Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[N:14][OH:15])[C:10]([NH:12][CH3:13])=[O:11].[C:16](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.CC(C)=O>O>[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]
Reactant: O=C([O-])[O-]
Reactant: CNC(=O)C(=NO)c1ccccc1CO
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: O
Solvent: CC(C)=O
Product: CNC(=O)C(=NOC)c1ccccc1CO
Temperature: 25 °C
Reaction time: 6 h
Yield: 70 %

Procedure:
A mixture of 2-(2-hydroxymethylphenyl)-2-hydroxyimino-N-methylacetamide (521 mg, E/Z≠93/7), potassium carbonate (415 mg), 95% dimethyl sulfate (365 mg) and acetone (5.0 ml) was stirred at room temperature for 6 hours. A few pieces of ice were added, and the mixture was stirred for 30 minutes. Water (about 50 ml) was added, and the mixture was extracted with ethyl acetate three times. The combined ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave the crude product (E/Z≠9 97/3). The crude product was crystallized from ethyl acetate-hexane to obtain the title compound as crystals (389 mg) (E/Z=97/3, yield: 70.0%).
Reaction SMILES: C([O:8][C:9]1[C:10]([C:28]([O:30][CH3:31])=[O:29])=[N:11][N:12]2[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:14](=[O:27])[C:13]=12)C1C=CC=CC=1>C(O)(=O)C>[F:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:15]2[CH2:16][CH2:17][CH2:18][N:12]3[N:11]=[C:10]([C:28]([O:30][CH3:31])=[O:29])[C:9]([OH:8])=[C:13]3[C:14]2=[O:27])=[CH:25][CH:24]=1
Reactant: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(Cc1ccc(F)cc1)CCC2
Solvent: CC(=O)O
Product: COC(=O)c1nn2c(c1O)C(=O)N(Cc1ccc(F)cc1)CCC2
Reaction time: 2 h

Procedure:
The title compound was prepared from methyl 3-benzyloxy-5-(4-fluorobenzyl)-4-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate using a hydrogenation procedure similar to that found in Example 1, Step 5, except that the mixture was treated with acetic acid (3 drops) and the reaction time totaled 2 hours. 1H NMR (400 MHz, CD3OD) δ 7.42-7.38 (m, 2H), 7.10-7.06 (m, 2M), 4.75 (s, 2H), 4.40-4.36 (t, 2H), 3.89 (s, 3H), 3.56-3.53 (m, 2H), 2.22-2.16 (m, 2H); ES MS (M+1)=334.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]1[CH:13]([OH:14])[CH2:12][O:11][CH2:10]1>>[O:11]1[CH2:10][CH2:9][C@H:13]([O:14][C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH2:12]1
Reactant: OC1CCOC1
Reactant: Brc1ccc(Br)nc1
Product: Brc1ccc(O[C@H]2CCOC2)nc1

Procedure:
Prepared from 2,5-dibromopyridine and S-3-hydroxytetrahydrofuran by the method of Example 10 (b).
Reaction SMILES: [CH:1](=O)[CH3:2].[CH3:4][O:5][C:6]1[CH:11]=[C:10]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:9]=[CH:8][C:7]=1[NH:18][C:19]1[N:24]=[C:23]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:33][C:34]([NH2:36])=[O:35])[C:22]([C:37]([F:40])([F:39])[F:38])=[CH:21][N:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO.C(Cl)Cl>CO.C(OCC)(=O)C>[CH2:1]([N:15]1[CH2:16][CH2:17][CH:12]([C:10]2[CH:9]=[CH:8][C:7]([NH:18][C:19]3[N:24]=[C:23]([CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH2:33][C:34]([NH2:36])=[O:35])[C:22]([C:37]([F:38])([F:39])[F:40])=[CH:21][N:20]=3)=[C:6]([O:5][CH3:4])[CH:11]=2)[CH2:13][CH2:14]1)[CH3:2]
Reactant: COc1cc(C2CCNCC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(N)=O)n1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.7 %

Procedure:
Acetaldehyde (18 mg, 0.39 mmol) was added to a stirred solution of 2-(2-(2-(2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (2) (40 mg, 78 μmol) in dry MeOH (2 mL). Sodium triacetoxyborohydride (83 mg, 0.39 mmol) was added under nitrogen and the resulting mixture was stirred at room temperature for 2 hours. The crude mixture was diluted with ethyl acetate and adsorbed onto silica gel. Chromatography (SiO2, 0-20% MeOH/DCM) gave the title compound (4) (10 mg, 24%) as a light coloured solid; 1H NMR (400 MHz, CD2Cl2) δ 8.52 (s, 1H), 8.34 (d, J=8.3 Hz, 1H), 7.92 (s, 7.28-7.14 (m, 4H), 6.92 (d, J=8.3 Hz, 1H), 6.82 (d, J=1.7 Hz, 1H), 5.91 (bs, 1H), 5.87 (bs, 1H), 3.91 (s, 3H), 3.66 (s, 2H), 3.63 (m, 2H), 3.20-3.01 (m, 6H), 2.73 (d, J=11.7 Hz, 2H), 2.42-2.21 (m, 3H), 2.02 (d, J=18.0 Hz, 4H), 1.37 (t, J=7.3 Hz, 3H). LCMS Method C: rt 4.96 min; m/z 542.2 [M+1]+, 540.1 [M−1]−.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]2[C:5]([CH:6]([CH2:16][C:17]([OH:19])=[O:18])[CH2:7][C:8]32[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)=[CH:4][CH:3]=1.[CH:20]12[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH:21]1[N:30]=[C:31]=[O:32])[CH2:27]2.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[CH:22]12[CH2:28][CH:26]3[CH2:25][CH:24]([CH2:29][CH:20]([CH2:27]3)[CH:21]1[NH:30][C:31]([N:11]1[CH2:10][CH2:9][C:8]3([C:14]4[C:5](=[CH:4][CH:3]=[C:2]([CH3:1])[CH:15]=4)[CH:6]([CH2:16][C:17]([OH:19])=[O:18])[CH2:7]3)[CH2:13][CH2:12]1)=[O:32])[CH2:23]2
Reactant: O=C=NC1C2CC3CC(C2)CC1C3
Reactant: Cc1ccc2c(c1)C1(CCNCC1)CC2CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc2c(c1)C1(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC1)CC2CC(=O)O
Reaction time: 1 h
Yield: 65.8 %

Procedure:
(±)-2-(6-Methyl-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid (0.071 mmol), 2-adamantyl isocyanate (14 mg, 1 equiv) and i-Pr2NEt (37 μL, 3 equiv.) were dissolved in CH2Cl2 (3 mL) and put on a shaker for 1 h at rt. The mixture was diluted with EtOAc (10 mL), washed with 3% aq HCl (2×4 mL), concentrated and purified by preparative HPLC to afford (±)-2-(1′-((2-adamantyl)carbamoyl)-6-methyl-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetic acid (20.4 mg, 66% yield). LC-MS Method 1 tR=1.93 min, m/z=437; 1H NMR (CDCl3) 7.05 (q, 2H), 6.96 (s, 1H), 4.94 (br s, 1H), 3.98 (s, 2H), 3.89 (d, 1H), 3.59 (m, 1H), 3.10-2.93 (m, 3H), 2.63 (dd, 1H), 2.43 (dd, 1H), 2.33 (s, 3H), 2.09 (td, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[NH:12][C:11](=[O:23])[CH2:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.CI.[CH2:26](I)[CH3:27]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]([CH2:26][CH3:27])[C:11](=[O:23])[CH2:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: COc1cc2c(cc1OC)C(c1cccc(Br)c1)=NCC(=O)N2
Solvent: CI
Product: CCN1C(=O)CN=C(c2cccc(Br)c2)c2cc(OC)c(OC)cc21
Yield: 17 %

Procedure:
By replacing 5-(4-bromophenyl)-7,8-dimethoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIaf) in example IIba by 5-(3-bromophenyl)-7,8-dimethoxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one (XXIIak), and MeI by ethyl iodide, and proceeding in the same manner, the abovenamed product is obtained. Yield: 17%. M: 122–126° C. 1H-NMR (CDCl3, 300 MHz): d 1.14 (s, 3H, CH3), 3.79–3.85 (m, 4H, 1H CH2+OCH3), 3.99 (AB system, ? d=0.62, JAB=13.9, 2H, —NCH2), 4.04 (s, 3H, OCH3), 4.78 (m, 1H, CH2), 6.65 (s, 1H Ar), 6.86 (s, 1H Ar), 7.26–7.31 (m, 2H Ar), 7.52–7.62 (m, 2H Ar), 7.86 (s, 1H Ar).
Reaction SMILES: C([S:4][CH2:5][CH2:6][C:7]([N:9]1[CH2:16][C@@H:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=O)C.N>>[SH:4][CH2:5][CH2:6][C:7]([N:9]1[CH2:16][C@@H:15]([O:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8]
Reactant: CC(=O)SCCC(=O)N1C[C@@H](Oc2ccccc2)C[C@H]1C(=O)O
Agent: N
Product: O=C(O)[C@@H]1C[C@H](Oc2ccccc2)CN1C(=O)CCS

Procedure:
Hydrolysis of 1-[3-(acetylthio)-1-oxopropyl]-cis-4-phenoxy-L-proline with an aqueous ammonia solution according to the procedure of Example 2 yields 1-(3-mercapto-1-oxopropyl)-cis-4-phenoxy-L-proline.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]3[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:15]=3[CH:16]([C:17]3[C:18](=O)[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:10]=2[N:9]=[C:8]1[CH3:31])(=[O:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>>[C:1]([O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]3[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:15]=3[CH:16]([C:17]3[C:18](=[S:41])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:10]=2[N:9]=[C:8]1[CH3:31])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCn1c(C)nc2c1C=Cc1cc(Cl)ccc1C2c1cn(C)c(=O)[nH]c1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CC(=O)OCCn1c(C)nc2c1C=Cc1cc(Cl)ccc1C2c1cn(C)c(=O)[nH]c1=S

Procedure:
The title compound was prepared from the product of step (iv) (0.3 g) and Lawesson's reagent (1.376 g) according to the method of example 34 step (iv). Purification was by biotage chromatography on silica eluting with 3% methanol in dichloromethane with 1% 0.880 ammonia present to give a yellow glass.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=1)=[O:16].[CH2:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH3:25]>C(Cl)(Cl)Cl>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[CH:18]=[N:19][C:20]([N:29]2[CH2:30][CH2:31][N:26]([CH2:24][CH3:25])[CH2:27][CH2:28]2)=[CH:21][CH:22]=1)=[O:16]
Reactant: CCN1CCNCC1
Reactant: O=C(NCCCCCCCCCCCCO)c1ccc(Cl)nc1
Solvent: ClC(Cl)Cl
Product: CCN1CCN(c2ccc(C(=O)NCCCCCCCCCCCCO)cn2)CC1
Temperature: 160 °C
Reaction time: 0.5 h

Procedure:
To 0.6 g of N-(12-hydroxydodecyl)-6-chloropyridine-3-carboxamide was added 5 ml of 1-ethylpiperazine and the mixture was stirred at 160° C. for 30 minutes. The reaction solution was diluted with chloroform, washed with water, dried over anhydrous sodium sulfate and distilled off under reduced pressure. The residue was chromatographed over a silica gel column to afford the title compound.
Reaction SMILES: C([NH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([I:21])=[C:16]([O:19][CH3:20])[CH:17]=2)[CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1.ClC[CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+].ClCCl>C(O)(=O)C.Br>[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([I:21])=[C:16]([O:19][CH2:20][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:17]=2)[CH:12]=[CH:11][N:10]=1
Reactant: COc1cc2c(NCc3ccccc3)nccc2cc1I
Reactant: CC(C)(C)OC(=O)NCCCl
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCOc1cc2c(N)nccc2cc1I
Temperature: 140 °C
Reaction time: 8 h

Procedure:
10.4 g (26.7 mmol) of benzyl-(6-iodo-7-methoxyisoquinoline-1-yl)amine was dissolved in a mixture of 8 ml of acetic acid and 40 ml of hydrobromic acid, and the obtained solution was stirred at 140° C. overnight. The solvent was evaporated, and the residue was dissolved in 50 ml of DMF. 14.6 g (65.2 mmol) of t-butyl (2-chloroethyl)carbamate and 4.95 g (163 mmol) of potassium carbonate were added to the obtained solution, and they were stirred at 70° C. overnight. After the treatment with dichloromethane as the extraction solvent in an ordinary manner, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:49])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:42])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]3[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][CH:34]=3)=[CH:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1.[H][H]>CO.C(OCC)(=O)C.[Pd]>[O:49]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:45][CH2:44][C@@H:43]([CH:46]([CH3:47])[CH3:48])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:42])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C:20]([C:33]3[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][CH:34]=3)=[CH:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 5.6 %

Procedure:
A mixture of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxido-4-thiomorpholinyl)ethyl)amino)-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (100 mg, 0.145 mmol) and 10% Pd/C (90 mg, 0.087 mmol) in methanol (5 mL) and ethyl acetate (5 mL) was loaded onto a PARR shaker reactor and treated with hydrogen for 25 hours under 40 psi at room temperature. The reaction mixture was filtered through a celite pad to remove the catalyst. The filtrate was purified by HPLC to provide the title compound as a white solid (5.6 mg, 28%). LCMS: m/e 693.46 (M+H)+, 2.46 min (method 10). 1H NMR (500 MHz, Acetic acid d4) δ ppm 8.04 (d, J=8.2 Hz, 2H), 7.31 (d, J=8.2 Hz, 2H), 5.39 (d, J=4.6 Hz, 1H), 3.50-3.36 (m, 1H), 3.36-3.21 (m, 6H), 3.21-2.98 (m, 5H), 2.31-1.29 (m, 24H), 1.29 (s, 3H), 1.13 (s, 6H), 1.03 (s, 3H), 1.01 (s, 3H), 0.94 (d, J=6.7 Hz, 3H), 0.86 (d, J=6.7 Hz, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH:33]4[CH2:38][CH2:37][N:36]([CH2:39][C:40]([O:42]C(C)(C)C)=[O:41])[CH2:35][CH2:34]4)=[N:21][N:22]3[CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.O.[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]>>[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[F:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:22]2[C:23]3[C:19](=[CH:18][CH:17]=[C:16](/[CH:15]=[CH:14]/[CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:24]=3)[C:20]([CH:33]3[CH2:38][CH2:37][N:36]([CH2:39][C:40]([OH:42])=[O:41])[CH2:35][CH2:34]3)=[N:21]2)=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)CN1CCC(c2nn(Cc3ccc(F)cc3)c3cc(/C=C/C4CCN(C(=O)OC(C)(C)C)CC4)ccc23)CC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN1CCC(c2nn(Cc3ccc(F)cc3)c3cc(/C=C/C4CCNCC4)ccc23)CC1

Procedure:
4-{2-[3-(1-tert-Butoxycarbonylmethyl-piperidin-4-yl)-1-(4-fluoro-benzyl)-1H-indazol-6-yl]-(E)-vinyl}piperidine-1-carboxylic acid tert-butyl ester (181 mg, 0.29 mmol) was stirred in trifluoroacetic acid (10 ml), containing water (1 ml) at +25° for 2.5 h. The solution was evaporated in vacuo and the residue purified by preparative h.p.l.c. using standard conditions (gradient profile 10-30% (ii) in 1 min, 30% (ii) isochratic for 30 min, 30-10% (ii) in 1 min), but with a flow rate of 20 ml/min. The collected eluant (Rf 21.2 min) was evaporated in vacuo and triturated with ether to give the title compound as a cream solid (80 mg). Analytical h.p.l.c. (gradient profile 10-90% (ii) in 25 min) Rf 12.5 min
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]([OH:21])=[O:20])([O-:8])=[O:7].[CH3:22]O>>[N+:6]([C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]([O:21][CH3:22])=[O:20])([O-:8])=[O:7]
Reactant: O=C(O)c1cccc2c([N+](=O)[O-])cccc12
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc2c([N+](=O)[O-])cccc12
Temperature: 20 °C

Procedure:
1 cm3 of 97% sulphuric acid is added to a suspension of 4.7 g of 5-nitro-1-naphthoic acid in 50 cm3 of methanol and the reaction mixture is then brought to reflux for 12 hours. The solution is cooled to a temperature in the region of 20° C. and the precipitate formed is filtered off by centrifuge and washed twice with 5 cm3 of ice-cold methanol and then dried to constant weight. 4.56 g of methyl 5-nitro-1-naphthoate are obtained, melting at 105° C. 21.5 g of tin(II) chloride dihydrate are added to a solution of 4.45 g of methyl 5-nitro-1-naphthoate in a mixture of 150 cm3 of ethyl acetate and 35 cm3 of ethanol. The solution is heated to a temperature in the region of 70° C. for 30 minutes and then cooled to a temperature in the region of 20° C. The reaction mixture is poured onto 200 cm3 of ice and the pH of the solution is progressively brought to 7-8 by addition of a 5% (w/v) sodium hydrogen carbonate solution. The mixture obtained is filtered on a sintered glass covered with Celite, the organic phase is separated by settling and the aqueous phase is extracted twice with 150 cm3 of ethyl acetate. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. 4.5 g of methyl 5-amino-1-naphthoate are obtained in the form of an oil which are used in the following stage without other purification. 14.75 g of S-triphenylmethyl-N-(tert-butoxycarbonyl)cysteinal, 0.14 cm3 of concentrated acetic acid, molecular sieves (3Å) and then 4.15 g of sodium cyanoborohydride are added to a solution of 4.5 g of methyl 5-amino-1-naphthoate in 30 cm3 of methanol. The reaction mixture is stirred for 2 days at a temperature in the region of 20° C. and then filtered on sintered glass covered with Celite. The sintered glass is washed with methanol. The filtrate is concentrated under reduced pressure, redissolved in 150 cm3 of ethyl acetate and washed with 100 cm3 of a 10% (w/v) aqueous sodium hydrogen carbonate solution, with 100 cm3 of a 10% (w/v) aqueous citric acid solution, with 100 cm3 of distilled water, with 100 cm3 of a 10% (w/v) aqueous sodium hydrogen carbonate solution and finally with 100 cm3 of a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. The product is purified by chromatography on silica [eluent: cyclohexane/ethyl acetate (85/15 by volume)]. 3.5 g of methyl 5-(2(R)-tert-butoxycarbonylamino-3-(triphenylmethylthio)-propylamino)-1-naphthoate are obtained in the form of a beige foam which are used in the following stage without other purification.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([CH2:20][CH:21]([CH3:23])[CH3:22])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:33][O:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][C:44]=1[O:45][CH3:46])[N:41]=[CH:40][N:39]=[C:38]2[S:47][C:48]1[CH:49]=[C:50]([CH:52]=[CH:53][CH:54]=1)[NH2:51]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:51][C:50]2[CH:52]=[CH:53][CH:54]=[C:48]([S:47][C:38]3[C:37]4[C:42](=[CH:43][C:44]([O:45][CH3:46])=[C:35]([O:34][CH3:33])[CH:36]=4)[N:41]=[CH:40][N:39]=3)[CH:49]=2)=[O:19])[N:7]([CH2:20][CH:21]([CH3:22])[CH3:23])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: CC(C)Cn1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4CC(C)C)c3)c2cc1OC
Temperature: 60 °C
Yield: 32 %

Procedure:
A stirred solution of phenyl 3-tert-butyl-1-isobutyl-1H-pyrazol-5-ylcarbamate described in Example 332A(150 mg, 0.47 mmol), N,N-diisopropylethylamine (80 mg, 0.62 mmol) and 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (prepared as described in Example 115B) (100 mg, 0.31 mmol) in THF (1.0 mL) was heated at 60° C. for 15 h. After cooling to rt, the reaction solution was partitioned between dichloromethane and a saturated aqueous solution of sodium carbonate. The organic phase was separated and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography (eluting with a gradient of 40:1 to 20:1 dichloromethane: methanol) then reverse-phase preparative HPLC to afford 1-(3-tert-butyl-1-isobutyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea (52 mg, 32%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ9.07 (s, 1H), 8.70 (s, 1H), 8.48 (s, 1H), 7.85 (s, 1H), 7.24-7.53 (m, 5H), 6.07 (s, 1H), 4.00 (s, 6H), 3.72 (d, J=7.2 Hz, 2H), 2.07 (m, 1H), 1.20 (s, 9H), 0.83 (d, J=6.8 Hz, 6H); LC-MS (ESI) m/z 535 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6](/[CH:8]=[C:9](\[C:31]#[N:32])/[C:10]([NH:12][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH3:16])=[O:11])[CH:5]=[CH:4][CH:3]=1.[F:33]C1N=C(C=O)C=CC=1.C(CC(NC(C1C=CC(OCCN2CCCC2)=CC=1)CCC)=O)#N>>[C:31](/[C:9](=[CH:8]\[C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([F:33])[N:7]=1)/[C:10]([NH:12][CH:13]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]2[CH2:29][CH2:30][CH2:28][CH2:27]2)=[CH:19][CH:18]=1)[CH2:14][CH2:15][CH3:16])=[O:11])#[N:32]
Reactant: CCCC(NC(=O)/C(C#N)=C/c1cccc(Br)n1)c1ccc(OCCN(CC)CC)cc1
Reactant: O=Cc1cccc(F)n1
Agent: CCCC(NC(=O)CC#N)c1ccc(OCCN2CCCC2)cc1
Product: CCCC(NC(=O)/C(C#N)=C/c1cccc(F)n1)c1ccc(OCCN2CCCC2)cc1

Procedure:
The title compound was prepared by using a similar procedure as described for the preparation of 33 except that 6-fluoropicolinaldehyde was used instead of 6-bromopicolinaldehyde, and 2-cyano-N-(1-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)butyl)acetamide (31) was used instead of 2-cyano-N-(1-(4-(2-(diethylamino)ethoxy)phenyl)butyl)acetamide (29). This produced the crude product which was purified by flash silica gel column chromatography, eluting with 4:96 methanol/dichloromethane, to give 36 (65 mg, 35%) as a light yellow oil: MS (ES+) m/z 437.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH3:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:17]2[CH2:18][CH2:19][CH:14]([CH3:13])[CH2:15][CH2:16]2)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: CC1CCNCC1
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Solvent: CN(C)C=O
Product: Cc1csc2c(N3CCC(C)CC3)nc(Cl)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
In 10 ml of DMF was dissolved 1.0 g (4.6 mmol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine, and then 1.06 g (10.7 mmol) of 4-methylpiperidine was added dropwise to the resulting solution under ice cooling over 5 minutes. The reaction mixture was stirred at 0° C. for one hour and then allowed to resume to room temperature, followed by stirring for one hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/10) to give 1.20 g (yield: 93.3%) of the title compound.
Reaction SMILES: O1C2C=CC=CC=2OCC1CC=O.OC1(C2C=CC=CC=2)CCNCC1.[ClH:27].[OH:28][C:29]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:34][CH2:33][N:32]([CH:35]=[CH:36][CH:37]2[O:42][C:41]3[CH:43]=[CH:44][CH:45]=[CH:46][C:40]=3[O:39][CH2:38]2)[CH2:31][CH2:30]1.C([BH3-])#N.[Na+].[OH-].[Na+]>CO>[ClH:27].[OH:28][C:29]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:30][CH2:31][N:32]([CH2:35][CH2:36][CH:37]2[O:42][C:41]3[CH:43]=[CH:44][CH:45]=[CH:46][C:40]=3[O:39][CH2:38]2)[CH2:33][CH2:34]1
Reactant: OC1(c2ccccc2)CCN(C=CC2COc3ccccc3O2)CC1
Agent: Cl
Agent: O=CCC1COc2ccccc2O1
Agent: OC1(c2ccccc2)CCNCC1
Solvent: CO
Product: OC1(c2ccccc2)CCN(CCC2COc3ccccc3O2)CC1
Reaction time: 1 h

Procedure:
To the solution of 10 g of 1,4-benzodioxan-2-yl-acetaldehyde and 12.7 g of 4-hydroxy-4-phenylpiperidine in 300 ml of methanol is added 8 ml of 4.5 N ethanolic hydrogen chloride at which conditions the 2-[2-(4-hydroxy-4-phenylpiperidino)-vinyl]-1,4-benzodioxan is formed in situ. After standing for one hour, at room temperature the solution of 2.4 g of sodium cyanoborohydride in 30 ml of methanol is added dropwise while stirring. After one hour the solution is made strongly basic with aqueous sodium hydroxide, concentrated to a small volume and diluted with water. The mixture is extracted with ethyl acetate, the extract dried and evaporated. The residue is treated with ethanolic hydrogen chloride and the precipitate recrystallized from ethanoldiethyl ether, to yield the 2-[2-(4-hydroxy-4-phenylpiperidino)-ethyl]-1,4-benzodioxan hydrochloride melting at 203°.