11][CH3:12])[CH2:13][CH2:14][CH3:15])[C:3]=1[C:7]#[N:8]
Reactant: CCCN(CCC)C(N)=C(C#N)C(N)=S
Agent: OO
Solvent: CCO
Solvent: O
Product: CCCN(CCC)c1nsc(N)c1C#N
Temperature: 25 °C
Yield: 73.6 %

Procedure:
A solution of 9.6 g of 3-amino-2-cyano-3-(dipropylamino)propenethioamide in 50 ml of ethanol was heated to reflux temperature and 5 ml of 30% hydrogen peroxide (1.4 g H2O2) were added at such a rate as to maintain reflux. After complete addition the reaction mixture was heated under reflux during 10 minutes. To the reaction mixture was added 40 ml of water, which was then allowed to cool to ambient temperature. The solid precipitate was collected by filtration, and recrystallized from acetonitrile-water, to give 7.0 g of 5-amino-4-cyano-3-(dipropylamino)isothiazole; m.p. 136°-138°. The nmr and ir spectra were consistent with the assigned structure.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.CCN=C=NCCCN(C)C.OC1C2N=NNC=2C=CC=1.[F:33][C:34]([F:50])([F:49])[C:35]1[CH:40]=[CH:39][C:38]([CH2:41][NH2:42])=[C:37]([N:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH:36]=1>CN(C=O)C>[F:49][C:34]([F:33])([F:50])[C:35]1[CH:40]=[CH:39][C:38]([CH2:41][NH:42][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([NH2:1])[C:3]=2[OH:11])=[C:37]([N:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH:36]=1
Reactant: Nc1cccc(C(=O)O)c1O
Reactant: NCc1ccc(C(F)(F)F)cc1N1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: Nc1cccc(C(=O)NCc2ccc(C(F)(F)F)cc2N2CCCCC2)c1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 50.8 %

Procedure:
3-amino-2-hydroxybenzoic acid (1 g, 6.5 mmol) was dissolved in 20 ml of DMF and at 0° C. EDCI (1.4 g, 1.2 equiv.), hydroxybenzotriazole (1 g, 1.2 equiv.) and amine 2c (2 g, 1.2 equiv.) were added. The mixture was stirred at rt for 20 hours. The solvent was evaporated and the crude was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by chromatographic column using AcOEt 1/petroleum ether 9 as eluant gave 1.3 g of a beige solid. Yield=51% [M+1] 393.4 (C20H22F3N3O2 requires 393.4).
Reaction SMILES: N1(O[C:11]2[C:12]3[N:13]=[CH:14][N:15]([C:38]=3[N:39]=[CH:40][N:41]=2)[C@@H:16]2[O:37][C@H:27]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C@@H:18]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:17]2)C2C=CC=CC=2N=N1.[CH2:42]([NH2:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC>[Si:20]([O:19][C@@H:18]1[C@@H:27]([CH2:28][O:29][Si:30]([C:33]([CH3:35])([CH3:36])[CH3:34])([CH3:31])[CH3:32])[O:37][C@@H:16]([N:15]2[C:38]3[N:39]=[CH:40][N:41]=[C:11]([NH:49][CH2:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:12]=3[N:13]=[CH:14]2)[CH2:17]1)([C:23]([CH3:25])([CH3:26])[CH3:24])([CH3:22])[CH3:21]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(On4nnc5ccccc54)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(NCc4ccccc4)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 61.4 %

Procedure:
As described for the synthesis of 6-(morpholin-1-yl)-9-[2-deoxy-3,5-bis-O-(tert-butyldimethylsilyl)-β-D-erythro-pentofuranosyl]purine, the benzyl derivative was prepared by a reaction between O6-(benzotriazol-1-yl)-3′,5′-bis-O-(tert-butyldimethylsilyl)-2′-deoxyinosine (26) (59.8 mg, 0.100 mmol) and benzylamine (21.8 μL, 0.200 mmol) in the presence of Cs2CO3 (65.2 mg, 0.200 mmol) in dry DME (1.0 mL) at room temperature over 6 h. Chromatographic purification (SiO2, elution with 20% EtOAc in hexanes followed by 50% EtOAc in hexanes) afforded 35.0 mg (84% yield) of the title compound as a clear gum. Rf (3% MeOH in CH2Cl2)=0.07. 1H NMR (500 MHz, CDCl3): δ 8.41 (s, 1H, Ar—H), 8.11 (s, 1H, Ar—H), 7.38 (d, 2H, Ar—H, J=7.5), 7.33 (t, 2H, Ar—H, J=7.6), 7.28 (m, 1H, Ar—H), 6.45 (t, 1H, H-1′, J=6.6), 5.98 (br s, 1H, NH), 4.87 (br s, 2H, CH2), 4.61 (m, 1, H-3′), 4.01 (q, 1H, H-4′, J=3.4), 3.87 (dd, 1H, H-5′, J=5.9, 4.4), 3.77 (dd, 1H, H-5′, J=5.9, 4.4), 2.64 (quint, 1H, H-2′. J=6.3), 2.43 (ddd, 1H, H-2′, J=13.2, 6.4, 3.9), 0.91 (s, 18H, tert-Bu), 0.10, 0.09, 0.08 (3 s, 12H, SiCH3). 13C NMR (126 MHz, CDCl3): δ 154.6, 153.1, 138.4, 128.6, 127.8, 127.5, 120.2, 87.8, 84.3, 71.2, 62.8, 41.2, 25.9, 25.8, 18.4, 18.0, −4.7, −4.8, −5.4, −5.5. FAB HRMS calcd for C29H48N5O3Si2 (M++H) 570.3296. found 570.3279.
Reaction SMILES: C1CC(=O)C2C(=CC=CC=2)C1.[CH2:12]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]CC.C1C=CC=CC=1>O>[C:12]1(=[N:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][CH2:20][CH2:21]1
Reactant: CCCCCCCCCCCCNc1ccccc1
Agent: O=C1CCCc2ccccc21
Solvent: O
Solvent: c1ccccc1
Product: c1ccc(N=C2CCCc3ccccc32)cc1

Procedure:
A solution of α-tetralone (50 ml), dodecyl aniline (80 g) and benzene (150 ml) was refluxed in the presence of molecular sieve (100 g) with continuous removal of water. The crude product was crystallized from ethanol to give N-(1,2,3,4-tetrahydronaphthylidene) aniline (XXVI). XXVI had a melting point of 53° C.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(O[CH2:18][CH2:19][C:20]1[CH:35]=[CH:34][C:23]2[O:24][CH2:25][C:26]3[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=3[C:28](=[O:29])[C:22]=2[CH:21]=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].O>CO>[O:29]=[C:28]1[C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[CH2:25][O:24][C:23]2[CH:34]=[CH:35][C:20]([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:8][CH2:9]3)=[CH:21][C:22]1=2
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)OCCc1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C1c2ccccc2COc2ccc(CCN3CCN(c4ccccc4)CC3)cc21
Yield: 31.5 %

Procedure:
A mixture of 6.3 g (0.039 m) of N-phenylpiperazine, 4.32 g (0.013 m) of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)ethanol methanesulfonate of Example 1 and 1.79 g (0.013 m) of K2CO3 in 50 ml of MeOH was refluxed overnight. The reaction mixture was poured into water, extracted with CH2Cl2, dried (Na2SO4), filtered and evaporated to give the crude product (6.5 g). Two recrystallizations from absolute ethanol gave 1.63 g (32%) of crystals of 1-[2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)ethyl]-4-phenylpiperazine, m.p. 107°-108° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[B].[C:22]([O-])(=[O:24])C.[Na+]>CN(C)C=O>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:22]=[O:24])=[C:16]([CH3:20])[CH:15]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(=O)[O-]
Reactant: Cc1cccc(OCc2ccccc2)c1
Agent: [B]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccccc2)ccc1C=O
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 17 %

Procedure:
Dry N,N-dimethylformamide (34.2 ml, 444 mmol) was added dropwise with stirring and cooling under an argon atmosphere to phosphorous oxychloride (18.3 ml, 200 mmol) at such a rate that the temperature did not exceed 10° C. After 30 min stirring at 0° C., a solution of 1-benzyloxy-3-methyl-benzene (22 g, 111 mmol) in N,N-dimethylformamide (22 ml) was added dropwise within 30 min (for the preparation of 1-benzyloxy-3-methyl-benzene see: D. Bogdal, J. Pielichowski, A. Boron, Syn. Commun. 1998, 28, 3029-3039). The reaction mixture was stirred 30 min at ambient temperature and then continuously heated to 110° C. After 10 min at 110° C., the mixture was kept at 90° C. for 3.5 h, cooled to 10° C., neutralized with 25% aqueous sodium acetate, with cooling, and extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate and brine and dried over sodium sulfate. Removal of the solvent under reduced pressure gave a brown oil which was purified by column chromatography (silica gel, hexane/AcOEt=19/1) to give 4.3 g (19 mmol, 17%) of the title compound as yellow solid.
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])(=O)=O.[F:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([N:29]3[CH2:34][CH2:33][CH:32](O)[CH2:31][CH2:30]3)=[N:27][N:28]=2)[CH:25]=1.CCN(CC)CC>CN(C=O)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([N:29]3[CH2:34][CH2:33][CH:32]([O:6][Si:7]([CH:8]([CH3:9])[CH3:10])([CH:11]([CH3:12])[CH3:13])[CH:14]([CH3:15])[CH3:16])[CH2:31][CH2:30]3)=[N:27][N:28]=2)[CH:25]=1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: OC1CCN(c2nnc3ccc(F)cn23)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)[Si](OC1CCN(c2nnc3ccc(F)cn23)CC1)(C(C)C)C(C)C
Reaction time: 1 h

Procedure:
Triisopropylsilyl trifluoromethanesulfonate (395 mg, 1.29 mmol) was added dropwise to a solution of Intermediate 24c (254 mg, 1.07 mmol) and Et3N (0.20 mL, 1.40 mmol) in DMF (3 mL) at RT under N2. The mixture was stirred for 1 h then Et3N (0.10 ml, 0.70 mmol) and triisopropylsilyl trifluoromethanesulfonate (200 mg, 0.65 mmol) were added sequentially, and the mixture stirred for 1 h. The solvent was evaporated, the residue applied to an SCX-2 cartridge and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo left the title compound (339 mg, 80%). LCMS (Method 1): Rt 4.74 min, m/z 393 [MH+].
Reaction SMILES: C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[N:30]1[CH:35]=[C:34]([C:36]([NH:38][C:39]2([C:42]([OH:44])=O)[CH2:41][CH2:40]2)=[O:37])[CH:33]=[N:32][CH:31]=1.[Br:45][C:46]1[CH:60]=[CH:59][C:49]([O:50][C:51]2[CH:58]=[CH:57][C:54]([CH2:55][NH2:56])=[CH:53][CH:52]=2)=[C:48]([Cl:61])[CH:47]=1>CN(C=O)C>[Br:45][C:46]1[CH:60]=[CH:59][C:49]([O:50][C:51]2[CH:58]=[CH:57][C:54]([CH2:55][NH:56][C:42]([C:39]3([NH:38][C:36]([C:34]4[CH:33]=[N:32][CH:31]=[N:30][CH:35]=4)=[O:37])[CH2:40][CH2:41]3)=[O:44])=[CH:53][CH:52]=2)=[C:48]([Cl:61])[CH:47]=1
Reactant: NCc1ccc(Oc2ccc(Br)cc2Cl)cc1
Reactant: O=C(NC1(C(=O)O)CC1)c1cncnc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NC1(C(=O)NCc2ccc(Oc3ccc(Br)cc3Cl)cc2)CC1)c1cncnc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
7 μL (0.05 mmol) of triethylamine and 8.4 mg (0.03 mmol) of TBTU were added to a solution of 5.4 mg (0.03 mmol) of 1-[(pyrimidin-5-carbonyl)-amino]-cyclo-propanecarboxylic acid (from 1b) in 1 mL DMF and stirred for 5 min at RT. Then 8 mg (0.03 mmol) of 4-(4-bromo-2-chloro-phenoxy)-benzylamine was added and the mixture was stirred overnight at ambient temperature. The reaction mixture was purified by chromatography (reversed phase).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:12]([CH3:13])=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[CH3:14].[NH2:15][C:16]1[CH:31]=[CH:30][CH:29]=[CH:28][C:17]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)=[O:19].S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C.O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([N:20]2[C:18](=[O:19])[C:17]3[C:16](=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:15]=[C:9]2[C:8]2[CH:11]=[C:12]([CH3:13])[C:5]([O:4][CH2:3][CH2:2][OH:1])=[C:6]([CH3:14])[CH:7]=2)=[CH:22][CH:23]=1
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cc1
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(Cl)cc2)cc(C)c1OCCO
Temperature: 155 °C

Procedure:
To a mixture of 4-(2-hydroxyethoxy)-3,5-dimethyl-benzaldehyde (0.420 g, 2.17 mmol) and 2-amino-N-(4-chloro-phenyl)-benzamide (0.500 g, 2.17 mmol) in N,N-dimethylacetamide (5 mL) was added sodium hydrogensulfite (0.350 g, 3.26 mmol) and p-toluenesulfonic acid (0.21 g, 0.11 mmol). The reaction mixture was heated at 155° C. for 14 hours, cooled to room temperature, and diluted with cold water (20 mL), to produce the precipitate. The yellow solid was filtered, washed with cold water, then methanol, and dried under vacuum to provide crude product, which was purified by preparative HPLC (0.1% TFA in CH3CN/H2O as eluent) to give the title compound as a white solid. Yield: 0.23 g (14%). MP 101-103° C. 1H-NMR (400 MHz, CDCl3): δ 8.38 (d, 1H), 7.81-7.78 (m, 2H), 7.59-7.51 (m, 1H), 7.31-7.20 (m, 2H), 7.15-7.12 (m, 2H), 7.01-6.98 (d, 2H), 3.98-3.80 (m, 4H), 2.20 (s, 6H), 2.01 (t, 1H). MS (ES+) m/z: 421.05 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[O:30]1[C:34]2([CH2:39][CH2:38][NH+:37]([CH2:40][B-](F)(F)F)[CH2:36][CH2:35]2)[CH2:33][CH2:32][CH2:31]1>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:40][N:37]5[CH2:36][CH2:35][C:34]6([O:30][CH2:31][CH2:32][CH2:33]6)[CH2:39][CH2:38]5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Reactant: F[B-](F)(F)C[NH+]1CCC2(CCCO2)CC1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCC4(CCCO4)CC3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and (1-oxa-8-azonia-spiro[4.5]dec-8-yl)methyltrifluoroborate following a procedure analogous to that described for Intermediate 3. LC (method 1): tR=0.93 min; Mass spectrum (ESI+): m/z=546 [M+H]+.
Reaction SMILES: N1CCCNC[CH2:2]1.N1CCNCC1.[N:14]1([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.Cl>C=O.CO.C(O)=O>[CH3:2][N:17]1[CH2:18][CH2:19][CH2:20][N:14]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:15][CH2:16]1
Reactant: c1ccc(Oc2cnccc2N2CCCNCC2)cc1
Reactant: C1CNCCNC1
Agent: C1CNCCN1
Agent: C=O
Agent: Cl
Solvent: O=CO
Solvent: CO
Product: CN1CCCN(c2ccncc2Oc2ccccc2)CC1
Temperature: 100 °C

Procedure:
By substituting 30 g of hexahydro-1H-1,4-diazepine for the piperazine in Example 1, the product is 4-(hexahydro-1H-1,4-diazepin-1-yl)-3-phenoxy pyridine, bp 143°-145° C./0.13 mm). Three and four tenths g of this material is dissolved in a mixture of 4.5 g 37% formalin and 2 ml of methanol and is treated with 6 g of 97-100% formic acid. The mixture is heated at 100° C. for 18 hours. The mixture is cooled, treated with an excess of dilute hydrochloric acid and concentrated in vacuo. The residue is shaken with 100 ml of toluene and excess dilute aqueous sodium hydroxide. The organic phase is dried, concentrated and distilled to give 4-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)-3-phenoxypyridine; bp 130°-131° C./0.1 mm.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C@@H:26]4[CH2:30][CH2:29][CH2:28][NH:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:31])[NH:6]2.ClC(Cl)(Cl)[C:34]([N:36]=C=O)=[O:35]>N1C=CC=CC=1>[C:34]([N:27]1[CH2:28][CH2:29][CH2:30][C@H:26]1[CH2:25][O:24][C:18]1[CH:17]=[C:16]2[C:21]([C:12]([O:11][C:10]3[C:2]([F:1])=[C:3]4[C:7](=[CH:8][CH:9]=3)[NH:6][C:5]([CH3:31])=[CH:4]4)=[N:13][CH:14]=[N:15]2)=[CH:20][C:19]=1[O:22][CH3:23])(=[O:35])[NH2:36]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@@H]1CCCN1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@@H]1CCCN1C(N)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(2S)-pyrrolidin-2-ylmethoxy]quinazoline (60 mg, 0.14 mmol), (prepared as described for the starting material in Example 12), was dissolved in pyridine (3 ml) and cooled to 0° C. Trichloroacetyl isocyanate (17 μl, 0.14 mmol) was added and the mixture stirred for 2 hours. The solvent was removed under reduced pressure and the residue dissolved in 7N ammonia in methanol and stirred at ambient temperature overnight and then at 50° C. for 2 hours. The solvent was removed under reduced pressure. Column chromatography of the residue (2% to 5% methanol/dichloromethane) gave 7-[(2S)-1-carbamoylpyrrolidin-2-ylmethoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (40 mg, 69%) as a yellow solid.
Reaction SMILES: CN=C=O.[C:5]1([C:11]2[C:19]([CH:20]=[N:21]O)=[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]3[N:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(Cl)Cl.C(Cl)(Cl)Cl>[C:5]1([C:11]2[C:19]([C:20]#[N:21])=[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]3[N:12]=2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: ON=Cc1c(-c2ccccc2)nn2ccccc12
Agent: CN=C=O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: N#Cc1c(-c2ccccc2)nn2ccccc12
Reaction time: 8 h
Yield: 43.7 %

Procedure:
A solution of methyl isocyanate (0.19 g) in methylene chloride (2 ml) was added dropwise to a mixture of 2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde oxime (0.52 g) in chloroform (4 ml) with stirring and ice-cooling. The mixture was stirred at room temperature for 2 hours and allowed to stand at room temperature overnight. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel (20 g) with methylene chloride as an eluent The fractions containing the object compound were combined (20 ml) and evaporated in vacuo. The residue was recrystallized from ethyl acetate to give 2-phenylpyrazolo[1,5-a]pyridine-3-carbonitrile (0.21 g).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][C:3]=1[F:10].[CH3:11][C:12]1[NH:13][CH:14]=[CH:15][N:16]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C)C=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH3:11])=[CH:4][C:3]=1[F:10]
Reactant: Fc1cc(CBr)ccc1Br
Reactant: Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nccn1Cc1ccc(Br)c(F)c1
Reaction time: 2 h

Procedure:
To a solution of the product from Step A (ca. 42 mmol) in 50 mL of dimethylformamide was added 2-methylimidazole (3.47 g, 82.1 mmol) and potassium carbonate (7.53 g, 54.6 mmol). After stirring for two hours, the mixture was poured into EtOAc and washed with saturated NaHCO3 solution and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting solid was taken up in 100 mL of EtOAc, and excess HCl gas was bubbled through the solution. The precipitate was removed by filtration, partitioned between dichloromethane and dilute NaHCO3 solution, and the water phase was extracted repeatedly with dichloromethane. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to provide the desired product as a pale yellow oil.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)=[CH:10][CH:11]=2)[NH:6][CH:5]=1.Cl[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([S:29][CH3:30])[N:24]=1.O>CN(C=O)C>[Br:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)=[CH:10][CH:11]=2)[N:6]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([S:29][CH3:30])[N:24]=2)[CH:5]=1
Reactant: CSc1nccc(Cl)n1
Reactant: O=[N+]([O-])c1cccc(-c2ccc3c(Br)c[nH]c3c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nccc(-n2cc(Br)c3ccc(-c4cccc([N+](=O)[O-])c4)cc32)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.7 %

Procedure:
Sodium hydride (60% in mineral oil, 38 mg, 0.946 mmol) was added to a mixture solution of 3-bromo-6-(3-nitrophenyl)-1H-indole (100 mg, 0.315 mmol) in anhydrous DMF (2 mL) at room temperature. 10 minutes later, 4-chloro-2-(methylthio)pyrimidine (44 μL, 0.378 mmol) was added. After stirring at room temperature for 2 hours, water was added. Thus produced solid was filtered and dried. The target compound (140 mg) was obtained as white solid.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([C:7]2[N:8]=[CH:9][C:10]([NH:13][C:14](=[O:37])[C@@H:15]([N:20]3[CH2:24][C:23]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH3:34])[C:27]=4[F:35])=[CH:22][C:21]3=[O:36])[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:11][CH:12]=2)[CH2:4][O:3]1.Cl>O1CCCC1.C(OCC)(=O)C>[OH:6][C@@H:5]([C:7]1[N:8]=[CH:9][C:10]([NH:13][C:14](=[O:37])[C@@H:15]([N:20]2[CH2:24][C:23]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH3:34])[C:27]=3[F:35])=[CH:22][C:21]2=[O:36])[CH2:16][CH:17]([CH3:18])[CH3:19])=[N:11][CH:12]=1)[CH2:4][OH:3]
Reactant: CCOc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3cnc([C@H]4COC(C)(C)O4)cn3)C2)c1F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3cnc([C@H](O)CO)cn3)C2)c1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 67.5 %

Procedure:
A solution of (S)-2-[4-(3-ethoxy-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [5-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-yl]-amide (prepared in Example 150, 0.300 g, 0.57 mmol) in tetrahydrofuran (20 mL) was treated with 1N aqueous hydrochloric acid (10 mL). The reaction mixture was stirred for 20 h at room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate, a saturated sodium chloride solution and dried over magnesium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g; 10% to 100% (9:1 dichloromethane:methanol)/hexanes) to afford (S)-2-[4-(3-ethoxy-2-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [5-((S)-1,2-dihydroxy-ethyl)-pyrazin-2-yl]-amide (0.188 g, 68%) as a fluffy white solid: HR-ES-MS m/z calculated for C24H29FN4O6, [M+H]+ 489.2144 observed 489.2143; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.92 (d, J=6.9 Hz, 3H), 0.95 (d, J=6.9 Hz, 3H), 1.36 (t, J=6.9 Hz, 3H), 1.42-1.57 (m, 1H), 1.57-1.73 (m, 1H), 1.74-1.90 (m, 1H), 3.47-3.61 (m, 1H), 3.68 (dt, J=10.8, 5.3 Hz, 1H), 4.15 (q, J=6.9 Hz, 2H), 4.26 (d, J=18.4 Hz, 1H), 4.53-4.68 (m, 2H), 4.73 (t, J=5.7 Hz, 1H), 4.92 (s, 1H), 5.03 (dd, J=10.6, 4.2 Hz, 1H), 5.55 (d, J=4.8 Hz, 1H), 6.98-7.08 (m, 1H), 7.08-7.25 (m, 2H), 8.45 (s, 1H), 9.17 (s, 1H), 11.15 (s, 1H).
Reaction SMILES: [C:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH:7]([CH2:11][CH2:12][S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:6][C:5]1=[O:24])(=[O:3])[CH3:2].[OH:25]O.O>C(O)(=O)C>[C:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH:7]([CH2:11][CH2:12][S:13]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:18][CH:19]=2)=[O:25])[CH2:6][C:5]1=[O:24])(=[O:3])[CH3:2]
Reactant: OO
Reactant: CC(=O)C1C(=O)CC(CCSc2ccc(C(F)(F)F)cc2)CC1=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)C1C(=O)CC(CCS(=O)c2ccc(C(F)(F)F)cc2)CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a solution of 2.3 g of 2-acetyl-5-[2-(4-trifluoromethylphenylthio)ethyl]cyclohexane-1,3-dione in 10 ml of acetic acid, 1.8 g of 30% H2O2 was dropped under cooling with ice-water bath. After stirring for 1 hour at room temperature, the reaction solution was poured into water and extracted with ethyl acetate. Removal of solvent afforded 1.83 g of 2-acetyl-5-[2-(4-trifluoromethylphenylsulfinyl)ethyl]cyclohexane-1,3-dione. m.p. 99°-100° C.