Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:28])[C@H:9]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH:10]C(OCC2C=CC=CC=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCCCC=1>C(O)C.[Pd]>[C:1]1([NH:7][C:8](=[O:28])[C@H:9]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH2:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)Nc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: N[C@@H](Cc1ccccc1)C(=O)Nc1ccccc1

Procedure:
Nα -Benzyloxycarbonyl-L-phenylalanine-N-phenylamide (2.50 g, 6.68 mmol) was dissolved in ethanol (20 ml) and cyclohexene (5 ml) and 10% palladium on charcoal (250 mg) was added. The mixture was heated at reflux for 1 hour after which time no starting material was detectable (as indicated by TLC analysis). The catalyst was removed by filtration and the solvent evaporated to leave the title compound contaminated with residual ethanol (1.74 g). 1H-NMR; d (CD3OD), 7.45 (2H, m), 7.18 (7H, m), 7.04 (1H, m), 3.56 (1H, m), 3.04 (1H, dd, J=6.4, 13.3 Hz) and 2.85 (1H, dd, J=7.2, 13.3 Hz).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:32])[CH2:23][C:24]([C:26]1[S:27][CH:28]=[CH:29][C:30]=1[Cl:31])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:31][C:30]1[CH:29]=[CH:28][S:27][C:26]=1[C:24]1[CH2:23][C:22](=[O:32])[NH:21][C:9]2[CH:10]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:12]=[CH:13][C:8]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1sccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2sccc2Cl)=Nc2ccc(-c3ccc(F)cc3)cc2N1

Procedure:
Prepared from {3-[3-(3-chloro-thiophen-2-yl)-3-oxo-propionylamino]-4′-fluoro-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K61) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (232 mg).
Reaction SMILES: [C:1]1([OH:9])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[CH:2]=1.[S]Cl.C[S-].[Na+].[OH-].[Na+].C[S:18]SC.Cl>C(COC)OC>[SH:18][C:4]1[C:5]([CH3:7])=[CH:6][C:1]([OH:9])=[CH:2][C:3]=1[CH3:8]
Reactant: Cc1cc(C)cc(O)c1
Reactant: CSSC
Agent: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cc(O)cc(C)c1S
Reaction time: 0.03 h
Yield: 93 %

Procedure:
61 grams (0.5 mole) of 3,5-xylenol dissolved in 250 cc glyme was added to 67 grams (0.5 mole) of sulfur monochloride dissolved in 200 cc glyme at room temperature. The temperature rose immediately to about 50° C. After 2 minutes, the reaction mixture was poured into 2400 grams of an aqueous solution of about 227 grams (3.4 moles) of sodium methyl mercaptide and 217 grams (5.4 moles) of sodium hydroxide. The mixture was then heated to its boiling point. After the glyme and dimethyl disulfide had boiled off, the mixture was acidified with concentrated hydrochloric acid to precipitate a pale yellow oil which crystallized rapidly to a colorless solid. A 93% yield of 4-mercapto-3,5-xylenol was obtained.
Reaction SMILES: CC(C)([O-])C.[K+].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][C:17]([NH2:19])=[O:18])=[CH:8]1.C([O:22][C:23](=O)[C:24]([C:26]1[N:30]2[CH:31]=[C:32]([C:35]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[O:36][SiH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[N:33]=[CH:34][C:29]2=[N:28][C:27]=1[CH3:54])=O)C.[NH4+].[Cl-].C1CCN2C(=NCCC2)CC1>O1CCCC1.CCOC(C)=O.O>[C:38]([SiH2:37][O:36][C:35]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:32]1[N:33]=[CH:34][C:29]2[N:30]([C:26]([C:24]3[C:23](=[O:22])[NH:19][C:17](=[O:18])[C:16]=3[C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[NH:7][CH:8]=3)=[C:27]([CH3:54])[N:28]=2)[CH:31]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CCOC(=O)C(=O)c1c(C)nc2cnc(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)cn12
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1nc2cnc(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)cn2c1C1=C(c2c[nH]c3ccccc23)C(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Potassium tert-butoxide (1.0 M in THF, 0.86 ml, 0.86 mmol, 3.0 equiv) is added dropwise at room temperature under an atmosphere of argon to a solution of 2-(1H-indol-3-yl)-acetamide (50 mg, 0.29 mmol, 1.0 equiv) and of [6-(tert-butyl-diphenyl-silanyloxymethyl)-2-methyl-imidazo[1,2-a]pyrazin-3-yl]-oxo-acetic acid ethyl ester (158 mg, 0.32 mmol, 1.0 equiv) in anhydrous tetrahydrofuran (1.0 ml, dried over molecular sieves). The reaction mixture is stirred for 15 minutes at room temperature. It is then diluted with EtOAc and poured into a saturated aqueous NH4Cl solution. After three extractions with EtOAc, the combined organic layers are dried over Na2SO4, filtered and concentrated in vacuo. The residue is dissolved in N,N-dimethylformamide (1.0 ml), treated with DBU (0.43 ml, 2.9 mmol, 10 equiv) and stirred under an atmosphere of argon for 5 minutes at 110° C. After cooling, the reaction mixture is diluted with water and extracted three times with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated in vacuo.
Reaction SMILES: [CH:1]([Si:4]([CH:36]([CH3:38])[CH3:37])([CH:33]([CH3:35])[CH3:34])[O:5][CH2:6][C@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12]1[N:16]2[CH:17]=[C:18]([O:21][C@H:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C@@H:25]([NH2:32])[CH2:24][CH2:23]3)[CH:19]=[CH:20][C:15]2=[N:14][N:13]=1)([CH3:3])[CH3:2].ClC(Cl)(Cl)C[O:42][C:43](=O)[NH:44][C:45]1[N:46]([C:54]2[CH:59]=[CH:58][C:57]([CH3:60])=[CH:56][CH:55]=2)[N:47]=[C:48]([C:50]([CH3:53])([CH3:52])[CH3:51])[CH:49]=1.CCN(C(C)C)C(C)C.N>CN(C=O)C.CO.C(Cl)Cl>[C:50]([C:48]1[CH:49]=[C:45]([NH:44][C:43]([NH:32][C@@H:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@H:22]([O:21][C:18]3[CH:19]=[CH:20][C:15]4[N:16]([C:12]([N:8]5[CH2:9][CH2:10][CH2:11][C@@H:7]5[CH2:6][O:5][Si:4]([CH:1]([CH3:2])[CH3:3])([CH:33]([CH3:35])[CH3:34])[CH:36]([CH3:38])[CH3:37])=[N:13][N:14]=4)[CH:17]=3)[CH2:23][CH2:24]2)=[O:42])[N:46]([C:54]2[CH:59]=[CH:58][C:57]([CH3:60])=[CH:56][CH:55]=2)[N:47]=1)([CH3:53])([CH3:51])[CH3:52]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CC(C)[Si](OC[C@H]1CCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12)(C(C)C)C(C)C
Agent: N
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCC[C@@H]5CO[Si](C(C)C)(C(C)C)C(C)C)n4c3)c3ccccc32)cc1
Yield: 36 %

Procedure:
A solution of Intermediate 27c (50 mg, 0.093 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 56 mg, 0.140 mmol) and DIPEA (70 mg, 0.54 mmol) in DMF (2 mL) was stirred at 60° C. for 1 h. The reaction mixture was applied to an SCX-2 cartridge (5 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM, gave the title compound as an off-white foam (27 mg, 36%). LCMS (Method 4): Rt 4.58, m/z 791 [MH+].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][N:13]=NN=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:15]1([C:21](Cl)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>N1C=CC=CC=1>[CH:15]1([C:21]2[O:22][C:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)=[N:14][N:13]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1ccc(-c2nnn[nH]2)cc1
Reactant: O=C(Cl)C1CCCCC1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(-c2nnc(C3CCCCC3)o2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 69.8 %

Procedure:
A mixture of 5-(4-nitro-phenyl)-1H-tetrazole (0.5 g, 2.62 mmol) and cyclohexane carbonyl chloride (0.35 ml, 2.62 mmol) in 3 ml anhydrous pyridine was stirred at room temperature under nitrogen for 20 min, then heated to 60° C. for 1 hr and finally heated to 100° C. for 2 h. The reaction mixture was cooled to room temperature then poured onto ice (30 g) and the aqueous mixture was extracted with 30 ml ethyl acetate. The ethyl acetate solution was washed sequentially with 30 ml water, 30 ml 1N aqueous hydrochloric acid solution and 30 ml brine, dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The crude produce was purified by flash column chromatography (silica gel, 40 g), eluting with 4:1 hexane/ethyl acetate to yield the title compound as a yellowish solid (0.5 g, 100% yield). MS: 274.2 (M+1)
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:91]=[CH:92][CH:93]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:70]=[CH:69][C:68]([N:71]5[CH2:76][CH2:75][N:74]([CH2:77][C@H:78]([OH:80])[CH3:79])[CH2:73][CH2:72]5)=[CH:67][CH:66]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:91]=[CH:92][CH:93]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([N:71]5[CH2:72][CH2:73][N:74]([CH2:77][C@H:78]([OH:80])[CH3:79])[CH2:75][CH2:76]5)=[CH:69][CH:70]=4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C[C@@H](C)O)CC5)cc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cc2)CC1
Yield: 28.6 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, (R)-1-(4-(4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-1-yl)propan-2-ol (160 mg, 0.24 mmol) was hydrolyzed by lithium hydroxide (50 mg, 1.2 mmol) in THF/methanol/water (3/2/1 ml) to afford 35 mg (28.6% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.58-8.57 (d, 1H), 8.53 (s, 1H), 8.24 (s, 1H), 7.969-7.967 (d, 1H), 7.74 (s, 1H), 7.71-7.68 (d, 2H), 7.41-7.35 (m, 1H), 7.19-7.16 (d, 2H), 7.13-7.00 (m, 3H), 5.44 (s, 2H), 4.28-4.21 (m, 1H), 3.90-3.60 (m, 4H), 3.28-3.09 (m, 4H), 1.28-1.26 (d, 3H). MS: m/z=511.3 (M+1), HPLC: 95.39% in method B.
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([S:26](Cl)(=[O:28])=[O:27])[CH3:25]>N1C=CC=CC=1>[CH2:17]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[C:10]([CH3:16])=[C:11]([NH:15][S:26]([CH2:24][CH3:25])(=[O:28])=[O:27])[CH:12]=[CH:13][CH:14]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1c(N)cccc1N(Cc1ccccc1)Cc1ccccc1
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cccc(N(Cc2ccccc2)Cc2ccccc2)c1C

Procedure:
The product from Example 2B (0.03 g, 0.1 mmoles) in pyridine (2 mL) at 0° C. was treated with ethanesulfonyl chloride (0.01 g, 0.12 mmoles). The reaction mixture was quenched after 1 hour with water (2 mL), extracted with diethyl ether (5 mL), washed with water (2×2 mL), rinsed with brine (2 mL), dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by preparative HPLC (CH3CN:0.1% TFA in H2O) on a YMC ODS Guardpak column to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ1.22 (t, 3H, J=7.3 Hz), 2.40 (s, 3H), 3.02 (dd, 2H, J=14.6, 7.5 Hz), 4.05 (s, 4H), 6.94 (m, 2H), 7.01 (m, 1H), 7.20 (m, 2H), 7.27 (m, 7H), 8.92 (s, 1H); MS (APCI+) m/z 395 (M+H)+.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH3:34])[C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:25])[CH:18]=2)[CH:7]=[C:8]([F:16])[C:9]=1/[CH:10]=[CH:11]/[C:12]([O:14]C)=[O:13]>O1CCCC1.CO>[F:3][C:4]1[CH:5]=[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH3:34])[C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:25])[CH:18]=2)[CH:7]=[C:8]([F:16])[C:9]=1/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2cc(F)c(/C=C/C(=O)OC)c(F)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2cc(F)c(/C=C/C(=O)O)c(F)c2)c1
Yield: 74 %

Procedure:
In a manner similar to that of Example (19g), by reaction of 400 mg (10 mmol, 7.0 eq) of sodium hydroxide and 630 mg (1.41 mmol, 1 eq) of methyl (E)-3-[3,5-difluoro-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]acrylate in 15 ml of a tetrahydrofuran/methanol mixture (8/2), and after crystallization from dichloromethane/heptane, 450 mg of (E)-3-[3,5-difluoro-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]acrylic acid are obtained in the form of a white powder (m.p.=136° C.). Yield=74%
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:10])[CH3:9])=[N:6][CH:7]=1.[Li]CCCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.CO>C1COCC1>[CH3:9][N:8]([CH3:10])[C:5]1[N:6]=[CH:7][C:2]([B:16]([OH:21])[OH:17])=[CH:3][CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CN(C)c1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)c1ccc(B(O)O)cn1
Temperature: -72 °C
Reaction time: 1 h

Procedure:
A solution of 5-bromo-N,N-dimethylpyridin-2-amine (500 mg, 2.5 mmol) in THF (10 mL) was treated with n-BuLi (1.2 mL, 3 mmol) at −72° C. for 2 hours. Triisopropyl borate (705 mg, 3.75 mmol) was then added dropwise. After the completion of the addition, the mixture was stirred at −72° C. for an additional 1 hour and slowly warmed up and stirred at the ambient temperature overnight. MeOH was carefully added, and the volatiles were removed under reduced pressure to give the title compound. MS (m/z): 167 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][C:20]([CH3:28])([CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:21]#[N:22]>>[C:21]([C:20]([NH:19][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])([CH3:28])[CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])#[N:22]
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Reactant: CC(N)(C#N)CS(C)(=O)=O
Product: CC(C#N)(CS(C)(=O)=O)NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and 2-Amino-3-methanesulfonyl-2-methyl-propionitrile (example 80a) as starting materials and isolated (1.22 g, 98%); MS (ESI, m/z): 406.6 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=[N:13][OH:14])[CH2:7][CH:6]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH2:5][C:4]=2[N:3]=1.[H-].[Na+].[CH3:30][N:31]([CH3:62])[CH2:32][CH2:33][CH2:34]ON=C1CC(C2C=C(F)C=CC=2C2C=CC=CC=2)CC2N=C(N)N=C(C)C1=2>O>[CH3:30][N:31]([CH3:62])[CH2:32][CH2:33][CH2:34][O:14][N:13]=[C:8]1[CH2:7][CH:6]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH2:5][C:4]2[N:3]=[C:2]([NH2:1])[N:11]=[C:10]([CH3:12])[C:9]1=2
Reactant: Cc1nc(N)nc2c1C(=NOCCCN(C)C)CC(c1cc(F)ccc1-c1ccccc1)C2
Reactant: Cc1nc(N)nc2c1C(=NO)CC(c1ccc(F)cc1-c1cccnc1)C2
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1nc(N)nc2c1C(=NOCCCN(C)C)CC(c1ccc(F)cc1-c1cccnc1)C2

Procedure:
The title compound was prepared from 2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime, compound 89, (100 mg, 0.275 mmol), 3-dimethyl-aminopropyl chloride hydrochloride (52 mg, 0.330 mmol) and sodium hydride (60% dispersion in oil) (35 mg, 0.881 mmol) following the same procedure used for 2-amino-7-(4-fluoro-biphenyl-2-yl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O-(3-dimethylamino-propyl)-oxime (compound 88) except after addition of water the solvent was removed under reduced pressure. The crude material was then extracted with ethyl acetate (20 ml), filtered and the resulting organic phase was concentrated under reduced pressure. The resulting material was washed with diethyl ether yielding the title compound.
Reaction SMILES: [O:1]=[C:2]([CH3:10])[CH2:3]P(=O)(OC)OC.[Li+].[Cl-].[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([CH:23]=O)[CH:14]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([CH:23]=[CH:3][C:2](=[O:1])[CH3:10])[CH:14]=1
Reactant: COP(=O)(CC(C)=O)OC
Reactant: O=Cc1cnc2ccccc2c1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)C=Cc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dimethyl (2-oxopropyl)phosphonate (3.1 g,19.1 mmol), anhydrous LiCl (972 mg, 23 mmol), and 3-quinoline carboxaldehyde 6-1 (3.0 g,19.1 mmol) in anhydrous acetonitrile (70 mL), was treated with DBU (2.9 mL, 19.1 mmol) and the resulting suspension stirred at room temperature for 1 h. The solvent was removed at reduced pressure and the resulting residue partitioned between brine and methylene chloride. The organic layer was removed, dried, and concentrated to afford a yellow solid which was recrystallized from ethyl acetate/hexanes to afford 22-1 as an off-white solid.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:15][CH2:14]1.C(=O)([O-])N.[K+]>CN(C=O)C>[C:22]([O:21][C:20](=[O:26])[NH:19][CH:16]1[CH2:17][CH2:18][N:13]([C:2]2[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=2)[CH2:14][CH2:15]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: NC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(c2ncc(C(F)(F)F)cc2Cl)CC1
Temperature: 150 °C
Yield: 71.1 %

Procedure:
A mixture of 2,3-dichloro-5-(trifluoromethyl)pyridine (2.0 g, 9.26 mmol), tert-butyl piperidine-4-ylcarbamate (2.2 g, 11.11 mmol) and anhydrous potassium carbamate (3.8 g, 27.78 mmol) in DMF (15 ml) was heated in a microwave reactor at 150° C. for 10 min. The mixture was concentrated, water and EtOAc were added to the residue and the aqueous phase was extracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated. The crude product was purified by flash column chromatography (hexane/EtOAc 90:10) to yield the title compound (2.5 g, 70%). 1H NMR (500 MHz, CDCl3): δ 1.47 s, 9H), 1.53-1.60 (m, 2H), 2.07-2.09 (m, 2H), 3.01-3.06 (m, 2H), 3.72 (br.s., 1H), 3.97-4.00 (m, 2H, 4.54 (br.s., 1H), 7.75 (s, 1H), 8.38 (s, 1H); Mass Spectrum: M+H+ 380.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:25]=[N:26][C:27]([CH:30]=O)=[CH:28][CH:29]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.CC(O)=O.[NH2:37][CH2:38][CH2:39][CH2:40][C:41]([OH:43])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C.O>[CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:25]=[N:26][C:27]([CH2:30][N:37]6[CH2:38][CH2:39][CH2:40][C:41]6=[O:43])=[CH:28][CH:29]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: NCCCC(=O)O
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCCC5=O)nc4)sc23)c(F)c1)NC1CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 3.6 %

Procedure:
To a stirred solution of aldehyde 282 (0.5 g, 1.115 mmol) and AcOH (128 μl, 2.23 mmol) in DMF (10 mL) was added 4-aminobutyric acid (345 mg, 3.34 mmol). After 40 min, sodium triacetoxyborohydride (945 mg, 4.46 mmol) was added and the reaction was stirred at RT for 22 h. The reaction mixture was then diluted with water to form a precipitate that was collected by filtration, dried under vacuum and purified by Biotage (SNAP 50 g cartridge; 2% of ammonium hydroxide in MeOH/DCM: 0/100 to 15/85 over 20 CV) and by Gilson (Phenomenex, Luna 15 μl, C18(2) 100A, 250×50.0 mm, 15 μm; 0.05% of formic acid in both MeOH/water:30/80 to 95/5 over 60 min, flow; 30 mL/min), to afford the title compound 283 (20 mg, 0.04 mmol, 3% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.28 (s, 1H), 9.06 (d, J=2.4 Hz, 1H), 8.53 (d, J=5.6 Hz, 1H), 8.42 (bs, 1H), 8.26 (dd, J=2.4 and 8.0 Hz, 1H), 8.25 (s, 1H), 7.74 (dd, J=2.0 and 13.6 Hz, 1H), 7.41-7.34 (m, 2H), 7.24-7.20 (m, 1H), 7.08 (bs, 1H), 6.62 (d, J=5.6 Hz, 1H), 4.53 (s, 2H), 2.58-2.51 (m, 1H), 2.32 (t, J=8.0 Hz, 2H), 1.98 (quin, J=7.2 Hz, 2H), 0.65-0.60 (m, 2H), 0.45-0.40 (m, 2H). MS (m/z): 518.5 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[S:11]([F:14])(=[O:13])=[O:12]>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[S:11]([F:14])(=[O:12])=[O:13]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)F)c1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1ccc(Cl)c(S(=O)(=O)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The 2-chloro-5-nitro benzene sulphonylfluoride (2.4 parts) was stirred. in glacial acetic acid (25 parts) with iron powder (2 parts). Heated to reflux and stirred at reflux for 2.5 hours, then cooled to room temperature, poured onto ice/water and allowed to stand at room temperature overnight. The resultant precipitate was filtered off and dried in air to yield the product 2-chloro-5-amino benzene sulphonylfluoride (0.8 parts).
Reaction SMILES: CC12C3(C)[N:6]4[CH:7]([CH2:17][OH:18])[CH2:8][N:9]3[CH2:10][CH2:11][N:12]1[CH2:13][CH2:14][N:3]2[CH2:4][CH2:5]4.Cl>C(O)C>[NH:6]1[CH2:5][CH2:4][NH:3][CH2:14][CH2:13][NH:12][CH2:11][CH2:10][NH:9][CH2:8][CH:7]1[CH2:17][OH:18]
Reactant: CC12N3CCN1CCN1C(CO)CN(CC3)C12C
Agent: Cl
Solvent: CCO
Product: OCC1CNCCNCCNCCN1

Procedure:
A solution of 1.00 g (3.99 mmol) of compound 10 obtained in the preceding stage in 50 ml of absolute ethanol is brought to reflux. 10 ml of a 35% aqueous hydrochloric acid solution are added in small amounts. Reflux is maintained for 48 hours. After evaporation of the solvents, the residue is taken up in the minimum amount of ice-cold ethanol. The precipitate formed is filtered off and washed with ice-cold methanol. The filtrate is evaporated and then the residue is taken up in the minimum amount of methanol. The precipitate formed is filtered off and washed with ice-cold methanol. Compound 11·4HCl is isolated in the form of a white powder (0.80 g, Yd =57%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([C:15]([O:17]CC)=O)[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1>CC(C)CCN>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([C:15](=[O:17])[NH:12][CH2:13][CH2:14][CH:7]([CH3:8])[CH3:6])[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: CCOC(=O)c1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Agent: CC(C)CCN
Product: CC(C)CCNC(=O)c1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1

Procedure:
95 mg (0.30 mmol) of 4-(3-chloro-anilino)-6-ethoxycarbonyl-7H-pyrrolo[2,3-d]pyrimidine in 1 ml of (3-methyl-but-1-yl)-amine are heated at 80° C. for 12 hours. The reaction mixture is concentrated by evaporation, the residue is dissolved in THF, concentrated by evaporation again, stirred with diethyl ether and filtered, yielding the title compound; m.p. 304-306° C.; FAB-MS: (M+H)+ =358.
Reaction SMILES: F[C:2]1[C:3]([F:21])=[CH:4][C:5]2[S:9][C:8]([CH2:10][O:11][C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[CH2:15][OH:16])=[N:7][C:6]=2[CH:20]=1.FC1C=CC2SC(COC3C=C(C=CC=3)CO)=NC=2C=1.ClC1C=C2C(C=CC(COC3C=C(C=CC=3)CO)=N2)=CC=1.N1C=CC=CC=1COC1C=C(C=CC=1)CO>>[F:21][C:3]1[CH:2]=[CH:20][C:6]2[N:7]=[C:8]([CH2:10][O:11][C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[CH2:15][OH:16])[S:9][C:5]=2[CH:4]=1
Reactant: OCc1cccc(OCc2nc3cc(F)c(F)cc3s2)c1
Agent: OCc1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Agent: OCc1cccc(OCc2ccccn2)c1
Agent: OCc1cccc(OCc2nc3cc(F)ccc3s2)c1
Product: OCc1cccc(OCc2nc3ccc(F)cc3s2)c1

Procedure:
By a similar procedure 3-(5,6-difluorobenzothiazol-2-ylmethyloxy)benzyl alcohol, m.p. 98°-100° C., 3-(5-fluorobenzothiazol-2-ylmethoxy)benzyl alcohol, m.p. 139°-140° C., 3-(7-chloroquinol-2-ylmethoxy)benzyl alcohol, m.p. 128°-129° C., and 3-(2-pyridylmethoxy)benzyl alcohol, NMR (300 MHz, CDCl3) 5.10 (s, 2H) were prepared.