Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7].[Cl:35][C:36]1[CH:41]=[C:40](Cl)[N:39]=[CH:38][N:37]=1>>[F:32][C:29]([F:31])([F:30])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][N:13]([C:40]3[CH:41]=[C:36]([Cl:35])[N:37]=[CH:38][N:39]=3)[C:12]2=[O:23])[CH2:24][CH2:25]1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1Cl
Reactant: Clc1cc(Cl)ncn1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(c1cc(Cl)ncn1)CN2c1ccccc1Cl

Procedure:
The title compound, MS: m/e=618.0 (100, M+H+), 620.0 (80, M+H+), was prepared in accordance with the general method of example 71 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-(2-chloro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one and 4,6-dichloropyrimidine.
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([OH:14])[CH2:6][CH2:5]1.F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][C@@H:26]3[CH3:31])=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C>[CH3:31][C@H:26]1[CH2:27][O:28][CH2:29][CH2:30][N:25]1[C:22]1[N:20]2[CH:21]=[C:16]([O:14][C@H:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C@@H:4]([NH2:3])[CH2:5][CH2:6]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: C[C@H]1COCCN1c1nnc2ccc(F)cn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1COCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 56.3 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 187 mg, 4.68 mmol) in DMF (6.0 mL) was added Intermediate A (191 mg, 1.17 mmol) and the reaction stirred for 20 min. Intermediate 139b (276 mg, 1.17 mmol) was added in DMF (2.00 mL) and the reaction heated to 60° C. for 1 h. The reaction was cooled and quenched by dropwise addition of methanol, before being diluted with methanol and loaded onto an SCX-2 cartridge, which was washed with MeOH. The product was eluted with 2M NH3 in MeOH. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound (250 mg, 56%). LCMS (Method 4): Rt 1.83, m/z 380 [MH+].
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:4][C:5]([F:18])=[C:6]([C:13](OCC)=[O:14])[C:7]=1[C:8](OCC)=[O:9].O.[NH2:26][NH2:27]>C(O)C>[NH2:1][C:2]1[C:7]2[C:8](=[O:9])[NH:27][NH:26][C:13](=[O:14])[C:6]=2[C:5]([F:18])=[N:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1c(F)nc(-c2ccccc2)c(N)c1C(=O)OCC
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nc1c(-c2ccccc2)nc(F)c2c(=O)[nH][nH]c(=O)c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In 1 ml of ethanol was dissolved 90 mg of 3-amino-6-fluoro-4,5-diethoxycarbonyl-2-phenylpyridine, followed by addition of 2 ml of hydrazine monohydrate. The mixture was stirred at room temperature for 4 hours. After the solvent was distilled off, the resulting crystals were collected by filtration with ethanol. Water was added to the crystals, and the mixture was neutralized with 1N hydrochloric acid, followed by collection by filtration. A methanol solution of the crystals was mixed with silica gel and purified by silica gel column chromatography (eluent:ethyl acetate→ethyl acetate/methanol 1:1), followed by collection by filtration with water.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.ClCCl.[C:21](Cl)([O:23][CH2:24][CH:25]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22]>N1C=CC=CC=1>[C:21]([O:7][CH2:6][C@H:5]1[O:8][C@@H:1]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2][C@@H:3]1[OH:4])([O:23][CH2:24][CH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:32]2[C:37]1=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:22]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](COC(=O)OCC3c4ccccc4-c4ccccc43)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Thymidine (10 mmol) was dried by coevaporation with dry pyridine (2×30 ml), re-dissolved in dry pyridine (50 ml) and cooled using an acetone/carbon dioxide bath to a temperature of −20° C. The thymidine solution was magnetically stirred and a dichloromethane solution of FMOC-Cl (12 mmol, 1.2 eq. in 20 ml DCM) was added over a period of 60 minutes. The reaction mixture was warmed to room temperature and stirred for additional 60 minutes. The reaction mixture was partitioned between saturated sodium hydrogen carbonate (250 ml) and dichloromethane (3×100 ml). The organic phase was saved, combined, evaporated and dried by coevaporation with toluene (2×50 ml) forming an oily residue. A pure product was crystallized from the oily residue using dichloromethane (30 ml) and benzene (50 ml) as solvent. Yield 76%—white crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2OC)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:31]C1C=CC=CC=1C[Mg]Br>>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Br:31])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Br[Mg]Cc1ccccc1Br
Reactant: COc1ccccc1CC(O)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Product: OC(Cc1ccccc1Br)(c1ccccc1)C1CN(Cc2ccccc2)CCO1

Procedure:
The procedure for the synthesis of example 1a, 1-(4-Benzyl-morpholin-2-yl)-2-(2-methoxy-phenyl)-1-phenyl-ethanol, was followed using commercially available 2-bromobenzylmagnesium bromide (available from Rieke-Metals) as starting material and making non-critical variations, to yield the title compound. FIA [M+H]+=452/454.
Reaction SMILES: [CH2:1]([N:3]([CH2:46][CH3:47])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([C:14]1[C@H:15]([CH3:45])[C@@H:16]2[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH3:35])[C:32](=[O:44])[N:17]2[C:18]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])=O)=[O:5])[CH3:2].N1(C(C2C=CC=CC=2S)=O)CCCC[CH2:50][CH2:49]1>>[N:3]1([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12][C:14]2[C@H:15]([CH3:45])[C@@H:16]3[C@@H:33]([C@H:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH3:35])[C:32](=[O:44])[N:17]3[C:18]=2[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[O:20])=[O:5])[CH2:46][CH2:47][CH2:50][CH2:49][CH2:2][CH2:1]1
Reactant: CCN(CC)C(=O)c1ccccc1S(=O)C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]2[C@H]1C
Reactant: O=C(c1ccccc1S)N1CCCCCC1
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Sc3ccccc3C(=O)N3CCCCCC3)[C@H](C)[C@H]12
Yield: 95 %

Procedure:
Following a procedure similar to that described in Example 18, but using 4-nitrobenzyl (1R, 5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate (prepared as described in Example 39) and 2-(1-perhydroazepinylcarbonyl)phenylmercaptan as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 95%. This compound was found to be the same as the compound prepared as described in Example 36 and had the same physicochemical properties.
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:27]=[C:28]([CH3:36])[C:29]3[N:33]=[C:32]([CH3:34])[NH:31][C:30]=3[CH:35]=2)[CH:20]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:34][C:32]1[NH:31][C:30]2[CH:35]=[C:26]([O:25][C:21]3[N:22]=[CH:23][N:24]=[C:19]([N:14]4[CH2:13][CH2:12][C:5]5([O:4][C:3](=[O:17])[NH:2][C:7]6[N:8]=[CH:9][CH:10]=[CH:11][C:6]5=6)[CH2:16][CH2:15]4)[CH:20]=3)[CH:27]=[C:28]([CH3:36])[C:29]=2[N:33]=1
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Reactant: Cc1nc2c(C)cc(Oc3cc(Cl)ncn3)cc2[nH]1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc2c(C)cc(Oc3cc(N4CCC5(CC4)OC(=O)Nc4ncccc45)ncn3)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.15 g (0.59 mmol) spiro[piperidine-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 0.15 g (0.55 mmol) 6-(6-chloro-pyrimidin-4-yloxy)-2,4-dimethyl-1H-benzimidazole and 0.31 mL (1.8 mmol) DIPEA were combined in 1.5 mL DMF and stirred first of all overnight at RT then for 2 h at 50° C. The reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and the acetonitrile was evaporated down. The residue was made alkaline with 4N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried under HV.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH3:11].C([Li])(C)(C)C.CN([CH:20]=[O:21])C>O1CCCC1.CCOCC>[CH3:11][C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[C:7]([CH3:8])[C:2]=1[CH:20]=[O:21]
Reactant: COc1cc(C)c(Br)c(C)c1
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(C)c(C=O)c(C)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
To 4-bromo-3,5-dimethylanisole (20 g, 93.0 mmol) in 500 mL of tetrahydrofuran at -78° C. was added 120 mL of tert-Butyllithium (1.7M in pentane). The reaction mixture was stirred for 30 minutes at -78° C. and then DMF (136.0 g, 186.0 mmol) was added. The reaction mixture was stirred for 1 hour at -78° C. and for 1.5 hours at room temperature, diluted with 300 mL of ether, washed with 300 mL of water, acidified 1N HCl , and 5×100 mL of brine. The organic portion was dried (MgSO4), filtered, and evaporated to give the crude product, which was purified by flash column chromatography (silica gel, 90:10 hexane/ethylacetate) to yield 2,6-dimethyl-4-methoxybenzaldehyde (6), (9.50 g, 57.8 mmol, 62%) as a white solid; 1HNMR (CDCl3 δ 2.61 (s, 6H), 3.83 (s, 3H), 6.6 (s, 2H), 10.5 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:20])=[C:9]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14](Cl)[N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:21]1([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][N:23]=[N:22]1.C(N(C(C)C)CC)(C)C>CC(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:20])=[C:9]([NH:11][C:12]2[C:17]([F:18])=[CH:16][N:15]=[C:14]([N:29]3[CH2:28][CH2:27][CH:26]([N:21]4[CH:25]=[CH:24][N:23]=[N:22]4)[CH2:31][CH2:30]3)[N:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1cn(C2CCNCC2)nn1
Reactant: Cc1ccc(C(C)(C)C)cc1Nc1nc(Cl)ncc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1ccc(C(C)(C)C)cc1Nc1nc(N2CCC(n3ccnn3)CC2)ncc1F
Yield: 34.3 %

Procedure:
A solution of the product of Step 1 (123 mg, 0.42 mmol), 4-(1H-1,2,3-triazol-1-yl)piperidine (94 mg, 0.50 mmol) and diisopropylethylamine (2 mL) was irradiated in 2-propanol (2 mL), in a microwave oven, at 150° C. for 2 h. The mixture was cooled and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel Biotage 40S, eluting with EtOAc/hexane (0%-100%) to give the product (59 mg, 34%) as a solid.
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[O:11][N:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:8]=2[CH:7]=[C:6]([Cl:20])[C:5]=1[OH:21])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:30])C=1.O.[OH-].[Na+]>C(Cl)Cl>[Cl:20][C:6]1[C:5]2[O:21][CH:2]([CH2:3][OH:30])[CH2:1][C:4]=2[C:12]2[O:11][N:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:8]=2[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1c(O)c(Cl)cc2c(-c3ccccc3Cl)noc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: OCC1Cc2c(c(Cl)cc3c(-c4ccccc4Cl)noc23)O1
Temperature: 0 °C
Yield: 97.4 %

Procedure:
To the ice-cooled solution of 7-allyl-5-chloro-3-(2-chlorophenyl)-6-hydroxy-1,2-benzisoxazole (4.5 g) in methylene chloride (200 ml), 6.6 g of m-chloroperbenzoic acid was added in small portions under agitation, and the mixture was subsequently refluxed for 4 hours. After cooling the mixture, water and 50 ml of an aqueous solution of 2N sodium hydroxide were added and the mixture was extracted with methylene chloride. The methylene chloride layer was washed with water and dried. By distilling off the solvent, 4.6 g of 5-chloro-3-(2-chlorophenyl)-7,8-dihydrofuro[2,3-g]-1,2-benzisoxazole-7-methanol was obtained. m.p. 162°-163° C. This compound exhibited a mass spectrum having a molecular ion peak at m/e 335.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:16]=[N:15][C:14]3[C:13](=[O:17])[NH:12][C:11]([NH2:18])=[N:10][C:9]2=3)C=CC=CC=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][O:42][CH2:43]Cl)=[CH:35][CH:34]=1.CCO>CN(C=O)C>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][O:42][CH2:43][N:15]2[C:14]3[C:13](=[O:17])[NH:12][C:11]([NH2:18])=[N:10][C:9]=3[N:8]=[CH:16]2)=[CH:35][CH:34]=1
Reactant: Nc1nc2c(ncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1
Reactant: COc1ccc(OCCOCCl)cc1
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccc(OCCOCn2cnc3nc(N)[nH]c(=O)c32)cc1
Yield: 88.6 %

Procedure:
Compound 8 (2.72 g, 8.20 mmol) was prepared in 82% yield from 6 (3.64 g, 9.25 mmol) and (2-(p-methoxyphenyloxy)ethoxy)methyl chloride (2.18 g, 10.1 mmol) in DMF (100 mL) by the method used for the synthesis of 7: mp>250° C. (dec.); Rf(hexanes/EtOAc=1:2) 0.18; UV (EtOH) λmax 290 (ε 16,500); 1H NMR (DMSO-d6) δ 3.70 (s, 3 H, OCH3), 4.02-4.10 (m, 4 H, O(CH2)2O), 5.74 (s, 2 H, H2C1′), 5.88 (s, 2 H, NH2), 6.67, 6.70 (AA′BB′, J=9.30 Hz, 4 H, C6H4), 7.50 (s, 1 H, NH), 8.85 (s, 1 H, HC8); 13C NMR (DMSO-d6) δ 56.12 (CH3), 68.74 (OCH2), 70.20 (CH2Oph), 75.31(C1′), 107.25 (C5), 144.02 (C8), 153.25 (C4), 154.48 (C2), 159.26 (C6), 115.55, 116.38, 153.51, 155.56 (C6H4); MS m/z 331 (M+). Anal (C15H17N5O4) C, H, N; calcd (%): 54.37, 5.17, 21.13; found (%): 54.26, 5.20, 21.19.
Reaction SMILES: S(Cl)([Cl:3])=O.[O:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[C:6]1[C:14]([OH:16])=O>C1C=CC=CC=1>[O:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[C:6]1[C:14]([Cl:3])=[O:16]
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)c1cc2ccccc2o1
Temperature: 25 °C

Procedure:
Thionyl chloride (12.5 ml) was added to a suspension of benzofuran-2-carboxylic acid (20 g) in anhydrous benzene (250 ml). The mixture was refluxed for 3 hours, then allowed to cool down to room temperature. Removal of the volatiles left the desired acid chloride (21.8 g, 98%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8][C:9]([O:11]CC)=O)=[O:7].[NH2:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[CH:18]2>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:7])[CH2:8][C:9]([NH:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][N:19]=[CH:18]2)=[O:11]
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: CCOC(=O)CC(=O)c1ccco1
Product: O=C(CC(=O)c1ccco1)Nc1ccc2[nH]ncc2c1
Temperature: 180 °C

Procedure:
Ethyl 2-(fur-2-oyl)acetate (3 mL) was mixed with 5-aminoindazole (0.50 g) and heated in a SmithSynthesizer to 180° C. for 300 seconds. The crude mixture was then purified by silica gel chromatography to yield the title compound as a light purple solid. 1H NMR (keto tautomer) (400 MHz, DMSO-D6) δ ppm 12.99 (s, 1H), 10.22 (s, 1H), 8.11 (s, 1H), 8.05 (s, 1H), 8.02 (s, 1H), 7.58 (d, 1H), 7.49 (d, 1H), 7.40 (dd, 1H), 6.77 (dd, 1H), 3.96 (s, 2H). MS m/z 270 (M+1)+.
Reaction SMILES: [Na].[Cl:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([Cl:10])[C:4]=1[NH:11][S:12]([C:15]1[N:25]=[C:18]2[N:19]=[C:20]([CH3:24])[CH:21]=[C:22](Cl)[N:17]2[N:16]=1)(=[O:14])=[O:13].Cl.[CH2:27]([OH:29])[CH3:28]>>[Cl:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([Cl:10])[C:4]=1[NH:11][S:12]([C:15]1[N:25]=[C:18]2[N:19]=[C:20]([CH3:24])[CH:21]=[C:22]([O:29][CH2:27][CH3:28])[N:17]2[N:16]=1)(=[O:13])=[O:14]
Reactant: Cc1cc(Cl)n2nc(S(=O)(=O)Nc3c(Cl)ccc(C)c3Cl)nc2n1
Reactant: CCO
Agent: Cl
Agent: [Na]
Product: CCOc1cc(C)nc2nc(S(=O)(=O)Nc3c(Cl)ccc(C)c3Cl)nn12
Reaction time: 0.25 h

Procedure:
Sodium (0.69 g, 30 mmol) was added to about 50 ml of ethanol and allowed to react. The mixture was allowed to cool and then 4.0 g (9.8 mmol) of N-(2,6-dichloro-3-methylphenyl)-7-chloro-5-methyl-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide was added with stirring. After 15 minutes no starting material remained by thin layer chromatographic analysis although complete solution was never attained. The mixture was acidified with 6N hydrochloric acid and concentrated under reduced pressure. The residue was triturated with water and the solid removed by filtration and washed with water. It was then dissolved in aqueous sodium hydroxide using a minimum amount of the base and the aqueous solution was twice extracted with ether and acidified with 6N hydrochloric acid. The solid that formed was collected by filtration, washed with water, and dried. This was extracted with about 500 ml of boiling chloroform. The chloroform solution was concentrated to about 150 ml and allowed to cool to form a precipitate which was collected by filtration and dried to obtain 1.7 g (42 percent of theory) of the title compound as a white solid, m.p. 228°-9° C.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]2[NH:11][C:12](=[O:22])[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:3]=12.C(N(CC)CC)C.[CH:30]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:30]1([S:33]([N:11]2[C:4]3=[CH:5][C:6]4[S:10][CH:9]=[N:8][C:7]=4[C:2]([F:1])=[C:3]3[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:12]2=[O:22])(=[O:35])=[O:34])[CH2:32][CH2:31]1
Reactant: O=c1[nH]c2cc3scnc3c(F)c2n1-c1ccc(I)cc1F
Reactant: O=S(=O)(Cl)C1CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1n(-c2ccc(I)cc2F)c2c(F)c3ncsc3cc2n1S(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-fluoro-5-(2-fluoro-4-iodophenyl)-5H-imidazo[4′,5′:4,5]benzo[1,2-d]thiazol-6(7H)-one (70 mg, 0.16 mmol) in CH2Cl2 (5 mL) was added triethylamine (48 mg, 0.49 mmol) at 0° C. followed by cyclopropanesulfonyl chloride (35 mg, 0.25 mmol) and DMAP (10 mg). The mixture was stirred at room temperature for 1 h and washed with saturated NaHCO3 (aq.). The aqueous layer was extracted with CH2Cl2 (10 mL×2). The combined organic phase was washed with water (10 mL) and brine (10 mL) successively, dried over
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[N+:15]([O-])=O)[CH:5]=[CH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[H][H]>O1CCCC1.C(O)C.[C].[Pd]>[NH2:15][C:14]1[CH:13]=[CH:12][C:4]([CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:3][C:2]=1[OH:1]
Reactant: CCOC(=O)C=Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(N)c(O)c1
Yield: 105.9 %

Procedure:
In 30 ml of tetrahydrofuran and 130 ml of ethanol was dissolved 3.32 g of ethyl 3-hydroxy-4-nitrocinnamate. To the solution was added 100 mg of 10% palladium-carbon. The mixture was stirred under normal pressure in a hydrogen flow until absorption of hydrogen was discontinued. The catalyst was filtered off by suction and the filtrate was concentrated under reduced pressure to obtain 3.10 g of crude ethyl 4-amino-3-hydroxybenzenepropionate as an oily substance.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:25])[C:9]=1[NH:10][C:11]1[C:20]2[C:15](=[C:16]([OH:23])[C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[NH:14][C:13](=[O:24])[CH:12]=1.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>CS(C)=O>[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:25])[C:9]=1[NH:10][C:11]1[C:20]2[C:15](=[C:16]([O:23][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[NH:14][C:13](=[O:24])[CH:12]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1O
Reactant: CCOC(=O)CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)CCCCCOc1c(OC)ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c12
Temperature: 30 °C
Reaction time: 1 h

Procedure:
Sodium hydride (54 mg, 1.35 mmol) was added to a solution of 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-one (380 mg, 1.08 mmol) and DMSO (20, ml) room temperature under N2. After 1 h, ethyl 6-bromohexanoate (770 mg, 3.45 mmol) was added, and the mixture was heated at 30° C. for 5 h. The reaction was quenched with drops of water, poured into 0.5 M KH2PO4, and extracted with ethyl acetate (100 mL×3). The combined extracts were washed with water and then brine, dried, filtered, concentrated, and purified by silica gel chromatography (ethyl acetate: pet. ether) to give ethyl 6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-1,2-dihydroquinolin-8-yloxy)hexanoate: MS (ESI): 494.0.
Reaction SMILES: [C:1]([NH:20][C@@H:21]([CH2:25][CH3:26])[C:22](=[O:24])[CH3:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][Mg]I.O>CCOCC>[CH3:23][C:22]([OH:24])([C@@H:21]([NH:20][C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:25][CH3:26])[CH3:27]
Reactant: CC[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)=O
Reactant: C[Mg]I
Solvent: O
Solvent: CCOCC
Product: CC[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)(C)O

Procedure:
To a stirred solution of (3S)-3-(trityl-amino)-pentan-2-one (0.59 g, 1 eq, 1.72 mmol) in Et2O (100 mL) under an argon atmosphere at room temperature, was added methylmagnesium iodide (3 M in Et2O, 1.72 mL, 3 eq, 5.16 mmol) dropwise. The solution was placed in a preheated oil bath at 45° C. and refluxed at this temperature for 16 h. The mixture was recooled to 0° C., H2O (100 mL) added, the solution filtered through Celite, and the Celite washed with more Et2O (50 mL). The combined organic phase was separated, the aqueous phase was extracted with Et2O (2×50 mL), and the combined organic phase washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by silica gel column chromatography, eluted with hexane: Et2O (100:0→90:10) to afford the title compound as a light yellow oil. Yield: 0.10 g (16%). 1H-NMR (d6-DMSO, 250 MHz): δ 0.27 (t, J=7.10 Hz, —NHCH(CH2CH3(CH3)OH), 0.99 & 1.25 (2×s, 6H, —NHCH(CH2CH3)C(CH3)2OH), 0.75-1.42 (m, 2H, —NHCH(CH2CH3)C(CH3)2OH), 1.88 (m, 1H, —NHCH(CH2 CH3)C(CH3)2OH), 2.92 (m, 1H, —NHCH(CH2CH3)C(CH3)2OH), 4.32 (s, 1H, —NHCH (CH2CH3)C(CH3)2OH), 7.18-7.46 (m, 15H, 3×Ph).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:11](Cl)(=[O:15])/[CH:12]=[CH:13]/[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[C:11]([C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1)(=[O:15])/[CH:12]=[CH:13]/[CH3:14]
Reactant: c1ccc2ccccc2c1
Reactant: C/C=C/C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C/C=C/C(=O)c1cccc2ccccc12
Yield: 64.3 %

Procedure:
Naphthalene (128 mg), crotonoyl chloride (124 mg), and aluminium chloride (180 mg) were reacted in dichloromethane (1.5 mL) at from −20° C. to room temperature for 4 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (126 mg).