Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:23]1[C:32]2[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[C:27]=2[CH:26]=[CH:25][N:24]=1>>[F:18][C:17]1[C:12]2[N:13]([C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:28]4[CH:29]=[CH:30][CH:31]=[C:32]5[C:27]=4[CH:26]=[CH:25][N:24]=[CH:23]5)[CH:3]=3)=[CH:10][N:11]=2)[CH:14]=[CH:15][C:16]=1[C:19]([OH:22])([CH3:21])[CH3:20]
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: OB(O)c1cccc2cnccc12
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cccc5cnccc45)c3)cnc2c1F
Yield: 5 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and isoquinoline-5-boronic acid were coupled in the same way as in Example 30 to give 2-{8-fluoro-3-[4-fluoro-3-(isoquinolin-5-yl)phenyl]imidazo[1,2-α]pyridin-7-yl}propan-2-ol as an off-white solid (7 mg, 5%): m/z (ES+) 416 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:20][CH2:19][N:11]3[C:12]4[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=4[CH:18]=[C:10]3[C:9]2=[O:21])[C:3]=1[CH2:22][OH:23].C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>ClCCl>[C:31]([O:23][CH2:22][C:3]1[C:4]([N:8]2[CH2:20][CH2:19][N:11]3[C:12]4[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=4[CH:18]=[C:10]3[C:9]2=[O:21])=[N:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: O=C1c2cc3c(n2CCN1c1nccc(Cl)c1CO)CCCC3
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCc1c(Cl)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 25 °C
Yield: 0.1 %

Procedure:
To a mixture of 113g (900 mg, 2.7 mol) and triethylamine (900 mg, 9.0 mol) in dichloromethane (5 mL) was added dropwise acetyl chloride (600 mg, 6.0 mol) while stirring at room temperature and stirred for another 1 h. The reaction mixture was concentrated and purified by silica-gel column chromatography eluting with dichloromethane to afford 113h as white solid (950 mg, 94%). MS: [M+H]+ 374.
Reaction SMILES: [C:1]1([C:9]([C:11]([C:13]2[CH:20]=[CH:19][C:16]([O:17]C)=[CH:15][CH:14]=2)=[O:12])=[O:10])[CH:8]=[CH:7][C:4]([O:5]C)=[CH:3][CH:2]=1.C1(C(C(C2C=CC(OC)=CC=2)O)=O)C=CC(OC)=CC=1.C(O)(=O)C.Br>N1C=CC=CC=1.S([O-])([O-])(=O)=O.[Cu+2]>[OH:5][C:4]1[CH:3]=[CH:2][C:1]([C:9]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([OH:17])=[CH:19][CH:20]=2)=[O:12])=[O:10])=[CH:8][CH:7]=1
Reactant: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Agent: [Cu+2]
Agent: Br
Agent: COc1ccc(C(=O)C(O)c2ccc(OC)cc2)cc1
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: O=C(C(=O)c1ccc(O)cc1)c1ccc(O)cc1
Yield: 94.4 %

Procedure:
Anisil (6.5 g), made by the oxidation of anisoin with copper sulphate in pyridine, was added to acetic acid (50 g) and heated to reflux to form a solution. Hydrobromic acid (s.g. 1.48) was added at reflux until anisil just started to precipitate (about 30 ml HBr being needed). After 2 hours' reflux, more hydrobromic acid (50 ml) was added, and the solution was refluxed for a further 2 hours. After this time, thin layer chromatography showed complete conversion into a single product. The solution was poured into cold water (600 ml) to precipitate a white solid. This was filtered off, washed with water and dried to give 5.5 g of 4,4'-dihydroxybenzil. This was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27].C(O)(=O)C.Cl>O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27]
Reactant: CCOC(=O)CCCCCCOc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CC1(C2CCCC2)Cc2cc(OCCCCCCC(=O)O)c(Cl)c(Cl)c2C1=O

Procedure:
A mixture of ethyl 7-[(6,7-Dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]heptanoate (16 g., 0.035 mole), acetic acid (100 ml.) and 6N hydrochloric acid (50 ml.) is stirred and refluxed for 6 hours. The mixture is poured into water (400 ml.) where upon the product slowly solidifies. The product is removed by filtration, dried and recrystallized from a mixture of tetrahydrofuran, ether and petroleum ether (50, 100 and 200 ml., respectively) to give 7-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]heptanoic acid, 12.1 g., m.p. 107°-110° C.
Reaction SMILES: [OH:1][C@H:2]([CH2:18][O:19][C:20]1[CH:29]=[CH:28][C:23]2[N:24]=[C:25]([CH3:27])[S:26][C:22]=2[CH:21]=1)[CH2:3][N:4]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][C@@H:5]1[CH3:17]>FC(F)(F)C(O)=O>[CH3:17][C@H:5]1[CH2:6][NH:7][CH2:8][CH2:9][N:4]1[CH2:3][C@H:2]([OH:1])[CH2:18][O:19][C:20]1[CH:29]=[CH:28][C:23]2[N:24]=[C:25]([CH3:27])[S:26][C:22]=2[CH:21]=1
Reactant: Cc1nc2ccc(OC[C@@H](O)CN3CCN(C(=O)OC(C)(C)C)C[C@@H]3C)cc2s1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2ccc(OC[C@@H](O)CN3CCNC[C@@H]3C)cc2s1

Procedure:
tert-Butyl (3S)-4-[(2S)-2-hydroxy-3-(2-methylbenzothiazol-6-yloxy)propyl]-3-methylpiperazinecarboxylate (3 g) in trifluoroacetic acid (50 ml) was stirred at room temperature for 72 hours. The TFA was removed by evaporation under reduced pressure and the residue was dissolved in 50 ml of MEOH. The pH adjusted to between pH 8-pH 9 using tris-resin(Argonaut) rendering (2S)-1-((2S)-2-methylpiperazinyl)-3-(2-methylbenzothiazol-6-yloxy)propan-2-ol, which was used without further purification.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].I[C:10]1[C:18]2[NH:17][C:16]3[CH2:19][CH2:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][C:15]=3[C:14]=2[CH:13]=[CH:12][CH:11]=1.[N:30]1([CH2:36][CH2:37][OH:38])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>C(Cl)Cl.[Cu]I>[N:30]1([CH2:36][CH2:37][O:38][C:10]2[C:18]3[NH:17][C:16]4[CH2:19][CH2:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][C:15]=4[C:14]=3[CH:13]=[CH:12][CH:11]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3c(I)cccc3c2C1
Reactant: OCCN1CCCCC1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2[nH]c3c(OCCN4CCCCC4)cccc3c2C1
Temperature: 150 °C
Yield: 25 %

Procedure:
Tri-potassium orthophosphate (1.92 g, 9.04 mmol), tert-butyl 6-iodo-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (1.80 g, 4.52 mmol) and copper(I) iodide (0.430 g, 2.26 mmol) were suspended in 2-(piperidin-1-yl)ethanol (15 ml, large excess) and sealed into a microwave tube after bubbling argon through the solution for 5 minutes. The reaction was heated to 150° C. for 1.5 hours in the microwave reactor and cooled to RT. This reaction was repeat three times and the combined crude reaction mixture worked as follows. The mixture was diluted with DCM (50 mL) and washed with NaOH (3×30 mL), dried over sodium sulfate and the solvent removed under reduced pressure. The crude product was purified by preparative HPLC (0.1% HCOOH, CH3CN, H20). Fractions containing the desired compound were evaporated to dryness to afford tert-butyl 6-(2-(piperidin-1-yl)ethoxy)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (1.33 g, 25% yield) as a yellow gum.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[C:6]1([OH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[OH:12][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:2]([OH:3])[C:1]([OH:5])=[O:4]
Reactant: O=CC(=O)O
Reactant: Oc1ccccc1
Product: O=C(O)C(O)c1ccccc1O

Procedure:
reacting glyoxylic acid with a boric acid ester of a phenol of the formula: ##STR9## under acid conditions to form a boric acid ester of a 2-hydroxymandelic acid;
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C@H:12]([CH:17]([CH3:19])C)[C:13]([O:15][CH3:16])=[O:14])[C:8]2=[O:11])=[CH:4][CH:3]=1.Cl.N[C:22]1(C(OC)=O)CCC[CH2:23]1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C:12]3([C:13]([O:15][CH3:16])=[O:14])[CH2:17][CH2:19][CH2:23][CH2:22]3)[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: COC(=O)C1(N)CCCC1
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2ccc(Br)cc2C1=O
Agent: Cl
Product: COC(=O)C1(N2Cc3ccc(Br)cc3C2=O)CCCC1

Procedure:
The compound of example 341 was prepared analogous to compound of example 329 by reaction of the compound of example 328 and methyl 1-aminocyclopentanecarboxylate hydrochloride.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][C:6]=1C=O.OC1C=CC(C=O)=C[C:18]=1[N+:25]([O-])=O.Cl.NO.N1C=CC=CC=1.[Se](=O)=O>C(Cl)(Cl)Cl.C(O)C>[F:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:9][C:10]([C:18]#[N:25])=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14]
Reactant: O=Cc1cccc([N+](=O)[O-])c1OCCF
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Agent: Cl
Agent: NO
Agent: O=[Se]=O
Solvent: c1ccncc1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc(OCCF)c([N+](=O)[O-])c1

Procedure:
In a manner similar to Sosnovsky et al. (Synthesis, p 722, (1979)), the reaction of 3.0 grams (0.014 mole) of -(2-fluoroethoxy)-3-nitrobenzaldehyde (prepared by the method of Example 1 from 4-hydroxy-3-nitrobenzaldehyde), 1.1 gram (0.015 mole) of hydroxylamine hydrochloride, and 1.2 ml (0.014 mole) of pyridine (dissolved in 10 ml of chloroform) in 50 ml of chloroform and ethanol (70/30 mixture) followed by treatment with 1.6 gram (0.014 mole) of selenium dioxide yielded 2.3 grams of 4-cyano-2-nitrophenyl 2-fluoroethyl ether as a solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH2:7][C:8]1[C:9](=[N:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:10]([NH2:13])=[N:11][N:12]=1>CN(C=O)C>[NH2:13][C:10]1[C:9](=[N:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[C:8]([CH2:7][NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[N:12][N:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCC1=NN=C(N)C1=NNc1cccc(F)c1
Solvent: CN(C)C=O
Product: CS(=O)(=O)NCC1=NN=C(N)C1=NNc1cccc(F)c1
Yield: 52 %

Procedure:
Methanesulfonyl chloride was reacted with 5-(aminomethyl)-4-(3-fluorophenylhydrazono)-3-amino-4H-pyrazole (60 mg, 0.25 mmole) in DMF at ambient temperature to yield 43 mg (52%) of the title compound. 1H NMR (ppm, 300 MHz, DMSO-d6) δ 11.49 (br s, 1H), 7.20-7.50 (m, 3H), 6.70-7.10 (m, 2H), 6.45 (br s, NH2), 4.40 (d, 2H), 2.79 (s, 3H, CH3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[C:19]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH3:30])[CH:25]=[C:24]2[CH:31]1[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1)#[N:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.Cl>ClC(Cl)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([N:13]3[CH2:14][CH2:15][N:16]([C@@H:34]4[CH2:33][CH2:32][C@H:31]([C:24]5[C:23]6[C:27](=[CH:28][CH:29]=[C:21]([C:19]#[N:20])[CH:22]=6)[N:26]([CH3:30])[CH:25]=5)[CH2:36][CH2:35]4)[CH2:17][CH2:18]3)[N:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: Cn1cc(C2CCC(=O)CC2)c2cc(C#N)ccc21
Reactant: COc1cc2cccnc2c(N2CCNCC2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1cc2cccnc2c(N2CCN([C@H]3CC[C@@H](c4cn(C)c5ccc(C#N)cc54)CC3)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-methoxy-8-piperazin-1-yl-[1,7]naphthyridine (250 mg, 1.02 mmol), 4-(5-cyano-1-methyl-1H-indol-3-yl)-cyclohexanone (260 mg, 1.02 mmol), and sodium triacetoxyborohydride (320 mg, 1.53 mmol) in dichloroethane (50 mL) was added acetic acid (0.12 mL, 2.04 mmol) and stirred overnight at room temperature. The reaction was quenched with 1 M NaOH (50 mL) then extracted in CH2Cl2 (1×50 mL) and EtOAc (75 mL). The organic fractions were combined, dried over Na2SO4, concentrated, filtered and chromatographed (5% MeOH/EtOAc+NH4OH) affording 160 mg (33%) of the cis isomer as a yellow foam. The HCl salt was generated form EtOAc affording a pale yellow solid: mp 235-238° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:26][CH2:25][C:24]3[C:16](=[CH:17][C:18]4[C:19]([CH:23]=3)=[N:20][O:21][N:22]=4)[CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:27]>O1CCOCC1>[ClH:27].[N:11]1([CH:14]2[CH2:26][CH2:25][C:24]3[C:16](=[CH:17][C:18]4[C:19]([CH:23]=3)=[N:20][O:21][N:22]=4)[CH2:15]2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCc3cc4nonc4cc3C2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1c2c(cc3nonc13)CC(N1CCNCC1)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a flask charged with tert-Butyl-4-(5,6,7,8-tetrahydronaphtho[2,3-c][1,2,5]oxadiazol-6-yl)piperazine-1-carboxylate (50 mg, 0.14 mmol) was added 4N HCl in dioxane (1 mL). The mixture was allowed to stir for 30 minutes at RT. LC showed complete reaction. The solvent was removed under reduced pressure, and the resulting 6-Piperazin-1-yl-5,6,7,8-tetrahydronaphtho[2,3-c][1,2,5]oxadiazole hydrochloride was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([N+:19]([O-])=O)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.CCOC(C)=O.CC(O)=O.[H][H]>CO.[Pt]>[Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([NH2:19])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Sc2ccnc(Cl)c2)c2ccccc12
Agent: [Pt]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1ccc(Sc2ccnc(Cl)c2)c2ccccc12

Procedure:
A solution of 2-chloro-4-(4-nitronaphthalen-1-ylthio)pyridine (1.68 g, 5.30 mmol) in a mixture of MeOH (30 mL), EtOAc (100 mL) and AcOH (10 mL) was subjected to hydrogenation by two passages through a Thales H-cube (1.0 mL min−1, 50° C., 70 mm, 10% Pt—C Cat-Cart, full hydrogen mode) and was then evaporated in vacuo to afford 4-(2-chloropyridin-4-ylthio) naphthalen-1-amine as a brown oil (1.40 g, 90% purity (LCMS), 83%); Rt 4.50 min (Method 1 basic); m/z 287 (M+H)+ (ES+). The material so obtained was used in the next step without further purification.
Reaction SMILES: C([Si]([O:18][C@@H:19]1[C@H:26]2[C@H:22]([O:23][C:24]([CH3:28])([CH3:27])[O:25]2)[CH:21]=[C:20]1[F:29])(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[F:29][C:20]1[C@H:19]([OH:18])[C@@H:26]2[O:25][C:24]([CH3:27])([CH3:28])[O:23][C@@H:22]2[CH:21]=1
Reactant: CC1(C)O[C@@H]2[C@@H](C=C(F)[C@@H]2O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2[C@@H](C=C(F)[C@@H]2O)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tert-butyl((3aR,4R,6aR)-5-fluoro-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)diphenylsilane (5-5) (840 mg, 2.0 mmol, 1 eq) was dissolved in THF (10 mL) and TBAF (4.0 mL, 4.0 mmol, 2 equiv, 1M in THF) was added. The resulting mixture was stirred at ambient temperature for 2 hours. Upon disappearance of the starting material, the mixture was diluted with 50 mL EtOAc and washed with water (3×20 mL) and brine (20 mL). The organic layer was dried over MgSO4, filtered and concentrated. The crude residue was purified by flash chromatography (40 g SiO2, 0-60% EtOAc in hexanes) to yield (3aS,4R,6aR)-5-fluoro-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (5-6) as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 5.31 (s, 1H); 4.98 (td, J=6.0, 2.0 Hz, 1H); 4.74 (td, J=6.0, 3.0 Hz, 1H); 4.44 (s, 1H); 2.88 (brs, 1H); 1.49 (s, 3H); 1.41 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:12])[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[C:15]([OH:17])=O.C1(C)C=CC=CC=1.[CH2:25]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:26].S(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:26][CH2:25][N:27]([C:15]([C:3]1[C:4](=[O:14])[N:5]([CH3:13])[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([Cl:12])[C:11]=2[C:2]=1[OH:1])=[O:17])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Cn1c(=O)c(C(=O)O)c(O)c2c(Cl)cccc21
Reactant: CCNc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCN(C(=O)c1c(O)c2c(Cl)cccc2n(C)c1=O)c1ccccc1
Temperature: 7.5 °C
Reaction time: 7 h
Yield: 64 %

Procedure:
The mixture of 1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxylic acid (1 gm) and toluene (50 ml) was cooled to 5-10° C. under nitrogen atmosphere. Pyridine (1.09 gm) was added to the resulting mass at 5-10° C. to form a clear solution. The solution was followed by the addition of N-ethyl aniline (0.52 gm) in one portion at 5-10° C. and then thionyl chloride (0.61 gm) was added at 5-10° C. The resulting mixture was stirred for 7 hours followed by evaporation of toluene under vacuum. The resulting residue was dissolved in ethyl acetate (25 ml) followed by washings with 5% sodium hydroxide solution (6.5 ml) at 25-30° C. The resulting aqueous layer was cooled to 10-15° C. followed by adjusting pH of the mass to 1 by using 18% aqueous hydrochloric acid solution (2.5 ml). The resulting mass was stirred for 1 hour at 10-15° C. The separated white colored solid was filtered and dried at 55-60° C. to yield 0.9 gm of laquinimod (HPLC Purity: 97.3%).
Reaction SMILES: C([NH:4][C:5]([CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)([CH2:8][OH:9])[CH2:6][OH:7])(=O)C.[OH-].[Na+].Cl>CO>[NH2:4][C:5]([CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1)([CH2:6][OH:7])[CH2:8][OH:9]
Reactant: CC(=O)NC(CO)(CO)CCCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(CO)(CO)CCCc1ccc([N+](=O)[O-])cc1
Yield: 29.1 %

Procedure:
2-Acetamido-2-[3-(4-nitrophenyl)propyl]-1,3-propanediol (400 mg) was dissolved in 50 ml of methanol and 6.7 ml of a 1N aqueous-sodium hydroxide solution was added thereto. The mixture was refluxed under heating for 3 hours and neutralized with dilute hydrochloric acid. The solvent was distilled away and chloroform was added to the residue for extraction. The chloroform layer was washed and dried, and the solvent was distilled away. The residue was purified by silica gel column chromatography (methanol:chloroform=1:4) to give 100 mg of 2-amino-2-[3-(4-nitrophenyl)propyl]-1,3-propanediol as a red, oily substance.
Reaction SMILES: O[C@H]1C[C@@H](C2C=NC=CC=2)OC2(CCN([C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[C:14]([CH3:22])[CH:13]=3)=[O:11])CC2)C1.[H-].[Na+].C1(CBr)CC1.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C.O>[CH:19]([O:18][C:15]1[CH:16]=[CH:17][C:12]([CH:10]=[O:11])=[CH:13][C:14]=1[CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1cc(C(=O)N2CCC3(CC2)C[C@@H](O)C[C@@H](c2cccnc2)O3)ccc1OC(C)C
Agent: BrCC1CC1
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C=O)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To [cis-8-hydroxy-10-(3-pyridyl)-11-oxa-3-azaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (80 mg) in DMF at 0° C. was added sodium hydride (5 eq., 60 wt % in mineral oil). After stirring at room temperature for 5 minutes, the cyclopropylmethyl bromide (5 eq.) was added. The reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was stirred with saturated sodium bicarbonate solution (20 mL). The mixture was repartitioned between water (50 mL) and ethyl acetate (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to provide cis-4-(cyclopropylmethoxy)-2-(pyridin-3-yl)-1-oxa-9-azaspiro[5.5]undecan-9-yl)(4-isopropoxy-3-methylphenyl)methanone. 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.55 (d, J =3.9 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.30 (dd, J=7.8, 4.8 Hz, 1H), 7.23-7.11 (m, 2H), 6.80 (d, J=8.2 Hz, 1H), 4.70-4.51 (m, 1H), 4.56 (dq, J=12.1, 6.1 Hz, 1H), 4.37 (br s, 1H), 3.82-3.00 (m, 5H), 3.34 (d, J=6.8 Hz, 1H), 2.40-2.10 (m, 2H), 2.19 (s, 3H), 2.09-1.92 (m, 2H), 1.88-1.39 (m, 4H), 1.42-1.26 (m, 6H), 1.04 (td, J=7.0, 3.5 Hz, 1H), 0.64-0.47 (m, 2H), 0.30-0.12 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:20][C:12]3=[N:13][CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1F.[CH3:21][O:22][CH2:23][CH2:24][NH:25][CH2:26][CH2:27][O:28][CH3:29]>CN1C(=O)CCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:20][C:12]3=[N:13][CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[N:25]([CH2:26][CH2:27][O:28][CH3:29])[CH2:24][CH2:23][O:22][CH3:21]
Reactant: COCCNCCOC
Reactant: O=[N+]([O-])c1cnc2[nH]c(-c3ccc(F)c(F)c3)nc2c1
Solvent: CN1CCCC1=O
Product: COCCN(CCOC)c1ccc(-c2nc3cc([N+](=O)[O-])cnc3[nH]2)cc1F
Reaction time: 18 h

Procedure:
0.5 g 2-(3,4-Difluoro-phenyl)-6-nitro-3H-imidazo[4,5-b]pyridine, 0.1 ml NMP and 0.51 g bis(2-methoxyethyl)-amine were heated to 170° C. with stirring for 18 hrs. Volatile materials were removed under vacuum and the residue purified by chromatography, first on silica in dichloromethane/methanol mixtures, and subsequently by preparative HPLC.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[NH2:7][C:8]1[C:15]([Cl:16])=[CH:14][C:11]([CH:12]=[O:13])=[C:10]([O:17][CH3:18])[CH:9]=1>>[Cl:1][CH2:2][CH2:3][C:4]([NH:7][C:8]1[CH:9]=[C:10]([O:17][CH3:18])[C:11]([CH:12]=[O:13])=[CH:14][C:15]=1[Cl:16])=[O:5]
Reactant: COc1cc(N)c(Cl)cc1C=O
Reactant: O=C(Cl)CCCl
Product: COc1cc(NC(=O)CCCl)c(Cl)cc1C=O
Temperature: 20 °C
Reaction time: 2 h

Procedure:
3-Chloropropionyl chloride (98.4 ml, 1.0 mol) was added over 30 minutes to a stirred suspension of 4-amino-5-chloro-2-methoxybenzaldehyde (47.4 g, 0.26 mol) ensuring the reaction temperature did not exceed 20° C. After the addition was complete the reaction was stirred at 20° C. for a further 2 hours and then filtered. The filtrate was concentrated to 150 ml under reduced pressure and then diluted with ethyl acetate (100 ml) and water (400 ml). The mixture was stirred at 20° C. for 1 hour and then filtered to give 3-chloro-N-[2-chloro-4-formyl-5-(methyloxy)phenyl]propanamide as an off-white solid which was not isolated but suspended in tetrahydrofuran (730 ml) and treated with diisopropylethylamine (154 ml, 0.88 mol). The resulting mixture was stirred at 45° C. for 46 hours and then concentrated under reduced pressure to leave a residue which was diluted with ethyl acetate (300 ml), washed with 2M hydrochloric acid (4×100 ml) and concentrated under reduced pressure to give N-[2-chloro-4-formyl-5-(methyloxy)phenyl]-2-propenamide (37.8 g, 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1.C(N(C(C)C)C(C)C)C.[CH3:37][O:38][C:39]([CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[CH:45][CH:44]=1)=[O:40]>ClCCl>[CH3:37][O:38][C:39](=[O:40])[CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([S:49]([N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:13]([C:11]([C:10]3[C:5]([O:4][C:3]4[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:2]=4[Cl:1])=[N:6][CH:7]=[CH:8][CH:9]=3)=[O:12])[CH2:14][CH2:15]2)(=[O:50])=[O:51])=[CH:45][CH:44]=1
Reactant: O=C(c1cccnc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Reactant: COC(=O)CCc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CCc1ccc(S(=O)(=O)N2CCN(C(=O)c3cccnc3Oc3cc(Cl)ccc3Cl)c3ccccc32)cc1
Temperature: 25 °C
Yield: 35.1 %

Procedure:
To a solution of [2-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone (80 mg, 0.2 mmol, 1.0 equiv; Example 122) in anhydrous dichloromethane (2 mL) was added N-ethyldiisopropylamine (51.3 mg, 69 μL, 0.4 mmol, 2.0 equiv; [CAS RN 7087-68-5]) and methyl 3-(4-chlorosulphonyl)phenylproprionate (57.8 mg, 0.22 mmol, 1.1 equiv; [CAS RN 374537-95-8]) and the reaction mixture stirred at rt over night. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 44 mg (35%) of the title compound as a light off-white powder. MS (ISP): 626.2 [M+H]+.