Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-])(=[O:3])[CH3:2].[Na+].[C:6]([CH2:8][C:9]1[C:17]2[O:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)#[N:7]>C(OC(=O)C)(=O)C.[Ni]>[C:1]([NH:7][CH2:6][CH2:8][C:9]1[C:17]2[O:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc2cccc(CC#N)c2o1
Reactant: CC(=O)[O-]
Agent: [Ni]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc2cccc(CCNC(C)=O)c2o1

Procedure:
A suspension of 1.07 g of sodium acetate, 2.00 g of methyl 7-cyanomethylbenzofuran-2-carboxylate in 10.4 ml of acetic anhydride is hydrogenated in the presence of 0.22 g of Raney nickel at 50° C. over 5 hours. The reaction mixture is clarified by filtration and the filtrate is concentrated by evaporation. The residue is dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate solution, water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a white solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (6:1 EtOAc-heptane); Rt=3.23.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2([CH3:13])[CH2:12][O:11]2)=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[SH:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([CH3:13])([OH:11])[CH2:12][S:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[Cl:14])=[CH:4][CH:3]=1
Reactant: CC1(CCc2ccc(Cl)cc2)CO1
Reactant: Sc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(O)(CCc1ccc(Cl)cc1)CSc1ccccc1Cl

Procedure:
A mixture of 4 g. of 2-[2-(4-chlorophenyl)ethyl]-2-methyloxirane, 3.6 g. of 2-chlorothiophenol and 500 mg. of anhydrous potassium carbonate in 50 ml. of acetone is stirred at reflux for approximately 3 hours. The solvent is then evaporated and 200 ml. of ether is added to the residue. The resulting mixture is washed with water (3 × 40 ml.), dried (MgSO4) and evaporated to afford 4-(4-chlorophenyl)-1-(2-chlorophenylthio)-2-methyl-2-butanol which is used directly as described later in the procedure.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:9][N:10]([CH2:18][C:19]([O:21]CC)=[O:20])[CH2:11][CH2:12][C:13]=3[C:14]([CH3:17])([CH3:16])[O:15][C:6]=2[CH:5]=[C:4]([CH:24]([CH3:32])[CH:25]([CH3:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:3]=1.[OH-].[Na+]>CO>[OH:1][C:2]1[C:7]2[C:8]3[CH2:9][N:10]([CH2:18][C:19]([OH:21])=[O:20])[CH2:11][CH2:12][C:13]=3[C:14]([CH3:17])([CH3:16])[O:15][C:6]=2[CH:5]=[C:4]([CH:24]([CH3:32])[CH:25]([CH3:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:3]=1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)OCC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)O)CC1

Procedure:
The above-titled compound was obtained by hydrolyzing the product of Example 9 with dilute aqueous sodium hydroxide in methanol; m.p. 192-195°; after recrystallization from ethanol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN.C1C=CC2N(O)N=[N:28][C:26]=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C.C(Cl)Cl>[CH3:26][NH:28][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)c1ccccc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid (1.00 g, 3.98 mmol) in DMF (5 mL) and methylene chloride (5 mL) was added methylamine hydrochloride (403 mg, 5.97 mmol), HOBt (645 mg, 4.78 mmol), and Hunig's Base (1.73 mL, 9.95 mmol) and the resulting solution stirred at 0° C. for 10 minutes. EDCI (916 mg, 4.78 mmol) was added and the reaction stirred at 25° C. for 18 hours. The mixture was concentrated in vacuo, the resulting residue was diluted with ethyl acetate (45 mL), brine (10 mL), and 5% H3PO4 aqueous solution (10 mL), and the layers were separated. The organic layer was washed with 5% H3PO4 aqueous solution (10 mL), twice with saturated aqueous sodium bicarbonate solution (15 mL), water (15 mL), and brine (15 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound as a light colored solid. The crude material was taken on directly to the next step. (1.04 g, 99% yield) MS (ESI+) m/z=265 (M+H)+.
Reaction SMILES: C1(C)C=CC=CC=1.N1CCCCC1.[CH3:14][N:15]1[C:24]2[C:19](=[CH:20][C:21]([CH3:38])=[C:22]([C:25]3[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=3[O:33][C:34]([F:37])([F:36])[F:35])[CH:28]=O)[CH:23]=2)[C:18]([CH3:40])([CH3:39])[CH2:17][C:16]1=[O:41].[S:42]1[CH2:46][C:45](=[O:47])[NH:44][C:43]1=[O:48]>C(OCC)(=O)C.C(O)(=O)C>[CH3:14][N:15]1[C:24]2[C:19](=[CH:20][C:21]([CH3:38])=[C:22]([C:25]3[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=3[O:33][C:34]([F:35])([F:37])[F:36])[CH:28]=[C:46]3[S:42][C:43](=[O:48])[NH:44][C:45]3=[O:47])[CH:23]=2)[C:18]([CH3:39])([CH3:40])[CH2:17][C:16]1=[O:41]
Reactant: Cc1cc2c(cc1-c1cc(C=O)ccc1OC(F)(F)F)N(C)C(=O)CC2(C)C
Reactant: O=C1CSC(=O)N1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: Cc1cc2c(cc1-c1cc(C=C3SC(=O)NC3=O)ccc1OC(F)(F)F)N(C)C(=O)CC2(C)C
Temperature: 25 °C
Yield: 45.8 %

Procedure:
A mixture of toluene (80 mL), piperidine (380 μL), acetic acid (380 μL), 3-(1,4,4,6-Tetramethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trifluoromethoxy-benzaldehyde (7.5 g, 19.16 mmol) and 2,4-thiazolidinedione (2.25 g, 19.16 mmol) was heated at reflux overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water and brine, dried over MgSO4. The residue was recrystallized successively from ethanol, dichloromethane/hexane and ethanol to afford 4.3 g (46%) of 5-[3-(1,4,4,6-tetramethyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-4-trifluoromethoxy-benzylidene]-thiazolidine-2,4 dione. mp 182–184° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15](O)=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.[NH2:40][C:41]1[CH:42]=[N:43][CH:44]=[C:45]([CH:49]=1)[C:46]([NH2:48])=[O:47]>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15]([NH:40][C:41]4[CH:42]=[N:43][CH:44]=[C:45]([CH:49]=4)[C:46]([NH2:48])=[O:47])=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: NC(=O)c1cncc(N)c1
Reactant: COc1ccc(-c2ccc3cnc(O)nn23)cn1
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Product: COc1ccc(-c2ccc3cnc(Nc4cncc(C(N)=O)c4)nn23)cn1
Yield: 40 %

Procedure:
The titled compound was prepared in analogous fashion as Example 522 using 7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol, N-phenylbis(trifluoromethanesulphonimide) and 5-amino-nicotinamide to give 5-[7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-nicotinamide as a light brown solid (23.9 mg, 40% yield). M.p.=>250° C. LCMS (E/I+) 361 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 9.05 (s, 1H), 8.92 (s, 1H), 8.83 (s, 1H), 8.60 (m, 3H), 8.09 (s, 1H), 7.62 (s, 1H), 7.25 (d, 1H, J=4.7 Hz), 7.02 (m, 2H), 3.92 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@H:9]2[C:23]2[CH:33]=[CH:32][C:26]([O:27][CH2:28][C:29](O)=[O:30])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.Cl.[NH2:35][CH2:36][C:37]([NH:39][C@@H:40]([C:44]([O:46]C(C)(C)C)=[O:45])[CH:41]([CH3:43])[CH3:42])=[O:38].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[BH4-].[Na+].C([O-])(=O)C.[NH4+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([OH:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@H:9]2[C:23]2[CH:24]=[CH:25][C:26]([O:27][CH2:28][C:29]([NH:35][CH2:36][C:37]([NH:39][C@@H:40]([C:44]([OH:46])=[O:45])[CH:41]([CH3:42])[CH3:43])=[O:38])=[O:30])=[CH:32][CH:33]=2)=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H](NC(=O)CN)C(=O)OC(C)(C)C
Reactant: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccccc3)C(=O)N2c2ccc(F)cc2)cc1
Agent: CC(=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)[C@@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccccc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Reaction time: 0.08 h

Procedure:
(4-{(2R,3R)-1-(4-Fluorophenyl)-4-oxo-3-[(2-oxo-2-phenylethyl)thio}azetidin-2-yl]phenoxy)acetic acid (15 mg, 0.043 mmol), tert-butyl glycyl-D-valinate hydrochloride, (14.3 mg, 0.054 mmol) and N-methylmorpholine (14 μl, 0.13 mmol) were dissolved in DCM (2 ml). After 5 minutes, TBTU (16.9 mg, 0.053 mmol) was added and the reaction mixture was stirred for 2.5 h. The formation of the ester was confirmed. M/z: 678.35 (N+H). The solvent was removed under reduced pressure. The residue was dissolved in EtOAc:DCM (1:3) and purified on silica gel (1 g) using EtOAc:DCM (1:3) as eluent. The fractions were collected and concentrated. The residue (0.029 g) was dissolved in DCM (3 ml) and TFA (0.5 ml) was added. The reaction mixture was stirred overnight. The solvent was removed under reduced pressure and toluene was added and removed under reduced pressure. The yellowish residue was dissolved in MeOH (2 ml) and sodium borohydride (16.2 mg, 0.43 mmol) was added. The reaction mixture was stirred for 10 minutes. Ammonium acetate (31.4 mg) was added and the solvent was removed under reduced pressure. The residue was purified with preparative HPLC on a C8 column. A gradient from 20% to 50% MeCN in 0.1 M ammonium acetate buffer was used as eluent. After lyophilisation, the title compound was obtained as a white solid (7.6 mg, 28%). H-NMR (400 MHz, DMSO-d6): 0.79 (d, 3H), 0.81 (d, 3H) 1.95-2.05 (m, 1H), 2.84-2.96 (m, 2H), 3.79 (d, 2H), 3.98-4.04 (m, 1H), 4.27 (d, 0.5H), 4.30 (d, 0.5H), 4.51 (s, 2H), 4.66-4.75 (m, 1H), 5.02 (d, 0.5H), 5.04 (d, 0.5H), 6.98 (d, 2H), 7.10-7.17 (m, 2H), 7.19-7.32 (m, 7H), 7.36 (d, 2H), 7.77 (t, 1H), 8.26 (t, 1H). M/z: 622.1 (M−H) and 624.2 (M+H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][CH2:10][C:11](=[O:19])[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.[CH3:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1.CS(C)=O>O>[CH3:21][C:22]1[N:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][CH2:10][C:11](=[O:19])[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=2)[CH:24]=[CH:25][N:26]=1
Reactant: Cc1ncc[nH]1
Reactant: CCOC(=O)CCC(=O)CCC(=O)c1ccc(F)cc1
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CCC(=O)CCC(=O)c1ccc(-n2ccnc2C)cc1
Temperature: 180 °C
Yield: 27.1 %

Procedure:
Ethyl 7-(4-fluorophenyl)-4,7-dioxoheptanoate (2.00 g, 7.1 mmol) and 2-methyl-1H-imidazole (7.0 g, 86 mmol) were taken up into DMSO (4 mL). The mixture was heated to 180° C. under microwave for 72 min. Water (100 mL) was added and the mixture was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (DCM to DCM:MeOH=25:1) to afford the title compound as a dark brown solid (660 mg, yield 25%).
Reaction SMILES: C(OC[N:10]1[C:14]2[CH:15]=[N:16][NH:17][C:18](=[O:19])[C:13]=2[C:12]([CH2:20][C:21]2[CH:22]=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)=[C:11]1[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH:36]([F:38])[F:37])=[C:31]([O:39][CH:40]2[CH2:42][CH2:41]2)[CH:30]=1)C1C=CC=CC=1.C(OCN1C2C=NNC(=O)C=2C(CC2C=CC=CC=2F)=C1C1C=CC(OC(F)F)=C(OC2CC2)C=1)C1C=CC=CC=1>>[CH:40]1([O:39][C:31]2[CH:30]=[C:29]([C:11]3[NH:10][C:14]4[CH:15]=[N:16][NH:17][C:18](=[O:19])[C:13]=4[C:12]=3[CH2:20][C:21]3[CH:22]=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[CH:34]=[CH:33][C:32]=2[O:35][CH:36]([F:38])[F:37])[CH2:42][CH2:41]1
Reactant: COc1ccc(Cc2c(-c3ccc(OC(F)F)c(OC4CC4)c3)n(COCc3ccccc3)c3cn[nH]c(=O)c23)cn1
Agent: O=c1[nH]ncc2c1c(Cc1ccccc1F)c(-c1ccc(OC(F)F)c(OC3CC3)c1)n2COCc1ccccc1
Product: COc1ccc(Cc2c(-c3ccc(OC(F)F)c(OC4CC4)c3)[nH]c3cn[nH]c(=O)c23)cn1
Reaction time: 1 h
Yield: 17.9 %

Procedure:
Reaction was carried out in the same manner as in Example 22-(b) except for using 265 mg (1.79 mmol) of 1-benzyloxymethyl-2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-(6-methoxy-3-pyridylmethyl)-1,5-dihydropyrrolo[2,3-d]-pyridazin-4-one obtained in Example 29-(a) in place of 1-benzyloxymethyl-2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-(2-fluorobenzyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one. After completion of the reaction, the reaction suspension was filtered, the filtrate was concentrated under reduced pressure, methanol and 28% aqueous ammonia were added to the obtained solid, and the mixture was stirred for 1 hour. Then, the solution was concentrated under reduced pressure and the obtained residue was applied to silica gel column chromatography (Eluent; ethyl acetate), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 146 mg of the title compound as a white solid. (Yield: 69%)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[N:44]=[CH:43][C:42]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])=[CH:41][N:40]=2)=[CH:35][CH:34]=1.[O:54]1[C@@H:57]([CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[C@@H:55]1[CH3:56]>O1CCCC1>[CH2:45]([C:42]1[CH:43]=[N:44][C:39]([C:36]2[CH:35]=[CH:34][C:33]([O:32][CH2:56][C@H:55]3[C@H:57]([CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[O:54]3)=[CH:38][CH:37]=2)=[N:40][CH:41]=1)[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]
Reactant: CCCCC[C@@H]1O[C@H]1C
Reactant: CCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCc1cnc(-c2ccc(OC[C@@H]3O[C@H]3CCCCC)cc2)nc1
Reaction time: 0.33 h
Yield: 37.2 %

Procedure:
1.31 g (5 mmol) of triphenyl phosphine and 0.79 g (5 mmol) of diethyl azodicarboxylate are combined in 10 ml of tetrahydrofuran at 0° C. After 20 minutes, 1.49 g (5 mmol) of 2-(4-hydroxyphenyl)-5-n-nonylpyrimidine and 0.72 g (5 mmol) of (2S,3S)-2,3-epoxyoctane, each in 8 ml of tetrahydrofuran, are added. After 24 hours, the mixture is evaporated to dryness in vacuo, and the residue is chromatographed on silica gel (200 g) using CH2Cl2. After recrystallization from hexane, 0.79 g of colorless crystals is obtained; (α) D25 : -15.3° (c=5,CHCl3)
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[N:22]([C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:21]=[N:20][N:19]=2)=[CH:8][CH:7]=1)(=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[OH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[N:22]([C:23]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:21]=[N:20][N:19]=2)=[CH:8][CH:7]=1
Reactant: CC(=O)OCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 83 %

Procedure:
3.4 g of 4-(acetoxymethyl)-2'-(1-triphenylmethyltetrazol-5-yl)biphenyl dissolved in 30 ml of anhydrous THF, are dropped during 0.5h into a suspension of 0.5 g of LiAlH4 in 20 ml of anhydrous THF at 0° C. The mixture is stirred for 24h at 0° C., then a stoichiometric amount of water is added to decompose LiAlH4 and the precipitated salts are filtered off. The solution is evaporated and the residue is triturated with an hexane:ethyl acetate mixture (9:1). Upon filtration and drying, 2.6 g of a white powder are obtained (Yield: 83%).
Reaction SMILES: [F:1][C:2]1[CH:36]=[C:35]([N+:37]([O-])=O)[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[C:16]([CH:30]=[CH:31][CH:32]=3)[CH2:17][N:18]([CH2:26][CH2:27][O:28][CH3:29])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[S:13][C:6]=12.[BH4-].[Na+].Cl>C1COCC1.CO.Cl[Ni]Cl>[NH2:37][C:35]1[CH:34]=[CH:33][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]4[CH:15]=[C:16]([CH:30]=[CH:31][CH:32]=4)[CH2:17][N:18]([CH2:26][CH2:27][O:28][CH3:29])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[S:13][C:6]=23)=[C:2]([F:1])[CH:36]=1
Reactant: COCCN(Cc1cccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1)C(=O)OC(C)(C)C
Agent: Cl[Ni]Cl
Agent: Cl
Agent: [BH4-]
Solvent: CO
Solvent: C1CCOC1
Product: COCCN(Cc1cccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 74.8 %

Procedure:
To a solution of 73 (347 mg, 0.6 mmol) in THF (4 mL) and MeOH (2 mL), NiCl2 (372 mg, 1.6 mmol) was added and the solution was cooled to 0° C. NaBH4 (95 mg, 2.5 mmol) was added portion wise. After 20 minutes, the reaction was treated with 2 M HCl and solvents were removed under reduced pressure. The concentrated mixture was basified to pH 10 with ammonium hydroxide solution and the mixture was extracted with EtOAc, the extract was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography, eluent EtOAc, to afford the title compound 74 (235 mg, 72% yield) as a white solid. 1H NMR (DMSO) δ (ppm): 8.47 (d, J=5.6 Hz, 1H), 7.97 (s, 1H), 7.77 (d, J=7.2 Hz, 1H), 7.70 (s, 1H), 7.48 (t, J=7.6 Hz, 1H), 6.56-6.51 (m, 2H), 6.44 (dd, J=6.3 Hz, 1H), 5.54 (s, 2H), 4.84 (s, 2H), 3.43 (s, 2H), 3.23 (s, 3H), 2.50 (q, J=2.2 Hz, 4H), 1.46-1.35 (m, 9H).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH3:13])[CH:8]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:27]=[CH:28][C:29]=1[CH:30]([CH3:33])[CH:31]=[O:32])[O:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1.[NH4+].[Cl-]>CCCCCC.C1COCC1>[Cl:14][C:15]1[CH:16]=[C:17]([CH:27]=[CH:28][C:29]=1[CH:30]([CH3:33])[CH:31]([OH:32])[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH3:13])[CH:8]=1)[O:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1
Reactant: CC(C=O)c1ccc(Oc2ccc(C#N)cc2)cc1Cl
Reactant: Cc1cc(Br)ccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(C(O)C(C)c2ccc(Oc3ccc(C#N)cc3)cc2Cl)ccn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A 1.6 M solution of n-BuLi in hexane (1.05 ml) was added to 4-bromo-2-methylpyridin (CAS Reg. No. 22282-99-1, 289 mg) in THF (5 ml) at −78° C. The deep red solution was stirred for 10 min. A solution of 4-[3-chloro-4-(1-methyl-2-oxo-ethyl)-phenoxy]-benzonitrile (400 mg) in THF (5 ml) was added at −78° C. The mixture was allowed to warm to 0° C. and stirred for 15 min at that temperature. Saturated aqueous NH4Cl solution was added and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and then concentrated to an oil. The residue was purified by flash chromatography (SiO2, EtOAc/heptane 1:2) to give the title compound (200 mg) as a light yellow solid. MS (m/e)=379.2 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=3)[CH:15]=[CH:16][C:17]=1[Cl:18])[N:5]=2.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>N1C=CC=CC=1>[Cl:18][C:17]1[CH:16]=[CH:15][C:14]([NH:19][C:20](=[O:32])[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:28])[CH3:29])[CH:22]=2)=[CH:13][C:12]=1[O:11][C:6]1[N:5]=[C:4]2[S:3][C:2]([NH:1][C:36]([CH:33]3[CH2:35][CH2:34]3)=[O:37])=[N:10][C:9]2=[CH:8][CH:7]=1
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(Cl)c(Oc3ccc4nc(N)sc4n3)c2)c1
Solvent: c1ccncc1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(Cl)c(Oc3ccc4nc(NC(=O)C5CC5)sc4n3)c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 46.2 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-chlorophenyl}-3-(1-cyano-1-methylethyl)benzamide (464 mg, 1.00 mmol) in pyridine (10 mL) was added cyclopropanecarbonyl chloride (181 μL, 2.00 mmol), and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (50 mL), washed with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=60/40→0/100), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/hexane to give the title compound (246 mg, 46%) as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH3:18])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>O1CCOCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([C:19]3[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=3)([C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[CH3:18])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:33][S:34]([OH:36])(=[O:1])=[O:35]
Reactant: CS(=O)(=O)Cl
Agent: CC(C)(c1ccc(O)cc1)c1ccc(C(C)(c2ccc(O)cc2)c2ccc(O)cc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CS(=O)(=O)O

Procedure:
One (1.0) mole of 1-[1-(4-hydroxyphenyl)isopropyl]-4-[1,1-bis(4-hydroxyphenyl)ethyl]benzene, naphthoquinone-1,2-diazido-5-sulfonyl chloride (2.0 moles) and methanesulfonyl chloride (0.5 moles) were dissolved in dioxane (4,000 g). To the resulting solution, dioxane (2,000 g) having triethylamine (500 g) dissolved therein was added dropwise over 10 minutes at a controlled temperature not higher than 30° C. The precipitating salt was separated by filtration and the thus recovered reaction product was washed and dried to yield esters of the 1-[1-(4-hydroxyphenyl)isopropyl]-4-[1,1-bis(4-hydroxyphenyl)ethyl]benzene with naphthoquinone-1,2-diazido-5-sulfonic acid and methanesulfonic acid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([N:17](C(OC(C)(C)C)=O)[NH:18][C:19](OC(C)(C)C)=O)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33]C(O)=O>>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][C:13]3[N:12]([C:19]([CH3:33])=[N:18][N:17]=3)[C:11]=2[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cnn2Cc2ccccc2)n1
Product: Cc1nnc2ccc3c(cnn3Cc3ccccc3)n12
Yield: 40 %

Procedure:
di-tert-Butyl 1-(1-benzyl-1H-pyrazolo[4,3-b]pyridin-5-yl)hydrazine-1,2-dicarboxylate (0.030 g, 0.068 mmol, from Step 2) in AcOH (3 mL) was heated in the microwave to 180° C. for 5 minutes. The AcOH was removed in vacuo, the residue was reconstituted in MeOH, and purified via preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) to afford product (8 mg, 40%).