Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:21]=[CH:20][C:17]([CH2:18]O)=[CH:16][CH:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:24])=O>C(Cl)(Cl)Cl>[C:1]1([S:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:21]=[CH:20][C:17]([CH2:18][Cl:24])=[CH:16][CH:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)(CCCOc1ccc(CO)cc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=S(=O)(CCCOc1ccc(CCl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.6 %

Procedure:
1.5 g of 4-(3-benzenesulfonylpropyloxy)benzyl alcohol were dissolved in 30 ml of chloroform, and the resultant solution was further fed dropwise with 0.7 g of thionyl chloride and then stirred for 1 hour at room temperature. After completed the reaction, the solution reacted was poured into ice-water and extracted with chloroform. The organic layer resulted was dried with anhydrous magnesium sulfate, and the solvent used was removed by distillation under reduced pressure, thereby affording 1.6 g of 4-(3-benzenesulfonylpropyloxy)benzyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([O:10]COC)[C:7]([CH2:14][C:15]([CH3:17])=[CH2:16])=[C:6]([O:18]COC)[CH:5]=1.Cl>CO>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([OH:10])[C:7]2[CH2:14][C:15]([CH3:17])([CH3:16])[O:18][C:6]=2[CH:5]=1)=[O:22]
Reactant: C=C(C)Cc1c(OCOC)cc(C(=O)OC)cc1OCOC
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Yield: 53.9 %

Procedure:
To a solution of 3,5-bis-methoxymethoxy-4-(2-methyl-allyl)-benzoic acid methyl ester (3i) (3.6 g, 9.02 mmol) in methanol (5 mL) was added 1.3 mL concentrated aqueous HCl. The reaction mixture was heated to reflux for 1 hr, quenched with H2O (100 mL), extracted with EtOAc (2×100 mL), dried over MgSO4 and concentrated. The residue was purified by flash column chromatography eluting with 5% EtOAc in hexane to give a pale yellow solid (1.08 g, 54% yield). 1H NMR (400 MHz, CDCl3) δ 7.12 (d, J=1.26 Hz, 1 H) 7.00 (d, J=1.01 Hz, 1 H) 5.63 (s, 1 H) 3.89 (s, 3 H) 3.00 (s, 2H) 1.50 (s, 6 H); LCMS for C12H14O4 m/z 223.10 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH2:20])[C:12]#[CH:13]>>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:11][C:12]#[CH:13])([O-:10])=[O:9]
Reactant: C#CCOCCOCCN
Reactant: O=[N+]([O-])c1ccccc1Cl
Product: C#CCOCCOCCNc1ccccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 29.6 %

Procedure:
To 1-chloro-2-nitrobenzene (152 mg, 0.97 mmol, 1.0 equiv.) was added neat 2-(2-(prop-2-ynyloxy)ethoxy)ethanamine (s-5) (900 mg, 6.31 mmol, 6.5 equiv.), and the resulting slurry was heated to 100° C. for 6 hours during which time the solid dissolved. At the end of this period, the heating bath was removed, the reaction content was mixed with water (50 mL), and then extracted with CH2Cl2 (3×50 mL). The organic layers were combined, dried with Na2SO4, concentrated under reduced pressure, and chromatographed (silica gel, 1×25 cm, 0% CH3OH in CH2Cl2, then 10% CH3OH in CH2Cl2) to yield 2-nitro-N-(2-(2-(prop-2-ynyloxy)ethoxy)ethyl)aniline (s-6) as a dark yellow oil (76 mg, 30%). IR (thin film) 3378 (m), 3286 (m), 3085 (w), 2875 (m), 2114 (w), 1616 (s), 1570 (s), 1508 (s), 1417 (m), 1349 (m), 1228 (s), 1093 (s), 1034 (m), 740 (m), 670 (s); 1H NMR (500 MHz, CDCl3) δ 8.23 (bs, 1H), 8.18 (dd, J=8.6, 1.6 Hz, 1H), 7.43 (ddd, J=8.6, 7.0, 1.6 Hz, 1H), 6.86 (d, J=8.6 Hz, 1H), 6.65 (ddd, J=8.3, 7.0, 1.2 Hz, 1H), 4.22 (d, J=2.4 Hz, 2H), 3.80 (t, J=5.5 Hz, 2H), 3.73 (d, J=2.4 Hz, 4H), 3.52 (q, J=5.4 Hz, 2H), 2.43 (t, J=2.4 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 145.45, 136.13, 132.22, 126.94, 115.39, 113.78, 79.56, 74.61, 70.50, 69.20, 69.19, 58.52, 42.75; HRMS (ES+) calc'd for C13H16N2O4 (M+H) m/z 265.1144 Found 265.1181.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:16]1([CH2:22][S:23][CH:24]([C:28]([OH:30])=O)[C:25]([OH:27])=[O:26])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:31]1[CH2:35]O[CH2:33][CH2:32]1>>[OH:30][C:28]1[CH:33]=[C:32]([CH2:31][CH2:35][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:27][C:25](=[O:26])[C:24]=1[S:23][CH2:22][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Reactant: C1CCOC1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: O=c1oc(CCc2ccccc2)cc(O)c1SCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4-phenethylacetophenone (0.786 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (0.977 g, 5.84 mmol), chlorotrimethylsilane (0.741 mL, 5.84 mmol), THF (58 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol). m.p. 164-166° C.; 1H NMR (400 MHz, DMSO-d6) δ2.75 (t, 3 H), 2.85 (t, 2 H), 3.92 (s, 2 H), 5.92 (s, 1 H), 7.23 (m, 9H), 11.69 (bs, 1 H).
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:28][CH2:29][CH2:30][CH3:31])[N:24]([CH2:25][CH2:26][NH2:27])[C:20]=2[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1>>[NH2:11][C:12]1[C:21]2[N:22]=[C:23]([CH2:28][CH2:29][CH2:30][CH3:31])[N:24]([CH2:25][CH2:26][NH:27][C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([OH:1])[N:7]=3)=[O:10])[C:20]=2[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1
Reactant: O=C(O)c1cccc(O)n1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCN
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCNC(=O)c1cccc(O)n1
Yield: 21.8 %

Procedure:
Using the general method of Example 97 6-hydroxypicolinic acid (0.24 g, 1.7 mmole) was reacted with 2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine (0.5 g, 1.7 mmol) to provide 0.15 g of N-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-6-hydroxy-2-pyridinecarboxamide as a white powder, m.p. 258-260° C. Analysis: Calculated for C21H23N7O2+½ CH3CN: %C, 62.03; %H, 5.80; %N, 24.66. Found: %C, 61.87; %H, 5.70; %N, 24.60.
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH2:21].[CH3:22][C:23]1[O:27][C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:25]([C:34](Cl)=[O:35])[CH:24]=1>ClCCl>[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH:21][C:34]([C:25]1[CH:24]=[C:23]([CH3:22])[O:27][C:26]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:35]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: Cc1cc(C(=O)Cl)c(-c2ccccc2)o1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.5 %

Procedure:
Triethylamine (0.128 mL; 0.886 mmol) was added to a mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.082 g; 0.354 mmol) and 5-methyl-2-phenylfuran-3-carbonyl chloride (0.082 g; 0.372 mmol) in dichloromethane (7 mL) at room temperature. The reaction mixture was stirred at room temperature for 20 minutes and washed with water. The organic layer was concentrated under reduced pressure and the crude material was purified by flash chromatography on silica gel (eluent 2 to 10% ethyl acetate in dichloromethane) to afford 0.116 g (86%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-methyl-2-phenylfuran-3-carboxamide as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:12][CH:13]([CH3:17])[C:14](Cl)=O>>[Cl:12][CH:13]([C:17]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:2]=2[N:1]=1)[CH3:14]
Reactant: CC(Cl)C(=O)Cl
Reactant: Nc1c(F)cccc1C(=O)O
Product: CC(Cl)c1nc2c(F)cccc2c(=O)o1

Procedure:
A mixture of 9.3 g of 2-amino-3-fluoro-benzoic acid and 18,6 ml of α-chloropropionyl chloride was refluxed for 3 hours and excess acid chloride was distilled off. The residue was concentrated under reduced pressure at 70° C. for 2 hours to obtain 2-(1-chloroethyl)-8-fluoro-4H-3,1-benzoxazine-4-one which was used as is for the next step.
Reaction SMILES: [Cl-].[NH4+:2].C[Al](C)C.C1(C)C=CC=CC=1.C[O:15][C:16]([C:18]1[NH:19][C:20]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[N:35]=2)=[C:21]([C:23]2[CH:33]=[CH:32][C:26]3=[N:27][N:28]([CH2:30]C)[N:29]=[C:25]3[CH:24]=2)[N:22]=1)=O>C1C=CC=CC=1>[CH3:30][N:28]1[N:27]=[C:26]2[CH:32]=[CH:33][C:23]([C:21]3[N:22]=[C:18]([C:16]([NH2:2])=[O:15])[NH:19][C:20]=3[C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[N:35]=3)=[CH:24][C:25]2=[N:29]1
Reactant: [NH4+]
Reactant: CCn1nc2ccc(-c3nc(C(=O)OC)[nH]c3-c3cccc(C)n3)cc2n1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cccc(-c2[nH]c(C(N)=O)nc2-c2ccc3nn(C)nc3c2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 17.1 %

Procedure:
Suspension of ammonium chloride (12 mg, 0.21 mmol) in 2 ml dry benzene was cooled to 0° C. 2M solution of trimethylaluminum in toluene (105 μl, 0.21 mmol) was slowly added and the reaction warmed to room temperature and stirred for 2 hours. This suspension was added to separate suspension of 4-(2-ethyl-2H-benzotriazol-5-yl)-5-(6-methyl-pyridin-2-yl)-1H-imidazole-2-carboxylic acid methyl ester (25 mg, 0.07 mmol)(prepared according to procedures analogous to example 1) in 1 ml dry benzene and the reaction heated at 50° C. overnight. The reaction was quenched by the addition of excess 1 M aqueous solution of hydrochloric acid. The reaction was extracted three times with chloroform. Mass spectrometry analysis of organic extracts show no presence of desired product. The remaining aqueous layer was concentrated to dryness. The aqueous extract reside was purified on Biotage Flash 12S silica gel column using chloroform/methanol gradient system (99:1 to 80:20, respectively) as eluent to afford 4-(2-methyl-2H-benzotriazol-5-yl)-5-(6-methyl-pyridin-2-yl)-1H-imidazole-2-carboxylic acid amide (4 mg, 16% yield). HPLC tR=3.70 min, LC-MS=344 (M+1).
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][CH2:23][CH2:24][CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(Cl)Cl>[CH2:22]([O:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1)[CH2:23][CH2:24][CH3:25]
Reactant: O=C(c1ccc(O)nc1)N1CCC[C@H]1CN1CCCC1
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCCOc1ccc(C(=O)N2CCC[C@H]2CN2CCCC2)cn1
Temperature: 85 °C
Reaction time: 10 h
Yield: 50.6 %

Procedure:
A mixture of (6-hydroxy-pyridin-3-yl)-(S)(+)-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone (85 mg, 0.31 mmol), 1-bromo butane (0.04 mL, 0.36 mmol), cesium carbonate (195 mg, 0.60 mmol), and catalytic KI in dioxane (5 mL) is stirred under nitrogen at 80-90° C. for 10 h. The reaction is diluted with CH2Cl2, filtered, and washed with brine. The organic portion is dried over Na2SO4, filtered and evaporated. The crude product is partially purified by a SCX column (MeOH wash, elution with 2M NH3 in MeOH. Further purification is accomplished using silica-gel column chromatography (gradient: 100% CH2Cl2 to 10% 2M NH3 in MeOH/CH2Cl2) to give the title compound (52 mg, 50%). MS (ES+) 332.2 (M+H)+.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].CO>C(OCC)(=O)C>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:25]3[CH2:26][CH2:27][CH:22]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[F:15])[CH2:23][CH2:24]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Fc1ccccc1C1CCNCC1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2ccccc2F)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(2-fluorophenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 40% overall yield. FDMS m/e=368 (M+ of free base). α[D]589 =-12.31 (c=0.61, methanol).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:30])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:22]3[N:23]=[CH:24][CH:25]=[C:26]([C:27](O)=[O:28])[C:21]3=[N:20][N:19]=2)=[CH:14][CH:13]=1.Cl.[C:34]([O:38][C:39](=[O:45])[C@H:40]([CH:42]([CH3:44])[CH3:43])[NH2:41])([CH3:37])([CH3:36])[CH3:35].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:43][CH:42]([CH3:44])[C@H:40]([NH:41][C:27]([C:26]1[C:21]2[N:22]([C:18]([C:15]3[CH:14]=[CH:13][C:12]([NH:11][C:10]([NH:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:2]([F:31])([F:1])[F:32])=[O:30])=[CH:17][CH:16]=3)=[N:19][N:20]=2)[N:23]=[CH:24][CH:25]=1)=[O:28])[C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:45]
Reactant: O=C(Nc1ccc(-c2nnc3c(C(=O)O)ccnn23)cc1)Nc1ccccc1C(F)(F)F
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](NC(=O)c1ccnn2c(-c3ccc(NC(=O)Nc4ccccc4C(F)(F)F)cc3)nnc12)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.2 %

Procedure:
To a solution of 3-(4-(3-(2-(trifluoromethyl)phenyl)ureido)phenyl)-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylic acid (66H) (38 mg, 0.086 mmol) in anhydrous DMF (1 mL) was added L-valine tert-butyl ester hydrochloride (23.4 mg, 0.11 mmol), EDC (24.7 mg, 0.13 mmol), HOBt (17 mg, 0.13 mmol), followed by DIPEA (45 μL, 0.26 mmol). The reaction mixture was stirred at room temperature for 3 h. Analysis by LC/MS indicated the starting material was consumed. The reaction mixture was partitioned between EtOAc and water, then the separated EtOAc layer was washed with water, saturated aqueous NaHCO3, saturated aqueous NaCl, dried (anhydrous Na2SO4), and concentrated. The obtained crude residue was purified using a silica gel cartridge (12 g) eluting with a gradient of EtOAc (0-100%) in hexanes to afford 33 mg (63%) of the title compound as a yellow solid. HPLC/MS (Method B): retention time=4.04 min, [M+H]+=598.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([CH3:34])=[C:32]([CH:35]=O)[NH:31][C:30]=2[CH3:37])=[O:28])[CH:23]=[CH:22][N:21]=[N:20]1>C(O)C.N1CCCCC1>[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[C:33]([CH3:34])=[C:32]([CH:35]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=4)[NH:13][C:12]3=[O:18])[NH:31][C:30]=2[CH3:37])=[O:28])[CH:23]=[CH:22][N:21]=[N:20]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Reactant: COc1cccc(-c2cccc3c2CC(=O)N3)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cccc(-c2cccc3c2C(=Cc2[nH]c(C)c(C(=O)NCCn4ccnn4)c2C)C(=O)N3)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 14.9 %

Procedure:
To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (67.9 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times and dried under high vacuum to provide pure product 5-[4-(3-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)amide as a yellow solid (18 mg, 15%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13](=O)[CH3:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].BrBr.BrC(C1C=CC(S(C)(=O)=O)=C(F)C=1)C(=O)C.[C:34]([NH:37][C:38]([NH2:40])=[S:39])(=[O:36])[CH3:35]>O1CCOCC1.C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[S:39][C:38]([NH:37][C:34](=[O:36])[CH3:35])=[N:40][C:13]=2[CH3:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CC(=O)NC(N)=S
Reactant: CC(=O)Cc1ccc(S(C)(=O)=O)c(F)c1
Agent: BrBr
Agent: CC(=O)C(Br)c1ccc(S(C)(=O)=O)c(F)c1
Solvent: C1COCCO1
Solvent: CCO
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
1-(3-Fluoro-4-methanesulfonyl-phenyl)-propan-2-one (Example 64c) (1.0 g, 4.34 mmol) is dissolved in dioxane (35 ml) and the solution is cooled to 10° C. at which point the mixture is semi frozen. Bromine (0.067 ml, 1.2 mmol, 0.3 eq.) is added slowly and the mixture is stirred for an additional 15 min in a semi frozen state. The mixture is then allowed to warm to room temperature and the solvent is removed to give a brown oil containing starting material and 1-bromo-1-(3-fluoro-4-methanesulfonyl-phenyl)-propan-2-one. This material is dissolved in ethanol (30 ml) and N-acetylthiourea (0.369 g, 3.1 mmol) is added in one portion. The mixture is stirred at 60° C. for 30 minutes then allowed to cool whereupon the product crystallised. Filtration affords the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:6][CH2:5]2.[CH2:12]([O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)[C:13]#[CH:14].C(N(CC)CC)C>CN(C=O)C.C(OCC)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[O:15][CH2:12][C:13]#[C:14][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:6][CH2:5]2
Reactant: O=C1OCc2cc(Br)ccc21
Reactant: C#CCOC1CCCCO1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1OCc2cc(C#CCOC3CCCCO3)ccc21
Temperature: 65 °C

Procedure:
To a mixture of 5-bromophthalide (2.00 g, 9.39 mmol), tetrahydro-2-(2-propynyloxy)-2H-pyran (5.3 ml, 37.6 mmol), copper(I) iodide (0.645 g, 3.39 mmol), triethylamine (1.90 g, 18.8 mmol) in DMF (20 ml), was added tetrakis(triphenylphosphine)palladium (1.30 g, 1.13 mmol). The mixture was heated at 65° C. under argon for 16 hours, cooled to room temperature and diluted with diethyl ether (250 ml). The filtrate was washed with brine (4×100 ml), dried over anhydrous Na2SO4, and concentrated to give a dark-reddish residue. Purification of the residue mixture by silica gel column chromatography, eluted with a gradient of EtOAc, led to 5-[3-(tetrahydro-pyran-2-yloxy)-prop-1-ynyl]-3H-isobenzofuran-1-one as a white solid (2.23 g, 87%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:26][CH2:25][CH2:24][NH:23]2)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].Br[CH:34]([OH:36])[CH3:35]>C1COCC1>[OH:36][CH2:34][CH2:35][N:23]1[CH2:24][CH2:25][CH2:26][CH:22]1[C:19]1[CH:20]=[CH:21][C:16]([NH:15][CH:14]=[C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=3)[C:8](=[O:12])[NH:7][C:6]2=[O:13])=[CH:17][CH:18]=1
Reactant: CC(O)Br
Reactant: O=C1NC(=O)c2ccc(I)cc2C1=CNc1ccc(C2CCCN2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1NC(=O)c2ccc(I)cc2C1=CNc1ccc(C2CCCN2CCO)cc1

Procedure:
6-Iodo-4-[(4-pyrrolidin-2-yl-phenylamino)-methylene]-4H-isoquinoline-1,3-dione (250 mg, 0.54 mmol) and Na2CO3 (2.0 g, 18.9 mmol) in THF (10 mL) is heated to reflux and bromoethanol (0.15 mL) is added every 45 min for 4 hours. The resulting mixture is then allowed to reflux overnight. After TLC suggested no starting material left, the THF is removed and after an aqueous work up, the desired product is isolated through chromatography (75 mg, 28%). MS (ESI): 504.0 (M+1)+1.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:21])[C:14]=2[N+:18]([O-])=O)[C:9]1=[O:22])[CH3:7])(=[O:3])[CH3:2].C(O)C.[Cl-].[NH4+].O>[Fe].C(Cl)Cl>[C:1]([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:21])[C:14]=2[NH2:18])[C:9]1=[O:22])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@H](C)n1ccc2c([N+](=O)[O-])c(C)ccc2c1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CC(=O)OC[C@@H](C)n1ccc2c(N)c(C)ccc2c1=O
Temperature: 85 °C

Procedure:
A round bottom flask was charged with (R)-2-(6-methyl-5-nitro-1-oxoisoquinolin-2(1H)-yl)propyl acetate (110.0 mg, 0.0003615 mol), ethanol (10 mL, 0.2 mol) and the reaction heated at 85° C. and ammonium chloride (193.4 mg, 0.003615 mol) in water (2 mL, 0.1 mol) was added followed by iron (80.7 mg, 0.00144 mol) in two portions and continued to heat for 30 minutes. The reaction went to completion and was poured into DCM (50 mL) and extracted. The removal of the solvent under reduced pressure gave the pure product as an oil. MS m/z=275.4 (M+H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:15]=[CH:14][N:13]=2)[CH:5]=1.[NH2:25][NH2:26]>CCO>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]([NH:11][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=3[CH3:10])[C:3]([NH:25][NH2:26])=[O:2])[N:17]=2)[CH:19]=1
Reactant: COC(=O)c1ccc(C)c(Nc2nccc(-c3cccnc3)n2)c1
Reactant: NN
Solvent: CCO
Product: Cc1ccc(C(=O)NN)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 25 °C

Procedure:
4-Methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzoic acid methyl ester 4 (3.2 g, 10 mmol) and hydrazine (6 mmol) are dissolved in dry EtOH (20 mL) and heated at reflux overnight. The mixture is cooled to room temperature. The solid is filtered, washed with water and dried under vacuum overnight to afford the product 6 as a light yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 9.68 (s, 1H), 9.26 (m, 1H), 9.06 (s, 1H), 8.69 (dd, J=4.7, 1.5H, 1H), 8.52 (d, J=5.1, 1.2 Hz, 1H), 8.43 (m, 1H), 8.1 (dd, J=5.8, 1.6 Hz, 1H), 7.56 (m, 2H), 7.46 (dd, J=5.1, 1.6 Hz, 1H), 7.3 (d, J=7.9 Hz, 1H), 4.45 (s, 1H), 3.33 (s, 3H), 3.31 (s, 1H). MS (m/z) (M+1)+: 321.1.
Reaction SMILES: O.[OH-].[Li+].[OH:4][C:5]1([C:24]2[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]3[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=3)[N:16]=2)[CH2:7][CH2:6]1.O.CO>C1COCC1>[OH:4][C:5]1([C:24]2[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:25]=2)[CH2:6][CH2:7][N:8]([C:11]2[CH:12]=[CH:13][C:14]3[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=3)[N:16]=2)[CH2:9][CH2:10]1
Reactant: O=C([O-])COc1ccc(C2(O)CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)COc1ccc(C2(O)CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
Lithium hydroxide monohydrate (177 mg, 4.21 mmol) was added to 2-[4-[4-hydroxy-1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]acetate (380 mg, 0.84 mmol) in a mixture of THF (7 mL), water (3.5 mL) and MeOH (3.5 mL). The resulting mixture was stirred at ambient temperature for 16 hours. The solvents were evaporated, then the residues were suspended in water and acidified to pH 4 with 1M citric acid. The resulting precipitate was collected by filtration, washed with water and dried to afford 2-[4-[4-hydroxy-1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]acetic acid (297 mg, 81%) as a white solid.