Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([O:25][C:26]([F:29])([F:28])[F:27])[CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][C:6]1[C:7]([NH2:20])=[CH:8][CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=2)[CH:11]=1.S([O-])([O-])=O.[Na+].[Na+].[C:36](=[O:39])(O)[O-:37].[Na+]>C(O)C.O>[F:1][C:2]1[CH:24]=[C:23]([O:25][C:26]([F:27])([F:29])[F:28])[CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:6]2[CH:11]=[C:10]([O:12][CH2:13][C:14]3[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=3)[CH:9]=[CH:8][C:7]=2[N:20]=[C:4]1[C@H:3]1[CH2:21][CH2:22][CH2:23][CH2:24][C@H:2]1[C:36]([OH:37])=[O:39]
Reactant: Cn1ccc(COc2ccc(N)c(NCc3ccc(OC(F)(F)F)cc3F)c2)n1
Reactant: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cn1ccc(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(OC(F)(F)F)cc4F)c3c2)n1
Temperature: 25 °C
Reaction time: 65 h
Yield: 60.2 %

Procedure:
To a solution of N1-(2-fluoro-4-(trifluoromethoxy)benzyl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)benzene-1,2-diamine (74.5 g, 0.18 mol) in ethanol (750 mL) was added a solution of racemic cis-3-hydroxyhexahydroisobenzofuran-1(3H)-one (28.4 g, 0.18 mol) and sodium sulfite (46.7 g, 0.36 mol) in H2O (750 mL). The reaction mixture was left open to air and stirred vigorously at RT. After 65 h, saturated sodium bicarbonate (600 mL) was added and the organic solvents were concentrated to dryness. The resulting suspension was partitioned between TBME (1.5 L) and H2O (1.5 L). The aqueous layer was partitioned between EtOAc (1.5 L) and HCl was added (160 mL, 6 M). The organic layer was separated and the aqueous was further extracted with ethyl acetate (500 mL). The combined organic layers were dried with MgSO4, filtered and concentrated to dryness. The resulting residue was dissolved in ethanol (450 mL) and H2O (100 mL), seeded (500 mg, 0.9 mmol) and stirred at room temperature for 1 h. H2O (300 mL) was then added portion wise over 30 min. The precipitate was filtered, rinsed with H2O/ethanol (2:1, 2×120 mL) and hexanes (2×200 mL) yielding the title compound as a light pink solid (59.8 g, 60.2%). The racemic material was separated into its constituent enantiomers through chiral stationary phase chromatography (stationary phase 600 g of Chiralpak IC, diameter: 110 mm, detector: Knauer superpreparative cell (0.5 mm), temperature: 35° Celsius, eluent: 0-20 min 40% heptane, 40% ethanol, 20% DCM (500 ml/min) (there was 0.10 v/v % acetic acid added to the eluents) to provide the title compound. MS (ESI): mass calcd. for C27H26F4N4O4, 546.2; m/z found, 547.0 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 7.63-7.59 (d, J=8.9, 1H), 7.34-7.30 (d, J=2.2, 1H), 7.11-7.06 (m, 1H), 7.06-7.02 (dd, J=8.9, 2.3, 1H), 6.95-6.90 (d, J=8.6, 1H), 6.88-6.84 (d, J=2.3, 1H), 6.81-6.74 (m, 1H), 6.31-6.28 (d, J=2.2, 1H), 5.38-5.28 (s, 2H), 5.09-5.04 (s, 2H), 3.89-3.84 (s, 3H), 3.24-3.14 (d, J=11.5, 1H), 3.08-3.02 (d, J=3.0, 1H), 2.65-2.51 (m, 1H), 1.90-1.78 (m, 2H), 1.78-1.70 (m, 1H), 1.69-1.58 (d, J=14.2, 2H), 1.56-1.39 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9]CC)=[O:8])=[CH:5][NH:4][N:3]=1.[F:12][CH:13]([F:29])[C:14](=O)[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=1)=O.CO.S(=O)(=O)(O)O>C(O)(=O)C.[OH-].[K+].O>[F:29][CH:13]([F:12])[C:14]1[N:3]2[N:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[C:2]2[N:1]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][CH:19]=2)[CH:15]=1
Reactant: CCOC(=O)c1c[nH]nc1N
Reactant: O=C(CC(=O)C(F)F)c1ccc(C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 57.4 %

Procedure:
A stirred mixture of commercially available 3-amino-4-ethoxycarbonyl-pyrazole (3.38 g, 22 mmol) and 4,4-difluoro-1-(4-trifluoromethyl-phenyl)-butane-1,3-dione (5.8 g, 22 mmol) in acetic acid (45 ml) was heated under reflux conditions for 1.5 h. The reaction mixture was evaporated and the crude product (yellow solid, 8.5 g, 22 mmol) was dissolved in a mixture of 2M KOH in methanol (176.5 ml, 0.35 mol) and water (85 ml). The reaction mixture was stirred at 60° C. for 1.5 h, poured into ice/water (200 ml), acidified with 3N sulfuric acid (pH=4) and stirred at room temperature for 30 min. The precipitate was collected by filtration and further purified by crystallization from diethylether/methanol to give the title compound (4.51 g, 57%) as an off-white solid. MS (ISP) 356.1 [(M−H)−]; m.p. 261° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[F:12])[C:6]([OH:8])=O)#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.O[NH:47][C:48](=[NH:68])[C:49]1[CH:58]=[CH:57][CH:56]=[C:55]2[C:50]=1[CH:51]=[CH:52][N:53]=[C:54]2[CH2:59][CH2:60][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:8][N:47]=[C:48]([C:49]3[CH:58]=[CH:57][CH:56]=[C:55]4[C:50]=3[CH:51]=[CH:52][N:53]=[C:54]4[CH2:59][CH2:60][C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[N:68]=2)[CH:9]=[CH:10][C:11]=1[F:12])#[N:2]
Reactant: N#Cc1cc(C(=O)O)ccc1F
Reactant: CC(C)(C)OC(=O)CCc1nccc2c(C(=N)NO)cccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCc1nccc2c(-c3noc(-c4ccc(F)c(C#N)c4)n3)cccc12
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 9.5 %

Procedure:
3-Cyano-4-fluorobenzoic acid (D31; 0.288 g, 1.744 mmol) was stirred at room temperature in 5 ml of DMF with HATU (0.723 g, 1.903 mmol) and DIPEA (0.831 ml, 4.76 mmol) for 10 mins. 1,1-Dimethylethyl 3-{5-[(hydroxyamino)(imino)methyl]-1-isoquinolinyl}propanoate (D36, 0.5 g, 1.585 mmol) and 5 ml of DMF were added, and the resulting mixture was stirred in a Biotage Initiator microwave at 120° C. for 30 mins. The solvent was removed under vacuum and the residue was purified by column chromatography on silica, eluting with 0-40% ethyl acetate in cyclohexane, to give the title compound as a white solid (67 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7](=O)[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][C:11]([O:16][CH3:17])=[CH:10][CH:9]=3.[Cl-].[OH:20][NH3+:21].C(OCC)(=O)C>C(O)C.O>[OH:20][N:21]=[C:7]1[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2
Reactant: [NH3+]O
Reactant: COc1ccc2c(c1)-c1cc(OC)ccc1C2=O
Agent: [Cl-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)-c1cc(OC)ccc1C2=NO
Temperature: 0 °C
Yield: 85.4 %

Procedure:
4.7 g (0.0195 mol) of 3,6-dimethoxyfluoren-9-one and 2.7 g (0.039 mol) of hydroxylammonium chloride are heated at 90° C. in a mixture of 50 ml of ethanol and 20 ml of water. After five hours the solution is poured into ice/water and ethyl acetate is added. The resulting suspension is filtered and the product that has been filtered off is washed with water and dried in vacuo. 4.25 g (86%) of 9-hydroxyimino-3,6-dimethoxyfluorene are obtained in the form of a yellow solid having a melting point of 230-240° C. According to 1H-NMR, that crude product still contains amounts of 3,6-dimethoxyfluoren-9-one. The crude product is, however, used in the subsequent step without being further purified and 3,6-dimethoxyfluoren-9-one is not removed until the end product is purified. Elemental analysis: C15H13NO3 (255.27)
Reaction SMILES: [CH2:1]([CH:11]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[C:12]([NH:14][C:15]1[CH:16]=[C:17]([CH:22]=[C:23]([NH:25][C:26](=[O:50])[CH:27]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:24]=1)[C:18]([O:20]C)=[O:19])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[K+].CO.O>C(OCC)C>[CH2:1]([CH:11]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[C:12]([NH:14][C:15]1[CH:16]=[C:17]([CH:22]=[C:23]([NH:25][C:26](=[O:50])[CH:27]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:24]=1)[C:18]([OH:20])=[O:19])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCCCC(CCCCCCCCCC)C(=O)Nc1cc(NC(=O)C(CCCCCCCCCC)CCCCCCCCCCCC)cc(C(=O)OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: CCCCCCCCCCCCC(CCCCCCCCCC)C(=O)Nc1cc(NC(=O)C(CCCCCCCCCC)CCCCCCCCCCCC)cc(C(=O)O)c1
Temperature: 25 °C

Procedure:
Methyl 3,5-bis(2′-decyltetradecanamido)benzoate from Step 2, potassium hydroxide (0.38 g, 5.77 mmol), and methanol (20 mL) were added to a 50 mL vessel and heated to reflux. Deionized water (10 mL) was then added and the reaction was held at reflux overnight. The reaction was then cooled to room temperature, which resulted in the formation of an oil phase. Diethyl ether (20 mL) was added and the aqueous phase was removed. The organic phase was then washed successively with 1 Molar hydrochloric acid (30 mL), 0.1 Molar hydrochloric acid (30 mL), and deionized water twice (30 mL each), before concentrating the ether layer by rotary evaporation and drying in vacuo to give 3,5-bis(2′-decyltetradecanamido)benzoic acid as a light brown waxy solid (1.33 g, 99%). The product was identified by 1H and 13C NMR spectroscopy and ESI-MS and was of satisfactory purity. The product was believed to be of the formula
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)=[N:12][N:11]3[C:29]=2I)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:37][C:38]1[CH:43]=[C:42](B(O)O)[CH:41]=[CH:40][N:39]=1>O1CCCC1.O.C(Cl)(Cl)Cl.[Pd+2]>[Cl:37][C:38]1[CH:43]=[C:42]([C:29]2[N:11]3[N:12]=[C:13]([N:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)[CH:14]=[CH:15][C:10]3=[N:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:41]=[CH:40][N:39]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3nc(-c4ccc(F)cc4)c(I)n3n2)CC1
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3nc(-c4ccc(F)cc4)c(-c4ccnc(Cl)c4)n3n2)CC1
Yield: 78.1 %

Procedure:
To a suspension of 1.25 g (2.39 mmol) of tert-butyl 4-[2-(4-fluorophenyl)-3-iodoimidazo[1,2-b]pyridazin-6-yl]piperazine-1-carboxylate in a mixture of tetrahydrofuran and water are added 2.33 g (7.17 mmol) of cesium carbonate and 0.45 g (2.9 mmol) of 2-chloropyridine-4-boronic acid. After sparging with a stream of argon for a few moments, 0.18 g (0.21 mmol) of [1,1′-bis(diphenylphosphino)ferrocene]dichloro)palladium(II) (PdCl2(dppf)) is added and the reaction mixture is refluxed under argon for 18 hours. The solvent is then stripped off under reduced pressure, the residue is taken up in chloroform, the organic phase obtained is washed with water, dried over sodium sulfate and filtered, and the filtrate is concentrated under reduced pressure. The brown solid obtained is purified by chromatography on silica gel (50 g), eluting with a mixture of dichloromethane, methanol and aqueous ammonia (95/5/0.5). The product obtained is crystallized from 20 ml of refluxing acetonitrile to give 0.95 g of a white powder after cooling, filtering off and drying.
Reaction SMILES: [CH:1]1([NH:4][C:5]([CH:7]([NH:12][C:13]([CH:15]([C:20](=[CH2:24])[C:21]([OH:23])=[O:22])[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:14])[C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:3][CH2:2]1.[SH:25][C:26]1[S:27][CH:28]=[CH:29][CH:30]=1.C(OCC)C>CO>[CH:1]1([NH:4][C:5]([CH:7]([NH:12][C:13]([CH:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH:20]([CH2:24][S:25][C:26]2[S:27][CH:28]=[CH:29][CH:30]=2)[C:21]([OH:23])=[O:22])=[O:14])[C:8]([CH3:10])([CH3:9])[CH3:11])=[O:6])[CH2:3][CH2:2]1
Reactant: C=C(C(=O)O)C(CC(C)C)C(=O)NC(C(=O)NC1CC1)C(C)(C)C
Reactant: Sc1cccs1
Solvent: CO
Solvent: CCOCC
Product: CC(C)CC(C(=O)NC(C(=O)NC1CC1)C(C)(C)C)C(CSc1cccs1)C(=O)O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
2-[1-(1 -Cyclopropylcarbamoyl-2,2-dimethyl-propylcarbamoyl)-3-methyl-butyl]-acrylic acid (4.40 g, 12.4 mmol) was dissolved in methanol (10 ml) and placed under a blanket of argon prior to addition of 2-mercaptothiophene (4.5 ml). The mixture was stirred overnight at 60° C. under argon with the exclusion of light. The solvent was removed under reduced pressure to leave an oil to which was added cold diethyl ether (200 ml). The product precipitated on standing in an ice bath and was removed by filtration and washing with thoroughly with cold diethyl ether. The product was further purified by trituration with hot ethyl acetate and column chromatography (silica gel, gradient elution, 0-20% methanol in dichloromethane). Fractions were combined and evaporated to yield the title compound as an pale yellow solid (6.95 g, including minor impurities). 1H-NMR (CDCl3, partial deuterium exchange); δ 8.10 (1H, m), 7.85 (1H, d, J=9.2 Hz), 7.35 (1H, m), 7.03 (1H, m), 6.88 (1H, m), 4.06 (1H, d, J=9.2 Hz), 2.85 (1H, m), 2.67 (2H, m), 2.51 (1H, m), 1.53 (1H, m), 1.25 (1H, m), 1.02 (1H, m), 0.87 (9H, s), 0.76 (3H, d, J=6.4 Hz), 0.71 (3 H, d,J=6.5 Hz), 0.61 (2H, m) and 0.32 (2H, m).
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1Cl.[Cl-].[Al+3].[Cl-].[Cl-].Cl.[C:15]1([CH:22]=[CH:21][CH:20]=[C:18]([OH:19])[CH:17]=1)[OH:16].[CH3:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=1[CH3:30]>C1C=CC(Cl)=C(Cl)C=1.O>[OH:16][C:15]1[CH:17]=[C:18]([OH:19])[CH:20]=[CH:21][C:22]=1[C:2]1[N:4]=[C:5]([C:26]2[CH:27]=[CH:28][C:29]([CH3:30])=[C:24]([CH3:23])[CH:25]=2)[N:7]=[C:8]([C:26]2[CH:27]=[CH:28][C:29]([CH3:30])=[C:24]([CH3:23])[CH:25]=2)[N:1]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Cc1ccccc1C
Reactant: Oc1cccc(O)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: O
Product: Cc1ccc(-c2nc(-c3ccc(C)c(C)c3)nc(-c3ccc(O)cc3O)n2)cc1C
Temperature: 5 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
To a flask equipped with a reflux condenser, a nitrogen inlet, and a mechanical stirrer is added 50 gm of cyanuric chloride, 191 mL of ODCB and 108.4 gm of aluminum chloride. The mixture is cooled in an ice-bath to 5° C. and 6.5 gm of concentrated HCl was added over a period of 20 minutes. The mixture was allowed to warm to room temperature, and stirred for 2 hours. It was cooled back to 5° C. and then 54.7 gm of o-xylene was slowly added over a period of 3 hours, while allowing the temperature to go up to 21° C. The mixture was stirred at room temperature for additional 16 hours. The reaction mixture was heated to about 63° C. and 34 gm of resorcinol was added over a period of about 30 minutes. The mixture was held at about 75° C. for 3 hours. It was then added to 500 mL water and ODCB distilled off azeotropically. The precipitated solid was filtered off and washed with water. The material was dried in a vacuum oven to give 96 gm of crude 2-(2,4-dihydroxyphenyl)-4,6-bis(3,4-dimethylphenyl)-1,3,5-triazine. The HPLC analysis showed it to contain about 5% of polyresorcinol-triazines and 10.7% tris-o-xylyl-triazine.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[CH:21]=3)=[O:18])[CH2:14][OH:15])[CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:39](OC(=O)C)(=[O:41])[CH3:40]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:8][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[CH:21]=3)=[O:18])[CH2:14][O:15][C:39](=[O:41])[CH3:40])[CH2:10]2)=[CH:30][CH:31]=1
Reactant: COc1cc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(Cl)cc3)C2)cc(OC)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)N[C@@H](CCN2CC(Oc3ccc(Cl)cc3)C2)COC(C)=O)cc(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1-{(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(3,5-dimethoxy-phenyl)-urea (0.05 g, 0.111 mmol) and triethylamine (0.031 ml, 0.222 mmol) in DCM (3 ml) is treated with acetic anhydride and left to stir at room temperature for 3 hours. The reaction mixture is partitioned between DCM and water. The organic phase is washed with sodium bicarbonate solution, dried over magnesium sulphate and evaporated to afford acetic acid (S)-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-2-[3-(3,5-dimethoxy-phenyl)-ureido]-butyl ester. [M+H] 492.08
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[C:6](/Cl)=[N:7]\[OH:8])=[O:5].[CH3:10][CH:11]([O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)[CH2:12][C:13]#[CH:14].C(N(CC)CC)C>C(OCC)C>[O:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[O:15][CH:11]([CH3:10])[CH2:12][C:13]1[O:8][N:7]=[C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:14]=1
Reactant: CCOC(=O)/C(Cl)=N\O
Reactant: C#CCC(C)OC1CCCCO1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(CC(C)OC2CCCCO2)on1

Procedure:
Ethyl chlorooximidoacetate (1 g, 6.60 mmol) and 2-(pent-4-yn-2-yloxy)tetrahydro-2H-pyran (3.33 g, 19.80 mmol) were dissolved in diethyl ether (20 ml) and the mixture was stirred vigorously. Triethylamine (0.920 ml, 6.60 mmol) diluted with diethyl ether was added dropwise. The reaction mixture was extracted with water and the organic phase dried with MgSO4, filtered and evaporated. The product was used in the next step without further purifications. LC-MS: [M+1]=284.32.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Product: O=S(=O)(c1ccc(Br)cc1)N1CCOCC1
Yield: 96.3 %

Procedure:
Prepared by general procedure III from 4-bromobenzenesulfonyl chloride (5.0 g, 20 mmol) and morpholine (1.88 g, 22 mmol) to give the title compound (5.90 g, 98%) as a white crystalline solid. MS (ISP) 306.1 [(M+H)+].
Reaction SMILES: [C:1]([O-:14])(=[O:13])[CH2:2][CH2:3]CCCCCCCCC.[C:15]([O-:28])(=[O:27])[CH2:16][CH2:17]CCCCCCCCC.C([Sn+2]CCCC)CCC.COC1C=CC(O)=CC=1.O=C=[N:49]C1CC(C)(C)CC(C)(CN=C=O)C1.[C:63]([O:67][CH2:68][CH2:69]O)(=[O:66])C=C>C(OCCCC)(=O)C>[C:1]([OH:14])(=[O:13])[CH:2]=[CH2:3].[C:15]([OH:28])(=[O:27])[CH:16]=[CH2:17].[NH2:49][C:63]([O:67][CH2:68][CH3:69])=[O:66]
Reactant: C=CC(=O)OCCO
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Reactant: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Agent: COc1ccc(O)cc1
Solvent: CCCCOC(C)=O
Product: C=CC(=O)O
Product: CCOC(N)=O
Temperature: 55 °C
Reaction time: 3 h

Procedure:
Into a 1-liter 3-necked flask provided with a stirrer and thermometer were metered in 425 parts of dodecabutyleneglycol (tradename: PTG-850, manufactured by Hodogaya Chemical Industries Co., Ltd, molecular weight 850), 0.43 parts of di-n-butyltin dilaurate, 0.4 parts of hydroquinone monomethylether, followed by stirring at 55° C. and adding dropwise, 222 parts of isophorone diisocyanate in 3 hours. After completion of the dropwise addition, the reaction was further continued for 3 hours at 70° C. and then temperature was reduced to 60° C., then 122 parts of 2-hydroxyethyl acrylate was added dropwise in 2 hours. Since the viscosity increased, 193 parts of n-butyl acetate was added and the reaction was continued for 5 hours at 70° C. to give an urethane diacrylate (UPA-2) with a solids concentration of 80% by weight.
Reaction SMILES: [OH-].[Li+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[CH2:12][C:13]([O:15]C)=[O:14].CO>O.C1COCC1>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[CH2:12][C:13]([OH:15])=[O:14]
Reactant: COC(=O)Cc1cc2ccccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cc1cc2ccccc2[nH]1
Yield: 72.7 %

Procedure:
A solution of lithium hydroxide (346 mg, 8.25 mmol) in water (2 ml) was added to methyl indole-2-acetate (520 mg, 2.75 mmol) (prepared using the method of Capuano et al, Chem. Ber., 1986, 119, 2069) in THF (2 ml) and methanol (6 ml) and the mixture stirred for 1 h. The mixture was concentrated in vacuo, diluted with water (20 ml) and extracted with diethyl ether (2×10 ml). The aqueous layer was carefully acidified to pH 2 with 1M HCl and extracted into dichloromethane (3×20 ml). The extracts were dried (MgSO4) and evaporated in vacuo to give indole-2-acetic acid (350 mg, 72%) as a pink solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1.[NH3:29]>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:29])=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1
Reactant: N
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)Cl)cc3C)cc12
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(N)=O)cc3C)cc12

Procedure:
4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzamide was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzoyl chloride (Example 116/Step 2) and ammonia following the procedures described for Example 117. 1H NMR (CDCl3): δ 8.60 (s, 1H), 8.35 (s, 1H), 8.05 (d, 1H), 7.65 (s, 1H), 7.51-7.53 (m, 2H), 7.13-7.21 (m, 2H), 3.09-3.16 (m, 4H), 2.51 (s, 3H), 2.34 (s, 3H). LRMS [M+H]=371.2
Reaction SMILES: [OH-].[K+].O.O.[Cl:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]([Cl:15])[C:7]=1[S:16]([OH:19])(=O)=[O:17].P(Cl)(Cl)(Cl)(Cl)[Cl:21].O=P(Cl)(Cl)Cl>CO>[Cl:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]([Cl:15])[C:7]=1[S:16]([Cl:21])(=[O:19])=[O:17]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)O)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 96.6 %

Procedure:
Potassium hydroxide (12.07 g, 0.215 mol) was added to a solution of 2,6-dichloro-3-nitrobenzenesulfonic acid dihydrate (44.35 g, 0.144 mol) in MeOH (850 mL) and the reaction was allowed to stir at room temperature for 14 hr. The reaction mixture was concentrated and the resulting solid was dried in vacuo overnight. To this was added PCl5 (30.00 g, 0.144 mol) followed by POCl3 (475 mL) and the mixture was refluxed overnight. The reaction was then cooled to room temperature and concentrated. The resulting mixture was taken up in EtOAc and chilled in an ice bath. Ice chunks were slowly added to the reaction mixture to quench any leftover PClI. When bubbling ceased, water was added and the reaction mix was extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated to yield 2,6-Dichloro-3-nitrobenzenesulfonyl chloride (40.42 g, 97%). 1H NMR (DMSO-d6) δ 7.88 (d, 1H), 7.75 (d, 1H).