Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)(Cl)Cl>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Solvent: ClC(Cl)Cl
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)c1ccccc1
Yield: 34.6 %

Procedure:
Using the general method of Example 186 except that chloroform was used as the solvent, 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.50 g, 5.01 mmol) was reacted with benzoyl chloride (972 mg, 5.55 mmol) to provide 700 mg of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}benzamide as a white solid, m.p. 183.0-186.0° C. Analysis: Calculated for C23H25N5O2.0.5 H2O: % C, 66.97; % H, 6.35; % N, 16.98. Found: % C, 67.16; % H, 6.18; % N, 17.07.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=O)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[O:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]([NH2:36])[CH2:28][CH2:27]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([NH:36][CH:29]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:26][CH2:27][CH2:28]2)=[O:17])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: NC1CCOc2ccccc21
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NC3CCOc4ccccc43)c2c1N

Procedure:
Prepared as in Example 24a from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example 47b) and chroman-4-amine (Lu, Y. et al. PCT Int. Appl. 2008, WO 2008043019) as a brown solid (37%). MS 478 (MH+).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:20])[C:7]2[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][C:11]=3[C:10]([CH3:18])([CH3:17])[O:9][C:8]=2[CH:19]=1.[CH2:21]([CH:23]1[O:25][CH2:24]1)Cl>CS(C)=O.O>[CH3:3][C:4]1[CH:5]=[C:6]([O:20][CH2:21][CH:23]2[CH2:24][O:25]2)[C:7]2[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][C:11]=3[C:10]([CH3:18])([CH3:17])[O:9][C:8]=2[CH:19]=1
Reactant: ClCC1CO1
Reactant: Cc1cc(O)c2c(c1)OC(C)(C)C1=C2CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(OCC2CO2)c2c(c1)OC(C)(C)C1=C2CCCC1

Procedure:
To a stirred solution of NaOH (2.4 g, 0.06 m) in DMSO (125 ml) and water (125 ml) was added 7,8,9,10-tetrahydro-3,6,6-trimethyl-1-hydroxy-6H-dibenzo[b,d]pyran (13.1 g, 0.054 m) in DMSO (125 ml) and water (125 ml) and then epichlorohydrin (34.8 g, 0.376 m) and the mixture stirred for 5 hours, treated with water (0.5 L) and extracted with ether (3×300 ml). The combined ether extracts were dried over MgSO4 and evaporated to give 7,8,9,10-tetrahydro-3,6,6-trimethyl-1-(oxiranylmethoxy)-6H-dibenzo[b,d]pyran as a pale yellow oil, 14.0 g. This material was of sufficient purity to use as is for further chemical processing.
Reaction SMILES: C(O[C:4]([C:6]1[C:7](=[O:16])[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][N:10]=2)=O)C.[C:17]1([NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23].C(=O)(O)[O-].[Na+]>>[NH:23]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:24]=[C:4]1[C:6]1[C:7](=[O:16])[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][N:10]=2
Reactant: Nc1ccccc1N
Reactant: CCOC(=O)c1cc2cccnc2[nH]c1=O
Agent: O=C([O-])O
Agent: [Na+]
Product: O=c1[nH]c2ncccc2cc1-c1nc2ccccc2[nH]1
Temperature: 200 °C

Procedure:
A mixture of 5-3 (300 mg, 1.37 mmol, 1 equiv) and 1,2-phenylenediamine (223 mg, 2.06 mmol, 1.5 equiv) in polyphosphoric acid (8 mL) was heated at 200° C. for 16 h. The hot rxn mixture was poured into ice water (50 mL), and the resulting mixture was allowed to stand until all polyphosphoric acid had dissolved. The acidic suspension was neutralized with saturated aqueous sodium bicarbonate solution, then extracted with ethyl acetate (5×100 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was suspended in ethyl acetate (50 mL) aided by sonication, and the solids were filtered to give 3-(1H-benzoimidazol-2-yl)-1H-[1,8]naphthyridin-2-one (5-4) as a yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][C@H:6]1[CH3:20])=[O:4].[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([OH:33])=[C:26]([S:28]([NH:31][CH3:32])(=[O:30])=[O:29])[CH:27]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC.C(OCC)(=O)C>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:33][CH2:2][C:3]([N:5]2[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:7][C@H:6]2[CH3:20])=[O:4])=[C:26]([S:28]([NH:31][CH3:32])(=[O:29])=[O:30])[CH:27]=1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CCl
Reactant: CNS(=O)(=O)c1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: CNS(=O)(=O)c1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Yield: 52.5 %

Procedure:
To a solution of (2R, 5S)-2-Chloro-1-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-ethanone (375 mg, 1.26 mmol) in butanone (12 ml) was added 5-Chloro-2-hydroxy-N-methyl-benzenesulfonamide (280 mg, 1.26 mmol), potassium carbonate (348 mg, 2.52 mmol) and potassium iodide (209 mg, 1.26 mmol). The resulting reaction mixture was refluxed for 4 hours. It was allowed to cool, diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the above titled compound (320 mg, 53% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6](C(OCC)=O)[C:7]1[C:16]2[C:11](=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][C:8]=1[Br:20])=[O:5])[CH3:2].[Cl-].[Li+].O>CS(C)=O>[Br:20][C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:7]=1[CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18]
Reactant: CCOC(=O)C(C(=O)OCC)c1c(Br)cnc2c([N+](=O)[O-])cccc12
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)Cc1c(Br)cnc2c([N+](=O)[O-])cccc12
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 90.9 %

Procedure:
A mixture of 4-[bis(ethoxycarbonyl)methyl]-3-bromo-8-nitroquinoline (316 mg), lithium chloride (65.1 mg), water (13.8 mg) in dimethyl sulfoxide was stirred for 20 minutes at 130° C. The mixture was partitioned between ethyl acetate and water, and the organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give 3-bromo-4-ethoxycarbonylmethyl-8-nitroquinoline (236.8 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)#[N:20].CS(C)=O.[OH-].[Na+]>O>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[O:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]#[N:20])=[CH:22][CH:23]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(Oc2ccc([N+](=O)[O-])c(Oc3ccccc3)c2Cl)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 14.2 gm of 2,3-dichloro-6-nitro-1-phenoxy-benzene, 6.5 gm of 4-cyano-phenol, 40 ml of dimethylsulfoxide and 50 ml of 10 N sodium hydroxide was stirred for 3 hours at 100° C. Thereafter, the reaction mixture was diluted with water, the aqueous mixture was extracted with chloroform, the organic extract solution was dried, and the chloroform was distilled off. The residue was purified by passing it through a silicagel column and recrystallizing it from ethanol, yielding 11 gm (60.2% of theory) of the colorless crystalline title compound, m.p. 140°-142° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12]1[C:13]([OH:20])=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[O:16])[CH3:10]>C(#N)C>[Br:1][C:18]1[CH:19]=[C:12]([O:11][CH2:9][CH3:10])[C:13]([OH:20])=[C:14]([CH:17]=1)[CH:15]=[O:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOc1cccc(C=O)c1O
Solvent: CC#N
Product: CCOc1cc(Br)cc(C=O)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.6 %

Procedure:
After adding 5.59 g of N-bromosuccinimide to a solution of 5.11 g of 3-ethoxy-2-hydroxybenzaldehyde in 100 ml of acetonitrile, the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, water was added to the residue, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was recrystallized using t-butyl methyl ether-heptane to give 5-bromo-3-ethoxy-2-hydroxybenzaldehyde (2.53 g).
Reaction SMILES: Br[C:2]1[C:3]([C:19]#[N:20])=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].[Cl:21]Cl>ClC1C=CC=CC=1>[Cl:21][C:2]1[C:3]([C:19]#[N:20])=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8]
Reactant: Cn1c(-c2ccc(Cl)cc2)c(C#N)c(Br)c1C(F)(F)F
Reactant: ClCl
Solvent: Clc1ccccc1
Product: Cn1c(-c2ccc(Cl)cc2)c(C#N)c(Cl)c1C(F)(F)F
Temperature: 25 °C

Procedure:
A solution of 4-bromo-2-(p-chlorophenyl)-1-methyl-5-(trifluoromethyl)pyrrole-3-carbonitrile (20.0 g, 0.055 mol) in chlorobenzene at 60° C. is treated with chlorine gas at 60° C. over a 1/2 hour period, cooled to room temperature, washed sequentially with water, aqueous sodium metabisulfite and water, dried over sodium sulfate and concentrated in vacuo to give a residue. The residue is crystallized in heptane to give the title product as a pale yellow solid, 17.6 g (quantitative yield), mp 109.5°-110.5° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15](=[O:18])[NH:16][CH3:17])[CH:12]=[C:11]([Cl:19])[C:10]=1[F:20])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:14]=[C:13]([CH:12]=[C:11]([Cl:19])[C:10]=1[F:20])[C:15]([NH:16][CH3:17])=[O:18]
Reactant: CNC(=O)c1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cc(Cl)c(F)c(CN)c1

Procedure:
was prepared according to Scheme C3 (step B) from (3-chloro-2-fluoro-5-methylcarbamoyl-benzyl)-carbamic acid tert-butyl ester (99 mg, 0.3 mmol) and TFA (0.5 mL) in CH2Cl2. MS (LC-MS): 217.0 [M]+; tR (HPLC conditions c): 2.39 min.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][CH2:33][OH:34])[N:18]=[C:17]([C:35]3[N:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:42].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(OCC)(=O)C>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:16]=[C:17]([C:35]3[N:36]=[CH:37][CH:38]=[CH:39][N:40]=3)[N:18]=[C:19]([O:30][CH2:31][CH2:32][C:33]([OH:42])=[O:34])[C:20]=2[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ncccn2)nc1OCCCO
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ncccn2)nc1OCCC(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.4 %

Procedure:
To a solution of 4-t-butyl-N-[6-(3-hydroxypropyloxy)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]benzene sulfonamide (3.2 g) in dimethylformamide (50 ml) was added pyridinium dichromate (31.9 g). The mixture was stirred for 12 hours at room temperature, and subsequently supplemented with pyridinium dichromate (10.6 g), followed by stirring for 12 hours. Ethyl acetate was added, and the mixture was washed with 1N-HCl and then with water. The organic layer was extracted with sat. aq. NaHCO3, and the aqueous layer was washed with ethyl acetate. The aqueous layer was acidified with dilute HCL, and then extracted with ethyl acetate. The organic layer was washed with saturated brine. Drying over anhydrous magnesium sulfate and concentrating under reduced pressure gave 1.85 g of 3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyloxy]propionic acid as a pale yellow powder.
Reaction SMILES: [OH:1][C:2]1([CH2:15][SH:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25](=[O:29])[C:24](=[O:30])[CH:23]=[CH:22]2>C(#N)C>[OH:1][C:2]1([CH2:15][S:16][C:22]2[C:21]3[C:26](=[CH:27][CH:28]=[C:19]([O:18][CH3:17])[CH:20]=3)[C:25](=[O:29])[C:24](=[O:30])[CH:23]=2)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][CH2:3]1
Reactant: COc1ccc2c(c1)C=CC(=O)C2=O
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CS)CC1
Solvent: CC#N
Product: COc1ccc2c(c1)C(SCC1(O)CCN(C(=O)OC(C)(C)C)CC1)=CC(=O)C2=O

Procedure:
tert-butyl 4-hydroxy-4-{[(7-methoxy-3,4-dioxo-3,4-dihydronaphthalen-1-yl)thio]methyl}piperidine-1-carboxylate was synthesized using tert-butyl 4-hydroxy-4-(mercaptomethyl)piperidine-1-carboxylate, 6-methoxynaphthalene-1,2-dione, acetonitrile as the solvent and conditions outlined in procedure F [step (i)]. The crude intermediate was used in step (ii) without any further purification.
Reaction SMILES: [CH3:1][N:2]1[S:11](=[O:13])(=[O:12])[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]([OH:14])=[C:3]1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16].[C:24](=[O:33])([O:29][CH2:30][CH2:31][CH3:32])[O:25][CH:26](Cl)[CH3:27]>>[CH2:30]([O:29][C:24]([O:25][CH:26]([O:14][C:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[S:11](=[O:13])(=[O:12])[N:2]([CH3:1])[C:3]=1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16])[CH3:27])=[O:33])[CH2:31][CH3:32]
Reactant: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O
Reactant: CCCOC(=O)OC(C)Cl
Product: CCCOC(=O)OC(C)OC1=C(C(=O)Nc2ccccn2)N(C)S(=O)(=O)c2ccccc21

Procedure:
By the procedure of Example 6, piroxicam (3.00 g, 9.1 mmol) and alpha-chloroethyl propyl carbonate (4.52 g, 27.2 mmol) were converted to chromatographed title product, 3.47 g pale yellow foam (7.5 mmol, 83.0%) which gave 3.00 g white crystals from isopropyl alcohol: mp 150°-151° C.; IR (KBr) 1760, 1678 cm-1 : 1H NMR (CDCl3) delta 0.84 (t, J=7 Hz, 3H), 1.46-1.65 (m, 2H), 1.75 (d, J=6 Hz, 3H), 3.11 (s, 3H), 3.97 (t, J=7 Hz, 2H), 6.35 (q, J=6 Hz, 1H), 7.04-7.16 (m, 1H), 7.62-7.97 (m, 5H), 8.30-8.41 (m, 2H), 9.40 (br s, 1H): precise mass calcd for C21H23N3O7S m/e 461.1264, found 461.1260.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:11])=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)C=O.[OH:12]O>[OH-].[Na+]>[Br:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:4]([OH:12])[C:3]=1[OH:11]
Reactant: OO
Reactant: O=Cc1cc(Cl)cc(Br)c1O
Agent: [Na+]
Agent: [OH-]
Product: Oc1cc(Cl)cc(Br)c1O
Temperature: 25 °C
Yield: 99 %

Procedure:
To a stirred suspension of 3-bromo-5-chloro-2-hydroxybenzaldehyde (49.5 g, 0.21 mol) in 0.5N aqueous NaOH (500 ml, 0.25 mol) at 40° C. was added dropwise hydrogen peroxide (21.4 g of a 35% aqueous solution, 0.22 mol) over 15 minutes and the resultant mixture stirred for 16 hours. The mixture was cooled to room temperature, diluted with 1 N aqueous NaOH (200 ml) and washed with diethyl ether (3×300 ml). The aqueous layer was acidified with concentrated HCl to pH 2 and extracted with Et2O (3×200 ml). The organic extracts were combined, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford the desired product as a red/brown solid (46.0 g, 99%).
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH:25]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:18]1([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH2:16][N:25]3[CH2:29][CH2:28][C:27](=[O:30])[NH:26]3)=[CH:14][N:15]=2)=[O:9])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: O=C1CCNN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: O=C1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)N1
Yield: 15.8 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (42 mg. 0.125 mmol), 3-pyrazolidinone hydrochloride (23 mg, 0.188 mmol) and sodium triacetoxyborohydride (40 mg, 0.188 mmol) to afford 8 mg (16%) of the desired product after purification.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:23])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:24])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:28][C:29]1([CH3:36])[O:33][CH:32]([CH2:34]O)[CH2:31][O:30]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:23])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:24])[C:6]([C:25]([O:27][CH2:34][CH:32]3[CH2:31][O:30][C:29]([CH3:36])([CH3:28])[O:33]3)=[O:26])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CC1(C)OCC(CO)O1
Reactant: CCCN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)OCC2COC(C)(C)O2)cn3C2CC2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 89 %

Procedure:
1-cyclopropyl-6-fluoro-4-oxo-7-(4-propylpiperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid (8.86 g, 23.70 mmol) was dissolved in anhydrous dichloromethane (370 ml) under argon. 2,2-dimethyl-1,3-dioxolane-4-methanol (4.71 g, 35.60 mmol), triethylamine (9.59 g, 94.80 mmol) and HBTU (9.90 g, 26.10 mmol) were added and the reaction mixture was stirred at room temperature for three days (exclusion of light). The reaction mixture was washed with saturated NaHCO3 solution (500 ml), aqueous (pH 5) hydrochloric acid (500 ml) and water (500 ml) successively. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure, yielding 10.28 g (89%) of a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([I:9])=[CH:5][C:4]=1[Cl:10].[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K]>CN(C)C=O.C(OCC)(=O)C>[Cl:10][C:4]1[CH:5]=[C:6]([I:9])[CH:7]=[CH:8][C:3]=1[CH2:2][N:15]1[C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]2[C:11]1=[O:21]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Clc1cc(I)ccc1CBr
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(I)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
In a solution of 7.6 g of 1-bromomethyl-2-chloro-4-iodobenzene in 50 mL of N,N-dimethylformamide, 3.7 g of potassium phthalimide was added, and stirred at room temperature for 1 hour. After the completion of the reaction, the reaction mixture was diluted with 80 mL of ethyl acetate, washed with water (30 mL×2), and then dehydrated with and dried over saturated sodium chloride aqueous solution and anhydrous sodium sulfate in that order, and the solvent was distilled off under reduced pressure to obtain 5.7 g of the aimed product as white crystal.
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1)[CH3:2].[BrH:11]>>[CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Br:11])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(CO)cc1
Reactant: Br
Product: CCc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-ethylbenzyl alcohol (2.72 g, 20 mmol, purchased from Aldrich) and 50 ml of 47% hydrobromic acid (purchased from Wako Junyaku Kogyo) was stirred vigorously for 30 minutes at room temperature. The reaction mixture was extracted with hexane to give 3.98 g of 4-ethylbenzyl bromide as a colorless oil. Then to a hot solution (50° C.) of sodium cyanide (1.96 g, 40 mmol) in 20 ml of dimethyl sulfoxide was added the above 3.98 g of 4-ethylbenzyl bromide and the mixture was stirred for 3 hours at ambient temperature. To the resultant reaction mass was added water and extracted with hexane. The solvent was removed to give 2.70 g (yield: 93.1%) of 4-ethylphenylacetonitrile as a pale yellow oil.
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1[C:10]([C@H:11]([NH2:15])[C:12]([OH:14])=[O:13])=[CH:9][CH:8]=[C:7]([F:16])[CH:6]=1.[CH3:17]O>CCOC(C)=O>[NH2:15][C@@H:11]([C:10]1[CH:9]=[CH:8][C:7]([F:16])=[CH:6][CH:5]=1)[C:12]([O:14][CH3:17])=[O:13]
Reactant: N[C@H](C(=O)O)c1ccc(F)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](N)c1ccc(F)cc1
Yield: 100 %

Procedure:
Thionyl chloride (0.475 mL, 6.50 mmol) was added dropwise to a solution of (S)-4-fluorophenylglycine (commercially available from Sigma-Aldrich, Milwaukee, Wis.)(1.00 g, 5.91 mmol) in MeOH (25.0 mL), and the mixture was stirred at reflux for 2 hours. The reaction mixture was then concentrated to afford a brown oil. The residue was dissolved in EtOAc, and the solution was partitioned between EtOAc and saturated aqueous NaHCO3 solution. The aqueous phase was separated and extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford (S)-methyl 2-amino-2-(4-fluorophenyl)acetate (1.1 g, 6.0 mmol, 100% yield) as a brown oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.28 (br. s., 2H), 3.59 (s, 3H), 4.55 (s, 1H), 7.05-7.23 (m, 2H), 7.31-7.53 (m, 2H). m/z (ESI) 184 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[Br:18])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=2)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[Br:18])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=2
Reactant: COc1ccc2ncc(NC(=O)OC(C)(C)C)c(Br)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2ncc(N)c(Br)c2c1
Reaction time: 3.5 h
Yield: 101.1 %

Procedure:
(4-Bromo-6-methoxy-quinolin-3-yl)-carbamic acid tert-butyl ester (22.7 g, 0.0643 mole) was dissolved in CH2Cl2 (200 mL) and treated with trifluoroacetic acid (100 mL). After 3.5 hr at RT, the mixture was concentrated and the residue was dissolved in water. The solution was made basic with aqueous sodium carbonate. The precipitate was filtered off, washed with water, and dried at 40° C. in vacuo overnight, to give the title compound (16.46 g, 101%) as a white solid: MS (ES) m/e 254/256 (M+H)+.